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Sample records for premature aging progeria

  1. Progeria: A rare genetic premature ageing disorder

    OpenAIRE

    Jitendra Kumar Sinha; Shampa Ghosh; Manchala Raghunath

    2014-01-01

    Progeria is characterized by clinical features that mimic premature ageing. Although the mutation responsible for this syndrome has been deciphered, the mechanism of its action remains elusive. Progeria research has gained momentum particularly in the last two decades because of the possibility of revealing evidences about the ageing process in normal and other pathophysiological conditions. Various experimental models, both in vivo and in vitro, have been developed in an effort to understand...

  2. Progeria: a rare genetic premature ageing disorder.

    Science.gov (United States)

    Sinha, Jitendra Kumar; Ghosh, Shampa; Raghunath, Manchala

    2014-05-01

    Progeria is characterized by clinical features that mimic premature ageing. Although the mutation responsible for this syndrome has been deciphered, the mechanism of its action remains elusive. Progeria research has gained momentum particularly in the last two decades because of the possibility of revealing evidences about the ageing process in normal and other pathophysiological conditions. Various experimental models, both in vivo and in vitro, have been developed in an effort to understand the cellular and molecular basis of a number of clinically heterogeneous rare genetic disorders that come under the umbrella of progeroid syndromes (PSs). As per the latest clinical trial reports, Lonafarnib, a farnesyltranferase inhibitor, is a potent 'drug of hope' for Hutchinson-Gilford progeria syndrome (HGPS) and has been successful in facilitating weight gain and improving cardiovascular and skeletal pathologies in progeroid children. This can be considered as the dawn of a new era in progeria research and thus, an apt time to review the research developments in this area highlighting the molecular aspects, experimental models, promising drugs in trial and their implications to gain a better understanding of PSs.

  3. Progeria: A rare genetic premature ageing disorder

    Directory of Open Access Journals (Sweden)

    Jitendra Kumar Sinha

    2014-01-01

    Full Text Available Progeria is characterized by clinical features that mimic premature ageing. Although the mutation responsible for this syndrome has been deciphered, the mechanism of its action remains elusive. Progeria research has gained momentum particularly in the last two decades because of the possibility of revealing evidences about the ageing process in normal and other pathophysiological conditions. Various experimental models, both in vivo and in vitro, have been developed in an effort to understand the cellular and molecular basis of a number of clinically heterogeneous rare genetic disorders that come under the umbrella of progeroid syndromes (PSs. As per the latest clinical trial reports, Lonafarnib, a farnesyltranferase inhibitor, is a potent ′drug of hope′ for Hutchinson-Gilford progeria syndrome (HGPS and has been successful in facilitating weight gain and improving cardiovascular and skeletal pathologies in progeroid children. This can be considered as the dawn of a new era in progeria research and thus, an apt time to review the research developments in this area highlighting the molecular aspects, experimental models, promising drugs in trial and their implications to gain a better understanding of PSs.

  4. Molecular insights into the premature aging disease progeria.

    Science.gov (United States)

    Vidak, Sandra; Foisner, Roland

    2016-04-01

    Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare premature aging disease presenting many features resembling the normal aging process. HGPS patients die before the age of 20 years due to cardiovascular problems and heart failure. HGPS is linked to mutations in the LMNA gene encoding the intermediate filament protein lamin A. Lamin A is a major component of the nuclear lamina, a scaffold structure at the nuclear envelope that defines mechanochemical properties of the nucleus and is involved in chromatin organization and epigenetic regulation. Lamin A is also present in the nuclear interior where it fulfills lamina-independent functions in cell signaling and gene regulation. The most common LMNA mutation linked to HGPS leads to mis-splicing of the LMNA mRNA and produces a mutant lamin A protein called progerin that tightly associates with the inner nuclear membrane and affects the dynamic properties of lamins. Progerin expression impairs many important cellular processes providing insight into potential disease mechanisms. These include changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence. In this review, we discuss these pathways and their potential contribution to the disease pathologies as well as therapeutic approaches used in preclinical and clinical tests.

  5. LMNA-Associated Cardiocutaneous Progeria: a Novel Autosomal Dominant Premature Aging Syndrome with Late Onset

    Science.gov (United States)

    Kane, Megan S.; Lindsay, Mark E.; Judge, Daniel P.; Barrowman, Jemima; Rhys, Colette Ap; Simonson, Lisa; Dietz, Harry C.; Michaelis, Susan

    2013-01-01

    Hutchinson-Gilford Progeria Syndrome (HGPS) is a well-characterized premature aging disorder caused by mutations in LMNA, the gene encoding the nuclear scaffold proteins lamin A and C. In HGPS and related progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. Emerging evidence indicates that LMNA-linked progerias can be grouped into two classes: 1) the processing-deficient, early onset “typical” progerias (e.g. HGPS), and 2) the processing-proficient “atypical” progeria syndromes (APS) that are later in onset. Here we describe a novel progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based progeria disorders. The LMNA mutation that causes LCPS is a heterozygous missense mutation resulting in an amino acid substitution (D300G) in the coiled-coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors (FTIs), as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA progeria syndromes, and raise the possibility that typical and atypical progerias may converge upon a common mechanism to cause premature aging disease. PMID:23666920

  6. LMNA-associated cardiocutaneous progeria: an inherited autosomal dominant premature aging syndrome with late onset.

    Science.gov (United States)

    Kane, Megan S; Lindsay, Mark E; Judge, Daniel P; Barrowman, Jemima; Ap Rhys, Colette; Simonson, Lisa; Dietz, Harry C; Michaelis, Susan

    2013-07-01

    Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder caused by mutations in LMNA, which encodes the nuclear scaffold proteins lamin A and C. In HGPS and related progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. LMNA-linked progerias can be grouped into two classes: (1) the processing-deficient, early onset "typical" progerias (e.g., HGPS), and (2) the processing-proficient "atypical" progeria syndromes (APS) that are later in onset. Here we describe a previously unrecognized progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based progeria disorders. The LMNA mutation that caused LCPS in this family is a heterozygous c.899A>G (p.D300G) mutation predicted to alter the coiled-coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors, as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA progeria syndromes, and raise the possibility that typical and atypical progerias may converge upon a common mechanism to cause premature aging disease.

  7. Mechanisms of premature vascular aging in children with Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Gerhard-Herman, Marie; Smoot, Leslie B; Wake, Nicole; Kieran, Mark W; Kleinman, Monica E; Miller, David T; Schwartzman, Armin; Giobbie-Hurder, Anita; Neuberg, Donna; Gordon, Leslie B

    2012-01-01

    Hutchinson-Gilford progeria syndrome is a rare, segmental premature aging syndrome of accelerated atherosclerosis and early death from myocardial infarction or stroke. This study sought to establish comprehensive characterization of the fatal vasculopathy in Hutchinson-Gilford progeria syndrome and its relevance to normal aging. We performed cardiovascular assessments at a single clinical site on the largest prospectively studied cohort to date. Carotid-femoral pulse wave velocity was dramatically elevated (mean: 13.00±3.83 m/s). Carotid duplex ultrasound echobrightness, assessed in predefined tissue sites as a measure of arterial wall density, was significantly greater than age- and sex-matched controls in the intima-media (Pnormalizing trends of these noninvasive cardiovascular measures. The data demonstrate that, along with peripheral vascular occlusive disease, accelerated vascular stiffening is an early and pervasive mechanism of vascular disease in Hutchinson-Gilford progeria syndrome. There is considerable overlap with cardiovascular changes of normal aging, which reinforces the view that defining mechanisms of cardiovascular disease in Hutchinson-Gilford progeria syndrome provides a unique opportunity to isolate a subset of factors influencing cardiovascular disease in the general aging population.

  8. Aberrant DNA methylation profiles in the premature aging disorders Hutchinson-Gilford Progeria and Werner syndrome

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    Heyn, Holger; Moran, Sebastian; Esteller, Manel

    2013-01-01

    DNA methylation gradiently changes with age and is likely to be involved in aging-related processes with subsequent phenotype changes and increased susceptibility to certain diseases. The Hutchinson-Gilford Progeria (HGP) and Werner Syndrome (WS) are two premature aging diseases showing features of common natural aging early in life. Mutations in the LMNA and WRN genes were associated to disease onset; however, for a subset of patients the underlying causative mechanisms remain elusive. We aimed to evaluate the role of epigenetic alteration on premature aging diseases by performing comprehensive DNA methylation profiling of HGP and WS patients. We observed profound changes in the DNA methylation landscapes of WRN and LMNA mutant patients, which were narrowed down to a set of aging related genes and processes. Although of low overall variance, non-mutant patients revealed differential DNA methylation at distinct loci. Hence, we propose DNA methylation to have an impact on premature aging diseases. PMID:23257959

  9. Aberrant DNA methylation profiles in the premature aging disorders Hutchinson-Gilford Progeria and Werner syndrome.

    Science.gov (United States)

    Heyn, Holger; Moran, Sebastian; Esteller, Manel

    2013-01-01

    DNA methylation gradiently changes with age and is likely to be involved in aging-related processes with subsequent phenotype changes and increased susceptibility to certain diseases. The Hutchinson-Gilford Progeria (HGP) and Werner Syndrome (WS) are two premature aging diseases showing features of common natural aging early in life. Mutations in the LMNA and WRN genes were associated to disease onset; however, for a subset of patients the underlying causative mechanisms remain elusive. We aimed to evaluate the role of epigenetic alteration on premature aging diseases by performing comprehensive DNA methylation profiling of HGP and WS patients. We observed profound changes in the DNA methylation landscapes of WRN and LMNA mutant patients, which were narrowed down to a set of aging related genes and processes. Although of low overall variance, non-mutant patients revealed differential DNA methylation at distinct loci. Hence, we propose DNA methylation to have an impact on premature aging diseases.

  10. Investigation into the human premature ageing disease, Hutchinson Gilford Progeria syndrome, using hTERT immortalised fibroblasts

    OpenAIRE

    Worthington, Gemma Louise

    2016-01-01

    This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University London Hutchinson Gilford Progeria syndrome (HGPS) is a rare premature ageing disease affecting children. 80% of “classic” HGPS patients share the same mutation in the LMNA gene that gives rise to characteristics similar to normal human ageing and they usually die in their teens from heart attacks or strokes. Cells taken from progeria patients have a short replicative lifespan in culture an...

  11. Radiological Diagnosis of a Rare Premature Aging Genetic Disorder: Progeria (Hutchinson-Gilford Syndrome

    Directory of Open Access Journals (Sweden)

    Haji Mohammed Nazir

    2017-01-01

    Full Text Available Hutchinson-Gilford Progeria Syndrome (HGPS is a rare disease with a combination of short stature, bone abnormalities, premature ageing, and skin changes. Though the physical appearance of these patients is characteristic, there is little emphasis on the characteristic radiological features. In this paper, we report a 16-year-old boy with clinical and radiological features of this rare genetic disorder. He had a characteristic facial appearance with a large head, large eyes, thin nose with beaked tip, small chin, protruding ears, prominent scalp veins, and absence of hair.

  12. Prematurely aged children: molecular alterations leading to Hutchinson-Gilford progeria and Werner syndromes.

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    Domínguez-Gerpe, Lourdes; Araújo-Vilar, David

    2008-12-01

    Ageing is thought to be a polygenic and stochastic process in which multiple mechanisms operate at the same time. At the level of the individual organism ageing is associated with a progressive deterioration of health and quality of life, sharing common features such as: alopecia and grey hair, loss of audition, macular degeneration, neurodegeneration, cardiovascular diseases, osteoporosis, cataract formation, type-2 diabetes, lipodystrophies; a generally increased susceptibility to infection, autoimmune disorders and diseases such as cancer; and an impaired ability to cope with stress. Recent studies of mechanisms involved in the ageing process are contributing to the identification of genes involved in longevity. Monogenic heritable disorders causing premature ageing, and animal models have contributed to the understanding of some of the characteristic organism-level features associated with human ageing. Werner syndrome and Hutchinson-Gilford progeria syndrome are the best characterized human disorders. Werner syndrome patients have a median life expectancy of 47 years with clinical conditions from the second decade of life. Hutchinson-Gilford progeria syndrome patients die at a median age of 11-13 years with clinical conditions appearing soon after birth. In both syndromes, alterations in specific genes have been identified, with mutations in the WRN and LMNA genes respectively being the most closely associated with each syndrome. Results from molecular studies strongly suggest an increase in DNA damage and cell senescence as the underlying mechanism of pathological premature ageing in these two human syndromes. The same general mechanism has also been observed in human cells undergoing the normal ageing process. In the present article the molecular mechanisms currently proposed for explaining these two syndromes, which may also partly explain the normal ageing process, are reviewed.

  13. MECHANISMS OF PREMATURE VASCULAR AGING IN CHILDREN WITH HUTCHINSON-GILFORD PROGERIA SYNDROME

    Science.gov (United States)

    Gerhard-Herman, Marie; Smoot, Leslie B.; Wake, Nicole; Kieran, Mark W.; Kleinman, Monica E.; Miller, David T.; Schwartzman, Armin; Giobbie-Hurder, Anita; Neuberg, Donna; Gordon, Leslie B.

    2011-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare, segmental premature aging syndrome of accelerated atherosclerosis and early death from myocardial infarction or stroke. This study sought to establish comprehensive characterization of the fatal vasculopathy in HGPS and its relevance to normal aging. We performed cardiovascular assessments at a single clinical site on the largest prospectively studied cohort to date. Carotid-femoral pulse wave velocity was dramatically elevated (mean 13.00±3.83 m/s). Carotid duplex ultrasound echobrightness, assessed in predefined tissue sites as a measure of arterial wall density, was significantly greater than age- and gender-matched controls in the intima-media (P<0.02), near adventitia (P<0.003) and deep adventitia (P<0.01), as was internal carotid artery mean flow velocity (p<0.0001). Ankle-brachial indices were abnormal in 78% of patients. Effective disease treatments may be heralded by normalizing trends of these noninvasive cardiovascular measures. The data demonstrates that, along with peripheral vascular occlusive disease, accelerated vascular stiffening is an early and pervasive mechanism of vascular disease in HGPS. There is considerable overlap with cardiovascular changes of normal aging, which reinforces the view that defining mechanisms of cardiovascular disease in HGPS provides a unique opportunity to isolate a subset of factors influencing cardiovascular disease in the general aging population. PMID:22083160

  14. Néstor-Guillermo progeria syndrome: a novel premature aging condition with early onset and chronic development caused by BANF1 mutations.

    Science.gov (United States)

    Cabanillas, Rubén; Cadiñanos, Juan; Villameytide, José A F; Pérez, Mercedes; Longo, Jesús; Richard, José M; Alvarez, Rebeca; Durán, Noelia S; Illán, Rafael; González, Daniel J; López-Otín, Carlos

    2011-11-01

    Progeria syndromes are rare disorders that involve premature aging. Mutations in BANF1 have been recently reported to cause a new hereditary progeroid syndrome that we now propose to call the Néstor-Guillermo progeria syndrome (NGPS). We describe herein the clinical features of the first two NGPS patients, who phenocopy features of classic progerias (i.e., Hutchinson-Gilford progeria syndrome or mandibuloacral dysplasia), such as aged appearance, growth retardation, decreased subcutaneous fat, thin limbs, and stiff joints. However, these NGPS patients have a distinctive phenotype. In their early adulthood (32 and 24 years of age), they have no signs of cardiovascular impairment, diabetes mellitus, or hypertriglyceridemia. In contrast, they suffer profound skeletal abnormalities that affect their quality of life. The observed differences are of utmost importance to patients and their families and palliation of osseous manifestations is a priority, given their relatively long lifespan. We define NGPS as a chronic progeria because of its slow clinical course and relatively long survival, despite its early onset. Understanding the differences between progeria syndromes might contribute to the development of treatment strategies for common skeletal conditions, as well as aging itself.

  15. Sporadic premature aging in a Japanese monkey: a primate model for progeria.

    Directory of Open Access Journals (Sweden)

    Takao Oishi

    Full Text Available In our institute, we have recently found a child Japanese monkey who is characterized by deep wrinkles of the skin and cataract of bilateral eyes. Numbers of analyses were performed to identify symptoms representing different aspects of aging. In this monkey, the cell cycle of fibroblasts at early passage was significantly extended as compared to a normal control. Moreover, both the appearance of senescent cells and the deficiency in DNA repair were observed. Also, pathological examination showed that this monkey has poikiloderma with superficial telangiectasia, and biochemical assay confirmed that levels of HbA1c and urinary hyaluronan were higher than those of other (child, adult, and aged monkey groups. Of particular interest was that our MRI analysis revealed expansion of the cerebral sulci and lateral ventricles probably due to shrinkage of the cerebral cortex and the hippocampus. In addition, the conduction velocity of a peripheral sensory but not motor nerve was lower than in adult and child monkeys, and as low as in aged monkeys. However, we could not detect any individual-unique mutations of known genes responsible for major progeroid syndromes. The present results indicate that the monkey suffers from a kind of progeria that is not necessarily typical to human progeroid syndromes.

  16. Sporadic premature aging in a Japanese monkey: a primate model for progeria.

    Science.gov (United States)

    Oishi, Takao; Imai, Hiroo; Go, Yasuhiro; Imamura, Masanori; Hirai, Hirohisa; Takada, Masahiko

    2014-01-01

    In our institute, we have recently found a child Japanese monkey who is characterized by deep wrinkles of the skin and cataract of bilateral eyes. Numbers of analyses were performed to identify symptoms representing different aspects of aging. In this monkey, the cell cycle of fibroblasts at early passage was significantly extended as compared to a normal control. Moreover, both the appearance of senescent cells and the deficiency in DNA repair were observed. Also, pathological examination showed that this monkey has poikiloderma with superficial telangiectasia, and biochemical assay confirmed that levels of HbA1c and urinary hyaluronan were higher than those of other (child, adult, and aged) monkey groups. Of particular interest was that our MRI analysis revealed expansion of the cerebral sulci and lateral ventricles probably due to shrinkage of the cerebral cortex and the hippocampus. In addition, the conduction velocity of a peripheral sensory but not motor nerve was lower than in adult and child monkeys, and as low as in aged monkeys. However, we could not detect any individual-unique mutations of known genes responsible for major progeroid syndromes. The present results indicate that the monkey suffers from a kind of progeria that is not necessarily typical to human progeroid syndromes.

  17. Progeria

    OpenAIRE

    Mohamed Riyaz S; Jayachandran S

    2009-01-01

    Hutchinson Gilford Progeria Syndrome (HGPS) is a rare, sporadic, autosomal dominant syndrome that involves premature ageing and death at early age due to myocardial infarction or stroke. A 30-year-old male with clinical and radiologic features highly suggestive of HGPS is presented here with description of differential diagnosis, dental considerations and review of literature.

  18. Progeria

    Directory of Open Access Journals (Sweden)

    Mohamed Riyaz S

    2009-01-01

    Full Text Available Hutchinson Gilford Progeria Syndrome (HGPS is a rare, sporadic, autosomal dominant syndrome that involves premature ageing and death at early age due to myocardial infarction or stroke. A 30-year-old male with clinical and radiologic features highly suggestive of HGPS is presented here with description of differential diagnosis, dental considerations and review of literature.

  19. Reprogramming aging and progeria.

    Science.gov (United States)

    Freije, José M P; López-Otín, Carlos

    2012-12-01

    The aging rate of an organism depends on the ratio of tissue degeneration to tissue repair. As a consequence, molecular alterations that tip this balance toward degeneration cause accelerated aging. Conversely, interventions can be pursued to reduce tissue degeneration or to increase tissue repair with the aim of delaying the onset of age-associated manifestations. Recent studies on the biology of stem cells in aging have revealed the influence of systemic factors on their functionality and demonstrated the feasibility of reprogramming aged and progeroid cells. These results illustrate the reversibility of some aspects of the aging process and encourage the search for new anti-aging and anti-progeria interventions.

  20. Premature Aging-related Peripheral Neuropathy in a Mouse Model of Progeria

    Science.gov (United States)

    Goss, James R.; Stolz, Donna Beer; Robinson, Andria Rasile; Zhang, Mingdi; Arbujas, Norma; Robbins, Paul D.; Glorioso, Joseph C.; Niedernhofer, Laura J.

    2011-01-01

    Peripheral neuropathy is a common aging-related degenerative disorder that interferes with daily activities and leads to increased risk of falls and injury in the elderly. The etiology of most aging-related peripheral neuropathy is unknown. Inherited defects in several genome maintenance mechanisms cause tissue-specific accelerated aging, including neurodegeneration. We tested the hypothesis that a murine model of XFE progeroid syndrome, caused by reduced expression of ERCC1-XPF DNA repair endonuclease, develops peripheral neuropathy. Nerve conduction studies revealed normal nerve function in young adult (8 week) Ercc1−/Δ mice, but significant abnormalities in 20 week-old animals. Morphologic and ultrastructural analysis of the sciatic nerve from mutant mice revealed significant alterations at 20 but not 8 weeks of age. We conclude that Ercc1−/Δ mice have accelerated spontaneous peripheral neurodegeneration that mimics aging-related disease. This provides strong evidence that DNA damage can drive peripheral neuropathy and offers a rapid and novel model to test therapies. PMID:21596054

  1. Premature aging-related peripheral neuropathy in a mouse model of progeria.

    Science.gov (United States)

    Goss, James R; Stolz, Donna Beer; Robinson, Andria Rasile; Zhang, Mingdi; Arbujas, Norma; Robbins, Paul D; Glorioso, Joseph C; Niedernhofer, Laura J

    2011-08-01

    Peripheral neuropathy is a common aging-related degenerative disorder that interferes with daily activities and leads to increased risk of falls and injury in the elderly. The etiology of most aging-related peripheral neuropathy is unknown. Inherited defects in several genome maintenance mechanisms cause tissue-specific accelerated aging, including neurodegeneration. We tested the hypothesis that a murine model of XFE progeroid syndrome, caused by reduced expression of ERCC1-XPF DNA repair endonuclease, develops peripheral neuropathy. Nerve conduction studies revealed normal nerve function in young adult (8 week) Ercc1(-/Δ) mice, but significant abnormalities in 20 week-old animals. Morphologic and ultrastructural analysis of the sciatic nerve from mutant mice revealed significant alterations at 20 but not 8 weeks of age. We conclude that Ercc1(-/Δ) mice have accelerated spontaneous peripheral neurodegeneration that mimics aging-related disease. This provides strong evidence that DNA damage can drive peripheral neuropathy and offers a rapid and novel model to test therapies.

  2. Progeria syndromes and ageing: what is the connection?

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    Burtner, Christopher R; Kennedy, Brian K

    2010-08-01

    One of the many debated topics in ageing research is whether progeroid syndromes are really accelerated forms of human ageing. The answer requires a better understanding of the normal ageing process and the molecular pathology underlying these rare diseases. Exciting recent findings regarding a severe human progeria, Hutchinson-Gilford progeria syndrome, have implicated molecular changes that are also linked to normal ageing, such as genome instability, telomere attrition, premature senescence and defective stem cell homeostasis in disease development. These observations, coupled with genetic studies of longevity, lead to a hypothesis whereby progeria syndromes accelerate a subset of the pathological changes that together drive the normal ageing process.

  3. Genetics of aging, progeria and lamin disorders.

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    Ghosh, Shrestha; Zhou, Zhongjun

    2014-06-01

    Premature aging disorders, like Werner syndrome, Bloom's syndrome, and Hutchinson-Gilford Progeria Syndrome (HGPS), have been the subjects of immense interest as they recapitulate many of the phenotypes observed in physiological aging. They, therefore, not only provide model systems to study normal aging processes but also give valuable insights into the intricate mechanisms underlying senescence. Recent works on HGPS have revealed alterations in a spectrum of cellular and molecular pathways involved in the maintenance of genomic integrity, thus suggesting a profound impact of the nuclear lamina in nuclear organization, chromatin dynamics, regulation of gene expression and epigenetics.

  4. Progeria, rapamycin and normal aging: recent breakthrough

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    Blagosklonny, Mikhail V.

    2011-01-01

    A recent discovery that rapamycin suppresses a pro-senescent phenotype in progeric cells not only suggests a non-toxic therapy for progeria but also implies its similarity with normal aging. For one, rapamycin is also known to suppress aging of regular human cells. Here I discuss four potential scenarios, comparing progeria with both normal and accelerated aging. This reveals further indications of rapamycin both for accelerated aging in obese and for progeria. PMID:21743107

  5. Progeria, rapamycin and normal aging: recent breakthrough

    OpenAIRE

    Blagosklonny, Mikhail V.

    2011-01-01

    A recent discovery that rapamycin suppresses a pro-senescent phenotype in progeric cells not only suggests a non-toxic therapy for progeria but also implies its similarity with normal aging. For one, rapamycin is also known to suppress aging of regular human cells. Here I discuss four potential scenarios, comparing progeria with both normal and accelerated aging. This reveals further indications of rapamycin both for accelerated aging in obese and for progeria.

  6. Progeria, rapamycin and normal aging: recent breakthrough.

    Science.gov (United States)

    Blagosklonny, Mikhail V

    2011-07-01

    A recent discovery that rapamycin suppresses a pro-senescent phenotype in progeric cells not only suggests a non-toxic therapy for progeria but also implies its similarity with normal aging. For one, rapamycin is also known to suppress aging of regular human cells. Here I discuss four potential scenarios, comparing progeria with both normal and accelerated aging. This reveals further indications of rapamycin both for accelerated aging in obese and for progeria.

  7. Stem cell aging in adult progeria.

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    Cheung, Hoi-Hung; Pei, Duanqing; Chan, Wai-Yee

    2015-01-01

    Aging is considered an irreversible biological process and also a major risk factor for a spectrum of geriatric diseases. Advanced age-related decline in physiological functions, such as neurodegeneration, development of cardiovascular disease, endocrine and metabolic dysfunction, and neoplastic transformation, has become the focus in aging research. Natural aging is not regarded as a programmed process. However, accelerated aging due to inherited genetic defects in patients of progeria is programmed and resembles many aspects of natural aging. Among several premature aging syndromes, Werner syndrome (WS) and Hutchinson-Gilford progeria syndrome (HGPS) are two broadly investigated diseases. In this review, we discuss how stem cell aging in WS helps us understand the biology of aging. We also discuss briefly how the altered epigenetic landscape in aged cells can be reversed to a "juvenile" state. Lastly, we explore the potential application of the latest genomic editing technique for stem cell-based therapy and regenerative medicine in the context of aging.

  8. Stem cell aging in adult progeria

    Directory of Open Access Journals (Sweden)

    Hoi-Hung Cheung

    2015-01-01

    Full Text Available Aging is considered an irreversible biological process and also a major risk factor for a spectrum of geriatric diseases. Advanced age-related decline in physiological functions, such as neurodegeneration, development of cardiovascular disease, endocrine and metabolic dysfunction, and neoplastic transformation, has become the focus in aging research. Natural aging is not regarded as a programmed process. However, accelerated aging due to inherited genetic defects in patients of progeria is programmed and resembles many aspects of natural aging. Among several premature aging syndromes, Werner syndrome (WS and Hutchinson–Gilford progeria syndrome (HGPS are two broadly investigated diseases. In this review, we discuss how stem cell aging in WS helps us understand the biology of aging. We also discuss briefly how the altered epigenetic landscape in aged cells can be reversed to a “juvenile” state. Lastly, we explore the potential application of the latest genomic editing technique for stem cell-based therapy and regenerative medicine in the context of aging.

  9. Premature aging syndrome.

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    Coppedè, Fabio

    2012-01-01

    Hutchinson-Gilford progeria syndrome and Werner syndrome are two of the best characterized human progeroid diseases with clinical features mimicking physiological aging at an early age. Both disorders have been the focus of intense research in recent years since they might provide insights into the pathology of normal human aging. The chapter contains a detailed description of the clinical features of both disorders and then it focuses on the genetics, the resulting biochemical alterations at the protein level and the most recent findings and hypotheses concerning the molecular basis of the premature aging phenotypes. A description of available diagnostic and therapeutic approaches is included.

  10. Progeria and the early aging in children: a case report.

    Science.gov (United States)

    Carvalho, Vania O; Celli, Adriane; Bancke Laverde, Bruno Leonardo; Cunico, Caroline; Santos Piedade, Guilherme; Lucas de Mello, Manuela; Beirao Junior, Paulo Sergio

    2016-02-17

    The Hutchinson-Gilford syndrome or progeria is a rare autosomal dominant syndrome characterized by premature aging and involvement of internal systems, such as the circulatory and locomotor. The diagnosis is essentially clinical and the manifestations become more evident from the first year of life. Long term outcome data from Progeria Research Foundation clinical trials have demonstrated an increase in survival in recent years. Even though new trials are ongoing, the recognition of this syndrome is essential to prevent cardiovascular and cerebrovascular complications. A patient, initially asymptomatic, who developed characteristic signs of the syndrome at the age of 6 months is reported. She was referred for evaluation only when she was two years and eleven months old. The diagnosis of Hutchinson-Gilford syndrome was suspected owing to clinical characteristics. The diagnosis was confirmed by genetic testing. A mutation c.1824C> T in exon 11 of the LMNA gene was detected. She was registered in the Progeria Research Foundation and was invited to participate in the weighing and supplementation program. She was included in the lonafarnib protocol study. This medication is a farnesyl transferase inhibitor that prevents the production of progerina and slows cardiovascular and neurological complications of the syndrome. This case highlights the importance of diagnosing progeria patients because they may be referred to the Progeria Research Foundation, which offers genetic screening and inclusion in clinical and therapeutic follow-up protocols without any costs. Progeria trials and research may also contribute to new drug developments related to prevention of aging and atherosclerosis in the near future.

  11. Progeria

    Directory of Open Access Journals (Sweden)

    Kaur Charandeep

    2000-01-01

    Full Text Available A case of progeria is being reported in a 7-year old boy. He had characteristic facies, short stature, alopecia, high pitched voice, coxa valga and sclerodermatous changes in skin.

  12. Aging of Hutchinson-Gilford progeria syndrome fibroblasts is characterised by hyperproliferation and increased apoptosis.

    Science.gov (United States)

    Bridger, Joanna M; Kill, Ian R

    2004-05-01

    Hutchinson-Gilford progeria syndrome is a rare genetic disorder that mimics certain aspects of aging prematurely. Recent work has revealed that mutations in the lamin A gene are a cause of the disease. We show here that cellular aging of Hutchinson-Gilford progeria syndrome fibroblasts is characterised by a period of hyperproliferation and terminates with a large increase in the rate of apoptosis. The occurrence of cells with abnormal nuclear morphology reported by others is shown to be a result of cell division since the fraction of these abnormalities increases with cellular age. Similarly, the proportion of cells with an abnormal or absent A-type lamina increases with age. These data provide clues as to the cellular basis for premature aging in HGPS and support the view that cellular senescence and tissue homeostasis are important factors in the normal aging process.

  13. Progeria

    OpenAIRE

    Raval Ranjan; Bhatt Bhavin; Billiomoria Frenny

    1992-01-01

    An 8-year-old boy presented with clinical manifestations of progeria. He had senile looks, scanty scalp hair, stunted growth, and wrinkled skin with loss of subcutaneous fat. Sclerodermatous changes were found on both thighs and pelvic region, which was confirmed by histopathology.

  14. Progeria

    Directory of Open Access Journals (Sweden)

    Raval Ranjan

    1992-01-01

    Full Text Available An 8-year-old boy presented with clinical manifestations of progeria. He had senile looks, scanty scalp hair, stunted growth, and wrinkled skin with loss of subcutaneous fat. Sclerodermatous changes were found on both thighs and pelvic region, which was confirmed by histopathology.

  15. Autophagy and aging: lessons from progeria models.

    Science.gov (United States)

    Mariño, Guillermo; Fernández, Alvaro F; López-Otín, Carlos

    2010-01-01

    Autophagy is an evolutionarily conserved process essential for cellular homeostasis and organismal viability. In fact, this pathway is one of the major protein degradation mechanisms in eukaryotic cells. It has been repeatedly reported that the autophagic activity of living cells decreases with age, probably contributing to the accumulation of damaged macromolecules and organelles during aging. Moreover, autophagy modulation in different model organisms has yielded very promising results suggesting that the maintenance of a proper autophagic activity contributes to extend longevity. On the other hand, recent findings have shown that distinct premature-aging murine models exhibit an extensive basal activation of autophagy instead of the characteristic decline in this process occurring during normal aging. This unexpected autophagic increase in progeroid models is usually associated with a series of metabolic alterations resembling those occurring under calorie restriction or in other situations reported to prolong life-span. In this chapter, we will discuss the current knowledge on the relationship between the autophagy pathway and aging with a special emphasis on the unexpected and novel link between premature aging and autophagy up-regulation.

  16. Molecular ageing in progeroid syndromes: Hutchinson-Gilford progeria syndrome as a model

    Directory of Open Access Journals (Sweden)

    da Nóbrega Raphael

    2009-04-01

    Full Text Available Abstract Hutchinson-Gilford progeria syndrome (HGPS is a rare premature aging disorder that belongs to a group of conditions called laminopathies which affect nuclear lamins. Mutations in two genes, LMNA and ZMPSTE24, have been found in patients with HGPS. The p.G608G LMNA mutation is the most commonly reported mutation. The aim of this work was to compile a comprehensive literature review of the clinical features and genetic mutations and mechanisms of this syndrome as a contribution to health care workers. This review shows the necessity of a more detailed clinical identification of Hutchinson-Gilford progeria syndrome and the need for more studies on the pharmacologic and pharmacogenomic approach to this syndrome.

  17. The two-faced progeria gene and its implications in aging and metabolism.

    Science.gov (United States)

    Chatzispyrou, Iliana A; Houtkooper, Riekelt H

    2014-05-01

    Premature aging syndromes have gained much attention, not only because of their devastating symptoms but also because they might hold a key to some of the mechanisms underlying aging. The Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutation in the LMNA gene, which normally produces lamins A and C through alternative splicing. Due to this mutation, HGPS patients express an incompletely processed form of lamin A called progerin. In this issue of EMBO Reports, the Tazi group demonstrates how mice expressing different LMNA isoforms present opposite phenotypes in longevity, fat storage and mitochondrial function.

  18. Progeria (Hutchison - Gilford syndrome in siblings: In an autosomal recessive pattern of inheritance

    Directory of Open Access Journals (Sweden)

    Raghu Tanjore

    2001-09-01

    Full Text Available Progeria is an autosomal dominant, premature aging syndrome. Six and three year old female siblings had sclcrodermatous changes over the extremities, alopecia, beaked nose, prominent veins and bird-like facies. Radiological features were consistent with features of progeria. The present case highlights rarity of progeria in siblings with a possible autosomal recessive pattern.

  19. Progeria (Hutchison-Gilford syndrome) in siblings: in an autosomal recessive pattern of inheritance.

    Science.gov (United States)

    Raghu, T Y; Venkatesulu, G A; Kantharaj, G R; Suresh, T; Veeresh, V; Hanumanthappa, Y

    2001-01-01

    Progeria is an autosomal dominant, premature aging syndrome. Six and three year old female siblings had sclerodermatous changes over the extremities, alopecia, beaked nose, prominent veins and bird-like facies. Radiological features were consistent with features of progeria. The present case highlights rarity of progeria in siblings with a possible autosomal recessive pattern.

  20. Hutchinson-Gilford progeria syndrome

    OpenAIRE

    Agarwal Uma; Sitaraman S; Mehta Sharad; Panse Gauri

    2010-01-01

    Progeria is a rare genetic disorder characterized by premature aging, involving the skin, bones, heart, and blood vessels. We report a 4-year-old boy who presented with clinical manifestations of progeria. He had characteristic facies, prominent eyes, scalp and leg veins, senile look, loss of scalp hair, eyebrows and eyelashes, stunted growth, and sclerodermatous changes. The present case is reported due to its rarity.

  1. Progeria syndrome: A case report

    Directory of Open Access Journals (Sweden)

    Rastogi Rajul

    2008-01-01

    Full Text Available Progeria is a rare and peculiar combination of dwarfism and premature aging. The incidence is one in several million births. It occurs sporadically and is probably an autosomal recessive syndrome. Though the clinical presentation is usually typical, conventional radiological and biochemical investigations help in confirming the diagnosis. We present a rare case of progeria with most of the radiological features as a pictorial essay.

  2. Hutchinson-Gilford progeria syndrome

    Directory of Open Access Journals (Sweden)

    Agarwal Uma

    2010-01-01

    Full Text Available Progeria is a rare genetic disorder characterized by premature aging, involving the skin, bones, heart, and blood vessels. We report a 4-year-old boy who presented with clinical manifestations of progeria. He had characteristic facies, prominent eyes, scalp and leg veins, senile look, loss of scalp hair, eyebrows and eyelashes, stunted growth, and sclerodermatous changes. The present case is reported due to its rarity.

  3. The epidemiology of premature aging and associated comorbidities

    Directory of Open Access Journals (Sweden)

    Coppedè F

    2013-08-01

    Full Text Available Fabio Coppedè Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy Abstract: Hutchinson–Gilford Progeria Syndrome and Werner syndrome, also known as childhood- and adulthood-progeria, respectively, represent two of the best characterized human progeroid diseases with clinical features mimicking physiological aging at an early age. The discovery of their genetic basis has led to the identification of several gene mutations leading to a spectrum of progeroid phenotypes ranging from moderate and mild–severe to very aggressive forms. In parallel, the creation of disease registers and databases provided available data for the design of relatively large-scale epidemiological studies, thereby allowing a better understanding of the nature and frequency of the premature aging-associated signs and symptoms. The aim of this article is to review the most recent findings concerning the epidemiology of premature aging disorders, their genetic basis, and the most recent reports on the frequency of associated diseases. Keywords: Hutchinson–Gilford Progeria Syndrome, Werner syndrome, premature aging disorders, epidemiology, cardiovascular diseases, cancer, atherosclerosis, genetics, sign and symptoms

  4. Mouse models and aging: longevity and progeria.

    Science.gov (United States)

    Liao, Chen-Yu; Kennedy, Brian K

    2014-01-01

    Aging is a complex, multifactorial process that is likely influenced by the activities of a range of biological pathways. Genetic approaches to identify genes modulating longevity have been highly successful and recent efforts have extended these studies to mammalian aging. A variety of genetic models have been reported to have enhanced lifespan and, similarly, many genetic interventions lead to progeroid phenotypes. Here, we detail and evaluate both sets of models, focusing on the insights they provide about the molecular processes modulating aging and the extent to which mutations conferring progeroid pathologies really phenocopy accelerated aging.

  5. Metformin Alleviates Aging Cellular Phenotypes in Hutchinson-Gilford Progeria Syndrome Dermal Fibroblasts.

    Science.gov (United States)

    Park, Seul-Ki; Shin, Ok Sarah

    2017-02-13

    Metformin is a popular antidiabetic biguanide, which has been considered as a candidate drug for cancer treatment and aging prevention. Hutchinson-Gilford progeria syndrome (HGPS) is a devastating disease characterized by premature aging and severe age-associated complications leading to death. The effects of metformin on HGPS dermal fibroblasts remain largely undefined. In this study, we investigated whether metformin could exert a beneficial effect on nuclear abnormalities and delay senescence in fibroblasts derived from HGPS patients. Metformin treatment partially restored normal nuclear phenotypes, delayed senescence, activated the phosphorylation of AMP-activated protein kinase, and decreased reactive oxygen species formation in HGPS dermal fibroblasts. Interestingly, metformin reduced the number of phosphorylated histone variant H2AX-positive DNA damage foci and suppressed progerin protein expression, compared to the control. Furthermore, metformin-supplemented aged mice showed higher splenocyte proliferation and mRNA expression of the antioxidant enzyme, superoxide dismutase 2 than the control mice. Collectively, our results show that metformin treatment alleviates the nuclear defects and premature aging phenotypes in HGPS fibroblasts. Thus, metformin can be considered a promising therapeutic approach for life extension in HGPS. This article is protected by copyright. All rights reserved.

  6. Progeria 101/FAQ

    Science.gov (United States)

    ... Progeria, but also may shed light on the phenomenon of aging and cardiovascular disease.” v “Recurrent de ... Statistics Is Progeria passed down from parent to child? HGPS is not usually passed down in families. ...

  7. Age-Dependent Loss of MMP-3 in Hutchinson–Gilford Progeria Syndrome

    Science.gov (United States)

    Harten, Ingrid A.; Zahr, Rima S.; Lemire, Joan M.; Machan, Jason T.; Moses, Marsha A.; Doiron, Robert J.; Curatolo, Adam S.; Rothman, Frank G.; Wight, Thomas N.; Toole, Bryan P.

    2011-01-01

    Hutchinson–Gilford progeria syndrome (HGPS) is a rare, progressive segmental premature aging disease that includes scleroderma-like skin, progressive joint contracture, and atherosclerosis. Affected individuals die prematurely of heart attacks or strokes. Extracellular matrix dysregulation is implicated as a factor in disease progression. We analyzed messenger RNA and protein levels for matrix metalloproteinases (MMPs)-2,-3, and -9 in HGPS primary human dermal fibroblasts using real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and gelatin zymography. MMP-3 messenger RNA and protein levels decreased significantly with increasing donor age in HGPS fibroblasts but not in controls. MMP-2 messenger RNA also showed a donor age–dependent decrease in HGPS fibroblasts, but levels of secreted protein were unchanged. MMP-9 was similar in HGPS and control cultures. The decreased MMP-3 may represent a shift in the inherent extracellular matrix–degrading proteolytic balance in favor of matrix deposition in HGPS. This metalloproteinase has the potential to serve as a biomarker of therapeutic efficacy when assessing treatments for HGPS. PMID:21852285

  8. Hutchinson-Gilford progeria syndrome as a model for vascular aging.

    Science.gov (United States)

    Brassard, Jonathan A; Fekete, Natalie; Garnier, Alain; Hoesli, Corinne A

    2016-02-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder caused by a de novo genetic mutation that leads to the accumulation of a splicing isoform of lamin A termed progerin. Progerin expression alters the organization of the nuclear lamina and chromatin. The life expectancy of HGPS patients is severely reduced due to critical cardiovascular defects. Progerin also accumulates in an age-dependent manner in the vascular cells of adults that do not carry genetic mutations associated with HGPS. The molecular mechanisms that lead to vascular dysfunction in HGPS may therefore also play a role in vascular aging. The vascular phenotypic and molecular changes observed in HGPS are strikingly similar to those seen with age, including increased senescence, altered mechanotransduction and stem cell exhaustion. This article discusses the similarities and differences between age-dependent and HGPS-related vascular aging to highlight the relevance of HGPS as a model for vascular aging. Induced pluripotent stem cells derived from HGPS patients are suggested as an attractive model to study vascular aging in order to develop novel approaches to treat cardiovascular disease.

  9. Hutchinson-Gilford progeria syndrome

    OpenAIRE

    Amar Singh Bhukya; Bellum Siva Nagi Reddy

    2015-01-01

    Hutchinson-Gilford Progeria syndrome (HGPS) is a rare pediatric genetic syndrome associated with a characteristic aged appearance very early in life, generally leading to death in the second decade of life. Apart from premature aging, the other notable characteristics of children with HGPS include extreme short stature, prominent superficial veins, poor weight gain, alopecia, as well as various skeletal and cardiovascular pathologies associated with advanced age. The pattern of inheritance of...

  10. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson–Gilford progeria syndrome

    National Research Council Canada - National Science Library

    Leslie B. Gordon; Monica E. Kleinman; David T. Miller; Donna S. Neuberg; Anita Giobbie-Hurder; Marie Gerhard-Herman; Leslie B. Smoot; Catherine M. Gordon; Robert Cleveland; Brian D. Snyder; Brian Fligor; W. Robert Bishop; Paul Statkevich; Amy Regen; Andrew Sonis; Susan Riley; Christine Ploski; Annette Correia; Nicolle Quinn; Nicole J. Ullrich; Ara Nazarian; Marilyn G. Liang; Susanna Y. Huh; Armin Schwartzman; Mark W. Kieran

    2012-01-01

    Hutchinson–Gilford progeria syndrome (HGPS) is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA that produces the farnesylated aberrant lamin A protein, progerin...

  11. Physical Therapy and Occupational Therapy in Progeria

    Science.gov (United States)

    Physical Therapy and Occupational Therapy in Progeria Information for Families and Caretakers from The Progeria Research Foundation Written ... accelerated aging in children. Children with Progeria need Physical Therapy (PT) and Occupational Therapy (OT) as often as ...

  12. Rapamycin activates autophagy in Hutchinson-Gilford progeria syndrome: implications for normal aging and age-dependent neurodegenerative disorders.

    Science.gov (United States)

    Graziotto, John J; Cao, Kan; Collins, Francis S; Krainc, Dimitri

    2012-01-01

    While rapamycin has been in use for years in transplant patients as an antirejection drug, more recently it has shown promise in treating diseases of aging, such as neurodegenerative disorders and atherosclerosis. We recently reported that rapamycin reverses the cellular phenotype of fibroblasts from children with the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). We found that the causative aberrant protein, progerin, was cleared through autophagic mechanisms when the cells were treated with rapamycin, suggesting a new potential treatment for HGPS. Recent evidence shows that progerin is also present in aged tissues of healthy individuals, suggesting that progerin may contribute to physiological aging. While it is intriguing to speculate that rapamycin may affect normal aging in humans, as it does in lower organisms, it will be important to identify safer analogues of rapamycin for chronic treatments in humans in order to minimize toxicity. In addition to its role in HGPS and normal aging, we discuss the potential of rapamycin for the treatment of age-dependent neurodegenerative diseases.

  13. Progeria: a paradigm for translational medicine.

    Science.gov (United States)

    Gordon, Leslie B; Rothman, Frank G; López-Otín, Carlos; Misteli, Tom

    2014-01-30

    Rare diseases are powerful windows into biological processes and can serve as models for the development of therapeutic strategies. The progress made on the premature aging disorder Progeria is a shining example of the impact that studies of rare diseases can have. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Signaling pathway activation drift during aging: Hutchinson-Gilford Progeria Syndrome fibroblasts are comparable to normal middle-age and old-age cells.

    Science.gov (United States)

    Aliper, Alexander M; Csoka, Antonei Benjamin; Buzdin, Anton; Jetka, Tomasz; Roumiantsev, Sergey; Moskalev, Alexy; Zhavoronkov, Alex

    2015-01-01

    For the past several decades, research in understanding the molecular basis of human aging has progressed significantly with the analysis of premature aging syndromes. Progerin, an altered form of lamin A, has been identified as the cause of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), and may be a contributing causative factor in normal aging. However, the question of whether HGPS actually recapitulates the normal aging process at the cellular and organismal level, or simply mimics the aging phenotype is widely debated. In the present study we analyzed publicly available microarray datasets for fibroblasts undergoing cellular aging in culture, as well as fibroblasts derived from young, middle-age, and old-age individuals, and patients with HGPS. Using GeroScope pathway analysis and drug discovery platform we analyzed the activation states of 65 major cellular signaling pathways. Our analysis reveals that signaling pathway activation states in cells derived from chronologically young patients with HGPS strongly resemble cells taken from normal middle-aged and old individuals. This clearly indicates that HGPS may truly represent accelerated aging, rather than being just a simulacrum. Our data also points to potential pathways that could be targeted to develop drugs and drug combinations for both HGPS and normal aging.

  15. Model of human aging: Recent findings on Werner’s and Hutchinson-Gilford progeria syndromes

    Directory of Open Access Journals (Sweden)

    Shian-ling Ding

    2008-09-01

    Full Text Available Shian-ling Ding1, Chen-Yang Shen2,3,41Department of Nursing, Kang-Ning Junior College of Medical Care and Management, Taipei, Taiwan; 2Institute of Biomedical Sciences, and 3Life Science Library, Academia Sinica, Taipei, Taiwan; 4Graduate Institute of Environmental Science, China Medical University, Taichong, TaiwanAbstract: The molecular mechanisms involved in human aging are complicated. Two progeria syndromes, Werner’s syndrome (WS and Hutchinson-Gilford progeria syndrome (HGPS, characterized by clinical features mimicking physiological aging at an early age, provide insights into the mechanisms of natural aging. Based on recent findings on WS and HGPS, we suggest a model of human aging. Human aging can be triggered by two main mechanisms, telomere shortening and DNA damage. In telomere-dependent aging, telomere shortening and dysfunction may lead to DNA damage responses which induce cellular senescence. In DNA damage-initiated aging, DNA damage accumulates, along with DNA repair deficiencies, resulting in genomic instability and accelerated cellular senescence. In addition, aging due to both mechanisms (DNA damage and telomere shortening is strongly dependent on p53 status. These two mechanisms can also act cooperatively to increase the overall level of genomic instability, triggering the onset of human aging phenotypes.Keywords: human aging, Hutchinson-Gilford Progeria syndrome, Werner syndrome

  16. Accumulation of Mutant Lamin A Causes Progressive Changes in Nuclear Architecture in Hutchinson-Gilford Progeria Syndrome

    National Research Council Canada - National Science Library

    Robert D. Goldman; Dale K. Shumaker; Michael R. Erdos; Maria Eriksson; Anne E. Goldman; Leslie B. Gordon; Yosef Gruenbaum; Satya Khuon; Melissa Mendez; Renée Varga; Francis S. Collins

    2004-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder, commonly caused by a point mutation in the lamin A gene that results in a protein lacking 50 aa near the C terminus, denoted LAΔ50...

  17. Stem cell depletion in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Rosengardten, Ylva; McKenna, Tomás; Grochová, Diana; Eriksson, Maria

    2011-12-01

    Hutchinson-Gilford progeria syndrome (HGPS or progeria) is a very rare genetic disorder with clinical features suggestive of premature aging. Here, we show that induced expression of the most common HGPS mutation (LMNA c.1824C>T, p.G608G) results in a decreased epidermal population of adult stem cells and impaired wound healing in mice. Isolation and growth of primary keratinocytes from these mice demonstrated a reduced proliferative potential and ability to form colonies. Downregulation of the epidermal stem cell maintenance protein p63 with accompanying activation of DNA repair and premature senescence was the probable cause of this loss of adult stem cells. Additionally, upregulation of multiple genes in major inflammatory pathways indicated an activated inflammatory response. This response has also been associated with normal aging, emphasizing the importance of studying progeria to increase the understanding of the normal aging process.

  18. A Prospective Study of Radiographic Manifestations in Hutchinson-Gilford Progeria Syndrome

    Science.gov (United States)

    Cleveland, Robert H.; Gordon, Leslie B.; Kleinman, Monica E.; Miller, David T.; Gordon, Catherine M.; Snyder, Brian D.; Nazarian, Ara; Giobbie-Hurder, Anita; Neuberg, Donna; Kieran, Mark W.

    2014-01-01

    Background/Objective Progeria is a rare segmental premature aging disease with significant skeletal abnormalities. Defining the full scope of radiologic abnormalities requires examination of a large proportion of the world’s Progeria population (estimated at 1 in 4 million). There has been no comprehensive prospective study describing the skeletal abnormalities associated with Progeria. We define characteristic radiographic features of this syndrome. Materials and Methods Thirty-nine children with classic Progeria, ages 2–17 years, from 29 countries were studied at a single site. Comprehensive radiographic imaging studies were performed. Results Sample included 23 females/16 males, the largest number of prospectively evaluated patients with Progeria to date. Eight new and two little known Progeria-associated radiologic findings were identified (frequencies of 3–36%). Additionally, 23 commonly reported findings were evaluated. Of these, 2 were not encountered, 21 were present and ranked according to their frequency. Nine abnormalities were associated with increasing patient age (P=0.02–0.0001). Conclusion This study considerably expands the radiographic morphologic spectrum of Progeria. A better understanding of the radiologic abnormalities associated with Progeria and improved understanding of the biology of progerin (the molecule responsible for this disease), will improve our ability to treat the spectrum of bony abnormalities. PMID:22752073

  19. A prospective study of radiographic manifestations in Hutchinson-Gilford progeria syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Cleveland, Robert H. [Harvard Medical School, Pediatric Radiology, Children' s Hospital Boston, Boston, MA (United States); Gordon, Leslie B. [Harvard Medical School, Department of Anesthesia, Children' s Hospital Boston, Boston, MA (United States); Warren Alpert Medical School of Brown University, Department of Pediatrics, Hasbro Children' s Hospital, Providence, RI (United States); Kleinman, Monica E. [Harvard Medical School, Department of Anesthesia, Children' s Hospital Boston, Boston, MA (United States); Miller, David T. [Harvard Medical School, Division of Genetics, Children' s Hospital Boston, Boston, MA (United States); Gordon, Catherine M. [Harvard Medical School, Division of Endocrinology and Adolescent Medicine, Children' s Hospital Boston, Boston, MA (United States); Snyder, Brian D. [Harvard Medical School, Department of Orthopedic Surgery, Children' s Hospital Boston, Boston, MA (United States); Nazarian, Ara [Harvard Medical School, Boston, MA (United States); Giobbie-Hurder, Anita [Dana-Farber Cancer Institute, Department of Biostatistics and Computational Biology, Boston, MA (United States); Neuberg, Donna [Dana-Farber Cancer Institute, Department of Biostatistics and Computational Biology, Boston, MA (United States); Harvard School of Public Health, Department of Biostatistics, Boston, MA (United States); Kieran, Mark W. [Dana-Farber Cancer Institute and Children' s Hospital Boston, Division of Pediatric Oncology, Boston, MA (United States)

    2012-09-15

    Progeria is a rare segmental premature aging disease with significant skeletal abnormalities. Defining the full scope of radiologic abnormalities requires examination of a large proportion of the world's progeria population (estimated at 1 in 4 million). There has been no comprehensive prospective study describing the skeletal abnormalities associated with progeria. To define characteristic radiographic features of this syndrome. Thirty-nine children with classic progeria, ages 2-17 years, from 29 countries were studied at a single site. Comprehensive radiographic imaging studies were performed. Sample included 23 girls and 16 boys - the largest number of patients with progeria evaluated prospectively to date. Eight new and two little known progeria-associated radiologic findings were identified (frequencies of 3-36%). Additionally, 23 commonly reported findings were evaluated. Of these, 2 were not encountered and 21 were present and ranked according to their frequency. Nine abnormalities were associated with increasing patient age (P = 0.02-0.0001). This study considerably expands the radiographic morphological spectrum of progeria. A better understanding of the radiologic abnormalities associated with progeria and improved understanding of the biology of progerin (the molecule responsible for this disease), will improve our ability to treat the spectrum of bony abnormalities. (orig.)

  20. Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Ullrich, Nicole J; Gordon, Leslie B

    2015-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare, uniformly fatal, segmental "premature aging" disease in which children exhibit phenotypes that may give us insights into the aging process at both the cellular and organismal levels. Initial presentation in early childhood is primarily based on growth and dermatologic findings. Primary morbidity and mortality for children with HGPS is from atherosclerotic cardiovascular disease and strokes with death occurring at an average age of 14.6 years. There is increasing data to support a unique phenotype of the craniofacial and cerebrovascular anatomy that accompanies the premature aging process. Strokes in HGPS can occur downstream of carotid artery and/or vertebral artery occlusion, stenosis, and calcification, with prominent collateral vessel formation. Both large and small vessel disease are present, and strokes are often clinically silent. Despite the presence of multisystem premature aging, children with HGPS do not appear to have cognitive deterioration, suggesting that some aspects of brain function may be protected from the deleterious effects of progerin, the disease-causing protein. Based on limited autopsy material, there is no pathologic evidence of dementia or Alzheimer-type changes. In a transgenic mouse model of progeria with expression of the most common HGPS mutation in brain, skin, bone, and heart, there are distortions of neuronal nuclei at the ultrastructural level with irregular shape and severe invaginations, but no evidence of inclusions or aberrant tau in brain sections. Importantly, the nuclear distortions did not result in significant changes in gene expression in hippocampal neurons. This chapter will discuss both preclinical and clinical aspects of the genetics, pathobiology, clinical phenotype, clinical care, and treatment of HGPS, with special attention toward neurologic and cutaneous findings.

  1. Neonatal progeria: increased ratio of progerin to lamin A leads to progeria of the newborn

    Science.gov (United States)

    Reunert, Janine; Wentzell, Rüdiger; Walter, Michael; Jakubiczka, Sibylle; Zenker, Martin; Brune, Thomas; Rust, Stephan; Marquardt, Thorsten

    2012-01-01

    Hutchinson–Gilford progeria syndrome (HGPS) is an important model disease for premature ageing. Affected children appear healthy at birth, but develop the first symptoms during their first year of life. They die at an average age of 13 years, mostly because of myocardial infarction or stroke. Classical progeria is caused by the heterozygous point mutation c.1824C>T in the LMNA gene, which activates a cryptic splice site. The affected protein cannot be processed correctly to mature lamin A, but is modified into a farnesylated protein truncated by 50 amino acids (progerin). Three more variations in LMNA result in the same mutant protein, but different grades of disease severity. We describe a patient with the heterozygous LMNA mutation c.1821G>A, leading to neonatal progeria with death in the first year of life. Intracellular lamin A was downregulated in the patient's fibroblasts and the ratio of progerin to lamin A was increased when compared with HGPS. It is suggestive that the ratio of farnesylated protein to mature lamin A determines the disease severity in progeria. PMID:22419169

  2. Neonatal progeria: increased ratio of progerin to lamin A leads to progeria of the newborn.

    Science.gov (United States)

    Reunert, Janine; Wentzell, Rüdiger; Walter, Michael; Jakubiczka, Sibylle; Zenker, Martin; Brune, Thomas; Rust, Stephan; Marquardt, Thorsten

    2012-09-01

    Hutchinson-Gilford progeria syndrome (HGPS) is an important model disease for premature ageing. Affected children appear healthy at birth, but develop the first symptoms during their first year of life. They die at an average age of 13 years, mostly because of myocardial infarction or stroke. Classical progeria is caused by the heterozygous point mutation c.1824C>T in the LMNA gene, which activates a cryptic splice site. The affected protein cannot be processed correctly to mature lamin A, but is modified into a farnesylated protein truncated by 50 amino acids (progerin). Three more variations in LMNA result in the same mutant protein, but different grades of disease severity. We describe a patient with the heterozygous LMNA mutation c.1821G>A, leading to neonatal progeria with death in the first year of life. Intracellular lamin A was downregulated in the patient's fibroblasts and the ratio of progerin to lamin A was increased when compared with HGPS. It is suggestive that the ratio of farnesylated protein to mature lamin A determines the disease severity in progeria.

  3. Progeria, the nucleolus and farnesyltransferase inhibitors.

    Science.gov (United States)

    Mehta, Ishita S; Bridger, Joanna M; Kill, Ian R

    2010-02-01

    HGPS (Hutchinson-Gilford progeria syndrome) is a rare genetic disease affecting children causing them to age and die prematurely. The disease is typically due to a point mutation in the coding sequence for the nuclear intermediate-type filament protein lamin A and gives rise to a dominant-negative splice variant named progerin. Accumulation of progerin within nuclei causes disruption to nuclear structure, causes and premature replicative senescence and increases apoptosis. Now it appears that accumulation of progerin may have more widespread effects than previously thought since the demonstration that the presence and distribution of some nucleolar proteins are also adversely affected in progeria cells. One of the major breakthroughs both in the lamin field and for this syndrome is that many of the cellular defects observed in HGPS patient cells and model systems can be restored after treatment with a class of compounds known as FTIs (farnesyltransferase inhibitors). Indeed, it is demonstrated that FTI-277 is able to completely restore nucleolar antigen localization in treated progeria cells. This is encouraging news for the HGPS patients who are currently undergoing clinical trials with FTI treatment.

  4. Progeria Research Foundation, Inc.

    Science.gov (United States)

    About Progeria Progeria 101/FAQ The Connection to Other Diseases The Science Behind Progeria The FTI Drug Lonafarnib For School Reports About ... Profile Our Brochure and Logo Quick Facts Chapters Progeria en espanol Meet the Kids Life According to ...

  5. Hutchinson-Gilford Progeria Syndrome

    Directory of Open Access Journals (Sweden)

    Gopal G

    2014-08-01

    Full Text Available Hutchinson-Gilford Progeria syndrome (HGPS is a rare pediatric genetic syndrome associated with a characteristic aged appearance very early in life, generally leading to death in the second decade of life. Apart from premature aging, the other notable characteristics of children with HGPS include extreme short stature, prominent superficial veins, poor weight gain, alopecia, as well as various skeletal and cardiovascular pathologies associated with advanced age. The pattern of inheritance of HGPS is uncertain, though both autosomal dominant and autosomal recessive modes have been described. Recent genetic studies have demonstrated mutations in the LMNA gene in children with HGPS. In this article, we report a 16 years old girl who had the phenotypic features of HGPS and was later confirmed to have LMNA mutation by genetic analysis.

  6. Progeria Research Day at Brunel University

    Science.gov (United States)

    Eskiw, Christopher H.; Makarov, Evgeny M.; Tree, David; Kill, Ian R.

    2011-01-01

    Hutchinson-Gilford Progeria Syndrome (HGPS) is a severe premature aging syndrome that affects children. These children display characteristics associated with normal aging and die young usually from cardiovascular problems or stroke. Classical HGPS is caused by mutations in the gene encoding the nuclear structural protein lamin A. This mutation leads to a novel version of lamin A that retains a farnesyl group from its processing. This protein is called Progerin and is toxic to cellular function. Pre-lamin A is an immature version of lamin A and also has a farnesylation modification, which is cleaved in the maturation process to create lamin A. PMID:22064469

  7. Cloned Sheep May Age Prematurely

    Institute of Scientific and Technical Information of China (English)

    Joseph; B.Verrengia; 孙颖

    1999-01-01

    1996年的头条科技新闻之一是:多利羊被克隆成功。世人曾为消息雀跃,以为克隆技术马上可以造福人类了,而且科幻作家也开始忙碌起来。而今,当多利羊过3岁生日时,人们却伤感地发现: In Dolly’s case,she is 3,but her genetic material is aging at the rate of the6-year-old sheep from which she was cloned. 这就是所谓aging prematurely。这则消息给人们带来的忧虑有两条。一是:被克隆的动物的预期寿命比人们想象的要短;二是:人们是否能够有效利用克隆的人体细胞去治疗疾病。目前,科学家们的担心还是集中于后者。本书收入的另一篇有关克隆的文章(It’s A Boy!Scientists Clone First Male Mammal)和本篇构成了强烈的对照,可谓一喜一忧。然而,无论喜忧,人类在克隆技术方面正在以坚实的步伐向前迈进。

  8. Labor Market Progeria.

    Science.gov (United States)

    Rodeheaver, Dean

    1990-01-01

    Social ambivalence toward women's roles, sexuality, appearance, and aging combine with social standards of attractiveness to create both age and sex discrimination in the workplace. The life expectancy of presentability is shorter among women than men, thus creating an accelerated aging process termed labor market progeria. (SK)

  9. Increased expression of the Hutchinson-Gilford progeria syndrome truncated lamin A transcript during cell aging.

    Science.gov (United States)

    Rodriguez, Sofia; Coppedè, Fabio; Sagelius, Hanna; Eriksson, Maria

    2009-07-01

    Most cases of the segmental progeroid syndrome, Hutchinson-Gilford progeria syndrome (HGPS), are caused by a de novo dominant mutation within a single codon of the LMNA gene. This mutation leads to the increased usage of an internal splice site that generates an alternative lamin A transcript with an internal deletion of 150 nucleotides, called lamin A Delta 150. The LMNA gene encodes two major proteins of the inner nuclear lamina, lamins A and C, but not much is known about their expression levels. Determination of the overall expression levels of the LMNA gene transcripts is an important step to further the understanding of the HGPS. In this study, we have performed absolute quantification of the lamins A, C and A Delta 150 transcripts in primary dermal fibroblasts from HGPS patients and unaffected age-matched and parent controls. We show that the lamin A Delta 150 transcript is present in unaffected controls but its expression is >160-fold lower than that in samples from HGPS patients. Analysis of transcript expression during in vitro aging shows that although the levels of lamin A and lamin C transcripts remain unchanged, the lamin A Delta 150 transcript increases in late passage cells from HGPS patients and parental controls. This study provides a new method for LMNA transcript analysis and insights into the expression of the LMNA gene in HGPS and normal cells.

  10. Growth hormone therapy in progeria.

    Science.gov (United States)

    Sadeghi-Nejad, Ab; Demmer, Laurie

    2007-05-01

    Catabolic processes seen in Hutchinson-Gilford progeria resemble those of normal aging and, in the affected children, usually result in death at an early age. In addition to its growth promoting effects, growth hormone (GH) has potent anabolic properties. Administration of GH ameliorates some of the catabolic effects of normal aging. We report the results of GH treatment in a young child with progeria.

  11. Hutchinson-Gilford Progeria Syndrome

    National Research Council Canada - National Science Library

    Gopal G; Belavadi GB

    2014-01-01

    Hutchinson-Gilford Progeria syndrome (HGPS) is a rare pediatric genetic syndrome associated with a characteristic aged appearance very early in life, generally leading to death in the second decade of life...

  12. An inherited LMNA gene mutation in atypical Progeria syndrome.

    Science.gov (United States)

    Doubaj, Yassamine; De Sandre-Giovannoli, Annachiara; Vera, Esteves-Vieira; Navarro, Claire Laure; Elalaoui, Siham Chafai; Tajir, Mariam; Lévy, Nicolas; Sefiani, Abdelaziz

    2012-11-01

    Hutchinson-Gilford Progeria syndrome (HGPS) is a rare genetic disorder, characterized by several clinical features that begin in early childhood, recalling an accelerated aging process. The diagnosis of HGPS is based on the recognition of common clinical features and detection of the recurrent heterozygous c.1824C>T (p.Gly608Gly) mutation within exon 11 in the Lamin A/C encoding gene (LMNA). Besides "typical HGPS," several "atypical progeria" syndromes (APS) have been described, in a clinical spectrum ranging from mandibuloacral dysplasia to atypical Werner syndrome. These patients's clinical features include progeroid manifestations, such as short stature, prominent nose, premature graying of hair, partial alopecia, skin atrophy, lipodystrophy, skeletal anomalies, such as mandibular hypoplasia and acroosteolyses, and in some cases severe atherosclerosis with metabolic complications. APS are due in several cases to de novo heterozygous LMNA mutations other than the p.Gly608Gly, or due to homozygous BAFN1 mutations in Nestor-Guillermo Progeria syndrome (NGPS). We report here and discuss the observation of a non-consanguineous Moroccan patient presenting with atypical progeria. The molecular studies showed the heterozygous mutation c.412G>A (p.Glu138Lys) of the LMNA gene. This mutation, previously reported as a de novo mutation, was inherited from the apparently healthy father who showed a somatic cell mosaicism.

  13. Hutchinson-Gilford progeria syndrome: a rare case report

    Directory of Open Access Journals (Sweden)

    Kalegowda Deepadarshan

    2016-04-01

    Full Text Available Progeroid syndromes are characterised by clinical features of physiological aging at an early age. Hutchinson-Gilford progeria syndrome is a type of progeroid syndrome, characterised by abnormal facies, bone abnormalities, sclerodermatous skin changes and retarded physical development. Average life expectancy of progeria patients is 13 years. Herein we are reporting a case of progeria who is 21 years old.

  14. Estimation of vessel age and early diagnose of atherosclerosis in progeria syndrome by using echo-tracking.

    Science.gov (United States)

    Várady, E; Feher, E; Levai, A; Battyany, I

    2010-01-01

    The stiffness of the arteries normally increases with age. Radiofrequency echo-tracking is a non-invasive ultrasound method which is able to detect the stiffness of the arteries, represented by the beta stiffness index. The estimation of biological age of vessels is possible on the basis of the normal age-group specific beta stiffness values. The beta stiffness index becomes higher in early stages of atherosclerosis as well, before any visible morphological changes. Hutchinson-Gilford progeria syndrome (HGPS) is rare genetic disorder resulting in accelerated aging including appearance of progressive atherosclerosis at an early age which determines the quality and term of life of these patients. Determination of vascular age and early diagnosis of atherosclerosis seems crucial. According to our knowledge, the estimation of vascular age detected with radiofrequency echo-tracking in HGPS patients, in contrast to the normal age-specific beta stiffness values, has not been published yet.

  15. Simultaneous Shoulder and Hip Dislocation in a 12-Year-Old Girl with Hutchinson-Gilford Progeria Syndrome

    Directory of Open Access Journals (Sweden)

    Shirin Mardookhpour

    2012-06-01

    Full Text Available Hutchinson-Gilford progeria syndrome (HGPS is a rare premature ageing disorder that is characterized by accelerated degenerative changes of the cutaneous, musculoskeletal and cardiovascular systems. Mean age at diagnosis is 2.9 years and generally leading to death at approximately 13 years of age due to myocardial infarction or stroke. Orthopedic manifestations of HGPS are multiple and shoulder dislocation is a rare skeletal trauma in progeria syndrome. Our patient had simultaneous shoulder and hip dislocation associated with a low energy trauma. This subject has not been reported. Treatment accomplished as close reduction under general anesthesia and immobilization.

  16. Premature and accelerated ageing: HIV or HAART?

    Directory of Open Access Journals (Sweden)

    Reuben Luke Smith

    2013-01-01

    Full Text Available Highly Active Anti-Retroviral Therapy (HAART has significantly increased life expectancy of the HIV-positive population. Nevertheless, the average lifespan of HIV patients remains shorter compared to uninfected individuals. Immunosenescence, a current explanation for this difference invokes heavily on viral stimulus despite HAART efficiency in viral suppression. We propose here that the premature and accelerated ageing of HIV patients can also be caused by adverse effects of antiretroviral drugs, specifically those that affect the mitochondria. The Nucleoside Reverse Transcriptase Inhibitor (NRTI antiretroviral drug class for instance, is known to cause depletion of mitochondrial DNA via inhibition of the mitochondrial specific DNA polymerase-ƴ. Besides NRTIs, other antiretroviral drug classes such as Protease Inhibitors also cause severe mitochondrial damage by increasing oxidative stress and diminishing mitochondrial function. We also discuss important areas for future research and argue in favour of the use of C. elegans as a novel model system for studying these effects.

  17. Speeding up the clock: The past, present and future of progeria.

    Science.gov (United States)

    Swahari, Vijay; Nakamura, Ayumi

    2016-01-01

    Progeria is a devastating disorder in which patients exhibit signs of premature aging. The most well-known progeroid syndromes include Hutchinson-Gilford Progeria Syndrome (HGPS) and Werner Syndrome (WS). While HGPS and WS are rare, they often result in severe age-associated complications starting in the early developmental period or after the pubertal growth spurt during adolescence, respectively. In addition, patients with HGPS ultimately die of diseases normally seen in the elderly population, with stroke and myocardial infarction as the leading causes of death. Many WS patients develop similar cardiovascular complications but also have an increased predisposition to developing multiple rare malignancies. These premature aging disorders, as well as animal and cell culture models that recapitulate these diseases, have provided insight into the genetics and cellular pathways that underlie these human conditions and have also uncovered possible mechanisms behind normal aging. Here we discuss the history, the types of progeria, and the various pathophysiological mechanisms that drive these diseases. We also address recent medical advances and treatment modalities for patients with progeria.

  18. Premature aging in mice activates a systemic metabolic response involving autophagy induction.

    Science.gov (United States)

    Mariño, Guillermo; Ugalde, Alejandro P; Salvador-Montoliu, Natalia; Varela, Ignacio; Quirós, Pedro M; Cadiñanos, Juan; van der Pluijm, Ingrid; Freije, José M P; López-Otín, Carlos

    2008-07-15

    Autophagy is a highly regulated intracellular process involved in the turnover of most cellular constituents and in the maintenance of cellular homeostasis. It is well-established that the basal autophagic activity of living cells decreases with age, thus contributing to the accumulation of damaged macromolecules during aging. Conversely, the activity of this catabolic pathway is required for lifespan extension in animal models such as Caenorhabditis elegans and Drosophila melanogaster. In this work, we describe the unexpected finding that Zmpste24-null mice, which show accelerated aging and are a reliable model of human Hutchinson-Gilford progeria, exhibit an extensive basal activation of autophagy instead of the characteristic decline in this process occurring during normal aging. We also show that this autophagic increase is associated with a series of changes in lipid and glucose metabolic pathways, which resemble those occurring in diverse situations reported to prolong lifespan. These Zmpste24(-/-) mice metabolic alterations are also linked to substantial changes in circulating blood parameters, such as leptin, glucose, insulin or adiponectin which in turn lead to peripheral LKB1-AMPK activation and mTOR inhibition. On the basis of these results, we propose that nuclear abnormalities causing premature aging in Zmpste24(-/-) mice trigger a metabolic response involving the activation of autophagy. However, the chronic activation of this catabolic pathway may turn an originally intended pro-survival strategy into a pro-aging mechanism and could contribute to the systemic degeneration and weakening observed in these progeroid mice.

  19. Ocular manifestations in the Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Chandravanshi, Shivcharan L; Rawat, Ashok Kumar; Dwivedi, Prem Chand; Choudhary, Pankaj

    2011-01-01

    The Hutchinson-Gilford progeria (HGP) syndrome is an extremely rare genetic condition characterized by an appearance of accelerated aging in children. The word progeria is derived from the Greek word progeros meaning 'prematurely old'. It is caused by de novo dominant mutation in the LMNA gene (gene map locus 1q21.2) and characterized by growth retardation and accelerated degenerative changes of the skin, musculoskeletal and cardiovascular systems. The most common ocular manifestations are prominent eyes, loss of eyebrows and eyelashes, and lagophthalmos. In the present case some additional ocular features such as horizontal narrowing of palpebral fissure, superior sulcus deformity, upper lid retraction, upper lid lag in down gaze, poor pupillary dilatation, were noted. In this case report, a 15-year-old Indian boy with some additional ocular manifestations of the HGP syndrome is described.

  20. Ocular manifestations in the Hutchinson-Gilford progeria syndrome

    Science.gov (United States)

    Chandravanshi, Shivcharan L; Rawat, Ashok Kumar; Dwivedi, Prem Chand; Choudhary, Pankaj

    2011-01-01

    The Hutchinson-Gilford progeria (HGP) syndrome is an extremely rare genetic condition characterized by an appearance of accelerated aging in children. The word progeria is derived from the Greek word progeros meaning ‘prematurely old’. It is caused by de novo dominant mutation in the LMNA gene (gene map locus 1q21.2) and characterized by growth retardation and accelerated degenerative changes of the skin, musculoskeletal and cardiovascular systems. The most common ocular manifestations are prominent eyes, loss of eyebrows and eyelashes, and lagophthalmos. In the present case some additional ocular features such as horizontal narrowing of palpebral fissure, superior sulcus deformity, upper lid retraction, upper lid lag in down gaze, poor pupillary dilatation, were noted. In this case report, a 15-year-old Indian boy with some additional ocular manifestations of the HGP syndrome is described. PMID:22011502

  1. Ocular manifestations in the Hutchinson-Gilford progeria syndrome

    Directory of Open Access Journals (Sweden)

    Shivcharan L Chandravanshi

    2011-01-01

    Full Text Available The Hutchinson-Gilford progeria (HGP syndrome is an extremely rare genetic condition characterized by an appearance of accelerated aging in children. The word progeria is derived from the Greek word progeros meaning ′prematurely old′. It is caused by de novo dominant mutation in the LMNA gene (gene map locus 1q21.2 and characterized by growth retardation and accelerated degenerative changes of the skin, musculoskeletal and cardiovascular systems. The most common ocular manifestations are prominent eyes, loss of eyebrows and eyelashes, and lagophthalmos. In the present case some additional ocular features such as horizontal narrowing of palpebral fissure, superior sulcus deformity, upper lid retraction, upper lid lag in down gaze, poor pupillary dilatation, were noted. In this case report, a 15-year-old Indian boy with some additional ocular manifestations of the HGP syndrome is described.

  2. Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria

    OpenAIRE

    V. Cenni; C. Capanni; Columbaro, M.; Ortolani, M.; M.R. D'Apice; Novelli, G; Fini, M.; S. Marmiroli; Scarano, E.; Maraldi, N.M.; Squarzoni, S.; S. Prencipe; Lattanzi, G

    2011-01-01

    Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying pre...

  3. Partial lipodystrophy with severe insulin resistance and adult progeria Werner syndrome.

    OpenAIRE

    Donadille, Bruno; D'Anella, Pascal; Auclair, Martine; Uhrhammer, Nancy; Sorel, Marc; Grigorescu, Romulus; Ouzounian, Sophie; Cambonie, Gilles; Boulot, Pierre; Laforêt, Pascal; Carbonne, Bruno; Christin-Maitre, Sophie; Bignon, Yves-Jean; Vigouroux, Corinne

    2013-01-01

    International audience; BACKGROUND: Laminopathies, due to mutations in LMNA, encoding A type-lamins, can lead to premature ageing and/or lipodystrophic syndromes, showing that these diseases could have close physiopathological relationships. We show here that lipodystrophy and extreme insulin resistance can also reveal the adult progeria Werner syndrome linked to mutations in WRN, encoding a RecQ DNA helicase. METHODS: We analysed the clinical and biological features of two women, aged 32 and...

  4. Hutchinson-Gilford progeria syndrome caused by an LMNA mutation: a case report.

    Science.gov (United States)

    Chu, Yan; Xu, Zi-Gang; Xu, Zhe; Ma, Lin

    2015-01-01

    Hutchinson-Gilford progeria syndrome is a rare genetic disorder characterized by premature aging of the skin, bones, heart, and blood vessels. We report a 6-year-old boy who was born at full term but presented with scleroderma-like appearance at 1 month of age and gradually developed clinical manifestations of progeria. He had characteristic facial features of prominent eyes, scalp, and leg veins; loss of scalp hair, eyebrows, and eyelashes; stunted growth; scleroderma-like changes of the skin; and a premature aged appearance. Metabolic investigations showed transient methylmalonic aciduria, and genetic testing of the peripheral blood identified the c.1824C>T heterozygous LMNA mutation. The present case is reported because of its rarity.

  5. Premature aging in telomerase-deficient zebrafish

    Directory of Open Access Journals (Sweden)

    Monique Anchelin

    2013-09-01

    The study of telomere biology is crucial to the understanding of aging and cancer. In the pursuit of greater knowledge in the field of human telomere biology, the mouse has been used extensively as a model. However, there are fundamental differences between mouse and human cells. Therefore, additional models are required. In light of this, we have characterized telomerase-deficient zebrafish (Danio rerio as the second vertebrate model for human telomerase-driven diseases. We found that telomerase-deficient zebrafish show p53-dependent premature aging and reduced lifespan in the first generation, as occurs in humans but not in mice, probably reflecting the similar telomere length in fish and humans. Among these aging symptoms, spinal curvature, liver and retina degeneration, and infertility were the most remarkable. Although the second-generation embryos died in early developmental stages, restoration of telomerase activity rescued telomere length and survival, indicating that telomerase dosage is crucial. Importantly, this model also reproduces the disease anticipation observed in humans with dyskeratosis congenita (DC. Thus, telomerase haploinsufficiency leads to anticipation phenomenon in longevity, which is related to telomere shortening and, specifically, with the proportion of short telomeres. Furthermore, p53 was induced by telomere attrition, leading to growth arrest and apoptosis. Importantly, genetic inhibition of p53 rescued the adverse effects of telomere loss, indicating that the molecular mechanisms induced by telomere shortening are conserved from fish to mammals. The partial rescue of telomere length and longevity by restoration of telomerase activity, together with the feasibility of the zebrafish for high-throughput chemical screening, both point to the usefulness of this model for the discovery of new drugs able to reactivate telomerase in individuals with DC.

  6. Hutchinson-Gilford Progeria Syndrome: A Rare Genetic Disorder

    Science.gov (United States)

    Panigrahi, Rajat G.; Panigrahi, Antarmayee; Vijayakumar, Poornima; Choudhury, Priyadarshini; Bhuyan, Sanat K.; Bhuyan, Ruchi; Maragathavalli, G.; Pati, Abhishek Ranjan

    2013-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare pediatric genetic syndrome with incidence of one per eight million live births. The disorder is characterised by premature aging, generally leading to death at approximately 13.4 years of age. This is a follow-up study of a 9-year-old male with clinical and radiographic features highly suggestive of HGPS and presented here with description of differential diagnosis and dental consideration. This is the first case report of HGPS which showed pectus carinatum structure of chest. PMID:24288630

  7. Hutchinson-Gilford Progeria Syndrome: A Rare Genetic Disorder

    Directory of Open Access Journals (Sweden)

    Rajat G. Panigrahi

    2013-01-01

    Full Text Available Hutchinson-Gilford progeria syndrome (HGPS is a rare pediatric genetic syndrome with incidence of one per eight million live births. The disorder is characterised by premature aging, generally leading to death at approximately 13.4 years of age. This is a follow-up study of a 9-year-old male with clinical and radiographic features highly suggestive of HGPS and presented here with description of differential diagnosis and dental consideration. This is the first case report of HGPS which showed pectus carinatum structure of chest.

  8. Accelerated Aging of Intervertebral Discs in a Mouse Model of Progeria

    Science.gov (United States)

    Vo, Nam; Seo, Hyoung-Yeon; Robinson, Andria; Sowa, Gwendolyn; Bentley, Douglas; Taylor, Lauren; Studer, Rebecca; Usas, Arvydas; Huard, Johnny; Alber, Sean; Watkins, Simon C.; Lee, Joon; Coehlo, Paulo; Wang, Dong; Loppini, Mattia; Robbins, Paul D.; Niedernhofer, Laura J.; Kang, James

    2012-01-01

    Intervertebral disc degeneration (IDD) is a common and debilitating disorder that results in reduced flexibility of the spine, pain, and reduced mobility. Risk factors for IDD include age, genetic predisposition, injury, and other environmental factors such as smoking. Loss of proteoglycans (PGs) contributes to IDD with advancing age. Currently there is a lack of a model for rapid investigation of disc aging and evaluation of therapeutic interventions. Here we examined progression of disc aging in a murine model of a human progeroid syndrome caused by deficiency of the DNA repair endonuclease, ERCC1–XPF (Ercc1−/Δ mice). The ERCC1-deficient mice showed loss of disc height and degenerative structural changes in their vertebral bodies similar to those reported for old rodents. Compared to their wild-type littermates, Ercc1−/Δ mice also exhibit other age-related IDD characteristics, including premature loss of disc PG, reduced matrix PG synthesis, and enhanced apoptosis and cell senescence. Finally, the onset of age-associated disc pathologies was further accelerated in Ercc1−/Δ mice following chronic treatment with the chemotherapeutic agent mechlorethamine. These results demonstrate that Ercc1−/Δ mice represent an accurate and rapid model of disc aging and provide novel evidence that DNA damage negatively impacts PG synthesis. PMID:20973062

  9. Transformation Resistance in a Premature Aging Disorder Identifies a Tumor-Protective Function of BRD4

    Directory of Open Access Journals (Sweden)

    Patricia Fernandez

    2014-10-01

    Full Text Available Advanced age and DNA damage accumulation are prominent risk factors for cancer. The premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS provides a unique opportunity for studying the interplay between DNA damage and aging-associated tumor mechanisms, given that HGPS patients do not develop tumors despite elevated levels of DNA damage. Here, we have used HGPS patient cells to identify a protective mechanism to oncogenesis. We find that HGPS cells are resistant to neoplastic transformation. Resistance is mediated by the bromodomain protein BRD4, which exhibits altered genome-wide binding patterns in transformation-resistant cells, leading to inhibition of oncogenic dedifferentiation. BRD4 also inhibits, albeit to a lower extent, the tumorigenic potential of transformed cells from healthy individuals. BRD4-mediated tumor protection is clinically relevant given that a BRD4 gene signature predicts positive clinical outcome in breast and lung cancer. Our results demonstrate a protective function for BRD4 and suggest tissue-specific roles for BRD4 in tumorigenesis.

  10. Hutchinson - Gilford progeria syndrome: A rare case report.

    Science.gov (United States)

    Kashyap, Subhash; Shanker, Vinay; Sharma, Neeraj

    2014-10-01

    Hutchinson - Gilford Progeria Syndrome is a rare genetic disorder characterized by premature aging involving the skin, bones, heart, and blood vessels. We report a three-year-old boy with clinical manifestations characteristic of this syndrome. He had a characteristic "plucked-bird" appearance, prominent eyes and scalp veins, senile look, loss of scalp hair, eyebrows, and eyelashes, stunted growth, and mottled pigmentation with sclerodermatous changes over the trunk and lower limbs. Radiological changes and decreased high-density lipoprotein (HDL) levels were also characteristic of the syndrome. This interesting case is reported for its rarity.

  11. Hutchinson – Gilford progeria syndrome: A rare case report

    Science.gov (United States)

    Kashyap, Subhash; Shanker, Vinay; Sharma, Neeraj

    2014-01-01

    Hutchinson – Gilford Progeria Syndrome is a rare genetic disorder characterized by premature aging involving the skin, bones, heart, and blood vessels. We report a three-year-old boy with clinical manifestations characteristic of this syndrome. He had a characteristic “plucked-bird” appearance, prominent eyes and scalp veins, senile look, loss of scalp hair, eyebrows, and eyelashes, stunted growth, and mottled pigmentation with sclerodermatous changes over the trunk and lower limbs. Radiological changes and decreased high-density lipoprotein (HDL) levels were also characteristic of the syndrome. This interesting case is reported for its rarity. PMID:25396134

  12. Hutchinson - Gilford progeria syndrome: A rare case report

    Directory of Open Access Journals (Sweden)

    Subhash Kashyap

    2014-01-01

    Full Text Available Hutchinson - Gilford Progeria Syndrome is a rare genetic disorder characterized by premature aging involving the skin, bones, heart, and blood vessels. We report a three-year-old boy with clinical manifestations characteristic of this syndrome. He had a characteristic "plucked-bird" appearance, prominent eyes and scalp veins, senile look, loss of scalp hair, eyebrows, and eyelashes, stunted growth, and mottled pigmentation with sclerodermatous changes over the trunk and lower limbs. Radiological changes and decreased high-density lipoprotein (HDL levels were also characteristic of the syndrome. This interesting case is reported for its rarity.

  13. PROGERIA IN SIBLINGS: A RARE CASE REPORT

    Science.gov (United States)

    Sowmiya, R; Prabhavathy, D; Jayakumar, S

    2011-01-01

    Progeria, also known as Hutchinson-Gilford syndrome, is an extremely rare, severe genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. It is an autosomal dominant disorder. It is not seen in siblings of affected children although there are very few case reports of progeria affecting more than one child in a family. Here we are presenting two siblings, a 14-year-old male and a 13-year-old female with features of progeria, suggesting a possible autosomal recessive inheritance. PMID:22121285

  14. Progeria in siblings: A rare case report

    OpenAIRE

    Sowmiya, R; Prabhavathy, D; S Jayakumar

    2011-01-01

    Progeria, also known as Hutchinson-Gilford syndrome, is an extremely rare, severe genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. It is an autosomal dominant disorder. It is not seen in siblings of affected children although there are very few case reports of progeria affecting more than one child in a family. Here we are presenting two siblings, a 14-year-old male and a 13-year-old female with features of progeria, suggesting a possible autosoma...

  15. Progeria in siblings: A rare case report

    Directory of Open Access Journals (Sweden)

    R Sowmiya

    2011-01-01

    Full Text Available Progeria, also known as Hutchinson-Gilford syndrome, is an extremely rare, severe genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. It is an autosomal dominant disorder. It is not seen in siblings of affected children although there are very few case reports of progeria affecting more than one child in a family. Here we are presenting two siblings, a 14-year-old male and a 13-year-old female with features of progeria, suggesting a possible autosomal recessive inheritance.

  16. Gene-rich chromosomal regions are preferentially localized in the lamin B deficient nuclear blebs of atypical progeria cells.

    Science.gov (United States)

    Bercht Pfleghaar, Katrin; Taimen, Pekka; Butin-Israeli, Veronika; Shimi, Takeshi; Langer-Freitag, Sabine; Markaki, Yolanda; Goldman, Anne E; Wehnert, Manfred; Goldman, Robert D

    2015-01-01

    More than 20 mutations in the gene encoding A-type lamins (LMNA) cause progeria, a rare premature aging disorder. The major pathognomonic hallmarks of progeria cells are seen as nuclear deformations or blebs that are related to the redistribution of A- and B-type lamins within the nuclear lamina. However, the functional significance of these progeria-associated blebs remains unknown. We have carried out an analysis of the structural and functional consequences of progeria-associated nuclear blebs in dermal fibroblasts from a progeria patient carrying a rare point mutation p.S143F (C428T) in lamin A/C. These blebs form microdomains that are devoid of major structural components of the nuclear envelope (NE)/lamina including B-type lamins and nuclear pore complexes (NPCs) and are enriched in A-type lamins. Using laser capture microdissection and comparative genomic hybridization (CGH) analyses, we show that, while these domains are devoid of centromeric heterochromatin and gene-poor regions of chromosomes, they are enriched in gene-rich chromosomal regions. The active form of RNA polymerase II is also greatly enriched in blebs as well as nascent RNA but the nuclear co-activator SKIP is significantly reduced in blebs compared to other transcription factors. Our results suggest that the p.S143F progeria mutation has a severe impact not only on the structure of the lamina but also on the organization of interphase chromatin domains and transcription. These structural defects are likely to contribute to gene expression changes reported in progeria and other types of laminopathies.

  17. Premature birth and age at onset of puberty.

    Science.gov (United States)

    Hui, Lai Ling; Leung, Gabriel M; Lam, Tai Hing; Schooling, C Mary

    2012-05-01

    Premature birth is associated with poor metabolic health in both sexes, potentially via earlier pubertal timing. We examined the associations of gestational age and premature birth (Premature girls reached puberty about 4 months later than girls with ≥ 41 weeks' gestation (time ratio = 1.04 [95% confidence interval = 1.01-1.06]), adjusted for mother' age of menarche, mother's place of birth, and smoking during pregnancy. Gestational age was not associated with onset of puberty in boys (test for interaction by sex, P Premature birth was not related to earlier onset of puberty; instead, premature girls had later onset of puberty. Thus, the association between premature birth and subsequent cardiovascular risk is probably not mediated through the timing of pubertal onset. It is unclear whether onset, duration, or tempo of puberty is more relevant to the detrimental consequences of early puberty. Further studies investigating intrauterine, infant, and childhood influences on the duration and tempo of puberty may help unravel the early origins of cardiovascular diseases.

  18. Median age at death as an indicator of premature mortality

    OpenAIRE

    Jannerfeldt, Eric; Hörte, Lars-Gunnar

    1988-01-01

    The median age at death from certain diseases was calculated for each year for 1969-85 and compared with that at death from all causes. The results indicated the impact of these diseases in terms of premature mortality and changes over time. Cancer was a more important cause of premature mortality among women than among men. For cancer of the cervix the median age at death increased appreciably whereas for cancer of the lung in women it slightly decreased. The median age at death is easy to c...

  19. Specific premature epigenetic aging of cartilage in osteoarthritis

    Science.gov (United States)

    Vidal-Bralo, Laura; Lopez-Golan, Yolanda; Mera-Varela, Antonio; Rego-Perez, Ignacio; Horvath, Steve; Zhang, Yuhua; del Real, Álvaro; Zhai, Guangju; Blanco, Francisco J; Riancho, Jose A.; Gomez-Reino, Juan J; Gonzalez, Antonio

    2016-01-01

    Osteoarthritis (OA) is a disease affecting multiple tissues of the joints in the elderly, but most notably articular cartilage. Premature biological aging has been described in this tissue and in blood cells, suggesting a systemic component of premature aging in the pathogenesis of OA. Here, we have explored epigenetic aging in OA at the local (cartilage and bone) and systemic (blood) levels. Two DNA methylation age-measures (DmAM) were used: the multi-tissue age estimator for cartilage and bone; and a blood-specific biomarker for blood. Differences in DmAM between OA patients and controls showed an accelerated aging of 3.7 years in articular cartilage (95 % CI = 1.1 to 6.3, P = 0.008) of OA patients. By contrast, no difference in epigenetic aging was observed in bone (0.04 years; 95 % CI = −1.8 to 1.9, P = 0.3) and in blood (−0.6 years; 95 % CI = −1.5 to 0.3, P = 0.2) between OA patients and controls. Therefore, premature epigenetic aging according to DNA methylation changes was specific of OA cartilage, adding further evidence and insight on premature aging of cartilage as a component of OA pathogenesis that reflects damage and vulnerability. PMID:27689435

  20. Mechanisms of cardiovascular disease in accelerated aging syndromes.

    Science.gov (United States)

    Capell, Brian C; Collins, Francis S; Nabel, Elizabeth G

    2007-07-06

    In the past several years, remarkable progress has been made in the understanding of the mechanisms of premature aging. These rare, genetic conditions offer valuable insights into the normal aging process and the complex biology of cardiovascular disease. Many of these advances have been made in the most dramatic of these disorders, Hutchinson-Gilford progeria syndrome. Although characterized by features of normal aging such as alopecia, skin wrinkling, and osteoporosis, patients with Hutchinson-Gilford progeria syndrome are affected by accelerated, premature arteriosclerotic disease that leads to heart attacks and strokes at a mean age of 13 years. In this review, we highlight recent advances in the biology of premature aging uncovered in Hutchinson-Gilford progeria syndrome and other accelerated aging syndromes, advances that provide insight into the mechanisms of cardiovascular diseases ranging from atherosclerosis to arrhythmias.

  1. Premature aging and cancer in nucleotide excision repair-disorders

    NARCIS (Netherlands)

    K.E.M. Diderich (Karin); M. Alanazi; J.H.J. Hoeijmakers (Jan)

    2011-01-01

    textabstractDuring the past decades, the major impact of DNA damage on cancer as 'disease of the genes' has become abundantly apparent. In addition to cancer, recent years have also uncovered a very strong association of DNA damage with many features of (premature) aging. The notion that DNA repair

  2. Impact of prematurity on language skills at school age.

    Science.gov (United States)

    Smith, Jamie Mahurin; DeThorne, Laura Segebart; Logan, Jessica A R; Channell, Ron W; Petrill, Stephen A

    2014-06-01

    The existing literature on language outcomes in children born prematurely focuses almost exclusively on standardized test scores rather than discourse-level abilities. The authors of this study looked longitudinally at school-age language outcomes and potential moderating variables for a group of twins born prematurely versus a control group of twins born at full term, analyzing both standardized test results and language sample data from the population-based Western Reserve Reading Project (WRRP; Petrill, Deater-Deckard, Thompson, DeThorne, & Schatschneider, 2006). Fifty-seven children born prematurely, at ≤32 weeks or children born at full term and were matched for age, gender, race, and parental education. Data included discourse-level language samples and standardized test results, collected at average ages 7, 8, and 10 years. The language samples were analyzed to yield a number of semantic and syntactic measures that were consolidated via factor analysis. Regression models showed significant differences between the 2 groups for standardized test results, although the mean score for both groups fell in the normal range. For the discourse-level language measures, however, differences never reached statistical significance. Parental education was significantly associated with improved standardized test scores. These findings suggest that in the absence of frank neurological impairment, sophisticated semantic and syntactic skills may be relatively intact in the discourse-level language of children born prematurely. Implications for assessment, particularly the potential role of attention and executive function in standardized testing tasks, are reviewed.

  3. Progeria Research Foundation Diagnostic Testing Program

    Science.gov (United States)

    About Progeria Progeria 101/FAQ The Connection to Other Diseases The Science Behind Progeria The FTI Drug Lonafarnib For School Reports About ... Profile Our Brochure and Logo Quick Facts Chapters Progeria en espanol Meet the Kids Life According to ...

  4. Schizophrenia as segmental progeria

    Science.gov (United States)

    Papanastasiou, Evangelos; Gaughran, Fiona; Smith, Shubulade

    2011-01-01

    Schizophrenia is associated with a variety of physical manifestations (i.e. metabolic, neurological) and despite psychotropic medication being blamed for some of these (in particular obesity and diabetes), there is evidence that schizophrenia itself confers an increased risk of physical disease and early death. The observation that schizophrenia and progeroid syndromes share common clinical features and molecular profiles gives rise to the hypothesis that schizophrenia could be conceptualized as a whole body disorder, namely a segmental progeria. Mammalian cells employ the mechanisms of cellular senescence and apoptosis (programmed cell death) as a means to control inevitable DNA damage and cancer. Exacerbation of those processes is associated with accelerated ageing and schizophrenia and this warrants further investigation into possible underlying biological mechanisms, such as epigenetic control of the genome. PMID:22048679

  5. Initial cutaneous manifestations of Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Rork, Jillian F; Huang, Jennifer T; Gordon, Leslie B; Kleinman, Monica; Kieran, Mark W; Liang, Marilyn G

    2014-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare, uniformly fatal, premature aging disease with distinct dermatologic features. We sought to identify and describe the initial skin and hair findings as potential diagnostic signs of the disease. We performed a chart review of the structured initial intake histories of 39 individuals with HGPS enrolled in clinical trials from 2007 to 2010 at Boston Children's Hospital, limited to cutaneous history from birth to 24 months. Medical photographs were provided through the clinical trials and the Progeria Research Foundation Medical and Research Database at Brown University Center for Gerontology and Healthcare Research. All 39 patients reported skin and hair abnormalities within the first 24 months of life. Pathologies included sclerodermoid change, prominent superficial veins, dyspigmentation, and alopecia. The mean age of presentation for each finding was <12 months. The most frequently reported skin feature was sclerodermoid change, which commonly involved the abdomen and bilateral lower extremities. Prominent superficial vasculature manifested as circumoral cyanosis and pronounced veins on the scalp and body. Hypo- and hyperpigmentation were observed over areas of sclerodermoid change. Scalp alopecia progressed in a distinct pattern, with preservation of the hair over the midscalp and vertex areas for the longest period of time. HGPS has distinct cutaneous manifestations during the first 2 years of life that may be the first signs of disease. Awareness of these findings could expedite diagnosis.

  6. Craniofacial abnormalities in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Ullrich, N J; Silvera, V M; Campbell, S E; Gordon, L B

    2012-09-01

    HGPS is a rare syndrome of segmental premature aging. Our goal was to expand the scope of structural bone and soft-tissue craniofacial abnormalities in HGPS through CT or MR imaging. Using The Progeria Research Foundation Medical and Research Database, 98 imaging studies on 25 patients, birth to 14.1 years of age, were comprehensively reviewed. Eight newly identified abnormalities involving the calvaria, skull base, and soft tissues of the face and orbits were present with prevalences between 43% and 100%. These included J-shaped sellas, a mottled appearance and increased vascular markings of the calvaria, abnormally configured mandibular condyles, hypoplastic articular eminences, small zygomatic arches, prominent parotid glands, and optic nerve kinking. This expanded craniofacial characterization helps link disease features and improves our ability to evaluate how underlying genetic and cellular abnormalities culminate in a disease phenotype.

  7. Vitamin D receptor signaling improves Hutchinson-Gilford progeria syndrome cellular phenotypes.

    Science.gov (United States)

    Kreienkamp, Ray; Croke, Monica; Neumann, Martin A; Bedia-Diaz, Gonzalo; Graziano, Simona; Dusso, Adriana; Dorsett, Dale; Carlberg, Carsten; Gonzalo, Susana

    2016-05-24

    Hutchinson-Gilford Progeria Syndrome (HGPS) is a devastating incurable premature aging disease caused by accumulation of progerin, a toxic lamin A mutant protein. HGPS patient-derived cells exhibit nuclear morphological abnormalities, altered signaling pathways, genomic instability, and premature senescence. Here we uncover new molecular mechanisms contributing to cellular decline in progeria. We demonstrate that HGPS cells reduce expression of vitamin D receptor (VDR) and DNA repair factors BRCA1 and 53BP1 with progerin accumulation, and that reconstituting VDR signaling via 1α,25-dihydroxyvitamin D3 (1,25D) treatment improves HGPS phenotypes, including nuclear morphological abnormalities, DNA repair defects, and premature senescence. Importantly, we discovered that the 1,25D/VDR axis regulates LMNA gene expression, as well as expression of DNA repair factors. 1,25D dramatically reduces progerin production in HGPS cells, while stabilizing BRCA1 and 53BP1, two key factors for genome integrity. Vitamin D/VDR axis emerges as a new target for treatment of HGPS and potentially other lamin-related diseases exhibiting VDR deficiency and genomic instability. Because progerin expression increases with age, maintaining vitamin D/VDR signaling could keep the levels of progerin in check during physiological aging.

  8. Premature ovarian failure (POF): discordance between somatic and reproductive aging.

    Science.gov (United States)

    Pal, Lubna; Santoro, Nanette

    2002-06-01

    Premature ovarian failure (POF) is a unique example of isolated organ senescence, with a population prevalence of approximately 1%. Though the phenotypic expression of POF is similar to that of age-appropriate natural menopause, the underlying pathophysiological mechanisms are diverse and not entirely clear. The impact of POF on the patient is profound, with myriad ramifications, ranging from psychological devastation to multi-system implications of estrogen deprivation and its sequelae. The hastening of degenerative changes noted in these patients however, are not entirely ameliorated with estrogen replacement and POF may indeed represent an acceleration of the aging process.

  9. Risk factors for premature death in middle aged men

    OpenAIRE

    Petersson, Bo; Trell, Erik; Henningsen, Nels-Christian; Hood, Bertil

    1984-01-01

    The causes of premature death and the associated risk factors were analysed in a cohort of 7935 middle aged men participating in a preventive population programme in Malmö. They were screened when aged 46-48 and then followed up for 3½-8 years. Two hundred and eighteen died, of whom 181 (83%) underwent necropsy. Three major causes of death were established: cancer in 61 (28%), deaths related to consumption of alcohol in 55 (25%), and coronary heart disease in 50 (23%).

  10. Premature ageing prevention: limitations and perspectives of pharmacological interventions.

    Science.gov (United States)

    Anisimov, Vladimir N

    2006-11-01

    A significant increase of the elderly in populations of developed countries is followed by increase morbidity and mortality from main age-related diseases--cardiovascular and neuro-degenerative, cancer, diabetes mellitus, declining in a resistance to infections. Obviously, the development of means of the prevention of the premature ageing and these diseases in humans are crucial at present. However, data on such type means rather scarce, contradictory and often not reliable from the points of view of the adequacy of the experiments to current scientific requirements, as well as the interpretation of the results and safety. Available data on the life span extension and adverse effects of chemical compounds and drugs suggested as geroprotectors are critically analyzed: antidiabetic drugs, growth and thyroid hormones, glucocorticoids, DHEA, sex steroids and contraceptives, melatonin and peptide preparations modulating the pineal gland, antioxidants, chelate agents and lathyrogens, adaptogens and herbs, neurotropic drugs, inhibitors of monoamine oxidase, immunomodulators and some other. Most of the results could not convincingly evidence the life span extension and safety of the suggested geroprotectors. We believe that it is necessary to establish an international program for the expert evaluation of the life span extension potential of pharmacological interventions for humans. The scope of the program should be to evaluate chemical, immunological, dietary and behavioural interventions that may lead to life span extension or retard premature ageing and the objective--preparation of critical reviews and evaluations on evidence of the life span extending properties of a wide range of potential geroprotectors and strategies by international groups of working experts. The program may assist national and international authorities in devising programs of health promotion and premature ageing prevention.

  11. Dental and craniofacial characteristics in a patient with Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Reichert, Christoph; Gölz, Lina; Götz, Werner; Wolf, Michael; Deschner, James; Jäger, Andreas

    2014-07-01

    The Hutchinson-Gilford progeria syndrome (HGPS) is an exceptionally rare medical disorder caused by mutations in the lamin A/C gene. Affected patients display typical features of premature aging. Beside general medical disorders, these patients have several specific features related to the craniofacial phenotype and the oral cavity. In this article, the dental and craniofacial characteristics of a 9-year-old girl with HGPS are presented. It is the first report addressing orthodontic tooth movement and microbiological features in a HGPS patient. We describe and discuss pathologic findings and provide a detailed histology of the teeth which had to be extracted during initial treatment.

  12. Cellular senescence in normal and premature lung aging.

    Science.gov (United States)

    Bartling, B

    2013-10-01

    The incidence of chronic respiratory diseases (e.g., chronic obstructive pulmonary disease, COPD) and interstitial lung diseases (e.g., pneumonia and lung fibrosis) increases with age. In addition to immune senescence, the accumulation of senescent cells directly in lung tissue might play a critical role in the increased prevalence of these pulmonary diseases. In the last couple of years, detailed studies have identified the presence of senescent cells in the aging lung and in diseased lungs of patients with COPD and lung fibrosis. Cellular senescence has been shown for epithelial cells of bronchi and alveoli as well as mesenchymal and vascular cells. Known risk factors for pulmonary diseases (cigarette smoke, air pollutions, bacterial infections, etc.) were identified in experimental studies as being possible mediators in the development of cellular senescence. The present findings indicate the importance of cellular senescence in normal lung aging and in premature aging of the lung in patients with COPD, lung fibrosis, and probably other respiratory diseases.

  13. DNA-damage accumulation and replicative arrest in Hutchinson–Gilford progeria syndrome

    Science.gov (United States)

    Musich, Phillip R.; Zou, Yue

    2013-01-01

    A common feature of progeria syndromes is a premature aging phenotype and an enhanced accumulation of DNA damage arising from a compromised repair system. HGPS (Hutchinson–Gilford progeria syndrome) is a severe form of progeria in which patients accumulate progerin, a mutant lamin A protein derived from a splicing variant of the lamin A/C gene (LMNA). Progerin causes chromatin perturbations which result in the formation of DSBs (double-strand breaks) and abnormal DDR (DNA-damage response). In the present article, we review recent findings which resolve some mechanistic details of how progerin may disrupt DDR pathways in HGPS cells. We propose that progerin accumulation results in disruption of functions of some replication and repair factors, causing the mislocalization of XPA (xeroderma pigmentosum group A) protein to the replication forks, replication fork stalling and, subsequently, DNA DSBs. The binding of XPA to the stalled forks excludes normal binding by repair proteins, leading to DSB accumulation, which activates ATM (ataxia telangiectasia mutated) and ATR (ATM- and Rad3-related) checkpoints, and arresting cell-cycle progression. PMID:22103522

  14. DNA-damage accumulation and replicative arrest in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Musich, Phillip R; Zou, Yue

    2011-12-01

    A common feature of progeria syndromes is a premature aging phenotype and an enhanced accumulation of DNA damage arising from a compromised repair system. HGPS (Hutchinson-Gilford progeria syndrome) is a severe form of progeria in which patients accumulate progerin, a mutant lamin A protein derived from a splicing variant of the lamin A/C gene (LMNA). Progerin causes chromatin perturbations which result in the formation of DSBs (double-strand breaks) and abnormal DDR (DNA-damage response). In the present article, we review recent findings which resolve some mechanistic details of how progerin may disrupt DDR pathways in HGPS cells. We propose that progerin accumulation results in disruption of functions of some replication and repair factors, causing the mislocalization of XPA (xeroderma pigmentosum group A) protein to the replication forks, replication fork stalling and, subsequently, DNA DSBs. The binding of XPA to the stalled forks excludes normal binding by repair proteins, leading to DSB accumulation, which activates ATM (ataxia telangiectasia mutated) and ATR (ATM- and Rad3-related) checkpoints, and arresting cell-cycle progression.

  15. Treatment considerations in hutchinson-gilford progeria syndrome: a case report.

    Science.gov (United States)

    Hazan-Molina, H; Aizenbud, D; Dror, Aizenbud D

    2015-01-01

    Hutchinson-Guilford progeria syndrome is an extremely rare condition classified as one of the premature ageing syndromes. This case presents a 16-year-old Israeli female patient, suffering from a variant of Hutchinson-Guilford progeria with a history of treatment with oral biphosphnates. The patient presented with typical cranial and facial features of the syndrome including delayed teeth eruption and root development probably due to insufficient jaw growth and severs retrognatic position of the maxilla and mandible. Orthodontic treatment considerations are described along with those required in light of the previous treatment by oral biphosphonates.All primary teeth were extracted in three appointments while creating as minimal trauma as possible to the surrounding tissue and alveolar bone. For now, the patient refuses to begin the orthodontic treatment course. There are no limitations to conduct any dental procedures in progeria patients, however, extreme caution must be exercised during oral surgery due to the inelasticity of tissues and dermal atrophy. Orthodontic procedure commencement should be early enough to manage the delayed development and eruption of teeth. Patients taking oral biphosphonates should be advised of this potential complication. If orthodontic treatment is considered appropriate, plans should be assessed and modified to include compromises.

  16. Hutchinson-Gilford progeria syndrome

    Directory of Open Access Journals (Sweden)

    Zahoor Hussain Daraz

    2017-06-01

    Full Text Available Hutchinson-Gilford progeria syndrome (HGPS is a rare genetic disease in which symptoms of aging are manifested at an early age. In the present report, we describe a 9 months old female child presented with a history of progressive coarsening of skin, failure to thrive and irregular bumps over thighs, buttocks and lower limbs for the last 7½ months. In the course of time, she developed alopecia, hyperpigmented spots over the abdomen with thickening and a typical facial profile of HGPS including micrognathia, absent ear lobules, prominent eyes, loss of eyelashes, eyebrows and a bluish hue over the nose.

  17. Skeletal muscle contractile function and neuromuscular performance in Zmpste24 -/- mice, a murine model of human progeria.

    Science.gov (United States)

    Greising, Sarah M; Call, Jarrod A; Lund, Troy C; Blazar, Bruce R; Tolar, Jakub; Lowe, Dawn A

    2012-08-01

    Human progeroid syndromes and premature aging mouse models present as segmental, accelerated aging because some tissues and not others are affected. Skeletal muscle is detrimentally changed by normal aging but whether it is an affected tissue in progeria has not been resolved. We hypothesized that mice which mimic Hutchinson-Gilford progeria syndrome would exhibit age-related alterations of skeletal muscle. Zmpste24 (-/-) and Zmpste24 (+/+) littermates were assessed for skeletal muscle functions, histo-morphological characteristics, and ankle joint mechanics. Twenty-four-hour active time, ambulation, grip strength, and whole body tension were evaluated as markers of neuromuscular performance, each of which was at least 33% lower in Zmpste24 (-/-) mice compared with littermates (p normal. Ankle range of motion was 70% lower and plantar- and dorsiflexion passive torques were nearly 3-fold greater in Zmpste24 (-/-) than Zmpste24 (+/+) mice (p ≤ 0.01). The combined factors of muscle atrophy, collagen accumulation, and perturbed joint mechanics likely contributed to poor neuromuscular performance and selective muscle weakness displayed by Zmpste24 (-/-)mice. In summary, these characteristics are similar to those of aged mice indicating accelerated aging of skeletal muscle in progeria.

  18. Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective.

    Science.gov (United States)

    Cau, Pierre; Navarro, Claire; Harhouri, Karim; Roll, Patrice; Sigaudy, Sabine; Kaspi, Elise; Perrin, Sophie; De Sandre-Giovannoli, Annachiara; Lévy, Nicolas

    2014-05-01

    Lamin A-related progeroid syndromes are genetically determined, extremely rare and severe. In the past ten years, our knowledge and perspectives for these diseases has widely progressed, through the progressive dissection of their pathophysiological mechanisms leading to precocious and accelerated aging, from the genes mutations discovery until therapeutic trials in affected children. A-type lamins are major actors in several structural and functional activities at the nuclear periphery, as they are major components of the nuclear lamina. However, while this is usually poorly considered, they also play a key role within the rest of the nucleoplasm, whose defects are related to cell senescence. Although nuclear shape and nuclear envelope deformities are obvious and visible events, nuclear matrix disorganization and abnormal composition certainly represent the most important causes of cell defects with dramatic pathological consequences. Therefore, lamin-associated diseases should be better referred as laminopathies instead of envelopathies, this later being too restrictive, considering neither the key structural and functional roles of soluble lamins in the entire nucleoplasm, nor the nuclear matrix contribution to the pathophysiology of lamin-associated disorders and in particular in defective lamin A processing-associated aging diseases. Based on both our understanding of pathophysiological mechanisms and the biological and clinical consequences of progeria and related diseases, therapeutic trials have been conducted in patients and were terminated less than 10 years after the gene discovery, a quite fast issue for a genetic disease. Pharmacological drugs have been repurposed and used to decrease the toxicity of the accumulated, unprocessed and truncated prelaminA in progeria. To date, none of them may be considered as a cure for progeria and these clinical strategies were essentially designed toward reducing a subset of the most dramatic and morbid features

  19. Blood cell mitochondrial DNA content and premature ovarian aging.

    Directory of Open Access Journals (Sweden)

    Marco Bonomi

    Full Text Available Primary ovarian insufficiency (POI is a critical fertility defect characterized by an anticipated and silent impairment of the follicular reserve, but its pathogenesis is largely unexplained. The frequent maternal inheritance of POI together with a remarkable dependence of ovarian folliculogenesis upon mitochondrial biogenesis and bioenergetics suggested the possible involvement of a generalized mitochondrial defect. Here, we verified the existence of a significant correlation between blood and ovarian mitochondrial DNA (mtDNA content in a group of women undergoing ovarian hyperstimulation (OH, and then aimed to verify whether mtDNA content was significantly altered in the blood cells of POI women. We recruited 101 women with an impaired ovarian reserve: 59 women with premature ovarian failure (POF and 42 poor responders (PR to OH. A Taqman copy number assay revealed a significant mtDNA depletion (P<0.001 in both POF and PR women in comparison with 43 women of similar age and intact ovarian reserve, or 53 very old women with a previous physiological menopause. No pathogenic variations in the mitochondrial DNA polymerase γ (POLG gene were detected in 57 POF or PR women with low blood mtDNA content. In conclusion, blood cell mtDNA depletion is a frequent finding among women with premature ovarian aging, suggesting that a still undetermined but generalized mitochondrial defect may frequently predispose to POI which could then be considered a form of anticipated aging in which the ovarian defect may represent the first manifestation. The determination of mtDNA content in blood may become an useful tool for the POI risk prediction.

  20. Blood Cell Mitochondrial DNA Content and Premature Ovarian Aging

    Science.gov (United States)

    Cacciatore, Chiara; Busnelli, Marta; Rossetti, Raffaella; Bonetti, Silvia; Paffoni, Alessio; Mari, Daniela; Ragni, Guido; Persani, Luca; Arosio, M.; Beck-Peccoz, P.; Biondi, M.; Bione, S.; Bruni, V.; Brigante, C.; Cannavo`, S.; Cavallo, L.; Cisternino, M.; Colombo, I.; Corbetta, S.; Crosignani, P.G.; D'Avanzo, M.G.; Dalpra, L.; Danesino, C.; Di Battista, E.; Di Prospero, F.; Donti, E.; Einaudi, S.; Falorni, A.; Foresta, C.; Fusi, F.; Garofalo, N.; Giotti, I.; Lanzi, R.; Larizza, D.; Locatelli, N.; Loli, P.; Madaschi, S.; Maghnie, M.; Maiore, S.; Mantero, F.; Marozzi, A.; Marzotti, S.; Migone, N.; Nappi, R.; Palli, D.; Patricelli, M.G.; Pisani, C.; Prontera, P.; Petraglia, F.; Radetti, G.; Renieri, A.; Ricca, I.; Ripamonti, A.; Rossetti, R.; Russo, G.; Russo, S.; Tonacchera, M.; Toniolo, D.; Torricelli, F.; Vegetti, W.; Villa, N.; Vineis, P.; Wasniewsk, M.; Zuffardi, O.

    2012-01-01

    Primary ovarian insufficiency (POI) is a critical fertility defect characterized by an anticipated and silent impairment of the follicular reserve, but its pathogenesis is largely unexplained. The frequent maternal inheritance of POI together with a remarkable dependence of ovarian folliculogenesis upon mitochondrial biogenesis and bioenergetics suggested the possible involvement of a generalized mitochondrial defect. Here, we verified the existence of a significant correlation between blood and ovarian mitochondrial DNA (mtDNA) content in a group of women undergoing ovarian hyperstimulation (OH), and then aimed to verify whether mtDNA content was significantly altered in the blood cells of POI women. We recruited 101 women with an impaired ovarian reserve: 59 women with premature ovarian failure (POF) and 42 poor responders (PR) to OH. A Taqman copy number assay revealed a significant mtDNA depletion (P<0.001) in both POF and PR women in comparison with 43 women of similar age and intact ovarian reserve, or 53 very old women with a previous physiological menopause. No pathogenic variations in the mitochondrial DNA polymerase γ (POLG) gene were detected in 57 POF or PR women with low blood mtDNA content. In conclusion, blood cell mtDNA depletion is a frequent finding among women with premature ovarian aging, suggesting that a still undetermined but generalized mitochondrial defect may frequently predispose to POI which could then be considered a form of anticipated aging in which the ovarian defect may represent the first manifestation. The determination of mtDNA content in blood may become an useful tool for the POI risk prediction. PMID:22879975

  1. Extended longevity mechanisms in short-lived progeroid mice: Identification of a preservative stress response associated with successful aging

    NARCIS (Netherlands)

    H.W.M. van de Ven (Marieke); J.-O. Andressoo (Jaan-Olle); V.B. Holcomb (Valerie); P. Hasty (Paul); Y. Suh (Yousin); H. van Steeg (Harry); G.A. Garinis (George); J.H.J. Hoeijmakers (Jan); J.R. Mitchell (James)

    2007-01-01

    textabstractSemantic distinctions between "normal" aging, "pathological" aging (or age-related disease) and "premature" aging (otherwise known as segmental progeria) potentially confound important insights into the nature of each of the complex processes. Here we review a recent, unexpected discover

  2. Extended longevity mechanisms in short-lived progeroid mice: Identification of a preservative stress response associated with successful aging

    NARCIS (Netherlands)

    H.W.M. van de Ven (Marieke); J.-O. Andressoo (Jaan-Olle); V.B. Holcomb (Valerie); P. Hasty (Paul); Y. Suh (Yousin); H. van Steeg (Harry); G.A. Garinis (George); J.H.J. Hoeijmakers (Jan); J.R. Mitchell (James)

    2007-01-01

    textabstractSemantic distinctions between "normal" aging, "pathological" aging (or age-related disease) and "premature" aging (otherwise known as segmental progeria) potentially confound important insights into the nature of each of the complex processes. Here we review a recent, unexpected discover

  3. Induced pluripotent stem cells reveal functional differences between drugs currently investigated in patients with hutchinson-gilford progeria syndrome.

    Science.gov (United States)

    Blondel, Sophie; Jaskowiak, Anne-Laure; Egesipe, Anne-Laure; Le Corf, Amelie; Navarro, Claire; Cordette, Véronique; Martinat, Cécile; Laabi, Yacine; Djabali, Karima; de Sandre-Giovannoli, Annachiara; Levy, Nicolas; Peschanski, Marc; Nissan, Xavier

    2014-04-01

    Hutchinson-Gilford progeria syndrome is a rare congenital disease characterized by premature aging in children. Identification of the mutation and related molecular mechanisms has rapidly led to independent clinical trials testing different marketed drugs with a preclinically documented impact on those mechanisms. However, the extensive functional effects of those drugs remain essentially unexplored. We have undertaken a systematic comparative study of the three main treatments currently administered or proposed to progeria-affected children, namely, a farnesyltransferase inhibitor, the combination of an aminobisphosphonate and a statin (zoledronate and pravastatin), and the macrolide antibiotic rapamycin. This work was based on the assumption that mesodermal stem cells, which are derived from Hutchinson-Gilford progeria syndrome-induced pluripotent stem cells expressing major defects associated with the disease, may be instrumental to revealing such effects. Whereas all three treatments significantly improved misshapen cell nuclei typically associated with progeria, differences were observed in terms of functional improvement in prelamin A farnesylation, progerin expression, defective cell proliferation, premature osteogenic differentiation, and ATP production. Finally, we have evaluated the effect of the different drug combinations on this cellular model. This study revealed no additional benefit compared with single-drug treatments, whereas a cytostatic effect equivalent to that of a farnesyltransferase inhibitor alone was systematically observed. Altogether, these results reveal the complexity of the modes of action of different drugs, even when they have been selected on the basis of a similar mechanistic hypothesis, and underscore the use of induced pluripotent stem cell derivatives as a critical and powerful tool for standardized, comparative pharmacological studies.

  4. [Gait characteristics of women with fibromyalgia: a premature aging pattern].

    Science.gov (United States)

    Góes, Suelen M; Leite, Neiva; de Souza, Ricardo M; Homann, Diogo; Osiecki, Ana C V; Stefanello, Joice M F; Rodacki, André L F

    2014-01-01

    Fibromyalgia is a condition which involves chronic pain. Middle-aged individuals with fibromyalgia seem to exhibit changes in gait pattern, which may prematurely expose them to a gait pattern which resembles that found in the elderly population. To determine the 3D spatial (linear and angular) gait parameters of middle-aged women with fibromyalgia and compare to elderly women without this condition. 25 women (10 in the fibromyalgia group and 15 in the elderly group) volunteered to participate in the study. Kinematics was performed using an optoelectronic system, and linear and angular kinematic variables were determined. There was no difference in walking speed, stride length, cadence, hip, knee and ankle joints range of motion between groups, except the pelvic rotation, in which the fibromyalgia group showed greater rotation (P<0.05) compared to the elderly group. Also, there was a negative correlation with pelvic rotation and gluteus pain (r = -0.69; P<0.05), and between pelvic obliquity and greater trochanter pain (r = -0.69; P<0.05) in the fibromyalgia group. Middle-aged women with fibromyalgia showed gait pattern resemblances to elderly, women, which is characterized by reduced lower limb ROM, stride length and walking speed. Copyright © 2014 Elsevier Editora Ltda. All rights reserved.

  5. Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria.

    Science.gov (United States)

    Xiong, Zheng-Mei; Choi, Ji Young; Wang, Kun; Zhang, Haoyue; Tariq, Zeshan; Wu, Di; Ko, Eunae; LaDana, Christina; Sesaki, Hiromi; Cao, Kan

    2016-04-01

    Hutchinson-Gilford progeria syndrome (HGPS), a fatal premature aging disease, is caused by a single-nucleotide mutation in the LMNA gene. Previous reports have focused on nuclear phenotypes in HGPS cells, yet the potential contribution of the mitochondria, a key player in normal aging, remains unclear. Using high-resolution microscopy analysis, we demonstrated a significantly increased fraction of swollen and fragmented mitochondria and a marked reduction in mitochondrial mobility in HGPS fibroblast cells. Notably, the expression of PGC-1α, a central regulator of mitochondrial biogenesis, was inhibited by progerin. To rescue mitochondrial defects, we treated HGPS cells with a mitochondrial-targeting antioxidant methylene blue (MB). Our analysis indicated that MB treatment not only alleviated the mitochondrial defects but also rescued the hallmark nuclear abnormalities in HGPS cells. Additional analysis suggested that MB treatment released progerin from the nuclear membrane, rescued perinuclear heterochromatin loss and corrected misregulated gene expression in HGPS cells. Together, these results demonstrate a role of mitochondrial dysfunction in developing the premature aging phenotypes in HGPS cells and suggest MB as a promising therapeutic approach for HGPS.

  6. The mutant form of lamin A that causes Hutchinson-Gilford progeria is a biomarker of cellular aging in human skin.

    Directory of Open Access Journals (Sweden)

    Dayle McClintock

    Full Text Available Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670 is a rare disorder characterized by accelerated aging and early death, frequently from stroke or coronary artery disease. 90% of HGPS cases carry the LMNA G608G (GGC>GGT mutation within exon 11 of LMNA, activating a splice donor site that results in production of a dominant negative form of lamin A protein, denoted progerin. Screening 150 skin biopsies from unaffected individuals (newborn to 97 years showed that a similar splicing event occurs in vivo at a low level in the skin at all ages. While progerin mRNA remains low, the protein accumulates in the skin with age in a subset of dermal fibroblasts and in a few terminally differentiated keratinocytes. Progerin-positive fibroblasts localize near the basement membrane and in the papillary dermis of young adult skin; however, their numbers increase and their distribution reaches the deep reticular dermis in elderly skin. Our findings demonstrate that progerin expression is a biomarker of normal cellular aging and may potentially be linked to terminal differentiation and senescence in elderly individuals.

  7. The mutant form of lamin A that causes Hutchinson-Gilford progeria is a biomarker of cellular aging in human skin.

    Science.gov (United States)

    McClintock, Dayle; Ratner, Desiree; Lokuge, Meepa; Owens, David M; Gordon, Leslie B; Collins, Francis S; Djabali, Karima

    2007-12-05

    Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare disorder characterized by accelerated aging and early death, frequently from stroke or coronary artery disease. 90% of HGPS cases carry the LMNA G608G (GGC>GGT) mutation within exon 11 of LMNA, activating a splice donor site that results in production of a dominant negative form of lamin A protein, denoted progerin. Screening 150 skin biopsies from unaffected individuals (newborn to 97 years) showed that a similar splicing event occurs in vivo at a low level in the skin at all ages. While progerin mRNA remains low, the protein accumulates in the skin with age in a subset of dermal fibroblasts and in a few terminally differentiated keratinocytes. Progerin-positive fibroblasts localize near the basement membrane and in the papillary dermis of young adult skin; however, their numbers increase and their distribution reaches the deep reticular dermis in elderly skin. Our findings demonstrate that progerin expression is a biomarker of normal cellular aging and may potentially be linked to terminal differentiation and senescence in elderly individuals.

  8. DNA repair defects and genome instability in Hutchinson-Gilford Progeria Syndrome.

    Science.gov (United States)

    Gonzalo, Susana; Kreienkamp, Ray

    2015-06-01

    The integrity of the nuclear lamina has emerged as an important factor in the maintenance of genome stability. In particular, mutations in the LMNA gene, encoding A-type lamins (lamin A/C), alter nuclear morphology and function, and cause genomic instability. LMNA gene mutations are associated with a variety of degenerative diseases and devastating premature aging syndromes such as Hutchinson-Gilford Progeria Syndrome (HGPS) and Restrictive Dermopathy (RD). HGPS is a severe laminopathy, with patients dying in their teens from myocardial infarction or stroke. HGPS patient-derived cells exhibit nuclear shape abnormalities, changes in epigenetic regulation and gene expression, telomere shortening, genome instability, and premature senescence. This review highlights recent advances in identifying molecular mechanisms that contribute to the pathophysiology of HGPS, with a special emphasis on DNA repair defects and genome instability.

  9. Defective ATM-Kap-1-mediated chromatin remodeling impairs DNA repair and accelerates senescence in progeria mouse model.

    Science.gov (United States)

    Liu, Baohua; Wang, Zimei; Ghosh, Shrestha; Zhou, Zhongjun

    2013-04-01

    ATM-mediated phosphorylation of KAP-1 triggers chromatin remodeling and facilitates the loading and retention of repair proteins at DNA lesions. Mouse embryonic fibroblasts (MEFs) derived from Zmpste24(-/-) mice undergo early senescence, attributable to delayed recruitment of DNA repair proteins. Here, we show that ATM-Kap-1 signaling is compromised in Zmpste24(-/-) MEFs, leading to defective DNA damage-induced chromatin remodeling. Knocking down Kap-1 rescues impaired chromatin remodeling, defective DNA repair and early senescence in Zmpste24(-/-) MEFs. Thus, ATM-Kap-1-mediated chromatin remodeling plays a critical role in premature aging, carrying significant implications for progeria therapy.

  10. Progeria 101/FAQ

    Science.gov (United States)

    ... Statistics Is Progeria passed down from parent to child? HGPS is not usually passed down in families. The gene change is almost always a chance occurrence that is extremely rare. Children with other types of “progeroid” syndromes which are not HGPS may have diseases that ...

  11. Rapamycin activates autophagy in Hutchinson-Gilford progeria syndrome

    Science.gov (United States)

    Graziotto, John J; Cao, Kan; Collins, Francis S

    2012-01-01

    While rapamycin has been in use for years in transplant patients as an antirejection drug, more recently it has shown promise in treating diseases of aging, such as neurodegenerative disorders and atherosclerosis. We recently reported that rapamycin reverses the cellular phenotype of fibroblasts from children with the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). We found that the causative aberrant protein, progerin, was cleared through autophagic mechanisms when the cells were treated with rapamycin, suggesting a new potential treatment for HGPS. Recent evidence shows that progerin is also present in aged tissues of healthy individuals, suggesting that progerin may contribute to physiological aging. While it is intriguing to speculate that rapamycin may affect normal aging in humans, as it does in lower organisms, it will be important to identify safer analogs of rapamycin for chronic treatments in humans in order to minimize toxicity. In addition to its role in HGPS and normal aging, we discuss the potential of rapamycin for the treatment of age-dependent neurodegenerative diseases. PMID:22170152

  12. Depleting the methyltransferase Suv39h1 improves DNA repair and extends lifespan in a progeria mouse model

    Science.gov (United States)

    Liu, Baohua; Wang, Zimei; Zhang, Le; Ghosh, Shrestha; Zheng, Huiling; Zhou, Zhongjun

    2013-01-01

    A de novo G608G mutation in LMNA gene leads to Hutchinson–Gilford progeria syndrome. Mice lacking the prelamin A-processing metalloprotease, Zmpste24, recapitulate many of the progeroid features of Hutchinson–Gilford progeria syndrome. Here we show that A-type lamins interact with SUV39H1, and prelamin A/progerin exhibits enhanced binding capacity to SUV39H1, protecting it from proteasomal degradation and, consequently, increasing H3K9me3 levels. Depletion of Suv39h1 reduces H3K9me3 levels, restores DNA repair capacity and delays senescence in progeroid cells. Remarkably, loss of Suv39h1 in Zmpste24−/− mice delays body weight loss, increases bone mineral density and extends lifespan by ∼60%. Thus, increased H3K9me3 levels, possibly mediated by enhanced Suv39h1 stability in the presence of prelamin A/progerin, compromise genome maintenance, which in turn contributes to accelerated senescence in laminopathy-based premature aging. Our study provides an explanation for epigenetic alterations in Hutchinson–Gilford progeria syndrome and a potential strategy for intervention by targeting SUV39H1-mediated heterochromatin remodelling. PMID:23695662

  13. Depleting the methyltransferase Suv39h1 improves DNA repair and extends lifespan in a progeria mouse model.

    Science.gov (United States)

    Liu, Baohua; Wang, Zimei; Zhang, Le; Ghosh, Shrestha; Zheng, Huiling; Zhou, Zhongjun

    2013-01-01

    A de novo G608G mutation in LMNA gene leads to Hutchinson-Gilford progeria syndrome. Mice lacking the prelamin A-processing metalloprotease, Zmpste24, recapitulate many of the progeroid features of Hutchinson-Gilford progeria syndrome. Here we show that A-type lamins interact with SUV39H1, and prelamin A/progerin exhibits enhanced binding capacity to SUV39H1, protecting it from proteasomal degradation and, consequently, increasing H3K9me3 levels. Depletion of Suv39h1 reduces H3K9me3 levels, restores DNA repair capacity and delays senescence in progeroid cells. Remarkably, loss of Suv39h1 in Zmpste24(-/-) mice delays body weight loss, increases bone mineral density and extends lifespan by ∼60%. Thus, increased H3K9me3 levels, possibly mediated by enhanced Suv39h1 stability in the presence of prelamin A/progerin, compromise genome maintenance, which in turn contributes to accelerated senescence in laminopathy-based premature aging. Our study provides an explanation for epigenetic alterations in Hutchinson-Gilford progeria syndrome and a potential strategy for intervention by targeting SUV39H1-mediated heterochromatin remodelling.

  14. Permanent farnesylation of lamin A mutants linked to progeria impairs its phosphorylation at serine 22 during interphase.

    Science.gov (United States)

    Moiseeva, Olga; Lopes-Paciencia, Stéphane; Huot, Geneviève; Lessard, Frédéric; Ferbeyre, Gerardo

    2016-02-01

    Mutants of lamin A cause diseases including the Hutchinson-Gilford progeria syndrome (HGPS) characterized by premature aging. Lamin A undergoes a series of processing reactions, including farnesylation and proteolytic cleavage of the farnesylated C-terminal domain. The role of cleavage is unknown but mutations that affect this reaction lead to progeria. Here we show that interphase serine 22 phosphorylation of endogenous mutant lamin A (progerin) is defective in cells from HGPS patients. This defect can be mimicked by expressing progerin in human cells and prevented by inhibition of farnesylation. Furthermore, serine 22 phosphorylation of non-farnesylated progerin was enhanced by a mutation that disrupts lamin A head to tail interactions. The phosphorylation of lamin A or non-farnesylated progerin was associated to the formation of spherical intranuclear lamin A droplets that accumulate protein kinases of the CDK family capable of phosphorylating lamin A at serine 22. CDK inhibitors compromised the turnover of progerin, accelerated senescence of HGPS cells and reversed the effects of FTI on progerin levels. We discuss a model of progeria where faulty serine 22 phosphorylation compromises phase separation of lamin A polymers, leading to accumulation of functionally impaired lamin A structures.

  15. New Lmna knock-in mice provide a molecular mechanism for the 'segmental aging' in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Jung, Hea-Jin; Tu, Yiping; Yang, Shao H; Tatar, Angelica; Nobumori, Chika; Wu, Daniel; Young, Stephen G; Fong, Loren G

    2014-03-15

    Lamins A and C (products of the LMNA gene) are found in roughly equal amounts in peripheral tissues, but the brain produces mainly lamin C and little lamin A. In HeLa cells and fibroblasts, the expression of prelamin A (the precursor to lamin A) can be reduced by miR-9, but the relevance of those cell culture studies to lamin A regulation in the brain was unclear. To address this issue, we created two new Lmna knock-in alleles, one (Lmna(PLAO-5NT)) with a 5-bp mutation in a predicted miR-9 binding site in prelamin A's 3' UTR, and a second (Lmna(PLAO-UTR)) in which prelamin A's 3' UTR was replaced with lamin C's 3' UTR. Neither allele had significant effects on lamin A levels in peripheral tissues; however, both substantially increased prelamin A transcript levels and lamin A protein levels in the cerebral cortex and the cerebellum. The increase in lamin A expression in the brain was more pronounced with the Lmna(PLAO-UTR) allele than with the Lmna(PLAO-5NT) allele. With both alleles, the increased expression of prelamin A transcripts and lamin A protein was greater in the cerebral cortex than in the cerebellum. Our studies demonstrate the in vivo importance of prelamin A's 3' UTR and its miR-9 binding site in regulating lamin A expression in the brain. The reduced expression of prelamin A in the brain likely explains why children with Hutchinson-Gilford progeria syndrome (a progeroid syndrome caused by a mutant form of prelamin A) are spared from neurodegenerative disease.

  16. Biomechanical Strain Exacerbates Inflammation on a Progeria-on-a-Chip Model

    NARCIS (Netherlands)

    Ribas, J.; Zhang, Y.S.; Pitrez, P.R.; Leijten, Jeroen Christianus Hermanus; Miscuglio, M.; Rouwkema, Jeroen; Dokmeci, M.R.; Nissan, X.; Ferreira, L.; Khademhosseini, A.

    2017-01-01

    A progeria-on-a-chip model is engineered to recapitulate the biomechanical dynamics of vascular disease and aging. The model shows an exacerbated injury response to strain and is rescued by pharmacological treatments. The progeria-on-a-chip is expected to drive the discovery of new drugs and to eluc

  17. Biomechanical Strain Exacerbates Inflammation on a Progeria-on-a-Chip Model

    NARCIS (Netherlands)

    Ribas, J.; Zhang, Y.S.; Pitrez, P.R.; Leijten, J.C.H.; Miscuglio, M.; Rouwkema, J.; Dokmeci, M.R.; Nissan, X.; Ferreira, L.; Khademhosseini, A.

    2017-01-01

    A progeria-on-a-chip model is engineered to recapitulate the biomechanical dynamics of vascular disease and aging. The model shows an exacerbated injury response to strain and is rescued by pharmacological treatments. The progeria-on-a-chip is expected to drive the discovery of new drugs and to eluc

  18. A 36 years old woman with Hutchinson-Gilford Progeria Syndrome: a case report

    Directory of Open Access Journals (Sweden)

    Akrami S M

    2007-10-01

    Full Text Available Background: Hutchinson-Gilford Progeria Syndrome (HGPS is a very rare genetic disorder with a frequency of 1 in 8 million live births. It is characterised by premature aging phenotype. The median age at death is 13.4 years. It is an autosomal dominat disease due to a de novo point mutation in the Lamin A gene exon 11 in the majority of cases. More than 100 cases have been reported world wide."nCase report: We describe here an exceptionally long-lived patient with HGPS, who is alive at age 36. She was referred by a cardiologist to our endocrinology clinic to be worked up for presence of a metabolic or genetic disorder before a heart surgery."nResults: Having more attention of clinicians about very rare diseases and referring the patients to geneticist are the main goals of this case report as well as describing the disease.

  19. Hutchinson-Gilford progeria syndrome, cardiovascular disease and oxidative stress.

    Science.gov (United States)

    Trigueros-Motos, Laia; Gonzalez, Jose M; Rivera, Jose; Andres, Vicente

    2011-06-01

    Hutchinson-Gilford Progeria Syndrome (HGPS), a rare human disease characterized by premature aging, is mainly caused by the abnormal accumulation of progerin, a mutant form of the mammalian nuclear envelope component lamin A. HGPS patients exhibit vascular alterations and die at an average age of 13 years, predominantly from myocardial infarction or stroke. Animal models of HGPS have been a valuable tool in the study of the pathological processes implicated in the origin of this disease and its associated cardiovascular alterations. Some of the molecular mechanisms of HGPS might be relevant to the process of normal aging, since progerin is detected in cells from normal elderly humans. Conversely, processes linked to normal aging, such as the increase in oxidative stress, might be relevant to the pathogenic mechanisms of HGPS. In this review, we discuss recent advances in the understanding of the molecular mechanisms underlying the cardiovascular alterations associated with HGPS, the potential role of oxidative stress, and therapeutic approaches for the treatment of this devastating disease.

  20. Congenital Heart Disease in Premature Infants 25-32 Weeks' Gestational Age.

    Science.gov (United States)

    Chu, Patricia Y; Li, Jennifer S; Kosinski, Andrzej S; Hornik, Christoph P; Hill, Kevin D

    2017-02-01

    To determine the birth prevalence of congenital heart defects (CHDs) across the spectrum of common defects in very/extremely premature infants and to compare mortality rates between premature infants with and without CHDs. The Kids' Inpatient Databases (2003-2012) were used to estimate the birth prevalence of CHDs (excluding patent ductus arteriosus) in very/extremely premature infants born between 25 and 32 weeks' gestational age. Birth prevalence was compared with term infants for a subset of "severe" defects expected to be near universally diagnosed in the neonatal period. Weighted multivariable logistic regression was used to calculate aORs of mortality comparing very and extremely premature infants with vs without CHDs. We identified 249 011 very/extremely premature infants, including 28 806 with CHDs. The overall birth prevalence of CHDs was 116 per 1000 very/extremely premature births. Severe CHDs had significantly higher birth prevalence in very/extremely premature infants when compared with term infants (7.4 per 1000 very/premature births vs 1.5 per 1000 term births; P premature infants with severe CHDs had an overall 26.3% in-hospital mortality and a 7.5-fold increased adjusted odds of death compared with those without CHDs. Mortality varied widely by defect in very/extremely premature infants, ranging from 12% for interrupted aortic arch to 67% for truncus arteriosus. Given the increased birth prevalence of severe CHDs in very/extremely premature infants, and significantly higher mortality, there is justification for intensive interventions aimed at decreasing the likelihood of premature delivery for patients where CHD is diagnosed in utero. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria

    Science.gov (United States)

    Cenni, V.; Capanni, C.; Columbaro, M.; Ortolani, M.; D'Apice, M.R.; Novelli, G.; Fini, M.; Marmiroli, S.; Scarano, E.; Maraldi, N.M.; Squarzoni, S.; Prencipe, S.; Lattanzi, G.

    2011-01-01

    Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying prelamin A turnover is critical for the development of clinically effective protein inhibitors that can avoid accumulation to toxic levels without impairing lamin A/C expression, which is essential for normal biological functions. Little is known about specific molecules that may target farnesylated prelamin A to elicit protein degradation. Here, we report the discovery of rapamycin as a novel inhibitor of progerin, which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts, including histone methylation status and BAF and LAP2α distribution patterns. Importantly, rapamycin treatment does not affect lamin C protein levels, but increases the relative expression of the prelamin A endoprotease ZMPSTE24. Thus, rapamycin, an antibiotic belonging to the class of macrolides, previously found to increase longevity in mouse models, can serve as a therapeutic tool, to eliminate progerin, avoid farnesylated prelamin A accumulation, and restore chromatin dynamics in progeroid laminopathies. PMID:22297442

  2. Bilateral stenosis of carotid siphon in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Narazaki, Ryo; Makimura, Mika; Sanefuji, Masafumi; Fukamachi, Shigeru; Akiyoshi, Hidetaka; So, Hidenori; Yamamura, Kenichiro; Doisaki, Sayoko; Kojima, Seiji; Ihara, Kenji; Hara, Toshiro; Ohga, Shouichi

    2013-08-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disease, caused by a de novo mutation of lamin-A gene, LMNA G608G. Accumulation of abnormal lamin-A (progerin) compromises nuclear membrane integrity and results in the accelerated senescence. Affected patients show a typical feature of birdlike face, alopecia, sclerotic skin, loss of subcutaneous fat, and short stature with advancing years. Neonatal scleroderma is the first presentation, although early diagnosis is challenging. The leading cause of death is cardio-/cerebro-vascular accidents associated with atherosclerosis. However, not all findings may recapitulate the aging process. We herein report a 9-year-old Japanese male with HGPS who developed cerebral infarction. The genetic study of peripheral blood-derived DNA determined a heterozygous c.1824C>T mutation, p.G608G. Telomere length of lymphocytes was normal. Bilateral stenosis of carotid siphons was prominent, while systemic arteriosclerosis was unremarkable assessed by the ankle-brachial index, carotid ultrasound imaging and funduscopic study. HGPS patients have marked loss and functional defects in vascular smooth muscle cells, leading to the vulnerability to circulatory stress. Symmetrical stenosis of siphons might occur as a distinctive cerebral vasculopathy of HGPS, rather than simple vascular senescence. Peripheral blood study on LMNA G608G and telomere length could screen progerias in infancy for early therapeutic intervention.

  3. Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria.

    Science.gov (United States)

    Cenni, V; Capanni, C; Columbaro, M; Ortolani, M; D'Apice, M R; Novelli, G; Fini, M; Marmiroli, S; Scarano, E; Maraldi, N M; Squarzoni, S; Prencipe, S; Lattanzi, G

    2011-10-19

    Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying prelamin A turnover is critical for the development of clinically effective protein inhibitors that can avoid accumulation to toxic levels without impairing lamin A/C expression, which is essential for normal biological functions. Little is known about specific molecules that may target farnesylated prelamin A to elicit protein degradation. Here, we report the discovery of rapamycin as a novel inhibitor of progerin, which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts, including histone methylation status and BAF and LAP2alpha distribution patterns. Importantly, rapamycin treatment does not affect lamin C protein levels, but increases the relative expression of the prelamin A endoprotease ZMPSTE24. Thus, rapamycin, an antibiotic belonging to the class of macrolides, previously found to increase longevity in mouse models, can serve as a therapeutic tool, to eliminate progerin, avoid farnesylated prelamin A accumulation, and restore chromatin dynamics in progeroid laminopathies.

  4. Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria

    Directory of Open Access Journals (Sweden)

    V. Cenni

    2011-10-01

    Full Text Available Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying prelamin A turnover is critical for the development of clinically effective protein inhibitors that can avoid accumulation to toxic levels without impairing lamin A/C expression, which is essential for normal biological functions. Little is known about specific molecules that may target farnesylated prelamin A to elicit protein degradation. Here, we report the discovery of rapamycin as a novel inhibitor of progerin, which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts, including histone methylation status and BAF and LAP2alpha distribution patterns. Importantly, rapamycin treatment does not affect lamin C protein levels, but increases the relative expression of the prelamin A endoprotease ZMPSTE24. Thus, rapamycin, an antibiotic belonging to the class of macrolides, previously found to increase longevity in mouse models, can serve as a therapeutic tool, to eliminate progerin, avoid farnesylated prelamin A accumulation, and restore chromatin dynamics in progeroid laminopathies.

  5. Phenotype-Dependent Coexpression Gene Clusters: Application to Normal and Premature Ageing.

    Science.gov (United States)

    Wang, Kun; Das, Avinash; Xiong, Zheng-Mei; Cao, Kan; Hannenhalli, Sridhar

    2015-01-01

    Hutchinson Gilford progeria syndrome (HGPS) is a rare genetic disease with symptoms of aging at a very early age. Its molecular basis is not entirely clear, although profound gene expression changes have been reported, and there are some known and other presumed overlaps with normal aging process. Identification of genes with agingor HGPS-associated expression changes is thus an important problem. However, standard regression approaches are currently unsuitable for this task due to limited sample sizes, thus motivating development of alternative approaches. Here, we report a novel iterative multiple regression approach that leverages co-expressed gene clusters to identify gene clusters whose expression co-varies with age and/or HGPS. We have applied our approach to novel RNA-seq profiles in fibroblast cell cultures at three different cellular ages, both from HGPS patients and normal samples. After establishing the robustness of our approach, we perform a comparative investigation of biological processes underlying normal aging and HGPS. Our results recapitulate previously known processes underlying aging as well as suggest numerous unique processes underlying aging and HGPS. The approach could also be useful in detecting phenotype-dependent co-expression gene clusters in other contexts with limited sample sizes.

  6. Genomic instability and DNA damage responses in progeria arising from defective maturation of prelamin A.

    Science.gov (United States)

    Musich, Phillip R; Zou, Yue

    2009-01-01

    Progeria syndromes have in common a premature aging phenotype and increased genome instability. The susceptibility to DNA damage arises from a compromised repair system, either in the repair proteins themselves or in the DNA damage response pathways. The most severe progerias stem from mutations affecting lamin A production, a filamentous protein of the nuclear lamina. Hutchinson-Gilford progeria syndrome (HGPS) patients are heterozygous for aLMNA gene mutation while Restrictive Dermopathy (RD) individuals have a homozygous deficiency in the processing protease Zmpste24. These mutations generate the mutant lamin A proteins progerin and FC-lamina A, respectively, which cause nuclear deformations and chromatin perturbations. Genome instability is observed even though genome maintenance and repair genes appear normal. The unresolved question is what features of the DNA damage response pathways are deficient in HGPS and RD cells. Here we review and discuss recent findings which resolve some mechanistic details of how the accumulation of progerin/FC-lamin A proteins may disrupt DNA damage response pathways in HGPS and RD cells. As the mutant lamin proteins accumulate they sequester replication and repair factors, leading to stalled replication forks which collapse into DNA double-strand beaks (DSBs). In a reaction unique to HGPS and RD cells these accessible DSB termini bind Xeroderma pigmentosum group A (XPA) protein which excludes normal binding by DNA DSB repair proteins. The bound XPA also signals activation of ATM and ATR, arresting cell cycle progression, leading to arrested growth. In addition, the effective sequestration of XPA at these DSB damage sites makes HGPS and RD cells more sensitive to ultraviolet light and other mutagens normally repaired by the nucleotide excision repair pathway of which XPA is a necessary and specific component.

  7. Hutchinson–Gilford progeria syndrome with severe calcific aortic valve stenosis

    Science.gov (United States)

    Hanumanthappa, Natesh B; Madhusudan, Ganigara; Mahimarangaiah, Jayaranganath; Manjunath, Cholenahally N

    2011-01-01

    Hutchinson–Gilford progeria syndrome (HGPS) is a rare premature aging syndrome that results from mutation in the Laminin A gene. This case report of a 12-year-old girl with HGPS is presented for the rarity of the syndrome and the classical clinical features that were observed in the patient. All patients with this condition should undergo early and periodic evaluation for cardiovascular diseases. However, the prognosis is poor and management is mainly conservative. There is no proven therapy available. Mortality in this uniformly fatal condition is primarily due to myocardial infarction, strokes or congestive cardiac failure between ages 7 and 21 years due to the rapidly progressive arteriosclerosis involving the large vessels. PMID:21976890

  8. Extradural hematoma surgery in a child with Hutchinson-Gilford progeria syndrome: Perioperative concerns.

    Science.gov (United States)

    Hansda, Upendra; Agarwal, Jyotsna; Patra, Chitralekha; Ganjoo, Pragati

    2013-05-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a very rare genetic disorder characterized by premature ageing, severe growth failure, and very early onset atherosclerosis. Psychologically and emotionally child-like, these patients suffer from physiological changes of old age. Early and progressive atherosclerosis of intra-cranial vessels in HGPS patients, along with a thin skin and fragile vessels, make these patients susceptible to intra-cranial hematomas following relatively trivial injuries and to severe intra-cranial disease. Anesthetizing HGPS patients for surgery can be challenging due to the presence of a possible difficult airway, multi-system derangements, and associated skin, bone and joint disease. We report here one such child with HGPS who underwent craniotomy and evacuation of an extradural hematoma that developed after minor head trauma. Securing his airway during surgery was difficult.

  9. Extradural hematoma surgery in a child with Hutchinson–Gilford progeria syndrome: Perioperative concerns

    Science.gov (United States)

    Hansda, Upendra; Agarwal, Jyotsna; Patra, Chitralekha; Ganjoo, Pragati

    2013-01-01

    Hutchinson–Gilford progeria syndrome (HGPS) is a very rare genetic disorder characterized by premature ageing, severe growth failure, and very early onset atherosclerosis. Psychologically and emotionally child-like, these patients suffer from physiological changes of old age. Early and progressive atherosclerosis of intra-cranial vessels in HGPS patients, along with a thin skin and fragile vessels, make these patients susceptible to intra-cranial hematomas following relatively trivial injuries and to severe intra-cranial disease. Anesthetizing HGPS patients for surgery can be challenging due to the presence of a possible difficult airway, multi-system derangements, and associated skin, bone and joint disease. We report here one such child with HGPS who underwent craniotomy and evacuation of an extradural hematoma that developed after minor head trauma. Securing his airway during surgery was difficult. PMID:24082942

  10. Extradural hematoma surgery in a child with Hutchinson-Gilford progeria syndrome: Perioperative concerns

    Directory of Open Access Journals (Sweden)

    Upendra Hansda

    2013-01-01

    Full Text Available Hutchinson-Gilford progeria syndrome (HGPS is a very rare genetic disorder characterized by premature ageing, severe growth failure, and very early onset atherosclerosis. Psychologically and emotionally child-like, these patients suffer from physiological changes of old age. Early and progressive atherosclerosis of intra-cranial vessels in HGPS patients, along with a thin skin and fragile vessels, make these patients susceptible to intra-cranial hematomas following relatively trivial injuries and to severe intra-cranial disease. Anesthetizing HGPS patients for surgery can be challenging due to the presence of a possible difficult airway, multi-system derangements, and associated skin, bone and joint disease. We report here one such child with HGPS who underwent craniotomy and evacuation of an extradural hematoma that developed after minor head trauma. Securing his airway during surgery was difficult.

  11. Hutchinson-Gilford progeria syndrome with severe calcific aortic valve stenosis

    Directory of Open Access Journals (Sweden)

    Natesh B Hanumanthappa

    2011-01-01

    Full Text Available Hutchinson-Gilford progeria syndrome (HGPS is a rare premature aging syndrome that results from mutation in the Laminin A gene. This case report of a 12-year-old girl with HGPS is presented for the rarity of the syndrome and the classical clinical features that were observed in the patient. All patients with this condition should undergo early and periodic evaluation for cardiovascular diseases. However, the prognosis is poor and management is mainly conservative. There is no proven therapy available. Mortality in this uniformly fatal condition is primarily due to myocardial infarction, strokes or congestive cardiac failure between ages 7 and 21 years due to the rapidly progressive arteriosclerosis involving the large vessels.

  12. Prematurity, smallness-for-gestational age and later hospital admissions

    DEFF Research Database (Denmark)

    Á Rogvi, Rasmus; Forman, Julie Lyng; Greisen, Gorm

    2015-01-01

    hospital admissions later in life. METHODS: Using Danish nation-wide registries we created a cohort of 1,348,106 persons born 1974-1996 and assessed all unique diagnoses registered in the Danish Patient Registry (DPR) for hospital admissions in the period 1994-2007 (n=27,910,558). We determined the odds...... in life. CONCLUSION: Being born premature or SGA was associated with significantly altered risks of being admitted to a hospital with a wide range of diseases later in life, affecting almost all organ systems throughout childhood and early adulthood. Our findings may motivate testing in other cohorts...

  13. In vitro pathological modelling using patient-specific induced pluripotent stem cells: the case of progeria.

    Science.gov (United States)

    Nissan, Xavier; Blondel, Sophie; Peschanski, Marc

    2011-12-01

    Progeria, also known as HGPS (Hutchinson-Gilford progeria syndrome), is a rare fatal genetic disease characterized by an appearance of accelerated aging in children. This syndrome is typically caused by mutations in codon 608 (C1804T) of the gene encoding lamins A and C, LMNA, leading to the production of a truncated form of the protein called progerin. Owing to their unique potential to self-renew and to differentiate into any cell types of the organism, pluripotent stem cells offer a unique tool to study molecular and cellular mechanisms related to this global and systemic disease. Recent studies have exploited this potential by generating human induced pluripotent stem cells from HGPS patients' fibroblasts displaying several phenotypic defects characteristic of HGPS such as nuclear abnormalities, progerin expression, altered DNA-repair mechanisms and premature senescence. Altogether, these findings provide new insights on the use of pluripotent stem cells for pathological modelling and may open original therapeutic perspectives for diseases that lack pre-clinical in vitro human models, such as HGPS.

  14. Hutchinson-Gilford progeria syndrome through the lens of transcription.

    Science.gov (United States)

    Prokocimer, Miron; Barkan, Rachel; Gruenbaum, Yosef

    2013-08-01

    Lamins are nuclear intermediate filaments. In addition to their structural roles, they are implicated in basic nuclear functions such as chromatin organization, DNA replication, transcription, DNA repair, and cell-cycle progression. Mutations in human LMNA gene cause several diseases termed laminopathies. One of the laminopathic diseases is Hutchinson-Gilford progeria syndrome (HGPS), which is caused by a spontaneous mutation and characterized by premature aging. HGPS phenotypes share certain similarities with several apparently comparable medical conditions, such as aging and atherosclerosis, with the conspicuous absence of neuronal degeneration and cancer rarity during the short lifespan of the patients. Cell lines from HGPS patients are characterized by multiple nuclear defects, which include abnormal morphology, altered histone modification patterns, and increased DNA damage. These cell lines provide insight into the molecular pathways including senescence that require lamins A and B1. Here, we review recent data on HGPS phenotypes through the lens of transcriptional deregulation caused by lack of functional lamin A, progerin accumulation, and lamin B1 silencing.

  15. Telomere length in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Decker, Michelle L; Chavez, Elizabeth; Vulto, Irma; Lansdorp, Peter M

    2009-06-01

    Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare premature aging disorder caused by mutations in the gene LMNA, which encodes the nuclear matrix protein lamin A. Previous research has shown that the average telomere length in fibroblasts from HGPS patients is shorter than in age-matched controls. How mutations in lamin A lead to shortened telomere lengths is not known nor is the contribution of individual chromosome ends to the low average length understood. To measure the telomere length of individual chromosomes, we used quantitative fluorescence in situ hybridization (Q-FISH). In agreement with previous studies, we found that the average telomere length in HPGS fibroblasts is greatly reduced; however, the telomere length at chromosome ends was variable. In contrast, the telomere length in hematopoietic cells which typically do not express lamin A, was within the normal range for three out of four HGPS patient samples. Our results suggest that mutant lamin A decreases telomere length via a direct effect and that expression of mutant LMNA is necessary for telomere loss in HGPS.

  16. Vascular disease modeling using induced pluripotent stem cells: Focus in Hutchinson-Gilford Progeria Syndrome.

    Science.gov (United States)

    Pitrez, P R; Rosa, S C; Praça, C; Ferreira, L

    2016-05-06

    Induced pluripotent stem cells (iPSCs) represent today an invaluable tool to create disease cell models for modeling and drug screening. Several lines of iPSCs have been generated in the last 7 years that changed the paradigm for studying diseases and the discovery of new drugs to treat them. In this article we focus our attention to vascular diseases in particular Hutchinson-Gilford Progeria Syndrome (HGPS), a devastating premature aging disease caused by a mutation in the lamin A gene. In general, patients die because of myocardial infarction or stroke. Because the patients are fragile the isolation of a particular type of cells is very difficult. Therefore in the last 5 years, researchers have used cells derived from iPSCs to model aspects of the HGPS and to screen libraries of chemicals to retard or treat the disease.

  17. Maternal age as risk factor of prematurity in Spain: Mediterranean area

    Directory of Open Access Journals (Sweden)

    E. Cortés Castell

    2013-10-01

    Full Text Available Background: Maternal age is a preponderant variable in the epidemiological analysis of the premature birth. Studies show that in the extreme ages of the maternal life there is a risk of premature birth that generates a high rate of neonatal morbidity. Objetives: Determine the effect on the extreme ages of women residents in the province of Alicante on the total of the premature births. Method: An explanatory, retrospective case-control study was conducted during the period from January 1st, 2008 to December 31st, 2011. The study was based on the revision of the newborn registers from the Neonatal Screening Center of the province of Alicante. All the preterm were included, this means between 22 & 36 complete weeks of pregnancy (5,295 out of 78,391 newborn which represents 6.75% of prematurity, and a random sample of the deliveries with 37 weeks or more of pregnancy (control group. The age of the mother was studied as independent variable and the prematurity as dependent variable. Results: Clearly shows an increased risk of prematurity among teenage mothers compared to the age group nearest to them, which is confirmed by a squared Chi test which gives a significantly different distribution (p < 0,0001 and an OD for very preterm of 2,41 (1,51-3,24 and of preterm of 1,71 (1,32-2,19. This probability is also higher among mothers over 40 years old with an OD of 1,86 (1,39-2,48 and 1,66 (1,44-1,91 for very preterm newborns and preterm newborns respectively. Discussion: The results clearly manifest that teenagers and older pregnant mothers are at higher prematurity and low birth weight risk, therefore imposes the need to trace educational interventions to minimize this problem from the results in this research.

  18. The Defective Nuclear Lamina in Hutchinson-Gilford Progeria Syndrome Disrupts the Nucleocytoplasmic Ran Gradient and Inhibits Nuclear Localization of Ubc9▿

    Science.gov (United States)

    Kelley, Joshua B.; Datta, Sutirtha; Snow, Chelsi J.; Chatterjee, Mandovi; Ni, Li; Spencer, Adam; Yang, Chun-Song; Cubeñas-Potts, Caelin; Matunis, Michael J.; Paschal, Bryce M.

    2011-01-01

    The mutant form of lamin A responsible for the premature aging disease Hutchinson-Gilford progeria syndrome (termed progerin) acts as a dominant negative protein that changes the structure of the nuclear lamina. How the perturbation of the nuclear lamina in progeria is transduced into cellular changes is undefined. Using patient fibroblasts and a variety of cell-based assays, we determined that progerin expression in Hutchinson-Gilford progeria syndrome inhibits the nucleocytoplasmic transport of several factors with key roles in nuclear function. We found that progerin reduces the nuclear/cytoplasmic concentration of the Ran GTPase and inhibits the nuclear localization of Ubc9, the sole E2 for SUMOylation, and of TPR, the nucleoporin that forms the basket on the nuclear side of the nuclear pore complex. Forcing the nuclear localization of Ubc9 in progerin-expressing cells rescues the Ran gradient and TPR import, indicating that these pathways are linked. Reducing nuclear SUMOylation decreases the nuclear mobility of the Ran nucleotide exchange factor RCC1 in vivo, and the addition of SUMO E1 and E2 promotes the dissociation of RCC1 and Ran from chromatin in vitro. Our data suggest that the cellular effects of progerin are transduced, at least in part, through reduced function of the Ran GTPase and SUMOylation pathways. PMID:21670151

  19. The defective nuclear lamina in Hutchinson-gilford progeria syndrome disrupts the nucleocytoplasmic Ran gradient and inhibits nuclear localization of Ubc9.

    Science.gov (United States)

    Kelley, Joshua B; Datta, Sutirtha; Snow, Chelsi J; Chatterjee, Mandovi; Ni, Li; Spencer, Adam; Yang, Chun-Song; Cubeñas-Potts, Caelin; Matunis, Michael J; Paschal, Bryce M

    2011-08-01

    The mutant form of lamin A responsible for the premature aging disease Hutchinson-Gilford progeria syndrome (termed progerin) acts as a dominant negative protein that changes the structure of the nuclear lamina. How the perturbation of the nuclear lamina in progeria is transduced into cellular changes is undefined. Using patient fibroblasts and a variety of cell-based assays, we determined that progerin expression in Hutchinson-Gilford progeria syndrome inhibits the nucleocytoplasmic transport of several factors with key roles in nuclear function. We found that progerin reduces the nuclear/cytoplasmic concentration of the Ran GTPase and inhibits the nuclear localization of Ubc9, the sole E2 for SUMOylation, and of TPR, the nucleoporin that forms the basket on the nuclear side of the nuclear pore complex. Forcing the nuclear localization of Ubc9 in progerin-expressing cells rescues the Ran gradient and TPR import, indicating that these pathways are linked. Reducing nuclear SUMOylation decreases the nuclear mobility of the Ran nucleotide exchange factor RCC1 in vivo, and the addition of SUMO E1 and E2 promotes the dissociation of RCC1 and Ran from chromatin in vitro. Our data suggest that the cellular effects of progerin are transduced, at least in part, through reduced function of the Ran GTPase and SUMOylation pathways.

  20. Sulforaphane enhances progerin clearance in Hutchinson–Gilford progeria fibroblasts

    Science.gov (United States)

    Gabriel, Diana; Roedl, Daniela; Gordon, Leslie B; Djabali, Karima

    2015-01-01

    Hutchinson–Gilford progeria syndrome (HGPS, OMIM 176670) is a rare multisystem childhood premature aging disorder linked to mutations in the LMNA gene. The most common HGPS mutation is found at position G608G within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, and the truncated protein is called progerin. Progerin only undergoes a subset of the normal post-translational modifications and remains permanently farnesylated. Several attempts to rescue the normal cellular phenotype with farnesyltransferase inhibitors (FTIs) and other compounds have resulted in partial cellular recovery. Using proteomics, we report here that progerin induces changes in the composition of the HGPS nuclear proteome, including alterations to several components of the protein degradation pathways. Consequently, proteasome activity and autophagy are impaired in HGPS cells. To restore protein clearance in HGPS cells, we treated HGPS cultures with sulforaphane (SFN), an antioxidant derived from cruciferous vegetables. We determined that SFN stimulates proteasome activity and autophagy in normal and HGPS fibroblast cultures. Specifically, SFN enhances progerin clearance by autophagy and reverses the phenotypic changes that are the hallmarks of HGPS. Therefore, SFN is a promising therapeutic avenue for children with HGPS. PMID:25510262

  1. Sulforaphane enhances progerin clearance in Hutchinson-Gilford progeria fibroblasts.

    Science.gov (United States)

    Gabriel, Diana; Roedl, Daniela; Gordon, Leslie B; Djabali, Karima

    2015-02-01

    Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare multisystem childhood premature aging disorder linked to mutations in the LMNA gene. The most common HGPS mutation is found at position G608G within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, and the truncated protein is called progerin. Progerin only undergoes a subset of the normal post-translational modifications and remains permanently farnesylated. Several attempts to rescue the normal cellular phenotype with farnesyltransferase inhibitors (FTIs) and other compounds have resulted in partial cellular recovery. Using proteomics, we report here that progerin induces changes in the composition of the HGPS nuclear proteome, including alterations to several components of the protein degradation pathways. Consequently, proteasome activity and autophagy are impaired in HGPS cells. To restore protein clearance in HGPS cells, we treated HGPS cultures with sulforaphane (SFN), an antioxidant derived from cruciferous vegetables. We determined that SFN stimulates proteasome activity and autophagy in normal and HGPS fibroblast cultures. Specifically, SFN enhances progerin clearance by autophagy and reverses the phenotypic changes that are the hallmarks of HGPS. Therefore, SFN is a promising therapeutic avenue for children with HGPS.

  2. In silico analysis of Progeria: A genetic disease and natural cardiovascular disorders preventive compounds

    OpenAIRE

    Shraddha Mulange; Satish Kulkarni; Vaishali Wadekar; L H Kamble

    2016-01-01

    Progeria (also known as "Hutchinson–Gilford progeria syndrome"(HGPS) is an extremely rare, severe, genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. The basic objective of this study is how is it responsible for faster ageing than normal? The study of its bioinformatics aspect explaining where the mutation occurs in normal LMNA gene to form mutated Progerin. We explain its sequential and structural aspects in domain and motif. Structural visualizat...

  3. Cardiovascular Risk in Women With Premature Ovarian Insufficiency Compared to Premenopausal Women at Middle Age

    NARCIS (Netherlands)

    Daan, Nadine M P; Muka, Taulant; Koster, Maria P H; Roeters van Lennep, Jaenine E; Lambalk, Cornelis B; Laven, Joop S E; Fauser, Clemens G K M; Meun, Cindy; de Rijke, Yolanda B; Boersma, Eric; Franco, Oscar H; Kavousi, Maryam; Fauser, Bart C J M

    2016-01-01

    CONTEXT: A young age at menopause has been associated with increased cardiovascular disease (CVD) risk. OBJECTIVE: To compare the cardiovascular risk profile between women with premature ovarian insufficiency (POI) and premenopausal controls of comparable age. DESIGN: Cross-sectional case control st

  4. Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice

    NARCIS (Netherlands)

    H.W.M. van de Ven (Marieke); J.-O. Andressoo (Jaan-Olle); V.B. Holcomb (Valerie); M.M. von Lindern (Marieke); W.M.C. Jong (Willeke); C.I. de Zeeuw (Chris); Y. Suh (Yousin); P. Hasty (Paul); J.H.J. Hoeijmakers (Jan); G.T.J. van der Horst (Gijsbertus); J.R. Mitchell (James)

    2006-01-01

    textabstractHow congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular senes

  5. Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice

    NARCIS (Netherlands)

    H.W.M. van de Ven (Marieke); J.-O. Andressoo (Jaan-Olle); V.B. Holcomb (Valerie); M.M. von Lindern (Marieke); W.M.C. Jong (Willeke); C.I. de Zeeuw (Chris); Y. Suh (Yousin); P. Hasty (Paul); J.H.J. Hoeijmakers (Jan); G.T.J. van der Horst (Gijsbertus); J.R. Mitchell (James)

    2006-01-01

    textabstractHow congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular senes

  6. Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice

    NARCIS (Netherlands)

    H.W.M. van de Ven (Marieke); J.-O. Andressoo (Jaan-Olle); V.B. Holcomb (Valerie); M.M. von Lindern (Marieke); W.M.C. Jong (Willeke); C.I. de Zeeuw (Chris); Y. Suh (Yousin); P. Hasty (Paul); J.H.J. Hoeijmakers (Jan); G.T.J. van der Horst (Gijsbertus); J.R. Mitchell (James)

    2006-01-01

    textabstractHow congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular

  7. The Premature Aging Hypothesis: Old Before Its Time?

    Science.gov (United States)

    Kramer, Joel H.; And Others

    1989-01-01

    Administered California Verbal Learning Test to young and old alcoholics and controls. Alcoholism and aging produced similar levels of immediate and delayed free recall. However, poor recognition memory and more frequent intrusion and false positive errors were associated with alcoholism but not with aging. Results suggest that alcoholism and…

  8. Premature aging in skeletal muscle lacking serum response factor.

    Directory of Open Access Journals (Sweden)

    Charlotte Lahoute

    Full Text Available Aging is associated with a progressive loss of muscle mass, increased adiposity and fibrosis that leads to sarcopenia. At the molecular level, muscle aging is known to alter the expression of a variety of genes but very little is known about the molecular effectors involved. SRF (Serum Response Factor is a crucial transcription factor for muscle-specific gene expression and for post-natal skeletal muscle growth. To assess its role in adult skeletal muscle physiology, we developed a post-mitotic myofiber-specific and tamoxifen-inducible SRF knockout model. Five months after SRF loss, no obvious muscle phenotype was observed suggesting that SRF is not crucial for myofiber maintenance. However, mutant mice progressively developed IIB myofiber-specific atrophy accompanied by a metabolic switch towards a more oxidative phenotype, muscular lipid accumulation, sarcomere disorganization and fibrosis. After injury, mutant muscles exhibited an altered regeneration process, showing smaller regenerated fibers and persistent fibrosis. All of these features are strongly reminiscent of abnormalities encountered in aging skeletal muscle. Interestingly, we also observed an important age associated decrease in SRF expression in mice and human muscles. Altogether, these results suggest that a naturally occurring SRF down-regulation precedes and contributes to the muscle aging process. Indeed, triggering SRF loss in the muscles of mutant mice results in an accelerated aging process.

  9. Uremia causes premature ageing of the T cell compartment in end-stage renal disease patients

    Directory of Open Access Journals (Sweden)

    Meijers Ruud WJ

    2012-09-01

    Full Text Available Abstract Background End-stage renal disease (ESRD patients treated with renal replacement therapy (RRT have premature immunologically aged T cells which may underlie uremia-associated immune dysfunction. The aim of this study was to investigate whether uremia was able to induce premature ageing of the T cell compartment. For this purpose, we examined the degree of premature immunological T cell ageing by examining the T cell differentiation status, thymic output via T cell receptor excision circle (TREC content and proliferative history via relative telomere length in ESRD patients not on RRT. Results Compared to healthy controls, these patients already had a lower TREC content and an increased T cell differentiation accompanied by shorter telomeres. RRT was able to enhance CD8+ T cell differentiation and to reduce CD8+ T cell telomere length in young dialysis patients. An increased differentiation status of memory CD4+ T cells was also noted in young dialysis patients. Conclusion Based on these results we can conclude that uremia already causes premature immunological ageing of the T cell system and RRT further increases immunological ageing of the CD8+ T cell compartment in particular in young ESRD patients.

  10. Leaving College Prematurely: The Experiences of Nontraditional-Age College Students With Depression

    Science.gov (United States)

    Thompson-Ebanks, Valerie

    2017-01-01

    This qualitative study examines the experiences of former nontraditional-age students with depression and reasons that led them to leave college prematurely. Constant comparative methods were used to illuminate themes within and across participants' stories. The findings showcase eight complex interlocking factors that these former students…

  11. Leaving College Prematurely: The Experiences of Nontraditional-Age College Students With Depression

    Science.gov (United States)

    Thompson-Ebanks, Valerie

    2017-01-01

    This qualitative study examines the experiences of former nontraditional-age students with depression and reasons that led them to leave college prematurely. Constant comparative methods were used to illuminate themes within and across participants' stories. The findings showcase eight complex interlocking factors that these former students…

  12. Replication Factor C1, the Large Subunit of Replication Factor C, Is Proteolytically Truncated in Hutchinson-Gilford Progeria Syndrome

    Science.gov (United States)

    Tang, Hui; Hilton, Benjamin; Musich, Phillip R.; Fang, Ding Zhi; Zou, Yue

    2011-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder due to a LMNA gene mutation which produces a mutant lamin A protein (progerin). Progerin also has been correlated to physiological aging and related diseases. However, how progerin causes the progeria remains unknown. Here we report that the large subunit (RFC1) of replication factor C is cleaved in HGPS cells, leading to the production of a truncated RFC1 of ~75 kDa which appears to be defective in loading PCNA and pol δ onto DNA for replication. Interestingly, the cleavage can be inhibited by a serine protease inhibitor, suggesting that RFC1 is cleaved by a serine protease. Due to the crucial role of RFC in DNA replication our findings provide a mechanistic interpretation for the observed replicative arrest and premature aging phenotypes of HPGS, and may lead to novel strategies in HGPS treatment. Furthermore, this unique truncated form of RFC1 may serve as a potential marker for HGPS. PMID:22168243

  13. Mechanisms controlling the smooth muscle cell death in progeria via down-regulation of poly(ADP-ribose) polymerase 1.

    Science.gov (United States)

    Zhang, Haoyue; Xiong, Zheng-Mei; Cao, Kan

    2014-06-03

    Hutchinson-Gilford progeria syndrome (HGPS) is a severe human premature aging disorder caused by a lamin A mutant named progerin. Death occurs at a mean age of 13 y from cardiovascular problems. Previous studies revealed loss of vascular smooth muscle cells (SMCs) in the media of large arteries in a patient with HGPS and two mouse models, suggesting a causal connection between the SMC loss and cardiovascular malfunction. However, the mechanisms of how progerin leads to massive SMC loss are unknown. In this study, using SMCs differentiated from HGPS induced pluripotent stem cells, we show that HGPS SMCs exhibit a profound proliferative defect, which is primarily caused by caspase-independent cell death. Importantly, progerin accumulation stimulates a powerful suppression of PARP1 and consequently triggers an activation of the error-prone nonhomologous end joining response. As a result, most HGPS SMCs exhibit prolonged mitosis and die of mitotic catastrophe. This study demonstrates a critical role of PARP1 in mediating SMC loss in patients with HGPS and elucidates a molecular pathway underlying the progressive SMC loss in progeria.

  14. Muscle wasting in myotonic dystrophies: a model of premature aging.

    Science.gov (United States)

    Mateos-Aierdi, Alba Judith; Goicoechea, Maria; Aiastui, Ana; Fernández-Torrón, Roberto; Garcia-Puga, Mikel; Matheu, Ander; López de Munain, Adolfo

    2015-01-01

    Myotonic dystrophy type 1 (DM1 or Steinert's disease) and type 2 (DM2) are multisystem disorders of genetic origin. Progressive muscular weakness, atrophy and myotonia are the most prominent neuromuscular features of these diseases, while other clinical manifestations such as cardiomyopathy, insulin resistance and cataracts are also common. From a clinical perspective, most DM symptoms are interpreted as a result of an accelerated aging (cataracts, muscular weakness and atrophy, cognitive decline, metabolic dysfunction, etc.), including an increased risk of developing tumors. From this point of view, DM1 could be described as a progeroid syndrome since a notable age-dependent dysfunction of all systems occurs. The underlying molecular disorder in DM1 consists of the existence of a pathological (CTG) triplet expansion in the 3' untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene, whereas (CCTG)n repeats in the first intron of the Cellular Nucleic acid Binding Protein/Zinc Finger Protein 9 (CNBP/ZNF9) gene cause DM2. The expansions are transcribed into (CUG)n and (CCUG)n-containing RNA, respectively, which form secondary structures and sequester RNA-binding proteins, such as the splicing factor muscleblind-like protein (MBNL), forming nuclear aggregates known as foci. Other splicing factors, such as CUGBP, are also disrupted, leading to a spliceopathy of a large number of downstream genes linked to the clinical features of these diseases. Skeletal muscle regeneration relies on muscle progenitor cells, known as satellite cells, which are activated after muscle damage, and which proliferate and differentiate to muscle cells, thus regenerating the damaged tissue. Satellite cell dysfunction seems to be a common feature of both age-dependent muscle degeneration (sarcopenia) and muscle wasting in DM and other muscle degenerative diseases. This review aims to describe the cellular, molecular and macrostructural processes involved in the muscular

  15. Muscle wasting in myotonic dystrophies: a model of premature aging.

    Directory of Open Access Journals (Sweden)

    Alba Judith eMateos-Aierdi

    2015-07-01

    Full Text Available Myotonic dystrophy type I (DM1 or Steinert’s disease and type II (DM2 are multisystem disorders of genetic origin. Progressive muscular weakness, atrophy and myotonia are the most prominent neuromuscular features of these diseases, and other clinical manifestations such as cardiomyopathy, insulin-resistance and cataracts are also common. From a clinical perspective, most DM symptoms are interpreted as a result of an accelerated aging (cataracts, muscular weakness and atrophy, cognitive decline, metabolic dysfunction, etc., including an increased risk of developing tumors. From this point of view, DM1 could be described as a progeroid syndrome since a notable age-dependent dysfunction of all systems occurs. The underlying molecular disorder in DM1 consists of the existence of a pathological (CTGn triplet expansion in the 3’ untranslated region of the DMPK gene, whereas (CCTGn repeats in the first intron of the CNBP/ZNF9 gene cause DM2. The expansions are transcribed into (CUGn and (CCUGn-containing RNA, respectively, which form secondary structures and sequester RNA-binding proteins, such as the splicing factor muscleblind-like protein (MBNL, forming nuclear aggregates known as foci. Other splicing factors, such as CUGBP, are also disrupted, leading to a spliceopathy of a large number of downstream genes linked to the clinical features of these diseases. Skeletal muscle regeneration relies on muscle progenitor cells, known as satellite cells, which are activated after muscle damage, and which proliferate and differentiate to muscle cells, thus regenerating the damaged tissue. Satellite cell dysfunction seems to be a common feature of both age-dependent muscle degeneration (sarcopenia and muscle wasting in DM and other muscle degenerative diseases. This review aims to describe the cellular, molecular and macrostructural processes involved in the muscular degeneration seen in DM patients, highlighting the similarities found with muscle aging.

  16. Genetics Home Reference: Hutchinson-Gilford progeria syndrome

    Science.gov (United States)

    ... Health Conditions Hutchinson-Gilford progeria syndrome Hutchinson-Gilford progeria syndrome Enable Javascript to view the expand/collapse ... PDF Open All Close All Description Hutchinson-Gilford progeria syndrome is a genetic condition characterized by the ...

  17. Importance of molecular cell biology investigations in human medicine in the story of the Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Raška, Ivan

    2010-09-01

    Ranged among laminopathies, Hutchinson-Gilford progeria syndrome is a syndrome that involves premature aging, leading usually to death at the age between 10 to 14 years predominatly due to a myocardial infarction or a stroke. In the lecture I shall overview the importance of molecular cell biology investigations that led to the discovery of the basic mechanism standing behind this rare syndrome. The genetic basis in most cases is a mutation at the nucleotide position 1824 of the lamin A gene. At this position, cytosine is substituted for thymine so that a cryptic splice site within the precursor mRNA for lamin A is generated. This results in a production of abnormal lamin A, termed progerin, its presence in cells having a deleterious dominant effect. Depending on the cell type and tissue, progerin induces a pleiotropy of defects that vary in different tissues. The present endeavour how to challenge this terrible disease will be also mentioned.

  18. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Goldman, Robert D; Shumaker, Dale K; Erdos, Michael R; Eriksson, Maria; Goldman, Anne E; Gordon, Leslie B; Gruenbaum, Yosef; Khuon, Satya; Mendez, Melissa; Varga, Renée; Collins, Francis S

    2004-06-15

    Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder, commonly caused by a point mutation in the lamin A gene that results in a protein lacking 50 aa near the C terminus, denoted LADelta50. Here we show by light and electron microscopy that HGPS is associated with significant changes in nuclear shape, including lobulation of the nuclear envelope, thickening of the nuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores. These structural defects worsen as HGPS cells age in culture, and their severity correlates with an apparent increase in LADelta50. Introduction of LADelta50 into normal cells by transfection or protein injection induces the same changes. We hypothesize that these alterations in nuclear structure are due to a concentration-dependent dominant-negative effect of LADelta50, leading to the disruption of lamin-related functions ranging from the maintenance of nuclear shape to regulation of gene expression and DNA replication.

  19. Cell autonomous and systemic factors in progeria development.

    Science.gov (United States)

    Osorio, Fernando G; Ugalde, Alejandro P; Mariño, Guillermo; Puente, Xose S; Freije, José M P; López-Otín, Carlos

    2011-12-01

    Progeroid laminopathies are accelerated aging syndromes caused by defects in nuclear envelope proteins. Accordingly, mutations in the LMNA gene and functionally related genes have been described to cause HGPS (Hutchinson-Gilford progeria syndrome), MAD (mandibuloacral dysplasia) or RD (restrictive dermopathy). Functional studies with animal and cellular models of these syndromes have facilitated the identification of the molecular alterations and regulatory pathways involved in progeria development. We have recently described a novel regulatory pathway involving miR-29 and p53 tumour suppressor which has provided valuable information on the molecular components orchestrating the response to nuclear damage stress. Furthermore, by using progeroid mice deficient in ZMPSTE24 (zinc metalloprotease STE24 homologue) involved in lamin A maturation, we have demonstrated that, besides these abnormal cellular responses to stress, dysregulation of the somatotropic axis is responsible for some of the alterations associated with progeria. Consistent with these observations, pharmacological restoration of the somatotroph axis in these mice delays the onset of their progeroid features, significantly extending their lifespan and supporting the importance of systemic alterations in progeria progression. Finally, we have very recently identified a novel progeroid syndrome with distinctive features from HGPS and MAD, which we have designated NGPS (Néstor-Guillermo progeria syndrome) (OMIM #614008). This disorder is caused by a mutation in BANF1, a gene encoding a protein with essential functions in the assembly of the nuclear envelope, further illustrating the importance of the nuclear lamina integrity for human health and providing additional support to the study of progeroid syndromes as a valuable source of information on human aging.

  20. Expression of progerin in aging mouse brains reveals structural nuclear abnormalities without detectible significant alterations in gene expression, hippocampal stem cells or behavior

    DEFF Research Database (Denmark)

    Baek, Jean-Ha; Schmidt, Eva; Viceconte, Nikenza;

    2015-01-01

    Hutchinson–Gilford progeria syndrome (HGPS) is a segmental progeroid syndrome with multiple features suggestive of premature accelerated aging. Accumulation of progerin is thought to underlie the pathophysiology of HGPS. However, despite ubiquitous expression of lamin A in all differentiated cells......, the HGPS mutation results in organ-specific defects. For example, bone and skin are strongly affected by HGPS, while the brain appears to be unaffected. There are no definite explanations as to the variable sensitivity to progeria disease among different organs. In addition, low levels of progerin have...

  1. Targeting Protein Prenylation in Progeria

    Science.gov (United States)

    Young, Stephen G.; Yang, Shao H.; Davies, Brandon S. J.; Jung, Hea-Jin; Fong, Loren G.

    2013-01-01

    A clinical trial of a protein farnesyltransferase inhibitor (lonafarnib) for the treatment of Hutchinson-Gilford progeria syndrome (HGPS) was recently completed. Here, we discuss the mutation that causes HGPS, the rationale for inhibiting protein farnesyltransferase, the potential limitations of this therapeutic approach, and new potential strategies for treating the disease. PMID:23390246

  2. Targeting Protein Prenylation in Progeria

    OpenAIRE

    Young, Stephen G.; Yang, Shao H.; Davies, Brandon S.J.; Jung, Hea-Jin; Fong, Loren G.

    2013-01-01

    A clinical trial of a protein farnesyltransferase inhibitor (lonafarnib) for the treatment of Hutchinson-Gilford progeria syndrome (HGPS) was recently completed. Here, we discuss the mutation that causes HGPS, the rationale for inhibiting protein farnesyltransferase, the potential limitations of this therapeutic approach, and new potential strategies for treating the disease.

  3. Targeting protein prenylation in progeria.

    Science.gov (United States)

    Young, Stephen G; Yang, Shao H; Davies, Brandon S J; Jung, Hea-Jin; Fong, Loren G

    2013-02-06

    A clinical trial of a protein farnesyltransferase inhibitor (lonafarnib) for the treatment of Hutchinson-Gilford progeria syndrome (HGPS) was recently completed. Here, we discuss the mutation that causes HGPS, the rationale for inhibiting protein farnesyltransferase, the potential limitations of this therapeutic approach, and new potential strategies for treating the disease.

  4. GDF11 administration does not extend lifespan in a mouse model of premature aging

    Science.gov (United States)

    Freitas-Rodríguez, Sandra; Rodríguez, Francisco; Folgueras, Alicia R.

    2016-01-01

    GDF11 has recently emerged as a powerful anti-aging candidate, found in young blood, capable of rejuvenating a number of aged tissues, such as heart, skeletal muscle and brain. However, recent reports have shown contradictory data questioning its capacity to reverse age-related tissue dysfunction. The availability of a mouse model of accelerated aging, which shares most of the features occurring in physiological aging, gives us an excellent opportunity to test in vivo therapies aimed at extending lifespan both in pathological and normal aging. On this basis, we wondered whether the proposed anti-aging functions of GDF11 would have an overall effect on longevity. We first confirmed the existence of a reduction in GDF11/8 levels in our mouse model of accelerated aging compared with wild-type littermates. However, we show herein that GDF11 daily administration does not extend lifespan of premature-aged mice. PMID:27507054

  5. Premature ageing of the immune system underlies immunodeficiency in ataxia telangiectasia.

    Science.gov (United States)

    Exley, Andrew Robert; Buckenham, Samantha; Hodges, Elizabeth; Hallam, Robert; Byrd, Phil; Last, James; Trinder, Claire; Harris, Susan; Screaton, Nicholas; Williams, Anthony P; Taylor, A Malcolm R; Shneerson, John M

    2011-07-01

    ATM kinase modulates pathways implicated in premature ageing and ATM genotype predicts survival, yet immunodeficiency in ataxia telangiectasia is regarded as mild and unrelated to age. We address this paradox in a molecularly characterised sequential adult cohort with classical and mild variant ataxia telangiectasia. Immunodeficiency has the characteristics of premature ageing across multiple cellular and molecular immune parameters. This immune ageing occurs without previous CMV infection. Age predicts immunodeficiency in genetically homogeneous ataxia telangiectasia, and in comparison with controls, calendar age is exceeded by immunological age defined by thymic naïve CD4+ T cell levels. Applying ataxia telangiectasia as a model of immune ageing, pneumococcal vaccine responses, characteristically deficient in physiological ageing, are predicted by thymic naïve CD4+ T cell levels. These data suggest inherited defects of DNA repair may provide valuable insight into physiological ageing. Thymic naïve CD4+ T cells may provide a biomarker for vaccine responsiveness in elderly cohorts. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. Impact of Farnesylation Inhibitors on Survival in Hutchinson-Gilford Progeria Syndrome

    Science.gov (United States)

    Gordon, Leslie B.; Massaro, Joe; D'Agostino, Ralph B.; Campbell, Susan E.; Brazier, Joan; Brown, W. Ted; Kleinman, Monica E; Kieran, Mark W.

    2014-01-01

    Background Hutchinson-Gilford progeria syndrome is an ultra-rare segmental premature aging disease resulting in early death from heart attack or stroke. There is no approved treatment, but starting in 2007, several recent single arm clinical trials have administered inhibitors of protein farnesylation aimed at reducing toxicity of the disease-producing protein progerin. No study has assessed whether treatments influence patient survival. The key elements necessary for this analysis are a robust natural history of survival and comparison with a sufficiently large patient population that has been treated for a sufficient time period with disease-targeting medications. Methods and Results We generated survival Kaplan-Meier survival analyses for the largest untreated Hutchinson-Gilford progeria syndrome cohort to date. Mean survival was 14.6 years. Comparing survival for treated versus age-and-gender-matched untreated cohorts, hazard ratio was 0.13 (95% CI 0.04-0.37; P<0.001) with median follow-up of 5.3 years from time of treatment initiation. There were 21/43 deaths in untreated versus 5/43 deaths among treated subjects. Treatment increased mean survival by 1.6 years. Conclusions This study provides a robust untreated disease survival profile, which can be utilized for comparisons now and in the future to assess changes in survival with treatments for HGPS. The current comparisons estimating increased survival with protein farnesylation inhibitors provide the first evidence of treatments influencing survival for this fatal disease. Clinical Trial Registration Information www.clinicaltrials.gov. Indentifiers: NCT00425607, NCT00879034 and NCT00916747. PMID:24795390

  7. The Effect of Gestational Age on Axial Length of the Eyes of Premature Infants

    Directory of Open Access Journals (Sweden)

    Mehmet Ali Sekeroglu

    2016-01-01

    Full Text Available Aim: The aim of the present study is to evaluate the axial length of the eyes of premature infants without retinopathy of prematurity and to document the relationship with gestational age and changes as infants grew-up. Material and Method: The axial length of the eyes were measured by using a mobile A-scan ultrasonographic biometry device just before the first retinopathy of prematurity screening examination and 4-weeks thereafter. Results: One-hundred and thirty-six infants with a mean gestational age of 31,7±2,7 weeks and a birth-weight of 1561.0±379.3 g were included in the study. Axial length measurements were done at a mean postconceptional age of 35.8 ±2.6 (31-40 and 39.8±2.7 (35-44 weeks, consecutively. The mean axial length at first and second visits were 16.43±0.42 mm (15.28-17.13 and 16.69±0.41 mm (15.60-17.70, consecutively (p

  8. Extended longevity mechanisms in short-lived progeroid mice: identification of a preservative stress response associated with successful aging.

    Science.gov (United States)

    van de Ven, Marieke; Andressoo, Jaan-Olle; Holcomb, Valerie B; Hasty, Paul; Suh, Yousin; van Steeg, Harry; Garinis, George A; Hoeijmakers, Jan H J; Mitchell, James R

    2007-01-01

    Semantic distinctions between "normal" aging, "pathological" aging (or age-related disease) and "premature" aging (otherwise known as segmental progeria) potentially confound important insights into the nature of each of the complex processes. Here we review a recent, unexpected discovery: the presence of longevity-associated characteristics typical of long-lived endocrine-mutant and dietary-restricted animals in short-lived progeroid mice. These data suggest that a subset of symptoms observed in premature aging, and possibly normal aging as well, may be indirect manifestations of a beneficial adaptive stress response to endogenous oxidative damage, rather than a detrimental result of the damage itself.

  9. Association of Maternal Age to Development and Progression of Retinopathy of Prematurity in Infants of Gestational Age under 33 Weeks

    Directory of Open Access Journals (Sweden)

    Atsuro Uchida

    2014-01-01

    Full Text Available Aim. To find predictive and indicative markers of risk for development of retinopathy of prematurity (ROP and its progression to the stage requiring laser treatment, in premature infants whose gestational age (GA was under 33 weeks. Methods. We retrospectively reviewed medical records of 197 premature infants born in 2005–2010 whose GA<33 weeks and underwent eye screening at Keio University Hospital. The association between candidate risk factors and development or progression of ROP was assessed. Results. Among the 182 eligible infants (median GA, 29.1 weeks; median birth weight (BW, 1028 g, 84 (46% developed any stage of ROP, of which 45 (25% required laser treatment. Multivariate analysis using a stepwise method showed that GA (P=0.002; 95% confidence interval (CI, 0.508–0.858, BW (P<0.001; 95% CI, 0.994–0.998, and lower maternal age (P=0.032; 95% CI, 0.819–0.991 were the risk factors for ROP development and GA (P<0.001; 95% CI, 0.387–0.609 and lower maternal age (P=0.012; 95% CI, 0.795–0.973 were for laser treatment. The odds ratio of requiring laser treatment was 3.3 when the maternal age was <33 years. Conclusion. ROP was more likely to be developed and progressed in infants born from younger mother and low GA.

  10. Cardiac electrical defects in progeroid mice and Hutchinson–Gilford progeria syndrome patients with nuclear lamina alterations

    Science.gov (United States)

    Rivera-Torres, José; Calvo, Conrado J.; Llach, Anna; Guzmán-Martínez, Gabriela; Caballero, Ricardo; González-Gómez, Cristina; Jiménez-Borreguero, Luis J.; Guadix, Juan A.; Osorio, Fernando G.; López-Otín, Carlos; Herraiz-Martínez, Adela; Cabello, Nuria; Vallmitjana, Alex; Benítez, Raul; Gordon, Leslie B.; Pérez-Pomares, José M.; Tamargo, Juan; Delpón, Eva; Hove-Madsen, Leif; Filgueiras-Rama, David; Andrés, Vicente

    2016-01-01

    Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disease caused by defective prelamin A processing, leading to nuclear lamina alterations, severe cardiovascular pathology, and premature death. Prelamin A alterations also occur in physiological aging. It remains unknown how defective prelamin A processing affects the cardiac rhythm. We show age-dependent cardiac repolarization abnormalities in HGPS patients that are also present in the Zmpste24−/− mouse model of HGPS. Challenge of Zmpste24−/− mice with the β-adrenergic agonist isoproterenol did not trigger ventricular arrhythmia but caused bradycardia-related premature ventricular complexes and slow-rate polymorphic ventricular rhythms during recovery. Patch-clamping in Zmpste24−/− cardiomyocytes revealed prolonged calcium-transient duration and reduced sarcoplasmic reticulum calcium loading and release, consistent with the absence of isoproterenol-induced ventricular arrhythmia. Zmpste24−/− progeroid mice also developed severe fibrosis-unrelated bradycardia and PQ interval and QRS complex prolongation. These conduction defects were accompanied by overt mislocalization of the gap junction protein connexin43 (Cx43). Remarkably, Cx43 mislocalization was also evident in autopsied left ventricle tissue from HGPS patients, suggesting intercellular connectivity alterations at late stages of the disease. The similarities between HGPS patients and progeroid mice reported here strongly suggest that defective cardiac repolarization and cardiomyocyte connectivity are important abnormalities in the HGPS pathogenesis that increase the risk of arrhythmia and premature death. PMID:27799555

  11. Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria.

    Science.gov (United States)

    Chojnowski, Alexandre; Ong, Peh Fern; Wong, Esther S M; Lim, John S Y; Mutalif, Rafidah A; Navasankari, Raju; Dutta, Bamaprasad; Yang, Henry; Liow, Yi Y; Sze, Siu K; Boudier, Thomas; Wright, Graham D; Colman, Alan; Burke, Brian; Stewart, Colin L; Dreesen, Oliver

    2015-08-27

    Hutchinson-Gilford progeria (HGPS) is a premature ageing syndrome caused by a mutation in LMNA, resulting in a truncated form of lamin A called progerin. Progerin triggers loss of the heterochromatic marker H3K27me3, and premature senescence, which is prevented by telomerase. However, the mechanism how progerin causes disease remains unclear. Here, we describe an inducible cellular system to model HGPS and find that LAP2α (lamina-associated polypeptide-α) interacts with lamin A, while its interaction with progerin is significantly reduced. Super-resolution microscopy revealed that over 50% of telomeres localize to the lamina and that LAP2α association with telomeres is impaired in HGPS. This impaired interaction is central to HGPS since increasing LAP2α levels rescues progerin-induced proliferation defects and loss of H3K27me3, whereas lowering LAP2 levels exacerbates progerin-induced defects. These findings provide novel insights into the pathophysiology underlying HGPS, and how the nuclear lamina regulates proliferation and chromatin organization.

  12. Expression of the Hutchinson-Gilford Progeria Mutation during Osteoblast Development Results in Loss of Osteocytes, Irregular Mineralization, and Poor Biomechanical Properties*

    Science.gov (United States)

    Schmidt, Eva; Nilsson, Ola; Koskela, Antti; Tuukkanen, Juha; Ohlsson, Claes; Rozell, Björn; Eriksson, Maria

    2012-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a very rare genetic disorder that is characterized by multiple features of premature aging and largely affects tissues of mesenchymal origin. In this study, we describe the development of a tissue-specific mouse model that overexpresses the most common HGPS mutation (LMNA, c.1824C>T, p.G608G) in osteoblasts. Already at the age of 5 weeks, HGPS mutant mice show growth retardation, imbalanced gait and spontaneous fractures. Histopathological examination revealed an irregular bone structure, characterized by widespread loss of osteocytes, defects in mineralization, and a hypocellular red bone marrow. Computerized tomography analysis demonstrated impaired skeletal geometry and altered bone structure. The skeletal defects, which resemble the clinical features reported for bone disease in HGPS patients, was associated with an abnormal osteoblast differentiation. The osteoblast-specific expression of the HGPS mutation increased DNA damage and affected Wnt signaling. In the teeth, irregular dentin formation, as was previously demonstrated in human progeria cases, caused severe dental abnormalities affecting the incisors. The observed phenotype also shows similarities to reported bone abnormalities in aging mice and may therefore help to uncover general principles of the aging process. PMID:22893709

  13. Expression of the Hutchinson-Gilford progeria mutation during osteoblast development results in loss of osteocytes, irregular mineralization, and poor biomechanical properties.

    Science.gov (United States)

    Schmidt, Eva; Nilsson, Ola; Koskela, Antti; Tuukkanen, Juha; Ohlsson, Claes; Rozell, Björn; Eriksson, Maria

    2012-09-28

    Hutchinson-Gilford progeria syndrome (HGPS) is a very rare genetic disorder that is characterized by multiple features of premature aging and largely affects tissues of mesenchymal origin. In this study, we describe the development of a tissue-specific mouse model that overexpresses the most common HGPS mutation (LMNA, c.1824C>T, p.G608G) in osteoblasts. Already at the age of 5 weeks, HGPS mutant mice show growth retardation, imbalanced gait and spontaneous fractures. Histopathological examination revealed an irregular bone structure, characterized by widespread loss of osteocytes, defects in mineralization, and a hypocellular red bone marrow. Computerized tomography analysis demonstrated impaired skeletal geometry and altered bone structure. The skeletal defects, which resemble the clinical features reported for bone disease in HGPS patients, was associated with an abnormal osteoblast differentiation. The osteoblast-specific expression of the HGPS mutation increased DNA damage and affected Wnt signaling. In the teeth, irregular dentin formation, as was previously demonstrated in human progeria cases, caused severe dental abnormalities affecting the incisors. The observed phenotype also shows similarities to reported bone abnormalities in aging mice and may therefore help to uncover general principles of the aging process.

  14. Prognostic value of neonatal electroencephalography in premature newborns less than 33 weeks of gestational age.

    Science.gov (United States)

    Marret, S; Parain, D; Ménard, J F; Blanc, T; Devaux, A M; Ensel, P; Fessard, C; Samson-Dollfus, D

    1997-03-01

    In a prospective study of 417 premature neonates born before 33 weeks' gestational age, neonatal tracings were reviewed to evaluate the use of EEG in prognosis of neurological injuries. The population was divided into two groups: Group 1, infants who died before the age of 1, and Group 2, survivors in which two categories of motor development were considered. Category A, were abnormal, and Category B, were always normal. Positive rolandic sharp waves (PRSW), which reflect white matter injury, occurred equally in both groups, indicating a similar incidence of white matter damage in Groups 1 and 2. In Group 2, there was a significant correlation of PRSW with developmental motor sequelae (Category A). A frequency of PRSW above 2/min (suggesting more severe periventricular white matter injury) and seizures were significantly more prevalent in Group 1 than in Group 2 and in Category A of Group 2 than in Category B. Background abnormalities occurred equally in both subgroups of extremely premature infants ( 28 weeks' gestation) and extremely (< or = 28 weeks' gestation) premature newborns.

  15. Homeostatic imbalance between apoptosis and cell renewal in the liver of premature aging Xpd mice.

    Science.gov (United States)

    Park, Jung Yoon; Cho, Mi-Ook; Leonard, Shanique; Calder, Brent; Mian, I Saira; Kim, Woo Ho; Wijnhoven, Susan; van Steeg, Harry; Mitchell, James; van der Horst, Gijsbertus T J; Hoeijmakers, Jan; Cohen, Pinchas; Vijg, Jan; Suh, Yousin

    2008-06-11

    Unrepaired or misrepaired DNA damage has been implicated as a causal factor in cancer and aging. Xpd(TTD) mice, harboring defects in nucleotide excision repair and transcription due to a mutation in the Xpd gene (R722W), display severe symptoms of premature aging but have a reduced incidence of cancer. To gain further insight into the molecular basis of the mutant-specific manifestation of age-related phenotypes, we used comparative microarray analysis of young and old female livers to discover gene expression signatures distinguishing Xpd(TTD) mice from their age-matched wild type controls. We found a transcription signature of increased apoptosis in the Xpd(TTD) mice, which was confirmed by in situ immunohistochemical analysis and found to be accompanied by increased proliferation. However, apoptosis rate exceeded the rate of proliferation, resulting in homeostatic imbalance. Interestingly, a metabolic response signature was observed involving decreased energy metabolism and reduced IGF-1 signaling, a major modulator of life span. We conclude that while the increased apoptotic response to endogenous DNA damage contributes to the accelerated aging phenotypes and the reduced cancer incidence observed in the Xpd(TTD) mice, the signature of reduced energy metabolism is likely to reflect a compensatory adjustment to limit the increased genotoxic stress in these mutants. These results support a general model for premature aging in DNA repair deficient mice based on cellular responses to DNA damage that impair normal tissue homeostasis.

  16. Homeostatic imbalance between apoptosis and cell renewal in the liver of premature aging Xpd mice.

    Directory of Open Access Journals (Sweden)

    Jung Yoon Park

    Full Text Available Unrepaired or misrepaired DNA damage has been implicated as a causal factor in cancer and aging. Xpd(TTD mice, harboring defects in nucleotide excision repair and transcription due to a mutation in the Xpd gene (R722W, display severe symptoms of premature aging but have a reduced incidence of cancer. To gain further insight into the molecular basis of the mutant-specific manifestation of age-related phenotypes, we used comparative microarray analysis of young and old female livers to discover gene expression signatures distinguishing Xpd(TTD mice from their age-matched wild type controls. We found a transcription signature of increased apoptosis in the Xpd(TTD mice, which was confirmed by in situ immunohistochemical analysis and found to be accompanied by increased proliferation. However, apoptosis rate exceeded the rate of proliferation, resulting in homeostatic imbalance. Interestingly, a metabolic response signature was observed involving decreased energy metabolism and reduced IGF-1 signaling, a major modulator of life span. We conclude that while the increased apoptotic response to endogenous DNA damage contributes to the accelerated aging phenotypes and the reduced cancer incidence observed in the Xpd(TTD mice, the signature of reduced energy metabolism is likely to reflect a compensatory adjustment to limit the increased genotoxic stress in these mutants. These results support a general model for premature aging in DNA repair deficient mice based on cellular responses to DNA damage that impair normal tissue homeostasis.

  17. Factors influencing the motor development of prematurely born school-aged children in Brazil.

    Science.gov (United States)

    Moreira, Rafaela S; Magalhães, Lívia C; Dourado, Jordana S; Lemos, Stela M A; Alves, Claudia R L

    2014-09-01

    Despite technological advances in neonatology, premature children are still susceptible to disruptions in neurological development. The current study aimed to analyze the factors that influence motor development in prematurely born school-aged children in Brazil. This cross-sectional study involved 100 "apparently normal" children, aged 8-10 years, born at less than 35 weeks of gestation or with birth weightmotor development was assessed using the Movement Assessment Battery for Children (MABC-2). The children's neuropsychological and academic performance was assessed with the Token Test (TT) and Teste de Desempenho Escolar (TDE), respectively. Parents answered questions regarding the child's clinical history and behavior using the Strengths and Difficulties Questionnaire (SDQ) and family environment resources (RAF). Hierarchical multivariate analyses revealed that 39% of the children scored lower on the MABC-2, as compared to that expected for their age (manual dexterity: 49%; balance: 35%; throwing/catching a ball: 26%). Multivariate analysis indicated that the lower the birth weight, the maternal age at childbirth, and the RAF score, the greater was the chance of impairment on the MABC-2 scores. The probability of having an impairment MABC-2 scores was four times higher when the mother was not employed. We also found associations between MABC-2 scores and the tasks of tying shoes and opening/closing zippers and buttons. Factors related to children's home environments and birth weight are associated with deficient motor performance in prematurely born Brazilian school-aged children. Deficient motor skills were also associated with difficulty in performing functional tasks requiring greater manual dexterity.

  18. Clinical sonography in premature infant: Sonographic analysis of incidence and grade of germinal metrixhemorrhage according to gestational age,risk

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jae Hyoung; Kim, I. W.; Yeon, K. M. [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    1989-12-15

    The authors reviewed 63 premature infants who was born from January 1986 to August 1988 at College of Medicine Seoul National University, to analyze grade of germinal metrixhemorrhage to gestational age, risk.

  19. Telomerase Protects Werner Syndrome Lineage-Specific Stem Cells from Premature Aging

    Directory of Open Access Journals (Sweden)

    Hoi-Hung Cheung

    2014-04-01

    Full Text Available Werner syndrome (WS patients exhibit premature aging predominantly in mesenchyme-derived tissues, but not in neural lineages, a consequence of telomere dysfunction and accelerated senescence. The cause of this lineage-specific aging remains unknown. Here, we document that reprogramming of WS fibroblasts to pluripotency elongated telomere length and prevented telomere dysfunction. To obtain mechanistic insight into the origin of tissue-specific aging, we differentiated iPSCs to mesenchymal stem cells (MSCs and neural stem/progenitor cells (NPCs. We observed recurrence of premature senescence associated with accelerated telomere attrition and defective synthesis of the lagging strand telomeres in MSCs, but not in NPCs. We postulate this “aging” discrepancy is regulated by telomerase. Expression of hTERT or p53 knockdown ameliorated the accelerated aging phenotypein MSC, whereas inhibition of telomerase sensitized NPCs to DNA damage. Our findings unveil a role for telomerase in the protection of accelerated aging in a specific lineage of stem cells.

  20. [Three cases of Hutchinson-Gilford progeria syndrome].

    Science.gov (United States)

    Doubaj, Y; Lamzouri, A; Elalaoui, S-C; Laarabi, F-Z; Sefiani, A

    2011-02-01

    Progeria, or Hutchinson-Gilford syndrome, is a rare genetic disease, characterized by several clinical features that develop in childhood, in particular, an accelerated aging aspect. Its incidence is 1-4 per 8 million newborns. Children with progeria syndrome usually appear normal at birth and in early infancy. Profound failure to thrive occurs during the 1st year. Characteristic facies, partial alopecia progressing to total alopecia, loss of subcutaneous fat, stiffness of joints, bone changes, and abnormal tightness of the skin over the abdomen and upper thighs usually become apparent during the 2nd to 3rd years. Motor and mental development is normal. Patients develop severe atherosclerosis. Death occurs as a result of complications of cardiac or cerebrovascular disease (heart attack or stroke) generally between ages 6 and 20 years. The diagnosis of Hutchinson-Gilford progeria syndrome (HGPS) is based on recognition of common clinical features and the detection of the recurrent p.Gly608Gly mutation in exon 11 of the LMNA gene, which is present in almost all individuals with HGPS. We present here 3 patients aged 5, 11, and 12 years referred to genetic consultation for dysmorphic facies and failure to thrive. After careful clinical examination and paraclinical assessment, the diagnosis of progeria syndrome was raised. We performed molecular analysis for the 3 patients by searching for the recurrent mutation c.1824C>T (p.Gly608Gly) of the LMNA gene, which was found only in 1 patient. We discuss the geneticist's role in the diagnosis of rare dysmorphic syndromes and their genetic counseling. We also analyze the clinical spectrum of HGPS by comparing the 3 patients.

  1. A case of progeria syndrome treated as VIP patient

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    Seema Mahant, Mahant PD, C.M. Reddy

    2014-11-01

    Full Text Available Progeria is rare autosomal recessive genetic disease with an incidence of about one in eight million. He was 16 years old boy lying on the couch. He was short stature thin with minimal subcutaneous tissue, skin was thin and fragile with loss of hair over scalp, eyebrows and eyelashes, and his face was dismorphic with prominent eyes, beaked nose, small jaw and large cranium with visible veins over it. His voice was thin and high pitched. Overall, this gives them an extremely aged nearly 70 -80 years old man look. The patient was a known case of progeria syndrome and he was treated as a VIP patient by all faculty members and staff, though he belongs low socioeconomic status, no political issue with them. But still he was a VIP.

  2. Characterization of monoaminergic systems in brain regions of prematurely ageing mice.

    Science.gov (United States)

    De la Fuente, Monica; Hernanz, Angel; Medina, Sonia; Guayerbas, Noelia; Fernández, Beatriz; Viveros, Maria Paz

    2003-07-01

    We have previously shown that differences in life span among members of Swiss mouse populations appear to be related to their exploration of a T-maze, with a slow exploration ("slow mice") being linked to increased levels of emotionality/anxiety, an impaired immune function and a shorter life span. Thus, we proposed the slow mice as prematurely ageing mice (PAM). We have now compared the monoaminergic systems of the PAM and of the non-prematurely ageing mice (NPAM), in discrete brain regions. PAM had decreased noradrenaline (NA) levels in all the brain regions analysed, whereas the 3-methoxy-4-hydroxyphenyl glycol (MHPG)/NA ratios were not significantly modified. PAM also showed decreased serotonine (5-HT) levels in hypothalamus, striatum and midbrain, as well as increased 5-hydroxyindol-3-acetic acid (5-HIAA)/5-HT ratios in hypothalamus and hippocampus. The dopamine (DA) content was lower in PAM in most regions, whereas the 3,4-dihydroxyphenylacetic acid (DOPAC)/DA and homovanillic acid (HVA)/DA ratios were either increased or unchanged depending on the region analysed. In most cases, the differences between PAM and NPAM involved both sexes. One exception was the hypothalamus where the differences only affected the male mice. The neurochemical alterations found in PAM resemble some changes reported for aged animals and are related with their behavioural features.

  3. Accelerated aging syndromes, are they relevant to normal human aging?

    Science.gov (United States)

    Dreesen, Oliver; Stewart, Colin L

    2011-09-01

    Hutchinson-Gilford Progeria (HGPS) and Werner syndromes are diseases that clinically resemble some aspects of accelerated aging. HGPS is caused by mutations in theLMNA gene resulting in post-translational processing defects that trigger Progeria in children. Werner syndrome, arising from mutations in the WRN helicase gene, causes premature aging in young adults. What are the molecular mechanism(s) underlying these disorders and what aspects of the diseases resemble physiological human aging? Much of what we know stems from the study of patient derived fibroblasts with both mutations resulting in increased DNA damage, primarily at telomeres. However, in vivo patients with Werner's develop arteriosclerosis, among other pathologies. In HGPS patients, including iPS derived cells from HGPS patients, as well as some mouse models for Progeria, vascular smooth muscle (VSM) appears to be among the most severely affected tissues. Defective Lamin processing, associated with DNA damage, is present in VSM from old individuals, indicating processing defects may be a factor in normal aging. Whether persistent DNA damage, particularly at telomeres, is the root cause for these pathologies remains to be established, since not all progeroid Lmna mutations result in DNA damage and genome instability.

  4. Determinants of Indices of Cerebral Volume in Former Very Premature Infants at Term Equivalent Age

    Science.gov (United States)

    Wirth, Maelle

    2017-01-01

    Conventional magnetic resonance imaging (MRI) at term equivalent age (TEA) is suggested to be a reliable tool to predict the outcome of very premature infants. The objective of this study was to determine simple reproducible MRI indices, in premature infants and to analyze their neonatal determinants at TEA. A cohort of infants born before 32 weeks gestational age (GA) underwent a MRI at TEA in our center. Two axial images (T2 weighted), were chosen to realize nine measures. We defined 4 linear indices (MAfhlv: thickness of lateral ventricle; CSI: cortex-skull index; VCI: ventricular-cortex index; BOI: bi occipital index) and 1 surface index (VS.A: volume slice area). Perinatal data were recorded. Sixty-nine infants had a GA (median (interquartile range)) of 30.0 weeks GA (27.0; 30.0) and a birth weight of 1240 grams (986; 1477). MRI was done at 41.0 (40.0; 42.0) weeks post menstrual age (PMA). The inter-investigator reproducibility was good. Twenty one MRI (30.5%) were quoted abnormal. We observed an association with retinopathy of prematurity (OR [95CI] = 4.205 [1.231–14.368]; p = 0.017), surgery for patent ductus arteriosus (OR = 4.688 [1.01–21.89]; p = 0.036), early onset infection (OR = 4.688 [1.004–21.889]; p = 0.036) and neonatal treatment by cefotaxime (OR = 3.222 [1.093–9.497]; p = 0.03). There was a difference for VCI between normal and abnormal MRI (0.412 (0.388; 0.429) vs. 0.432 (0.418; 0.449); p = 0,019); BOI was higher when fossa posterior lesions were observed; VS.A seems to be the best surrogate for cerebral volume, 80% of VS.As’ variance being explained by a multiple linear regression model including 7 variables (head circumference at birth and at TEA, PMA, dopamine, ibuprofen treatment, blood and platelets transfusions). These indices, easily and rapidly achievable, seem to be useful but need to be validated in a large population to allow generalization for diagnosis and follow-up of former premature infants. PMID:28125676

  5. The relationship of birth weight, gestational age, and postmenstrual age with ocular biometry parameters in premature infants

    Directory of Open Access Journals (Sweden)

    Ozdemir Ozdemir

    2015-06-01

    Full Text Available ABSTRACT Purpose: To analyze ocular biometry parameters and evaluate their relationship with gestational age, birth weight, and postmenstrual age in prematurely born infants. Methods: The right eyes of 361 premature infants born before the 36th gestational week were evaluated. Birth weight, gestational week, and gender were recorded. An A-scan Biometer was used for obtaining axial measurements, including anterior chamber depth, lens thickness, vitreous length, and total axial length. Results: Gestational age and birth weight values ranged from 23 to 36 weeks and from 560 to 2,670 g, respectively. The mean gestational age and birth weight were 30.8 ± 2.8 weeks and 1,497.9 ± 483.6 g, respectively. During the first examination (4-5 weeks of postnatal age, birth weight and gestational age of the infants correlated significantly and positively with lens thickness, vitreous length, and axial length (r>0.5, p<0.001, but not with anterior chamber depth (r<0.5. Increased vitreous and axial lengths correlated significantly with increasing postmenstrual age of the infants (r=0.669, p<0.001; r=0.845, p<0.001, respectively. Conclusions: Lens thickness, vitreous length, and axial length, but not anterior chamber depth, were significantly correlated with birth weight and gestational age. All four parameters increased with increasing postmenstrual age, with higher correlations for vitreous and axial lengths than for anterior chamber depth and lens thickness. It was concluded that axial elongation resulted primarily from increasing posterior chamber length.

  6. Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice.

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    Marieke van de Ven

    2006-12-01

    Full Text Available How congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular senescence is a likely contributing mechanism. Contrary to expectations, neither accelerated senescence nor acute oxidative stress hypersensitivity was detected in primary fibroblast or erythroblast cultures from multiple progeroid mouse models for defects in the nucleotide excision DNA repair pathway, which share premature aging features including postnatal growth retardation, cerebellar ataxia, and death before weaning. Instead, we report a prominent phenotypic overlap with long-lived dwarfism and calorie restriction during postnatal development (2 wk of age, including reduced size, reduced body temperature, hypoglycemia, and perturbation of the growth hormone/insulin-like growth factor 1 neuroendocrine axis. These symptoms were also present at 2 wk of age in a novel progeroid nucleotide excision repair-deficient mouse model (XPD(G602D/R722W/XPA(-/- that survived weaning with high penetrance. However, despite persistent cachectic dwarfism, blood glucose and serum insulin-like growth factor 1 levels returned to normal by 10 wk, with hypoglycemia reappearing near premature death at 5 mo of age. These data strongly suggest changes in energy metabolism as part of an adaptive response during the stressful period of postnatal growth. Interestingly, a similar perturbation of the postnatal growth axis was not detected in another progeroid mouse model, the double-strand DNA break repair deficient Ku80(-/- mouse. Specific (but not all types of genome instability may thus engage a conserved response to stress that evolved to cope with environmental pressures such as food shortage.

  7. Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice.

    Science.gov (United States)

    van de Ven, Marieke; Andressoo, Jaan-Olle; Holcomb, Valerie B; von Lindern, Marieke; Jong, Willeke M C; De Zeeuw, Chris I; Suh, Yousin; Hasty, Paul; Hoeijmakers, Jan H J; van der Horst, Gijsbertus T J; Mitchell, James R

    2006-12-15

    How congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular senescence is a likely contributing mechanism. Contrary to expectations, neither accelerated senescence nor acute oxidative stress hypersensitivity was detected in primary fibroblast or erythroblast cultures from multiple progeroid mouse models for defects in the nucleotide excision DNA repair pathway, which share premature aging features including postnatal growth retardation, cerebellar ataxia, and death before weaning. Instead, we report a prominent phenotypic overlap with long-lived dwarfism and calorie restriction during postnatal development (2 wk of age), including reduced size, reduced body temperature, hypoglycemia, and perturbation of the growth hormone/insulin-like growth factor 1 neuroendocrine axis. These symptoms were also present at 2 wk of age in a novel progeroid nucleotide excision repair-deficient mouse model (XPD(G602D/R722W)/XPA(-/-)) that survived weaning with high penetrance. However, despite persistent cachectic dwarfism, blood glucose and serum insulin-like growth factor 1 levels returned to normal by 10 wk, with hypoglycemia reappearing near premature death at 5 mo of age. These data strongly suggest changes in energy metabolism as part of an adaptive response during the stressful period of postnatal growth. Interestingly, a similar perturbation of the postnatal growth axis was not detected in another progeroid mouse model, the double-strand DNA break repair deficient Ku80(-/-) mouse. Specific (but not all) types of genome instability may thus engage a conserved response to stress that evolved to cope with environmental pressures such as food shortage.

  8. Adaptive Stress Response in Segmental Progeria Resembles Long-Lived Dwarfism and Calorie Restriction in Mice

    Science.gov (United States)

    Holcomb, Valerie B; von Lindern, Marieke; Jong, Willeke M. C; Zeeuw, Chris I. De; Suh, Yousin; Hasty, Paul; Hoeijmakers, Jan H. J; van der Horst, Gijsbertus T. J; Mitchell, James R

    2006-01-01

    How congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular senescence is a likely contributing mechanism. Contrary to expectations, neither accelerated senescence nor acute oxidative stress hypersensitivity was detected in primary fibroblast or erythroblast cultures from multiple progeroid mouse models for defects in the nucleotide excision DNA repair pathway, which share premature aging features including postnatal growth retardation, cerebellar ataxia, and death before weaning. Instead, we report a prominent phenotypic overlap with long-lived dwarfism and calorie restriction during postnatal development (2 wk of age), including reduced size, reduced body temperature, hypoglycemia, and perturbation of the growth hormone/insulin-like growth factor 1 neuroendocrine axis. These symptoms were also present at 2 wk of age in a novel progeroid nucleotide excision repair-deficient mouse model (XPDG602D/R722W/XPA−/−) that survived weaning with high penetrance. However, despite persistent cachectic dwarfism, blood glucose and serum insulin-like growth factor 1 levels returned to normal by 10 wk, with hypoglycemia reappearing near premature death at 5 mo of age. These data strongly suggest changes in energy metabolism as part of an adaptive response during the stressful period of postnatal growth. Interestingly, a similar perturbation of the postnatal growth axis was not detected in another progeroid mouse model, the double-strand DNA break repair deficient Ku80 −/− mouse. Specific (but not all) types of genome instability may thus engage a conserved response to stress that evolved to cope with environmental pressures such as food shortage. PMID:17173483

  9. A-type lamins and Hutchinson-Gilford progeria syndrome: pathogenesis and therapy.

    Science.gov (United States)

    Gonzalez, Jose M; Pla, Davinia; Perez-Sala, Dolores; Andres, Vicente

    2011-06-01

    Lamin A and lamin C (A-type lamins, both encoded by the LMNA gene) are major components of the mammalian nuclear lamina, a complex proteinaceous structure that acts as a scaffold for protein complexes that regulate nuclear structure and function. Abnormal accumulation of farnesylated-progerin, a mutant form of prelamin A, plays a key role in the pathogenesis of the Hutchinson-Gilford progeria syndrome (HGPS), a devastating disorder that causes the death of affected children at an average age of 13.5 years, predominantly from premature atherosclerosis and myocardial infarction or stroke. Remarkably, progerin is also present in normal cells and appears to progressively accumulate during aging of non-HGPS cells. Therefore, understanding how this mutant form of lamin A provokes HGPS may shed significant insight into physiological aging. In this review, we discuss recent advances into the pathogenic mechanisms underlying HGPS, the main murine models of the disease, and the therapeutic strategies developed in cellular and animal models with the aim of reducing the accumulation of farnesylated-progerin, as well as their use in clinical trials of HGPS.

  10. Defective lamin A-Rb signaling in Hutchinson-Gilford Progeria Syndrome and reversal by farnesyltransferase inhibition.

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    Jackleen Marji

    Full Text Available Hutchinson-Gilford Progeria Syndrome (HGPS is a rare premature aging disorder caused by a de novo heterozygous point mutation G608G (GGC>GGT within exon 11 of LMNA gene encoding A-type nuclear lamins. This mutation elicits an internal deletion of 50 amino acids in the carboxyl-terminus of prelamin A. The truncated protein, progerin, retains a farnesylated cysteine at its carboxyl terminus, a modification involved in HGPS pathogenesis. Inhibition of protein farnesylation has been shown to improve abnormal nuclear morphology and phenotype in cellular and animal models of HGPS. We analyzed global gene expression changes in fibroblasts from human subjects with HGPS and found that a lamin A-Rb signaling network is a major defective regulatory axis. Treatment of fibroblasts with a protein farnesyltransferase inhibitor reversed the gene expression defects. Our study identifies Rb as a key factor in HGPS pathogenesis and suggests that its modulation could ameliorate premature aging and possibly complications of physiological aging.

  11. Premature Birth and Large for Gestational Age Are Associated with Risk of Barrett's Esophagus in Adults.

    Science.gov (United States)

    Shiota, Seiji; El-Serag, Hashem B; Thrift, Aaron P

    2016-04-01

    Birth characteristics, including weight and gestational age, may be associated with risk of Barrett's esophagus (BE), the only known precursor for esophageal adenocarcinoma; however, data are limited. To examine associations between various birth characteristics and BE, and whether these associations are mediated by known risk factors for BE. Data were obtained from a cross-sectional study among eligible Veterans Affairs patients scheduled for an upper endoscopy, and a sample identified from primary care clinics. Participants underwent an esophagogastroduodenoscopy and completed a survey that captured information on sociodemographic and clinical factors, as well as birth information. We compared 263 patients with histologically confirmed BE to 1416 controls without BE on endoscopy. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated using multivariate logistic regression. Premature birth was independently associated with risk of BE after adjusted by age, sex, race, and other birth characteristics (OR 3.28, 95 % CI 1.22-8.79). On the other hand, large for gestational age was inversely associated with risk of BE (OR 0.46, 95 % CI 0.21-0.98). These effects were stronger for patients with long-segment BE than with short-segment BE. The associations were not mediated by gastroesophageal reflux disease symptoms, use of proton pump inhibitors, Helicobacter Pylori infection, waist-hip-ratio, height or the presence of hiatus hernia. Premature birth and large for gestational age may be associated with risk of BE in adults. These associations do not appear to be mediated through known risk factors for BE; however, additional studies are required to confirm our findings.

  12. Clinical and radiographic features of Hutchinson-Gilford progeria syndrome: A case report.

    Science.gov (United States)

    Alves, Daniel Berretta; Silva, Juliana Melo; Menezes, Tatiany Oliveira; Cavaleiro, Rosely Santos; Tuji, Fabrício Mesquita; Lopes, Marcio Ajudarte; Zaia, Alexandre Augusto; Coletta, Ricardo Della

    2014-03-16

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare dysmorphic syndrome characterized by several features of premature aging with clinical involvement of the skin, bones, and cardiovascular system. HGPS has an estimated incidence of one in four million to one in eight million births. The main clinical features of HGPS include short stature, craniofacial dimorphism, alopecia, bone fragility, and cardiovascular disorders. The most frequent cause of death is myocardial infarction at a mean age of 13 years old. Dental manifestations include delayed development and eruption of teeth, discoloration, crowding and rotation of teeth, and displaced teeth. Cone beam computed tomography images revealed the absence of the sphenoid, frontal, and maxillary sinus, flattening of the condyles and glenoid fossa, and bilateral hypoplasia of the mandibular condyles. The disease is caused by mutations in lamin A/C (LMNA). Here, we present a case report of an 11-year-old boy with classical features of HGPS, which was caused by a de novo germ-line mutation (C1824T, G608G) in exon 11 of the LMNA gene. Some uncommon HGPS-associated features in our patient, such as alterations in the facial sinuses and hypoplasia of the condyles, contributed to the expansion of the phenotypic spectrum of this syndrome from a dentomaxillofacial perspective.

  13. Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells.

    Science.gov (United States)

    Cao, Kan; Graziotto, John J; Blair, Cecilia D; Mazzulli, Joseph R; Erdos, Michael R; Krainc, Dimitri; Collins, Francis S

    2011-06-29

    Hutchinson-Gilford progeria syndrome (HGPS) is a lethal genetic disorder characterized by premature aging. HGPS is most commonly caused by a de novo single-nucleotide substitution in the lamin A/C gene (LMNA) that partially activates a cryptic splice donor site in exon 11, producing an abnormal lamin A protein termed progerin. Accumulation of progerin in dividing cells adversely affects the integrity of the nuclear scaffold and leads to nuclear blebbing in cultured cells. Progerin is also produced in normal cells, increasing in abundance as senescence approaches. Here, we report the effect of rapamycin, a macrolide antibiotic that has been implicated in slowing cellular and organismal aging, on the cellular phenotypes of HGPS fibroblasts. Treatment with rapamycin abolished nuclear blebbing, delayed the onset of cellular senescence, and enhanced the degradation of progerin in HGPS cells. Rapamycin also decreased the formation of insoluble progerin aggregates and induced clearance through autophagic mechanisms in normal fibroblasts. Our findings suggest an additional mechanism for the beneficial effects of rapamycin on longevity and encourage the hypothesis that rapamycin treatment could provide clinical benefit for children with HGPS.

  14. Atypical perceptual narrowing in prematurely born infants is associated with compromised language acquisition at 2 years of age.

    Science.gov (United States)

    Jansson-Verkasalo, Eira; Ruusuvirta, Timo; Huotilainen, Minna; Alku, Paavo; Kushnerenko, Elena; Suominen, Kalervo; Rytky, Seppo; Luotonen, Mirja; Kaukola, Tuula; Tolonen, Uolevi; Hallman, Mikko

    2010-07-30

    Early auditory experiences are a prerequisite for speech and language acquisition. In healthy children, phoneme discrimination abilities improve for native and degrade for unfamiliar, socially irrelevant phoneme contrasts between 6 and 12 months of age as the brain tunes itself to, and specializes in the native spoken language. This process is known as perceptual narrowing, and has been found to predict normal native language acquisition. Prematurely born infants are known to be at an elevated risk for later language problems, but it remains unclear whether these problems relate to early perceptual narrowing. To address this question, we investigated early neurophysiological phoneme discrimination abilities and later language skills in prematurely born infants and in healthy, full-term infants. Our follow-up study shows for the first time that perceptual narrowing for non-native phoneme contrasts found in the healthy controls at 12 months was not observed in very prematurely born infants. An electric mismatch response of the brain indicated that whereas full-term infants gradually lost their ability to discriminate non-native phonemes from 6 to 12 months of age, prematurely born infants kept on this ability. Language performance tested at the age of 2 years showed a significant delay in the prematurely born group. Moreover, those infants who did not become specialized in native phonemes at the age of one year, performed worse in the communicative language test (MacArthur Communicative Development Inventories) at the age of two years. Thus, decline in sensitivity to non-native phonemes served as a predictor for further language development. Our data suggest that detrimental effects of prematurity on language skills are based on the low degree of specialization to native language early in development. Moreover, delayed or atypical perceptual narrowing was associated with slower language acquisition. The results hence suggest that language problems related to

  15. Atypical perceptual narrowing in prematurely born infants is associated with compromised language acquisition at 2 years of age

    Directory of Open Access Journals (Sweden)

    Suominen Kalervo

    2010-07-01

    Full Text Available Abstract Background Early auditory experiences are a prerequisite for speech and language acquisition. In healthy children, phoneme discrimination abilities improve for native and degrade for unfamiliar, socially irrelevant phoneme contrasts between 6 and 12 months of age as the brain tunes itself to, and specializes in the native spoken language. This process is known as perceptual narrowing, and has been found to predict normal native language acquisition. Prematurely born infants are known to be at an elevated risk for later language problems, but it remains unclear whether these problems relate to early perceptual narrowing. To address this question, we investigated early neurophysiological phoneme discrimination abilities and later language skills in prematurely born infants and in healthy, full-term infants. Results Our follow-up study shows for the first time that perceptual narrowing for non-native phoneme contrasts found in the healthy controls at 12 months was not observed in very prematurely born infants. An electric mismatch response of the brain indicated that whereas full-term infants gradually lost their ability to discriminate non-native phonemes from 6 to 12 months of age, prematurely born infants kept on this ability. Language performance tested at the age of 2 years showed a significant delay in the prematurely born group. Moreover, those infants who did not become specialized in native phonemes at the age of one year, performed worse in the communicative language test (MacArthur Communicative Development Inventories at the age of two years. Thus, decline in sensitivity to non-native phonemes served as a predictor for further language development. Conclusion Our data suggest that detrimental effects of prematurity on language skills are based on the low degree of specialization to native language early in development. Moreover, delayed or atypical perceptual narrowing was associated with slower language acquisition. The

  16. Prelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion

    Science.gov (United States)

    de la Rosa, Jorge; Freije, José M. P.; Cabanillas, Rubén; Osorio, Fernando G.; Fraga, Mario F.; Fernández-García, M. Soledad; Rad, Roland; Fanjul, Víctor; Ugalde, Alejandro P.; Liang, Qi; Prosser, Haydn M.; Bradley, Allan; Cadiñanos, Juan; López-Otín, Carlos

    2013-01-01

    Defining the relationship between ageing and cancer is a crucial but challenging task. Mice deficient in Zmpste24, a metalloproteinase mutated in human progeria and involved in nuclear prelamin A maturation, recapitulate multiple features of ageing. However, their short lifespan and serious cell-intrinsic and cell-extrinsic alterations restrict the application and interpretation of carcinogenesis protocols. Here we present Zmpste24 mosaic mice that lack these limitations. Zmpste24 mosaic mice develop normally and keep similar proportions of Zmpste24-deficient (prelamin A accumulating) and Zmpste24-proficient (mature lamin A containing) cells throughout life, revealing that cell-extrinsic mechanisms are preeminent for progeria development. Moreover, prelamin A accumulation does not impair tumour initiation and growth, but it decreases the incidence of infiltrating oral carcinomas. Accordingly, silencing of ZMPSTE24 reduces human cancer cell invasiveness. Our results support the potential of cell-based and systemic therapies for progeria and highlight ZMPSTE24 as a new anticancer target. PMID:23917225

  17. Prelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion.

    Science.gov (United States)

    de la Rosa, Jorge; Freije, José M P; Cabanillas, Rubén; Osorio, Fernando G; Fraga, Mario F; Fernández-García, M Soledad; Rad, Roland; Fanjul, Víctor; Ugalde, Alejandro P; Liang, Qi; Prosser, Haydn M; Bradley, Allan; Cadiñanos, Juan; López-Otín, Carlos

    2013-01-01

    Defining the relationship between ageing and cancer is a crucial but challenging task. Mice deficient in Zmpste24, a metalloproteinase mutated in human progeria and involved in nuclear prelamin A maturation, recapitulate multiple features of ageing. However, their short lifespan and serious cell-intrinsic and cell-extrinsic alterations restrict the application and interpretation of carcinogenesis protocols. Here we present Zmpste24 mosaic mice that lack these limitations. Zmpste24 mosaic mice develop normally and keep similar proportions of Zmpste24-deficient (prelamin A-accumulating) and Zmpste24-proficient (mature lamin A-containing) cells throughout life, revealing that cell-extrinsic mechanisms are preeminent for progeria development. Moreover, prelamin A accumulation does not impair tumour initiation and growth, but it decreases the incidence of infiltrating oral carcinomas. Accordingly, silencing of ZMPSTE24 reduces human cancer cell invasiveness. Our results support the potential of cell-based and systemic therapies for progeria and highlight ZMPSTE24 as a new anticancer target.

  18. The relationship between premature ageing and immune responses in the oral cavity of Down syndrome

    Directory of Open Access Journals (Sweden)

    Yoko Tanaka

    2010-02-01

    Full Text Available Down syndrome (DS is the most common chromosomal disorder resulting in various abnormalities such as mental retardation, immunodeficiency and physical abnormities. Especially, abnormality of the immune function is important pathological features in this syndrome, and leads to increased susceptibility to viral or bacterial infections. Interestingly, several studies have showed that they have high susceptibility of severe periodontal disease, even though they have lower or equal prevalence of dental caries. Many studies have attempted to clarify this phenomenon but it remains unsolved. It is also well known that DS is a premature ageing syndrome. DS has been considered as a model of precocious, abnormal ageing of immune function in human. Age-related declines in immune function cause more susceptibility to infections in the elderly. In addition, it is well known that ageing is related with telomere shortening. Furthermore, DS has an accelerated telomere shortening. However, there are only a few reports that focus on the relations among ageing, telomere length and high susceptibility of oral infectious disease in individuals with DS. Therefore, we summarize our current knowledge on the relations between the oral disease and immunodeficiency in individuals with DS taking account of telomere shortening and ageing.

  19. Progerin impairs chromosome maintenance by depleting CENP-F from metaphase kinetochores in Hutchinson-Gilford progeria fibroblasts.

    Science.gov (United States)

    Eisch, Veronika; Lu, Xiang; Gabriel, Diana; Djabali, Karima

    2016-04-26

    Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare premature aging disorder that leads to death at an average age of 14.7 years due to myocardial infarction or stroke. The most common mutation in HGPS is at position G608G (GGC>GGT) within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, producing a truncated farnesylated protein called progerin. Lamins play important roles in the organization and structure of the nucleus. The nuclear build-up of progerin causes severe morphological and functional changes in interphase HGPS cells. In this study, we investigated whether progerin elicits spatiotemporal deviations in mitotic processes in HGPS fibroblasts. We analyzed the nuclear distribution of endogenous progerin during mitosis in relation to components of the nuclear lamina, nuclear envelope (NE) and nuclear pores. We found that progerin caused defects in chromosome segregation as early as metaphase, delayed NE reformation and trapped lamina components and inner NE proteins in the endoplasmic reticulum at the end of mitosis. Progerin displaced the centromere protein F (CENP-F) from metaphase chromosome kinetochores, which caused increased chromatin lagging, binucleated cells and genomic instability. This accumulation of progerin-dependent defects with each round of mitosis predisposes cells to premature senescence.

  20. Lifespan extension by dietary intervention in a mouse model of Cockayne syndrome uncouples early postnatal development from segmental progeria.

    Science.gov (United States)

    Brace, Lear E; Vose, Sarah C; Vargas, Dorathy F; Zhao, Shuangyun; Wang, Xiu-Ping; Mitchell, James R

    2013-12-01

    Cockayne syndrome (CS) is a rare autosomal recessive segmental progeria characterized by growth failure, lipodystrophy, neurological abnormalities, and photosensitivity, but without skin cancer predisposition. Cockayne syndrome life expectancy ranges from 5 to 16 years for the two most severe forms (types II and I, respectively). Mouse models of CS have thus far been of limited value due to either very mild phenotypes, or premature death during postnatal development prior to weaning. The cause of death in severe CS models is unknown, but has been attributed to extremely rapid aging. Here, we found that providing mutant pups with soft food from as late as postnatal day 14 allowed survival past weaning with high penetrance independent of dietary macronutrient balance in a novel CS model (Csa(-/-) | Xpa(-/-)). Survival past weaning revealed a number of CS-like symptoms including small size, progressive loss of adiposity, and neurological symptoms, with a maximum lifespan of 19 weeks. Our results caution against interpretation of death before weaning as premature aging, and at the same time provide a valuable new tool for understanding mechanisms of progressive CS-related progeroid symptoms including lipodystrophy and neurodysfunction.

  1. Homeostatic imbalance between apoptosis and cell renewal in the liver of premature aging XpdTTD mice

    NARCIS (Netherlands)

    J.Y. Park; M.O. Cho; S. Leonard (Shanique); B. Calder (Brent); I.S. Mian (Saira); W.H. Kim (Woo); S.W.P. Wijnhoven (Susan); H. van Steeg (Harry); J.R. Mitchell (James); G.T.J. van der Horst (Gijsbertus); J.H.J. Hoeijmakers (Jan); P. Cohen (Pinchas); J. Vijg (Jan); Y. Suh (Yousin)

    2008-01-01

    textabstractUnrepaired or misrepaired DNA damage has been implicated as a causal factor in cancer and aging. XpdTTDmice, harboring defects in nucleotide excision repair and transcription due to a mutation in the Xpd gene (R722W), display severe symptoms of premature aging but have a rduced incidence

  2. Homeostatic imbalance between apoptosis and cell renewal in the liver of premature aging XpdTTD mice

    NARCIS (Netherlands)

    J.Y. Park; M.O. Cho; S. Leonard (Shanique); B. Calder (Brent); I.S. Mian (Saira); W.H. Kim (Woo); S.W.P. Wijnhoven (Susan); H. van Steeg (Harry); J.R. Mitchell (James); G.T.J. van der Horst (Gijsbertus); J.H.J. Hoeijmakers (Jan); P. Cohen (Pinchas); J. Vijg (Jan); Y. Suh (Yousin)

    2008-01-01

    textabstractUnrepaired or misrepaired DNA damage has been implicated as a causal factor in cancer and aging. XpdTTDmice, harboring defects in nucleotide excision repair and transcription due to a mutation in the Xpd gene (R722W), display severe symptoms of premature aging but have a rduced incidence

  3. Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging.

    Science.gov (United States)

    Kang, S; Louboutin, J-P; Datta, P; Landel, C P; Martinez, D; Zervos, A S; Strayer, D S; Fernandes-Alnemri, T; Alnemri, E S

    2013-02-01

    mnd2 mice die prematurely as a result of neurodegeneration 30-40 days after birth due to loss of the enzymatic activity of the mitochondrial quality control protease HtrA2/Omi. Here, we show that transgenic expression of human HtrA2/Omi in the central nervous system of mnd2 mice rescues them from neurodegeneration and prevents their premature death. Interestingly, adult transgenic mnd2 mice develop accelerated aging phenotypes, such as premature weight loss, hair loss, reduced fertility, curvature of the spine, heart enlargement, increased autophagy, and death by 12-17 months of age. These mice also have elevated levels of clonally expanded mitochondrial DNA (mtDNA) deletions in their tissues. Our results provide direct genetic evidence linking mitochondrial protein quality control to mtDNA deletions and aging in mammals.

  4. Transgene silencing of the Hutchinson-Gilford progeria syndrome mutation results in a reversible bone phenotype, whereas resveratrol treatment does not show overall beneficial effects

    DEFF Research Database (Denmark)

    Strandgren, Charlotte; Nasser, Hasina Abdul; McKenna, Tomás

    2015-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder that is most commonly caused by a de novo point mutation in exon 11 of the LMNA gene, c.1824C>T, which results in an increased production of a truncated form of lamin A known as progerin. In this study, we used a mouse...... model to study the possibility of recovering from HGPS bone disease upon silencing of the HGPS mutation, and the potential benefits from treatment with resveratrol. We show that complete silencing of the transgenic expression of progerin normalized bone morphology and mineralization already after 7...... weeks. The improvements included lower frequencies of rib fractures and callus formation, an increased number of osteocytes in remodeled bone, and normalized dentinogenesis. The beneficial effects from resveratrol treatment were less significant and to a large extent similar to mice treated with sucrose...

  5. Ataxia-telangiectasia (A-T): An emerging dimension of premature ageing.

    Science.gov (United States)

    Shiloh, Yosef; Lederman, Howard M

    2017-01-01

    A-T is a prototype genome instability syndrome and a multifaceted disease. A-T leads to neurodegeneration - primarily cerebellar atrophy, immunodeficiency, oculocutaneous telangiectasia (dilated blood vessels), vestigial thymus and gonads, endocrine abnormalities, cancer predisposition and varying sensitivity to DNA damaging agents, particularly those that induce DNA double-strand breaks. With the recent increase in life expectancy of A-T patients, the premature ageing component of this disease is gaining greater awareness. The complex A-T phenotype reflects the ever growing number of functions assigned to the protein encoded by the responsible gene - the homeostatic protein kinase, ATM. The quest to thoroughly understand the complex A-T phenotype may reveal yet elusive ATM functions. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Abberent expression analysis of LMNA gene in hutchinson-gilford progeria syndrome

    Science.gov (United States)

    Navid, Afifa; Khan, Mohammad Haroon; Rashid, Hamid

    2012-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is caused by de novo dominant point mutations of the genes encoding nuclear lamina proteins, leading towards premature aging. A protein sequence is subjected to mutations in nature which can affect the function and folding pattern of the protein by different ways. Mutations involved in HGPS were identified and were substituted in the seed sequence retrieved from the UniProt database to get the mutated versions. Tertiary structure of the Lamin A protein was previously unpredicted so was performed for all the mutated as well as for the seed protein to analyze the effects of mutations on the protein structure, folding and interactions. All the predicted models were refined and validated through multiple servers for multiple parameters. The validated 3D structure of seed protein was then successfully submitted to the Protein Model Database and was assigned with the PMDB ID PM0077829. All the predicted structures were superimposed with a root mean square deviation value of 7.0 Å and a high Dali Z-score of 1.9. It was observed that mutations affected physiochemical properties as well as instability index and thus is affecting the domains in specific and the whole structure in general. It was further analyzed that HGPS is the result of affected Lamin a protein interactions with other integral and binding proteins in the inner nuclear membrane affecting the link in between the nuclear membrane and the network of the lamina. PMID:22493523

  7. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson–Gilford progeria syndrome

    Science.gov (United States)

    Gordon, Leslie B.; Kleinman, Monica E.; Miller, David T.; Neuberg, Donna S.; Giobbie-Hurder, Anita; Gerhard-Herman, Marie; Smoot, Leslie B.; Gordon, Catherine M.; Cleveland, Robert; Snyder, Brian D.; Fligor, Brian; Bishop, W. Robert; Statkevich, Paul; Regen, Amy; Sonis, Andrew; Riley, Susan; Ploski, Christine; Correia, Annette; Quinn, Nicolle; Ullrich, Nicole J.; Nazarian, Ara; Liang, Marilyn G.; Huh, Susanna Y.; Schwartzman, Armin; Kieran, Mark W.

    2012-01-01

    Hutchinson–Gilford progeria syndrome (HGPS) is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA that produces the farnesylated aberrant lamin A protein, progerin. This multisystem disorder causes failure to thrive and accelerated atherosclerosis leading to early death. Farnesyltransferase inhibitors have ameliorated disease phenotypes in preclinical studies. Twenty-five patients with HGPS received the farnesyltransferase inhibitor lonafarnib for a minimum of 2 y. Primary outcome success was predefined as a 50% increase over pretherapy in estimated annual rate of weight gain, or change from pretherapy weight loss to statistically significant on-study weight gain. Nine patients experienced a ≥50% increase, six experienced a ≥50% decrease, and 10 remained stable with respect to rate of weight gain. Secondary outcomes included decreases in arterial pulse wave velocity and carotid artery echodensity and increases in skeletal rigidity and sensorineural hearing within patient subgroups. All patients improved in one or more of these outcomes. Results from this clinical treatment trial for children with HGPS provide preliminary evidence that lonafarnib may improve vascular stiffness, bone structure, and audiological status. PMID:23012407

  8. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Gordon, Leslie B; Kleinman, Monica E; Miller, David T; Neuberg, Donna S; Giobbie-Hurder, Anita; Gerhard-Herman, Marie; Smoot, Leslie B; Gordon, Catherine M; Cleveland, Robert; Snyder, Brian D; Fligor, Brian; Bishop, W Robert; Statkevich, Paul; Regen, Amy; Sonis, Andrew; Riley, Susan; Ploski, Christine; Correia, Annette; Quinn, Nicolle; Ullrich, Nicole J; Nazarian, Ara; Liang, Marilyn G; Huh, Susanna Y; Schwartzman, Armin; Kieran, Mark W

    2012-10-09

    Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA that produces the farnesylated aberrant lamin A protein, progerin. This multisystem disorder causes failure to thrive and accelerated atherosclerosis leading to early death. Farnesyltransferase inhibitors have ameliorated disease phenotypes in preclinical studies. Twenty-five patients with HGPS received the farnesyltransferase inhibitor lonafarnib for a minimum of 2 y. Primary outcome success was predefined as a 50% increase over pretherapy in estimated annual rate of weight gain, or change from pretherapy weight loss to statistically significant on-study weight gain. Nine patients experienced a ≥50% increase, six experienced a ≥50% decrease, and 10 remained stable with respect to rate of weight gain. Secondary outcomes included decreases in arterial pulse wave velocity and carotid artery echodensity and increases in skeletal rigidity and sensorineural hearing within patient subgroups. All patients improved in one or more of these outcomes. Results from this clinical treatment trial for children with HGPS provide preliminary evidence that lonafarnib may improve vascular stiffness, bone structure, and audiological status.

  9. Drug screening on Hutchinson Gilford progeria pluripotent stem cells reveals aminopyrimidines as new modulators of farnesylation.

    Science.gov (United States)

    Blondel, S; Egesipe, A-L; Picardi, P; Jaskowiak, A-L; Notarnicola, M; Ragot, J; Tournois, J; Le Corf, A; Brinon, B; Poydenot, P; Georges, P; Navarro, C; Pitrez, P R; Ferreira, L; Bollot, G; Bauvais, C; Laustriat, D; Mejat, A; De Sandre-Giovannoli, A; Levy, N; Bifulco, M; Peschanski, M; Nissan, X

    2016-02-18

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by a dramatic appearance of premature aging. HGPS is due to a single-base substitution in exon 11 of the LMNA gene (c.1824C>T) leading to the production of a toxic form of the prelamin A protein called progerin. Because farnesylation process had been shown to control progerin toxicity, in this study we have developed a screening method permitting to identify new pharmacological inhibitors of farnesylation. For this, we have used the unique potential of pluripotent stem cells to have access to an unlimited and relevant biological resource and test 21,608 small molecules. This study identified several compounds, called monoaminopyrimidines, which target two key enzymes of the farnesylation process, farnesyl pyrophosphate synthase and farnesyl transferase, and rescue in vitro phenotypes associated with HGPS. Our results opens up new therapeutic possibilities for the treatment of HGPS by identifying a new family of protein farnesylation inhibitors, and which may also be applicable to cancers and diseases associated with mutations that involve farnesylated proteins.

  10. NRMT1 knockout mice exhibit phenotypes associated with impaired DNA repair and premature aging.

    Science.gov (United States)

    Bonsignore, Lindsay A; Tooley, John G; Van Hoose, Patrick M; Wang, Eugenia; Cheng, Alan; Cole, Marsha P; Schaner Tooley, Christine E

    2015-03-01

    Though defective genome maintenance and DNA repair have long been known to promote phenotypes of premature aging, the role protein methylation plays in these processes is only now emerging. We have recently identified the first N-terminal methyltransferase, NRMT1, which regulates protein-DNA interactions and is necessary for both accurate mitotic division and nucleotide excision repair. To demonstrate if complete loss of NRMT1 subsequently resulted in developmental or aging phenotypes, we constructed the first NRMT1 knockout (Nrmt1(-/-)) mouse. The majority of these mice die shortly after birth. However, the ones that survive, exhibit decreased body size, female-specific infertility, kyphosis, decreased mitochondrial function, and early-onset liver degeneration; phenotypes characteristic of other mouse models deficient in DNA repair. The livers from Nrmt1(-/-) mice produce less reactive oxygen species (ROS) than wild type controls, and Nrmt1(-/-) mouse embryonic fibroblasts show a decreased capacity for handling oxidative damage. This indicates that decreased mitochondrial function may benefit Nrmt1(-/-) mice and protect them from excess internal ROS and subsequent DNA damage. These studies position the NRMT1 knockout mouse as a useful new system for studying the effects of genomic instability and defective DNA damage repair on organismal and tissue-specific aging.

  11. Progeria syndrome with cardiac complications.

    Science.gov (United States)

    Ilyas, Saadia; Ilyas, Hajira; Hameed, Abdul; Ilyas, Muhammad

    2013-09-01

    A case report of 6-year-old boy with progeria syndrome, with marked cardiac complications is presented. The boy had cardiorespiratory failure. Discoloured purpuric skin patches, alopecia, prominent forehead, protuberant eyes, flattened nasal cartilage, malformed mandible, hypodentition, and deformed rigid fingers and toes were observed on examination. The boy was unable to speak. A sclerotic systolic murmur was audible over the mitral and aortic areas. Chest x-rays showed cardiac enlargement and the electrocardiogram (ECG) showed giant peaked P waves (right atrial hypertrophy) and right ventricular hypertrophy. Atherosclerotic dilated ascending aorta, thickened sclerotic aortic, mitral, and tricuspid valves with increased echo texture, left and right atrial and right ventricular dilatation, reduced left ventricular cavity, and thickened speckled atrial and ventricular septa were observed on echocardiography.

  12. Premature Aging of the Microcirculation in Patients with Advanced Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Oanh H.D. Thang

    2012-11-01

    Full Text Available Background: Increasing age and advanced chronic kidney disease (CKD are both associated with an attenuated vasodilator response of the skin microcirculation. In the present study, we investigated the effect of aging on microvascular reactivity in patients with advanced CKD. Methods: Acetylcholine (ACh-mediated endothelium-dependent vasodilation and sodium nitroprusside (SNP-mediated endothelium-independent vasodilation were assessed by iontophoresis combined with laser Doppler flowmetry. Microvascular function was compared between 52 patients with advanced CKD (stage 4–5: n = 16; end-stage renal disease: n = 36 and 33 healthy control subjects. As aging has an important effect on microvascular function, both control subjects and CKD patients were divided in subgroups younger and older than 45 years. Linear regression analysis was applied to assess potential associations between microvascular function and various demographic and clinical parameters. Results: There were three main findings. (1 In young patients with advanced CKD, both ACh- and SNP-mediated vasodilations were impaired if compared to young healthy controls (p = 0.04 and p = 0.056, respectively. (2 In young patients with advanced CKD, microvascular function was similar to old healthy controls and elderly patients with advanced CKD. (3 Whereas age was inversely associated with microvascular function in healthy controls (log ACh-mediated vasodilation R = –0.41; p = 0.02 and log SNP-mediated vasodilation R = –0.38; p = 0.03, no such relation was found in patients with advanced CKD. Conclusions: Our results are consistent with premature aging of the microvascular vasodilatory capacity in patients with advanced CKD.

  13. Modifiable causes of premature death in middle-age in Western Europe : Results from the EPIC cohort study

    NARCIS (Netherlands)

    Muller, David C.; Murphy, Neil; Johansson, Mattias; Ferrari, Pietro; Tsilidis, Konstantinos K.; Boutron-Ruault, Marie Christine; Clavel, Francoise; Dartois, Laureen; Li, Kuanrong; Kaaks, Rudolf; Weikert, Cornelia; Bergmann, Manuela; Boeing, Heiner; Tjønneland, Anne; Overvad, Kim; Redondo, M. Luisa; Agudo, Antonio; Molina-Portillo, Elena; Altzibar, Jone M.; Cirera, Lluís; Ardanaz, Eva; Khaw, Kay Tee; Wareham, Nicholas J.; Key, Timothy J.; Travis, Ruth C.; Bamia, Christina; Orfanos, Philippos; Trichopoulou, Antonia; Palli, Domenico; Pala, Valeria; Tumino, Rosario; Vineis, Paolo; Panico, Salvatore; Bueno-de-Mesquita, H. Bas; Verschuren, W. M Monique; Struijk, Ellen A.; Peeters, Petra H.; Engström, Gunnar; Melander, Olle; Sund, Malin; Weiderpass, Elisabete; Skeie, Guri; Lund, Eiliv; Norat, Teresa; Gunter, Marc; Riboli, Elio; Brennan, Paul

    2016-01-01

    Background: Life expectancy is increasing in Europe, yet a substantial proportion of adults still die prematurely before the age of 70 years. We sought to estimate the joint and relative contributions of tobacco smoking, hypertension, obesity, physical inactivity, alcohol and poor diet towards risk

  14. Modifiable causes of premature death in middle-age in Western Europe : results from the EPIC cohort study

    NARCIS (Netherlands)

    Muller, David C.; Murphy, Neil; Johansson, Mattias; Ferrari, Pietro; Tsilidis, Konstantinos K.; Boutron-Ruault, Marie-Christine; Clavel, Francoise; Dartois, Laureen; Li, Kuanrong; Kaaks, Rudolf; Weikert, Cornelia; Bergmann, Manuela; Boeing, Heiner; Tjonneland, Anne; Overvad, Kim; Luisa Redondo, M.; Agudo, Antonio; Molina-Portillo, Elena; Altzibar, Jone M.; Cirera, Lluis; Ardanaz, Eva; Khaw, Kay-Tee; Wareham, Nicholas J.; Key, Timothy J.; Travis, Ruth C.; Bamia, Christina; Orfanos, Philippos; Trichopoulou, Antonia; Palli, Domenico; Pala, Valeria; Tumino, Rosario; Vineis, Paolo; Panico, Salvatore; Bueno-de-Mesquita, H. Bas; Verschuren, W. M. Monique; Struijk, Ellen A.; Peeters, Petra H.; Engstrom, Gunnar; Melander, Olle; Sund, Malin; Weiderpass, Elisabete; Skeie, Guri; Lund, Eiliv; Norat, Teresa; Gunter, Marc; Riboli, Elio; Brennan, Paul

    2016-01-01

    Background: Life expectancy is increasing in Europe, yet a substantial proportion of adults still die prematurely before the age of 70 years. We sought to estimate the joint and relative contributions of tobacco smoking, hypertension, obesity, physical inactivity, alcohol and poor diet towards risk

  15. School performance at nine years of age in very premature and very low birth weight infants : Perinatal risk factors and predictors at five years of age

    NARCIS (Netherlands)

    Hille, E.T.M.; Ouden, A.L. den; Bauer, L.; Oudenrijn, C. van den; Brand, R.; Verloove-Vanhorick, S.P.

    1994-01-01

    To assess the impact of both perinatal disorders and developmental problems identified at preschool age on school performance, we followed a virtually complete birth cohort of very premature (<32 completed weeks of gestation) and very low birth weight infants until they were 9 years of age. In 84% o

  16. Attenuation of Replication Stress–Induced Premature Cellular Senescence to Assess Anti-Aging Modalities

    Science.gov (United States)

    Zhao, Hong; Darzynkiewicz, Zbigniew

    2014-01-01

    Described is an in vitro model of premature senescence in pulmonary adenocarcinoma A549 cells induced by persistent DNA replication stress in response to treatment with the DNA damaging drug mitoxantrone (Mxt). The degree of cellular senescence, based on characteristic changes in cell morphology, is measured by laser scanning cytometry. Specifically, the flattening of cells grown on slides (considered the hallmark of cellular senescence) is measured as the decline in local intensity of DNA-associated DAPI fluorescence (represented by maximal pixels). This change is paralleled by an increase in nuclear area. Thus, the ratio of mean intensity of maximal pixels to nuclear area provides a very sensitive morphometric biomarker for the degree of senescence. This analysis is combined with immunocytochemical detection of senescence markers, such as overexpression of cyclin kinase inhibitors (e.g., p21WAF1) and phosphorylation of ribosomal protein S6 (rpS6), a key marker associated with aging/senescence that is detected using a phospho-specific antibody. These biomarker indices are presented in quantitative terms defined as a senescence index (SI), which is the fraction of the marker in test cultures relative to the same marker in exponentially growing control cultures. This system can be used to evaluate the anti-aging potential of test agents by assessing attenuation of maximal senescence. As an example, the inclusion of berberine, a natural alkaloid with reported anti-aging properties and a long history of use in traditional Chinese medicine, is shown to markedly attenuate the Mxt-induced SI and phosphorylation of rpS6. The multivariate analysis of senescence markers by laser scanning cytometry offers a promising tool to explore the potential anti-aging properties of a variety agents. PMID:24984966

  17. Attenuation of replication stress-induced premature cellular senescence to assess anti-aging modalities.

    Science.gov (United States)

    Zhao, Hong; Darzynkiewicz, Zbigniew

    2014-01-01

    Described is an in vitro model of premature senescence in pulmonary adenocarcinoma A549 cells induced by persistent DNA replication stress in response to treatment with the DNA damaging drug mitoxantrone (Mxt). The degree of cellular senescence, based on characteristic changes in cell morphology, is measured by laser scanning cytometry. Specifically, the flattening of cells grown on slides (considered the hallmark of cellular senescence) is measured as the decline in local intensity of DNA-associated DAPI fluorescence (represented by maximal pixels). This change is paralleled by an increase in nuclear area. Thus, the ratio of mean intensity of maximal pixels to nuclear area provides a very sensitive morphometric biomarker for the degree of senescence. This analysis is combined with immunocytochemical detection of senescence markers, such as overexpression of cyclin kinase inhibitors (e.g., p21(WAF1) ) and phosphorylation of ribosomal protein S6 (rpS6), a key marker associated with aging/senescence that is detected using a phospho-specific antibody. These biomarker indices are presented in quantitative terms defined as a senescence index (SI), which is the fraction of the marker in test cultures relative to the same marker in exponentially growing control cultures. This system can be used to evaluate the anti-aging potential of test agents by assessing attenuation of maximal senescence. As an example, the inclusion of berberine, a natural alkaloid with reported anti-aging properties and a long history of use in traditional Chinese medicine, is shown to markedly attenuate the Mxt-induced SI and phosphorylation of rpS6. The multivariate analysis of senescence markers by laser scanning cytometry offers a promising tool to explore the potential anti-aging properties of a variety agents.

  18. [The relationship between metabolic disorders and small for gestational age with idiopathic premature adrenarche].

    Science.gov (United States)

    Mejorado Molano, Francisco Javier; Andrés Zallo, Laura; Fornos Rodríguez, Marta; Pérez Segura, Pilar; Gavela Pérez, Teresa; Sanz Calvo, María Luisa; Soriano Guillén, Leandro

    2016-11-09

    There is still controversy on the relationship between idiopathic premature adrenarche (IPA) and a history of small for gestational age, as well as the concomitant presence of obesity and other metabolic disturbances. An attempt is made to study these potential associations in a cohort of girls with IPA from our hospital. A descriptive cross-sectional study was conducted that included girls with a diagnosis of IPA from the Paediatric Department of the Fundación Jiménez Díaz (Madrid, Spain) between January 2007 and May 2015. A record was made of family and personal history with perinatal data, as well as anthropometric data and biochemical values at the time of diagnosis. Out of a total of 76 girls with IPA, 2.7% had a history of small for gestational age. When body mass index was analysed according to modified criteria of WHO 2007/Cole 2000, 11.8% were overweight, and 11.8% were obese at diagnosis. Using the criteria set by the Spanish Ministry of Health, 6.6% were overweight and 18.4% obese, with 21.2% of the girls being insulin resistance, and 13.95% having dyslipidaemia. None of them had hypertension. From a comparative analysis between normal and overweight and obesity IPA girls, the latter had significantly higher levels of triglycerides and insulin, a higher HOMA index, and lower levels of HDL cholesterol. IPA girls included in the study do not have a higher prevalence of small for gestational age compared to the general population. Prevalence of overweight and obesity in girls with IPA is not higher than the prevalence in the normal population. Copyright © 2016. Publicado por Elsevier España, S.L.U.

  19. Younger or older parental age and risk of suicidality, premature death, psychiatric illness, and criminality in offspring

    OpenAIRE

    Mok, Pearl; Antonsen, Sussie; Pedersen, Carsten Bøcker; Webb, Roger

    2017-01-01

    BackgroundYounger or older parental age has been linked with a range of adverse offspring endpoints. We investigated associations between parental age and nine adverse offspring outcomes in three correlated domains: (i) Premature death: suicide, unnatural death, natural death; (ii) Psychiatric morbidity: any mental illness, suicide attempt, substance misuse; (iii) Criminality: violent offending, imprisonment, driving whilst intoxicated.MethodsPersons born in Denmark 1966–1996 were followed fr...

  20. Prelamin A accumulation and stress conditions induce impaired Oct-1 activity and autophagy in prematurely aged human mesenchymal stem cell.

    Science.gov (United States)

    Infante, Arantza; Gago, Andrea; de Eguino, Garbiñe Ruiz; Calvo-Fernández, Teresa; Gómez-Vallejo, Vanessa; Llop, Jordi; Schlangen, Karin; Fullaondo, Ane; Aransay, Ana M; Martín, Abraham; Rodríguez, Clara I

    2014-04-01

    Aging, a time-dependent functional decline of biological processes, is the primary risk factor in developing diseases such as cancer, cardiovascular or degenerative diseases. There is a real need to understand the human aging process in order to increase the length of disease-free life, also known as "health span". Accumulation of progerin and prelamin A are the hallmark of a group of premature aging diseases but have also been found during normal cellular aging strongly suggesting similar mechanisms between healthy aging and LMNA-linked progeroid syndromes. How this toxic accumulation contributes to aging (physiological or pathological) remains unclear. Since affected tissues in age-associated disorders and in pathological aging are mainly of mesenchymal origin we propose a model of human aging based on mesenchymal stem cells (hMSCs) which accumulate prelamin A. We demonstrate that prelamin A-accumulating hMSCs have a premature aging phenotype which affects their functional competence in vivo. The combination of prelamin A accumulation and stress conditions enhance the aging phenotype by dysregulating the activity of the octamer binding protein Oct-1This experimental model has been fundamental to identify a new role for Oct-1 in hMSCs aging.

  1. Long-chain saturated and monounsaturated fatty acids associate with development of premature infants up to 18 months of age.

    Science.gov (United States)

    Strandvik, Birgitta; Ntoumani, Eleni; Lundqvist-Persson, Cristina; Sabel, Karl-Göran

    2016-04-01

    Myelination is important perinatally and highly dependent on long-chain saturated and monounsaturated fatty acids. Long-chain polyunsaturated fatty acids, nowadays often supplemented, inhibit oleic acid synthesis. Using data from a premature cohort, we studied if nervonic, lignoceric and oleic acids correlated to growth and early development up to 18 months corrected age. Small for gestational age infants had lower concentrations than infants appropriate for gestational age. Only oleic acid was negatively correlated to long-chain polyunsaturated fatty acids. Oleic and lignoceric acids correlated to social interaction at one month, and nervonic acid to mental, psychomotor and behavioral development at 6, 10 and 18 months, also when adjusted for several confounders. Negative association between oleic acid and long-chain polyunsaturated fatty acids suggests inhibition of delta-9 desaturase, and nervonic acid´s divergent correlation to lignoceric and oleic acids suggests different metabolism in neonatal period. Our results may have implications for the supplementation of premature infants.

  2. Immortalization of Werner syndrome and progeria fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Saito, H.; Moses, R.E. (Baylor College of Medicine, Houston, TX (USA))

    1991-02-01

    Human fibroblast cells from two different progeroid syndromes, Werner syndrome (WS) and progeria, were established as immortalized cell lines by transfection with plasmid DNA containing the SV40 early region. The lineage of each immortalized cell line was confirmed by VNTR analysis. Each of the immortalized cell lines maintained its original phenotype of slow growth. DNA repair ability of these cells was also studied by measuring sensitivity to killing by uv or the DNA-damaging drugs methyl methansulfonate, bleomycin, and cis-dichlorodiamine platinum. The results showed that both WS and progeria cells have normal sensitivity to these agents.

  3. Progeria of stem cells: stem cell exhaustion in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Halaschek-Wiener, Julius; Brooks-Wilson, Angela

    2007-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare, fatal genetic disorder that is characterized by segmental accelerated aging. The major causal mutation associated with HGPS triggers abnormal messenger RNA splicing of the lamin A gene leading to changes in the nuclear architecture. To date, two models have been proposed to explain how mutations in the lamin A gene could lead to HGPS, structural fragility and altered gene expression. We favor a compatible model that links HGPS to stem cell-driven tissue regeneration. In this model, nuclear fragility of lamin A-deficient cells increases apoptotic cell death to levels that exhaust tissues' ability for stem cell-driven regeneration. Tissue-specific differences in cell death or regenerative potential, or both, result in the tissue-specific segmental aging pattern seen in HGPS. We propose that the pattern of aging-related conditions present or absent in HGPS can provide insight into the genetic and environmental factors that contribute to normal aging.

  4. Leg ulcer in Werner syndrome (adult progeria): a case report.

    Science.gov (United States)

    Fumo, Giuseppe; Pau, Monica; Patta, Federico; Aste, Nicola; Atzori, Laura

    2013-03-15

    Werner syndrome (WS; MIM#277700) or adult progeria, is a rare disease, associated with mutations of a single gene (RECQL2 or WRN), located on chromosome 8 (8p12). It codes a DNA-helicase, whose defects cause genomic instability. The highest incidences are reported in Japan and Sardinia (Italy). On this major island of the Mediterranean Basin, the WS cases have been observed in the northern areas. The authors describe the apparently first case reported in southern Sardinia, a 51-year-old woman, who was born in and resides in the province of Cagliari. She presented with a 9-year history of an intractable leg ulcer and other characteristic symptoms, including "bird-like" face, high-pitched voice, premature greying, short stature, abdominal obesity in contrast with thin body type, scleroderma-like legs, decreased muscle mass, diabetes, atherosclerosis, and premature menopause. A specialized genetic Institute of Research (IRCCS-IDI, Rome) confirmed the clinical diagnosis. There is no cure or specific treatment and patients must be periodically screened for an increased risk of cardiovascular and cerebrovascular disease and malignancies. Among the many findings, leg ulcers significantly affect the patient's quality of life. This problem may send the patient to the dermatologist, who finally suspects the diagnosis. Poor response to medical treatment may require aggressive repeated surgery, with poor or temporary results.

  5. Epigenetic involvement in Hutchinson-Gilford progeria syndrome: a mini-review.

    Science.gov (United States)

    Arancio, Walter; Pizzolanti, Giuseppe; Genovese, Swonild I; Pitrone, Maria; Giordano, Carla

    2014-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare human genetic disease that leads to a severe premature ageing phenotype, caused by mutations in the LMNA gene. The LMNA gene codes for lamin-A and lamin-C proteins, which are structural components of the nuclear lamina. HGPS is usually caused by a de novo C1824T mutation that leads to the accumulation of a dominant negative form of lamin-A called progerin. Progerin also accumulates physiologically in normal ageing cells as a rare splicing form of lamin-A transcripts. From this perspective, HGPS cells seem to be good candidates for the study of the physiological mechanisms of ageing. Progerin accumulation leads to faster cellular senescence, stem cell depletion and the progeroid phenotype. Tissues of mesodermic origin are especially affected by HGPS. HGPS patients usually have a bad quality of life and, with current treatments, their life expectancy does not exceed their second decade at best. Though progerin can be expressed in almost any tissue, when death occurs, it is usually due to cardiovascular complications. In HGPS, severe epigenetic alterations have been reported. Histone-covalent modifications are radically different from control specimens, with the tendency to lose the bipartition into euchromatin and heterochromatin. This is reflected in an altered spatial compartmentalization and conformation of chromatin within the nucleus. Moreover, it seems that microRNAs and microRNA biosynthesis might play a role in HGPS. Exemplary in this connection is the suggested protective effect of miR-9 on the central nervous system of affected individuals. This mini-review will report on the state of the art of HGPS epigenetics, and there will be a discussion of how epigenetic alterations in HGPS cells can alter the cellular metabolism and lead to the systemic syndrome.

  6. The Reasons and Prevention of Ovarian Premature Aging%卵巢早衰的原因与预防

    Institute of Scientific and Technical Information of China (English)

    李莉

    2014-01-01

    Objective To analyze the factors that cause ovarian premature aging so as to provide a basis for clinical prevention and treatment of ovarian premature aging. Methods A questionnaire was used to investigate the 100 cases in the observation group and the control group, and the data was treated by logistic regression analysis. Results 12 variables such as the number of induced abortion, drinking, smoking, marital status, family and social relationship, bean products, mood, taking corticosteroids and so on are related to the occurrence of ovarian premature aging. Multiple factors analysis showed that marital status (OR = 6.03), number of induced abortion (OR = 2.14), smoking (OR =3.26), hair coloring (OR =2.74), mood (OR= 0.16), vegetables (OR = 0.34), mumps (OR = 10.23), and other factors are closely associated with ovarian premature aging. Conclusion Many factors can cause ovarian premature aging, so effective measures should be taken clinically to strengthen the prevention and treatment, thereby reducing the incidence of the disease and promoting the recovery of the patients as early as possible.%目的:分析卵巢早衰发生因素,为临床卵巢早衰的防治提供一定的依据。方法采用问卷调查方式对观察组和健康对照组共100例进行logistic回归分析。结果卵巢早衰发生因素与人工流产次数、饮酒、吸烟、婚姻状况以及家人社会相处关系、豆制品、心情和服用糖皮质激素等12个变量相关。多因素分析表明,婚姻状况(OR=6.03)、人工流产次数(OR=2.14)、吸烟(OR=3.26)、染发(OR=2.74)、心情(OR=0.16)、蔬菜(OR=0.34)、腮腺炎(OR=10.23)等因素与卵巢早衰密切相关。结论卵巢早衰发生因素较多,临床应采取有效的措施加强预防,治疗,以降低发病率,促进患者早日康复。

  7. Aging Study, Hints from Hutchinson-Gilford Progeria Syndrome%Hutchinson-Gilford早老症在衰老研究中的意义

    Institute of Scientific and Technical Information of China (English)

    宋昱; 郭翯; 郑璐; 陈琳; 黄昱

    2009-01-01

    Hutchinson-Gilford早老症是一种散发的常染体显性遗传病,是研究人类正常衰老理想的疾病模型.其发病机制在于核纤层蛋白A的基因发生突变,使其翻译产物缺少了50个氨基酸而变成早老蛋白,该蛋白质在细胞内积累,导致细胞增殖异常、端粒缩短、基因表达调控异常、基因组不稳定等,这些表现与正常衰老有诸多相似之处.正常衰老细胞中同样发现早老蛋白的存在,且随年龄增长而积累.本文比较了HGPS与正常衰老在表型上的异同,综述了HGPS加速衰老的分子机制研究进展,并着重介绍了HGPS研究成果对衰老研究的借鉴意义.%time. By comparing and contrasting the phenotype of HGPS with that of normal aging, we summarize the research progress in the molec-ular mechanism of HGPS, and focus on the results from HGPS which can be used on aging research.

  8. Homeostatic Imbalance between Apoptosis and Cell Renewal in the Liver of Premature Aging XpdTTD Mice

    Science.gov (United States)

    Park, Jung Yoon; Cho, Mi-Ook; Leonard, Shanique; Calder, Brent; Mian, I. Saira; Kim, Woo Ho; Wijnhoven, Susan; van Steeg, Harry; Mitchell, James; van der Horst, Gijsbertus T. J.; Hoeijmakers, Jan; Cohen, Pinchas; Vijg, Jan; Suh, Yousin

    2008-01-01

    Unrepaired or misrepaired DNA damage has been implicated as a causal factor in cancer and aging. XpdTTD mice, harboring defects in nucleotide excision repair and transcription due to a mutation in the Xpd gene (R722W), display severe symptoms of premature aging but have a reduced incidence of cancer. To gain further insight into the molecular basis of the mutant-specific manifestation of age-related phenotypes, we used comparative microarray analysis of young and old female livers to discover gene expression signatures distinguishing XpdTTD mice from their age-matched wild type controls. We found a transcription signature of increased apoptosis in the XpdTTD mice, which was confirmed by in situ immunohistochemical analysis and found to be accompanied by increased proliferation. However, apoptosis rate exceeded the rate of proliferation, resulting in homeostatic imbalance. Interestingly, a metabolic response signature was observed involving decreased energy metabolism and reduced IGF-1 signaling, a major modulator of life span. We conclude that while the increased apoptotic response to endogenous DNA damage contributes to the accelerated aging phenotypes and the reduced cancer incidence observed in the XpdTTD mice, the signature of reduced energy metabolism is likely to reflect a compensatory adjustment to limit the increased genotoxic stress in these mutants. These results support a general model for premature aging in DNA repair deficient mice based on cellular responses to DNA damage that impair normal tissue homeostasis. PMID:18545656

  9. Premature Contractions

    Science.gov (United States)

    ... Peripheral Artery Disease Venous Thromboembolism Aortic Aneurysm More Premature Contractions - PACs and PVCs Updated:Dec 15,2016 ... You felt this more-forceful beat. Types of premature contractions Premature atrial contractions (PACs) start in the ...

  10. Farnesyltransferase inhibitor treatment restores chromosome territory positions and active chromosome dynamics in Hutchinson-Gilford progeria syndrome cells

    Science.gov (United States)

    2011-01-01

    Background Hutchinson-Gilford progeria syndrome (HGPS) is a premature ageing syndrome that affects children leading to premature death, usually from heart infarction or strokes, making this syndrome similar to normative ageing. HGPS is commonly caused by a mutation in the A-type lamin gene, LMNA (G608G). This leads to the expression of an aberrant truncated lamin A protein, progerin. Progerin cannot be processed as wild-type pre-lamin A and remains farnesylated, leading to its aberrant behavior during interphase and mitosis. Farnesyltransferase inhibitors prevent the accumulation of farnesylated progerin, producing a less toxic protein. Results We have found that in proliferating fibroblasts derived from HGPS patients the nuclear location of interphase chromosomes differs from control proliferating cells and mimics that of control quiescent fibroblasts, with smaller chromosomes toward the nuclear interior and larger chromosomes toward the nuclear periphery. For this study we have treated HGPS fibroblasts with farnesyltransferase inhibitors and analyzed the nuclear location of individual chromosome territories. We have found that after exposure to farnesyltransferase inhibitors mis-localized chromosome territories were restored to a nuclear position akin to chromosomes in proliferating control cells. Furthermore, not only has this treatment afforded chromosomes to be repositioned but has also restored the machinery that controls their rapid movement upon serum removal. This machinery contains nuclear myosin 1β, whose distribution is also restored after farnesyltransferase inhibitor treatment of HGPS cells. Conclusions This study not only progresses the understanding of genome behavior in HGPS cells but demonstrates that interphase chromosome movement requires processed lamin A. PMID:21838864

  11. Pluripotent stem cells to model Hutchinson-Gilford progeria syndrome (HGPS): Current trends and future perspectives for drug discovery.

    Science.gov (United States)

    Lo Cicero, Alessandra; Nissan, Xavier

    2015-11-01

    Progeria, or Hutchinson-Gilford progeria syndrome (HGPS), is a rare, fatal genetic disease characterized by an appearance of accelerated aging in children. This syndrome is typically caused by mutations in codon 608 (p.G608G) of the LMNA, leading to the production of a mutated form of lamin A precursor called progerin. In HGPS, progerin accumulates in cells causing progressive molecular defects, including nuclear shape abnormalities, chromatin disorganization, damage to DNA and delays in cell proliferation. Here we report how, over the past five years, pluripotent stem cells have provided new insights into the study of HGPS and opened new original therapeutic perspectives to treat the disease.

  12. Attenuation of Replication Stress–Induced Premature Cellular Senescence to Assess Anti-Aging Modalities

    OpenAIRE

    Zhao, Hong; Darzynkiewicz, Zbigniew

    2014-01-01

    Described is an in vitro model of premature senescence in pulmonary adenocarcinoma A549 cells induced by persistent DNA replication stress in response to treatment with the DNA damaging drug mitoxantrone (Mxt). The degree of cellular senescence, based on characteristic changes in cell morphology, is measured by laser scanning cytometry. Specifically, the flattening of cells grown on slides (considered the hallmark of cellular senescence) is measured as the decline in local intensity of DNA-as...

  13. Interfacial binding and aggregation of lamin A tail domains associated with Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Kalinowski, Agnieszka; Yaron, Peter N; Qin, Zhao; Shenoy, Siddharth; Buehler, Markus J; Lösche, Mathias; Dahl, Kris Noel

    2014-12-01

    Hutchinson-Gilford progeria syndrome is a premature aging disorder associated with the expression of ∆50 lamin A (∆50LA), a mutant form of the nuclear structural protein lamin A (LA). ∆50LA is missing 50 amino acids from the tail domain and retains a C-terminal farnesyl group that is cleaved from the wild-type LA. Many of the cellular pathologies of HGPS are thought to be a consequence of protein-membrane association mediated by the retained farnesyl group. To better characterize the protein-membrane interface, we quantified binding of purified recombinant ∆50LA tail domain (∆50LA-TD) to tethered bilayer membranes composed of phosphatidylserine and phosphocholine using surface plasmon resonance. Farnesylated ∆50LA-TD binds to the membrane interface only in the presence of Ca(2+) or Mg(2+) at physiological ionic strength. At extremely low ionic strength, both the farnesylated and non-farnesylated forms of ∆50LA-TD bind to the membrane surface in amounts that exceed those expected for a densely packed protein monolayer. Interestingly, the wild-type LA-TD with no farnesylation also associates with membranes at low ionic strength but forms only a single layer. We suggest that electrostatic interactions are mediated by charge clusters with a net positive charge that we calculate on the surface of the LA-TDs. These studies suggest that the accumulation of ∆50LA at the inner nuclear membrane observed in cells is due to a combination of aggregation and membrane association rather than simple membrane binding; electrostatics plays an important role in mediating this association.

  14. Expression of progerin in aging mouse brains reveals structural nuclear abnormalities without detectible significant alterations in gene expression, hippocampal stem cells or behavior

    DEFF Research Database (Denmark)

    Baek, Jean-Ha; Schmidt, Eva; Viceconte, Nikenza

    2015-01-01

    Hutchinson–Gilford progeria syndrome (HGPS) is a segmental progeroid syndrome with multiple features suggestive of premature accelerated aging. Accumulation of progerin is thought to underlie the pathophysiology of HGPS. However, despite ubiquitous expression of lamin A in all differentiated cells...... also been found in several tissues from normal individuals, but it is not clear if low levels of progerin contribute to the aging of the brain. In an attempt to clarify the origin of this phenomenon, we have developed an inducible transgenic mouse model with expression of the most common HGPS mutation......, the HGPS mutation results in organ-specific defects. For example, bone and skin are strongly affected by HGPS, while the brain appears to be unaffected. There are no definite explanations as to the variable sensitivity to progeria disease among different organs. In addition, low levels of progerin have...

  15. Dedifferentiation rescues senescence of progeria cells but only while pluripotent

    Science.gov (United States)

    2011-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disease in which children develop pathologies associated with old age. HGPS is caused by a mutation in the LMNA gene, resulting in the formation of a dominant negative form of the intermediate filament, nuclear structural protein lamin A, termed progerin. Expression of progerin alters the nuclear architecture and heterochromatin, affecting cell cycle progression and genomic stability. Two groups recently reported the successful generation and characterization of induced pluripotent stem cells (iPSCs) from HGPS fibroblasts. Remarkably, progerin expression and senescence phenotypes are lost in iPSCs but not in differentiated progeny. These new HGPS iPSCs are valuable for characterizing the role of progerin in driving HGPS and aging and for screening therapeutic strategies to prevent or delay cell senescence. PMID:21639955

  16. A model of premature aging in mice based on altered stress-related behavioral response and immunosenescence.

    Science.gov (United States)

    Viveros, María-Paz; Arranz, Lorena; Hernanz, Angel; Miquel, Jaime; De la Fuente, Mónica

    2007-01-01

    The intensity of behavioral and neuroendocrine responses to stressful stimuli in rodent strains seems to be inversely related to their life span. We have previously shown that interindividual differences in members of outbred Swiss and inbred BALB/c mouse populations, both male and female, may be related to their behavior in a simple T-maze test. The animals that explore the maze slowly show impaired neuromuscular vigor and coordination, decreased locomotor activity, increased level of emotionality/anxiety, decreased levels of brain biogenic amines as well as immunosenescence and decreased life span, when compared to their control counterparts, which quickly explore the maze. These traits are similar to some of the alterations previously observed in aging animals and therefore we proposed that those 'slow mice' are biologically older than the fast animals and may be a model of prematurely aging mice (PAM). Although most of our work on this model has been performed on chronologically adult-mature animals, we have also shown that certain characteristics of PAM, such as increased anxiety and deficient immune response, are already present in chronologically young animals. Thus, it is tempting to hypothesize that chronic hyperreactivity to stress (trait anxiety) leading to immune dysfunction may have a causal relationship with impaired health and premature aging. In view of the link between oxidative stress and the aging process, the redox state of peritoneal leukocytes from PAM has been studied, showing an oxidative stress situation. In the present work we have determined the levels of a key antioxidant, reduced glutathione (GSH), and the oxidant malondialdehyde (MDA), a marker of lipid peroxidation, both in the spleen and brain of male and female PAM and non-PAM (NPAM). We found that GSH and MDA are decreased and increased, respectively, in PAM with respect to NPAM. Moreover, diet supplementation with antioxidants showed to be an effective strategy for protection

  17. Hutchinson-Gilford Progeria Syndrome with G608G LMNA Mutation

    Science.gov (United States)

    Kim, Hui Kwon; Lee, Jong Yoon; Bae, Eun Ju; Oh, Phil Soo; Park, Won Il; Lee, Dong Sung; Kim, Jong-Il

    2011-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare condition originally described by Hutchinson in 1886. Death result from cardiac complications in the majority of cases and usually occurs at average age of thirteen years. A 4-yr old boy had typical clinical findings such as short stature, craniofacial disproportion, alopecia, prominent scalp veins and sclerodermatous skin. This abnormal appearance began at age of 1 yr. On serological and hormonal evaluation, all values are within normal range. He was neurologically intact with motor and mental development. An echocardiogram showed calcification of aortic and mitral valves. Hypertrophy of internal layer at internal carotid artery suggesting atherosclerosis was found by carotid doppler sonography. He is on low dose aspirin to prevent thromboembolic episodes and on regular follow up. Gene study showed typical G608G (GGC- > GGT) point mutation at exon 11 in LMNA gene. This is a rare case of Hutchinson-Gilford progeria syndrome confirmed by genetic analysis in Korea. PMID:22148005

  18. Hutchinson-Gilford progeria syndrome with G608G LMNA mutation.

    Science.gov (United States)

    Kim, Hui Kwon; Lee, Jong Yoon; Bae, Eun Ju; Oh, Phil Soo; Park, Won Il; Lee, Dong Sung; Kim, Jong-Il; Lee, Hong Jin

    2011-12-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare condition originally described by Hutchinson in 1886. Death result from cardiac complications in the majority of cases and usually occurs at average age of thirteen years. A 4-yr old boy had typical clinical findings such as short stature, craniofacial disproportion, alopecia, prominent scalp veins and sclerodermatous skin. This abnormal appearance began at age of 1 yr. On serological and hormonal evaluation, all values are within normal range. He was neurologically intact with motor and mental development. An echocardiogram showed calcification of aortic and mitral valves. Hypertrophy of internal layer at internal carotid artery suggesting atherosclerosis was found by carotid doppler sonography. He is on low dose aspirin to prevent thromboembolic episodes and on regular follow up. Gene study showed typical G608G (GGC- > GGT) point mutation at exon 11 in LMNA gene. This is a rare case of Hutchinson-Gilford progeria syndrome confirmed by genetic analysis in Korea.

  19. Premature lung aging and cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and COPD/emphysema.

    Science.gov (United States)

    Chilosi, Marco; Carloni, Angelo; Rossi, Andrea; Poletti, Venerino

    2013-09-01

    Different anatomic and physiological changes occur in the lung of aging people that can affect pulmonary functions, and different pulmonary diseases, including deadly diseases such as chronic obstructive pulmonary disease (COPD)/emphysema and idiopathic pulmonary fibrosis (IPF), can be related to an acceleration of the aging process. The individual genetic background, as well as exposure to a variety of toxic substances (cigarette smoke in primis) can contribute significantly to accelerating pulmonary senescence. Premature aging can impair lung function by different ways: by interfering specifically with tissue repair mechanisms after damage, thus perturbing the correct crosstalk between mesenchymal and epithelial components; by inducing systemic and/or local alteration of the immune system, thus impairing the complex mechanisms of lung defense against infections; and by stimulating a local and/or systemic inflammatory condition (inflammaging). According to recently proposed pathogenic models in COPD and IPF, premature cellular senescence likely affects distinct progenitors cells (mesenchymal stem cells in COPD, alveolar epithelial precursors in IPF), leading to stem cell exhaustion. In this review, the large amount of data supporting this pathogenic view are discussed, with emphasis on the possible molecular and cellular mechanisms leading to the severe parenchymal remodeling that characterizes, in different ways, these deadly diseases.

  20. Premature infant

    Science.gov (United States)

    There are many support groups for parents of premature babies. Ask the social worker in the neonatal intensive care unit. ... Prematurity used to be a major cause of infant deaths. Improved ... Prematurity can have long-term effects. Many premature infants ...

  1. Effect of progerin on the accumulation of oxidized proteins in fibroblasts from Hutchinson Gilford progeria patients.

    Science.gov (United States)

    Viteri, Gabriela; Chung, Youn Wook; Stadtman, Earl R

    2010-01-01

    The mutation responsible for Hutchinson Gilford Progeria Syndrome (HGPS) causes abnormal nuclear morphology. Previous studies show that free radicals and reactive oxygen species play major roles in the etiology and/or progression of neurodegenerative diseases and aging. This study compares oxidative stress responses between progeric and normal fibroblasts. Our data revealed higher ROS levels in HGPS cells compared to age-matched controls. In response to oxidative challenge, progeric cells showed increased mRNA levels for mitochondrial superoxide dismutase (SOD) and SOD protein content. However, this did not prevent a drop in the ATP content of progeria fibroblasts. Previous studies have shown that declines in human fibroblast ATP levels interfere with programmed cell death and promote necrotic inflammation. Notably, in our investigations the ATP content of progeria fibroblasts was only approximately 50% of that found in healthy controls. Furthermore, HGPS fibroblast analysis revealed a decrease in total caspase-like proteasome activity and in the levels of two active proteolytic complex subunits (beta(5) and beta(7)). A number of studies indicate that the molecular mechanisms causing accelerated aging in progeric patients also occur in healthy cells of older individuals. Thus, the results of this study may also help explain some of the cellular changes that accompany normal aging.

  2. Progeria: Medical Aspects, Psychosocial Perspectives, and Intervention Guidelines.

    Science.gov (United States)

    Livneh, Hanoch; And Others

    1995-01-01

    Discusses progeria (or Hutchinson-Gilford syndrome), a rare childhood disorder that invariably results in death during adolescence. Describes the major medical aspects of progeria, and discusses the psychosocial implications of the disorder with particular emphasis on grief-triggered reactions. Presents an overview of psychosocial intervention…

  3. Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases.

    Science.gov (United States)

    Kudlow, Brian A; Kennedy, Brian K; Monnat, Raymond J

    2007-05-01

    Progeroid syndromes have been the focus of intense research in part because they might provide a window into the pathology of normal ageing. Werner syndrome and Hutchinson-Gilford progeria syndrome are two of the best characterized human progeroid diseases. Mutated genes that are associated with these syndromes have been identified, mouse models of disease have been developed, and molecular studies have implicated decreased cell proliferation and altered DNA-damage responses as common causal mechanisms in the pathogenesis of both diseases.

  4. Patch-based augmentation of Expectation-Maximization for brain MRI tissue segmentation at arbitrary age after premature birth.

    Science.gov (United States)

    Liu, Mengyuan; Kitsch, Averi; Miller, Steven; Chau, Vann; Poskitt, Kenneth; Rousseau, Francois; Shaw, Dennis; Studholme, Colin

    2016-02-15

    Accurate automated tissue segmentation of premature neonatal magnetic resonance images is a crucial task for quantification of brain injury and its impact on early postnatal growth and later cognitive development. In such studies it is common for scans to be acquired shortly after birth or later during the hospital stay and therefore occur at arbitrary gestational ages during a period of rapid developmental change. It is important to be able to segment any of these scans with comparable accuracy. Previous work on brain tissue segmentation in premature neonates has focused on segmentation at specific ages. Here we look at solving the more general problem using adaptations of age specific atlas based methods and evaluate this using a unique manually traced database of high resolution images spanning 20 gestational weeks of development. We examine the complimentary strengths of age specific atlas-based Expectation-Maximization approaches and patch-based methods for this problem and explore the development of two new hybrid techniques, patch-based augmentation of Expectation-Maximization with weighted fusion and a spatial variability constrained patch search. The former approach seeks to combine the advantages of both atlas- and patch-based methods by learning from the performance of the two techniques across the brain anatomy at different developmental ages, while the latter technique aims to use anatomical variability maps learnt from atlas training data to locally constrain the patch-based search range. The proposed approaches were evaluated using leave-one-out cross-validation. Compared with the conventional age specific atlas-based segmentation and direct patch based segmentation, both new approaches demonstrate improved accuracy in the automated labeling of cortical gray matter, white matter, ventricles and sulcal cortical-spinal fluid regions, while maintaining comparable results in deep gray matter.

  5. Gene expression and DNA repair in progeroid syndromes and human aging.

    Science.gov (United States)

    Kyng, Kasper J; Bohr, Vilhelm A

    2005-11-01

    Human progeroid syndromes are caused by mutations in single genes accelerating some but not all features of normal aging. Most progeroid disorders are linked to defects in genome maintenance, and while it remains unknown if similar processes underlie normal and premature aging, they provide useful models for the study of aging. Altered transcription is speculated to play a causative role in aging, and is involved in the pathology of most if not all progeroid syndromes. Previous studies demonstrate that there is a similar pattern of gene expression changes in primary cells from old and Werner syndrome compared to young suggesting a presence of common cellular aging mechanisms in old and progeria. Here we review the role of transcription in progeroid syndromes and discuss the implications of similar transcription aberrations in normal and premature aging.

  6. Premature Birth and Large for Gestational Age Are Associated with Risk of Barrett’s Esophagus in Adults

    Science.gov (United States)

    Shiota, Seiji; El-Serag, Hashem B.; Thrift, Aaron P.

    2015-01-01

    Background Birth characteristics, including weight and gestational age, may be associated with risk of Barrett’s esophagus (BE), the only known precursor for esophageal adenocarcinoma; however, data are limited. Aims To examine associations between various birth characteristics and BE, and whether these associations are mediated by known risk factors for BE. Methods Data were obtained from a cross-sectional study among eligible Veterans Affairs patients scheduled for an upper endoscopy, and a sample identified from primary care clinics. Participants underwent an esophagogastroduodenoscopy and completed a survey that captured information on sociodemographic and clinical factors, as well as birth information. We compared 263 patients with histologically confirmed BE to 1,416 controls without BE on endoscopy. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated using multivariate logistic regression. Results Premature birth was independently associated with risk of BE after adjusted by age, sex, race, and other birth characteristics (OR 3.28, 95% CI 1.22–8.79). On the other hand, large for gestational age was inversely associated with risk of BE (OR 0.46, 95% CI 0.21–0.98). These effects were stronger for patients with long-segment BE than short-segment BE. The associations were not mediated by gastroesophageal reflux disease symptoms, use of proton pump inhibitors, Helicobacter Pylori infection, waist-hip-ratio, height or presence of hiatus hernia. Conclusions Premature birth and large for gestational age may be associated with risk of BE in adults. These associations do not appear to be mediated through known risk factors for BE; however, additional studies are required to confirm our findings. PMID:26611860

  7. Investigation of age-related changes in LMNA splicing and expression of progerin in human skeletal muscles

    OpenAIRE

    Luo, Yue-Bei; Mitrpant, Chalermchai; Johnsen, Russell D; Fabian, Victoria A; Fletcher, Sue; Mastaglia, Frank L.; Steve D Wilton

    2013-01-01

    Age-related changes in splice-forms of LMNA, which encodes the nuclear lamina proteins lamin A/C, have not been investigated in skeletal muscle. In the rare premature ageing disease, Hutchinson-Gilford progeria syndrome (HGPS), de novo point mutations in LMNA activate a cryptic splice site in exon 11, resulting in a 150 base deletion in LMNA mRNA and accumulation of a truncated protein isoform, progerin. The LMNA Δ150 progerin transcript has also been found in trace quantities in tissues of h...

  8. All-trans retinoic acid and rapamycin normalize Hutchinson Gilford progeria fibroblast phenotype.

    Science.gov (United States)

    Pellegrini, Camilla; Columbaro, Marta; Capanni, Cristina; D'Apice, Maria Rosaria; Cavallo, Carola; Murdocca, Michela; Lattanzi, Giovanna; Squarzoni, Stefano

    2015-10-06

    Hutchinson Gilford progeria syndrome is a fatal disorder characterized by accelerated aging, bone resorption and atherosclerosis, caused by a LMNA mutation which produces progerin, a mutant lamin A precursor. Progeria cells display progerin and prelamin A nuclear accumulation, altered histone methylation pattern, heterochromatin loss, increased DNA damage and cell cycle alterations. Since the LMNA promoter contains a retinoic acid responsive element, we investigated if all-trans retinoic acid administration could lower progerin levels in cultured fibroblasts. We also evaluated the effect of associating rapamycin, which induces autophagic degradation of progerin and prelamin A. We demonstrate that all-trans retinoic acid acts synergistically with low-dosage rapamycin reducing progerin and prelamin A, via transcriptional downregulation associated with protein degradation, and increasing the lamin A to progerin ratio. These effects rescue cell dynamics and cellular proliferation through recovery of DNA damage response factor PARP1 and chromatin-associated nuclear envelope proteins LAP2α and BAF. The combined all-trans retinoic acid-rapamycin treatment is dramatically efficient, highly reproducible, represents a promising new approach in Hutchinson-Gilford Progeria therapy and deserves investigation in ageing-associated disorders.

  9. Accumulation of prelamin A compromises NF-κB-regulated B-lymphopoiesis in a progeria mouse model

    Science.gov (United States)

    2013-01-01

    Background Alteration in the immune system is one of the most profound aspects of aging. Progressive changes in the number of B lymphocyte progenitors during aging have been reported but the underlying mechanisms are still elusive. A heterozygous G608G mutation in the LMNA gene leads to a deletion of 50 amino acids in lamin A protein, termed progerin, and is the predominant cause of Hutchinson-Gilford progeria syndrome (HGPS). Lack of Zmpste24, a metalloproteinase responsible for prelamin A processing, leads to progeroid features resembling HGPS. Therefore Zmpste24-deficient mice provide an ideal mouse model to study the impact of lamin A and (premature) aging on the aging-related decline of B lymphopoiesis. Results Analysis of bone marrow (BM) nucleated cells revealed a decline of early B cell progenitors in Zmpste24−/− mice. BM transplantation in a congenic strain completely rescued the defects in B lymphopoiesis, indicating that the decline in B cell progenitors in Zmpste24−/− mice is attributable to defective BM microenvironments rather than to cell-intrinsic defects. Further investigation revealed downregulation of a set of important early B lymphopoiesis factors in Zmpste24−/− bone marrow stromal cells (BMSCs), such as Vcam-1, SDF-1α, Flt3L and TSLP, and most of them are under transcriptional control of NF-κB signaling. Though TNFα stimulates IκBα degradation and NF-κB nuclear translocation in Zmpste24−/− BMSCs, NF-κB fails to stimulate IκBα re-expression, which mediates a negative feedback loop of NF-κB signaling in wild-type BMSCs. Conclusions Our data demonstrate a cell-extrinsic defect of B cell development in a progeroid mouse model and a critical role for lamin A in the regulation of NF-κB signaling and cytokines that are essential for lymphopoiesis. PMID:24764515

  10. Genome-scale expression profiling of Hutchinson-Gilford progeria syndrome reveals widespread transcriptional misregulation leading to mesodermal/mesenchymal defects and accelerated atherosclerosis.

    Science.gov (United States)

    Csoka, Antonei B; English, Sangeeta B; Simkevich, Carl P; Ginzinger, David G; Butte, Atul J; Schatten, Gerald P; Rothman, Frank G; Sedivy, John M

    2004-08-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease with widespread phenotypic features resembling premature aging. HGPS was recently shown to be caused by dominant mutations in the LMNA gene, resulting in the in-frame deletion of 50 amino acids near the carboxyl terminus of the encoded lamin A protein. Children with this disease typically succumb to myocardial infarction or stroke caused by severe atherosclerosis at an average age of 13 years. To elucidate further the molecular pathogenesis of this disease, we compared the gene expression patterns of three HGPS fibroblast cell strains heterozygous for the LMNA mutation with three normal, age-matched cell strains. We defined a set of 361 genes (1.1% of the approximately 33,000 genes analysed) that showed at least a 2-fold, statistically significant change. The most prominent categories encode transcription factors and extracellular matrix proteins, many of which are known to function in the tissues severely affected in HGPS. The most affected gene, MEOX2/GAX, is a homeobox transcription factor implicated as a negative regulator of mesodermal tissue proliferation. Thus, at the gene expression level, HGPS shows the hallmarks of a developmental disorder affecting mesodermal and mesenchymal cell lineages. The identification of a large number of genes implicated in atherosclerosis is especially valuable, because it provides clues to pathological processes that can now be investigated in HGPS patients or animal models.

  11. Protective mechanism against cancer found in progeria patient cells

    Science.gov (United States)

    NCI scientists have studied cells of patients with an extremely rare genetic disease that is characterized by drastic premature aging and discovered a new protective cellular mechanism against cancer. They found that cells from patients with Hutchinson Gi

  12. Antenatal betamethasone and fetal growth in prematurely born children: implications for temperament traits at the age of 2 years.

    Science.gov (United States)

    Pesonen, Anu-Katriina; Räikkönen, Katri; Lano, Aulikki; Peltoniemi, Outi; Hallman, Mikko; Kari, M Anneli

    2009-01-01

    We explored whether repeated dose of antenatal betamethasone and variation in intrauterine growth of prematurely born children predict temperament characteristics at the age of 2 years. The patients (n = 142) were prematurely born children (mean gestational age: 31.0 weeks; range: 24.6-35.0 weeks) who participated in a randomized and blinded trial testing the effects of a repeated dose of antenatal betamethasone in imminent preterm birth. Fetal growth was estimated as weight, length, and head circumference in SDs according to Finnish growth charts. Parents assessed their toddlers' temperament with 201 items of the Early Childhood Temperament Questionnaire (mean child corrected age: 2.1 years). No significant main effects of repeated betamethasone on toddler temperament existed. However, a significant interaction between study group and duration of exposure to betamethasone emerged; those exposed to a repeated dose for >24 hours before delivery were more impulsive. One-SD increases in weight, length, and head circumference at birth were associated with 0.14- to 0.19-SD lower levels of negative affectivity (fearfulness, anger proneness, and sadness); 1-SD increases in length, weight, and head circumference at birth were associated with 0.14- to 0.18-SD higher levels of effortful control (self-regulation). Repeated antenatal betamethasone did not induce alterations in toddler temperament. The results, however, suggest that a longer duration of exposure is associated with higher impulsivity scores. Regardless of betamethasone exposure, slower fetal growth exerted influences on temperament. Our findings indicate prenatal programming of psychological development and imply that more attention is needed to support the development of infants born at the lower end of the fetal growth distribution.

  13. Premature ejaculation

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/001524.htm Premature ejaculation To use the sharing features on this page, please enable JavaScript. Premature ejaculation is when a man has an orgasm ...

  14. Correlation of serum KL-6 and CC16 levels with neurodevelopmental outcome in premature infants at 12 months corrected age

    Science.gov (United States)

    Zhang, Zhiqun; Lu, Hui; Zhu, Yunxia; Xiang, Junhua; Huang, Xianmei

    2015-01-01

    The aim of this study was to evaluate KL-6 and CC16 levels and their correlation with neurodevelopmental outcome among very low birth weight pre-term infants at 12 months corrected age. This prospective cohort study was performed from 2011 to 2013 by enrolling pre-term neonates of gestational age ≤ 32 weeks and birth weight ≤ 1500 g. Serum KL-6 and CC16 levels were determined 7 days after birth and their correlation with neurodevelopment was evaluated using Gesell Mental Developmental Scales. Of the 86 eligible pre-term infants, 63 completed follow-up, of which 15 had bronchopulmonary dysplasia. At 12 months corrected age, 49 infants had favorable outcomes and 14 infants had poor neurodevelopmental outcome. KL-6 levels were higher and CC16 levels were lower in infants with poor neurodevelopmental outcome compared with those infants who had favourable neurodevelopmental outcome. Serum KL-6 levels less than 90.0 ng/ml and CC16 levels greater than 320.0 pg/ml at 7 days of life were found to be predictive of a favourable outcome at 12 months corrected age. These biological markers could predict neurodevelopmental outcome at 12 months corrected age in very low birth weight premature infants, and help the clinician plan early therapeutic interventions to minimize or avoid poor neurodevelopmental outcome. PMID:25631862

  15. CDKN2A/p16INK4a expression is associated with vascular progeria in chronic kidney disease

    Science.gov (United States)

    Stenvinkel, Peter; Luttropp, Karin; McGuinness, Dagmara; Witasp, Anna; Rashid Qureshi, Abdul; Wernerson, Annika; Nordfors, Louise; Schalling, Martin; Ripsweden, Jonaz; Wennberg, Lars; Söderberg, Magnus; Bárány, Peter; Olauson, Hannes; Shiels, Paul G

    2017-01-01

    Patients with chronic kidney disease (CKD) display a progeric vascular phenotype linked to apoptosis, cellular senescence and osteogenic transformation. This has proven intractable to modelling appropriately in model organisms. We have therefore investigated this directly in man, using for the first time validated cellular biomarkers of ageing (CDKN2A/p16INK4a, SA-β-Gal) in arterial biopsies from 61 CKD patients undergoing living donor renal transplantation. We demonstrate that in the uremic milieu, increased arterial expression of CDKN2A/p16INK4a associated with vascular progeria in CKD, independently of chronological age. The arterial expression of CDKN2A/p16INK4a was significantly higher in patients with coronary calcification (p=0.01) and associated cardiovascular disease (CVD) (p=0.004). The correlation between CDKN2A/p16INK4a and media calcification was statistically significant (p=0.0003) after correction for chronological age. We further employed correlate expression of matrix Gla protein (MGP) and runt-related transcription factor 2 (RUNX2) as additional pathognomonic markers. Higher expression of CDKN2A/p16INK4a, RUNX2 and MGP were observed in arteries with severe media calcification. The number of p16INK4a and SA-β-Gal positive cells was higher in biopsies with severe media calcification. A strong inverse correlation was observed between CDKN2A/p16INK4a expression and carboxylated osteocalcin levels. Thus, impaired vitamin K mediated carboxylation may contribute to premature vascular senescence. PMID:28192277

  16. Hypoparathyroidism in an Egyptian child with Hutchinson-Gilford progeria syndrome: a case report

    Science.gov (United States)

    2012-01-01

    Introduction Hutchinson-Gilford progeria syndrome is a rare genetic disorder. It is reported to be present in one in eight million and is characterized by severe growth failure, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, early atherosclerosis and facial features that resemble those of an aged person. Apart from diabetes mellitus, there are no reported abnormalities of thyroid, parathyroid, pituitary or adrenal function. Here, we report the case of a 10-year-old Egyptian child with Hutchinson-Gilford progeria syndrome and hypoparathyroidism. Case presentation A 10-year-old Egyptian boy was referred to our institution for an evaluation of recurrent attacks of muscle cramps, paresthesia of his fingertips and perioral numbness of two months duration. On examination, we found dilated veins present over his scalp with alopecia and frontal bossing, a beaked nose, thin lips, protruding ears, a high pitched voice with sparse hair over his eyebrows and eyelashes and micrognathia but normal dentition. His eyes appeared prominent and our patient appeared to have poor sexual development. A provisional diagnosis of progeria was made, which was confirmed by molecular genetics study. Chvostek's and Trousseau's signs were positive. He had low total calcium (5.4 mg/dL), low ionized calcium (2.3 mg/dL), raised serum phosphate (7.2 mg/dL), raised alkaline phosphatase (118 U/L) and low intact parathyroid hormone (1.2 pg/mL) levels. He was started on oral calcium salt and vitamin D; his symptoms improved with the treatment and his serum calcium, urinary calcium and alkaline phosphates level were monitored every three months to ensure adequacy of therapy and to avoid hypercalcemia. Conclusion Routine checking of serum calcium, phosphorus and parathyroid hormone will help in the early detection of hypoparathyrodism among children with progeria. PMID:22251708

  17. Hypoparathyroidism in an Egyptian child with Hutchinson-Gilford progeria syndrome: a case report

    Directory of Open Access Journals (Sweden)

    Kalil Kotb

    2012-01-01

    Full Text Available Abstract Introduction Hutchinson-Gilford progeria syndrome is a rare genetic disorder. It is reported to be present in one in eight million and is characterized by severe growth failure, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, early atherosclerosis and facial features that resemble those of an aged person. Apart from diabetes mellitus, there are no reported abnormalities of thyroid, parathyroid, pituitary or adrenal function. Here, we report the case of a 10-year-old Egyptian child with Hutchinson-Gilford progeria syndrome and hypoparathyroidism. Case presentation A 10-year-old Egyptian boy was referred to our institution for an evaluation of recurrent attacks of muscle cramps, paresthesia of his fingertips and perioral numbness of two months duration. On examination, we found dilated veins present over his scalp with alopecia and frontal bossing, a beaked nose, thin lips, protruding ears, a high pitched voice with sparse hair over his eyebrows and eyelashes and micrognathia but normal dentition. His eyes appeared prominent and our patient appeared to have poor sexual development. A provisional diagnosis of progeria was made, which was confirmed by molecular genetics study. Chvostek's and Trousseau's signs were positive. He had low total calcium (5.4 mg/dL, low ionized calcium (2.3 mg/dL, raised serum phosphate (7.2 mg/dL, raised alkaline phosphatase (118 U/L and low intact parathyroid hormone (1.2 pg/mL levels. He was started on oral calcium salt and vitamin D; his symptoms improved with the treatment and his serum calcium, urinary calcium and alkaline phosphates level were monitored every three months to ensure adequacy of therapy and to avoid hypercalcemia. Conclusion Routine checking of serum calcium, phosphorus and parathyroid hormone will help in the early detection of hypoparathyrodism among children with progeria.

  18. Low birthweight and premature birth are both associated with type 2 diabetes in a random sample of middle-aged Danes.

    Science.gov (United States)

    Pilgaard, K; Færch, K; Carstensen, B; Poulsen, P; Pisinger, C; Pedersen, O; Witte, D R; Hansen, T; Jørgensen, T; Vaag, A

    2010-12-01

    We studied the associations of size at birth and prematurity with type 2 diabetes, insulin sensitivity and beta cell function in the Danish population-based Inter99 study (ClinicalTrials.gov NCT00289237). Information about size at birth and prematurity was identified from original midwife records in 4,744 middle-aged Danes. Type 2 diabetes status, insulin sensitivity (Matsuda index) and beta cell function (disposition index) were assessed using a 75 g oral glucose tolerance test. Participants born prematurely were compared with a group of at-term participants born small for gestational age. An increase in birthweight of 1 kg was associated with a 51% (OR 0.49, 95% CI 0.35-0.69) reduced risk of type 2 diabetes. Ponderal index, reflecting thinness at birth, was associated with type 2 diabetes to the same extent as birthweight. The prevalence of type 2 diabetes was increased to a similar degree in participants born prematurely and participants born small for gestational age, although the former had a higher ponderal index at birth. In addition, birthweight z-scores, reflecting fetal growth rate, were unrelated to the risk of type 2 diabetes and to other measures of glucose regulation in participants born prematurely. While low birthweight was inversely associated with insulin sensitivity and beta cell function, prematurity was associated solely with decreased insulin sensitivity. While the association between birthweight and risk of type 2 diabetes is mediated via combined effects on beta cell function and insulin sensitivity, prematurity seems to influence risk of type 2 diabetes via attenuated insulin sensitivity only and independently of fetal growth rates.

  19. Decreased repair of gamma damaged DNA in progeria

    Energy Technology Data Exchange (ETDEWEB)

    Rainbow, A.J.; Howes, M.

    1977-01-01

    A sensitive host-cell reactivation technique was used to examine the DNA repair ability of fibroblasts from two patients with classical progeria. Fibroblasts were infected with either non-irradiated or gamma-irradiated adenovirus type 2 and at 48 hrs after infection cells were examined for the presence of viral structural antigens using immunofluorescent staining. The production of viral structural antigens was considerably reduced in the progeria lines as compared to normal fibroblasts when gamma-irradiated virus was used, indicating a defect in the repair of gamma ray damaged DNA in the progeria cells.

  20. Progeria: translational insights from cell biology.

    Science.gov (United States)

    Gordon, Leslie B; Cao, Kan; Collins, Francis S

    2012-10-01

    Cell biologists love to think outside the box, pursuing many surprising twists and unexpected turns in their quest to unravel the mysteries of how cells work. But can cell biologists think outside the bench? We are certain that they can, and clearly some already do. To encourage more cell biologists to venture into the realm of translational research on a regular basis, we would like to share a handful of the many lessons that we have learned in our effort to develop experimental treatments for Hutchinson-Gilford progeria syndrome (HGPS), an endeavor that many view as a "poster child" for how basic cell biology can be translated to the clinic.

  1. Molecular Clues to Physiological and Premature Ageing Revealed | Center for Cancer Research

    Science.gov (United States)

    There are many theories about the molecular basis of ageing. One of the most popular ones postulates that organisms age by accumulating damage to their tissues, cells, and molecules. On the cellular level, ageing is associated with progressive changes in chromatin (a combination of DNA and proteins that makes up chromosomes). These changes include loss of chromatin structure, loss and/or modification of essential proteins, and accumulation of DNA damage.

  2. Absence of progeria-like disease phenotypes in knock-in mice expressing a non-farnesylated version of progerin.

    Science.gov (United States)

    Yang, Shao H; Chang, Sandy Y; Ren, Shuxun; Wang, Yibin; Andres, Douglas A; Spielmann, H Peter; Fong, Loren G; Young, Stephen G

    2011-02-01

    Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutant prelamin A, progerin, that terminates with a farnesylcysteine. HGPS knock-in mice (Lmna(HG/+)) develop severe progeria-like disease phenotypes. These phenotypes can be ameliorated with a protein farnesyltransferase inhibitor (FTI), suggesting that progerin's farnesyl lipid is important for disease pathogenesis and raising the possibility that FTIs could be useful for treating humans with HGPS. Subsequent studies showed that mice expressing non-farnesylated progerin (Lmna(nHG/+) mice, in which progerin's carboxyl-terminal -CSIM motif was changed to -SSIM) also develop severe progeria, raising doubts about whether any treatment targeting protein prenylation would be particularly effective. We suspected that those doubts might be premature and hypothesized that the persistent disease in Lmna(nHG/+) mice could be an unanticipated consequence of the cysteine-to-serine substitution that was used to eliminate farnesylation. To test this hypothesis, we generated a second knock-in allele yielding non-farnesylated progerin (Lmna(csmHG)) in which the carboxyl-terminal -CSIM motif was changed to -CSM. We then compared disease phenotypes in mice harboring the Lmna(nHG) or Lmna(csmHG) allele. As expected, Lmna(nHG/+) and Lmna(nHG/nHG) mice developed severe progeria-like disease phenotypes, including osteolytic lesions and rib fractures, osteoporosis, slow growth and reduced survival. In contrast, Lmna(csmHG/+) and Lmna(csmHG/csmHG) mice exhibited no bone disease and displayed entirely normal body weights and survival. The frequencies of misshapen cell nuclei were lower in Lmna(csmHG/+) and Lmna(csmHG/csmHG) fibroblasts. These studies show that the ability of non-farnesylated progerin to elicit disease depends on the carboxyl-terminal mutation used to eliminate protein prenylation.

  3. Enhanced SRSF5 Protein Expression Reinforces Lamin A mRNA Production in HeLa Cells and Fibroblasts of Progeria Patients.

    Science.gov (United States)

    Vautrot, Valentin; Aigueperse, Christelle; Oillo-Blanloeil, Florence; Hupont, Sébastien; Stevenin, James; Branlant, Christiane; Behm-Ansmant, Isabelle

    2016-03-01

    The Hutchinson Gilford Progeria Syndrome (HGPS) is a rare genetic disease leading to accelerated aging. Three mutations of the LMNA gene leading to HGPS were identified. The more frequent ones, c.1824C>T and c.1822G>A, enhance the use of the intron 11 progerin 5'splice site (5'SS) instead of the LMNA 5'SS, leading to the production of the truncated dominant negative progerin. The less frequent c.1868C>G mutation creates a novel 5'SS (LAΔ35 5'SS), inducing the production of another truncated LMNA protein (LAΔ35). Our data show that the progerin 5'SS is used at low yield in the absence of HGPS mutation, whereas utilization of the LAΔ35 5'SS is dependent upon the presence of the c.1868C>G mutation. In the perspective to correct HGPS splicing defects, we investigated whether SR proteins can modify the relative yields of utilization of intron 11 5'SSs. By in cellulo and in vitro assays, we identified SRSF5 as a direct key regulator increasing the utilization of the LMNA 5'SS in the presence of the HGPS mutations. Enhanced SRSF5 expression in dermal fibroblasts of HGPS patients as well as PDGF-BB stimulation of these cells decreased the utilization of the progerin 5'SS, and improves nuclear morphology, opening new therapeutic perspectives for premature aging.

  4. SU5416 induces premature senescence in endothelial progenitor cells from patients with age-related macular degeneration

    Science.gov (United States)

    Berna, Marc J.; Kunst, Frank; Wege, Henning; Strunnikova, Natalya V.; Gordiyenko, Natalya; Grierson, Rebecca; Richard, Gisbert; Csaky, Karl G.

    2011-01-01

    Purpose We recently demonstrated increased frequency and growth potential of late outgrowth endothelial progenitor cells (OECs) in patients with neovascular age-related macular degeneration (nvAMD). This study investigated the effects of short- and long-term in vitro inhibition of vascular endothelial growth factor (VEGF) Receptor-2 (VEGFR-2) signaling by SU5416 and other inhibitors of the VEGF signaling pathway in OECs. Methods OECs, from the peripheral blood of patients with nvAMD, and human umbilical vein endothelial cells were grown in the presence of SU5416, other VEGFR-2 tyrosine kinase inhibitors (TKIs), and inhibitors of phosphatidylinositol 3′-Kinase (PI3K)/protein kinase B (Akt) and protein kinase C (PKC) in complete angiogenic medium. Apotosis was assessed after 48 h using the fluorescein isothiocyanate Annexin V method. Cell counts were performed for 10 days, and features of senescence were analyzed using senescence-associated β-galactosidase staining, the telomeric repeat amplification protocol for telomerase activity, Southern blot analysis for mean telomere length, flow cytometric analysis for cell-cycle arrest, and western blot for p53 and p21. Control OECs, cells treated for 7 days with inhibitors, as well as naturally senescent OECs were analyzed for expression of different endothelial antigens, including VEGFR-2 and the receptor for stromal cell-derived factor 1, chemokine receptor 4 (CXCR-4). Migration in vitro to VEGF and stromal cell-derived factor 1 of OECs was assessed. Results SU5416, other VEGFR-2 TKIs, and inhibitors of PI3K, Akt, and PKC induced apoptosis, inhibited long-term proliferation, reduced telomerase activity, and induced premature senescence and cell-cycle arrest in OECs as well as in human umbilical vein endothelial cells. Naturally senescent cells and cells rendered senescent by VEGFR-2 TKIs had reduced VEGFR-2 and CXCR-4 expression and demonstrated reduced migratory ability to VEGF. Conclusions This study demonstrates

  5. Development of the Corticospinal and Callosal Tracts from Extremely Premature Birth up to 2 Years of Age.

    Science.gov (United States)

    Braga, Rodrigo M; Roze, Elise; Ball, Gareth; Merchant, Nazakat; Tusor, Nora; Arichi, Tomoki; Edwards, David; Rueckert, Daniel; Counsell, Serena J

    2015-01-01

    White matter tracts mature asymmetrically during development, and this development can be studied using diffusion magnetic resonance imaging. The aims of this study were i. to generate dynamic population-averaged white matter registration templates covering in detail the period from 25 weeks gestational age to term, and extending to 2 years of age based on DTI and fractional anisotropy, ii. to produce tract-specific probability maps of the corticospinal tracts, forceps major and forceps minor using probabilistic tractography, and iii. to assess the development of these tracts throughout this critical period of neurodevelopment. We found evidence for asymmetric development across the fiber bundles studied, with the corticospinal tracts showing earlier maturation (as measured by fractional anisotropy) but slower volumetric growth compared to the callosal fibers. We also found evidence for an anterior to posterior gradient in white matter microstructure development (as measured by mean diffusivity) in the callosal fibers, with the posterior forceps major developing at a faster rate than the anterior forceps minor in this age range. Finally, we report a protocol for delineating callosal and corticospinal fibers in extremely premature cohorts, and make available population-averaged registration templates and a probabilistic tract atlas which we hope will be useful for future neonatal and infant white-matter imaging studies.

  6. Drosophila Clock Is Required in Brain Pacemaker Neurons to Prevent Premature Locomotor Aging Independently of Its Circadian Function.

    Directory of Open Access Journals (Sweden)

    Alexandra Vaccaro

    2017-01-01

    Full Text Available Circadian clocks control many self-sustained rhythms in physiology and behavior with approximately 24-hour periodicity. In many organisms, oxidative stress and aging negatively impact the circadian system and sleep. Conversely, loss of the clock decreases resistance to oxidative stress, and may reduce lifespan and speed up brain aging and neurodegeneration. Here we examined the effects of clock disruptions on locomotor aging and longevity in Drosophila. We found that lifespan was similarly reduced in three arrhythmic mutants (ClkAR, cyc0 and tim0 and in wild-type flies under constant light, which stops the clock. In contrast, ClkAR mutants showed significantly faster age-related locomotor deficits (as monitored by startle-induced climbing than cyc0 and tim0, or than control flies under constant light. Reactive oxygen species accumulated more with age in ClkAR mutant brains, but this did not appear to contribute to the accelerated locomotor decline of the mutant. Clk, but not Cyc, inactivation by RNA interference in the pigment-dispersing factor (PDF-expressing central pacemaker neurons led to similar loss of climbing performance as ClkAR. Conversely, restoring Clk function in these cells was sufficient to rescue the ClkAR locomotor phenotype, independently of behavioral rhythmicity. Accelerated locomotor decline of the ClkAR mutant required expression of the PDF receptor and correlated to an apparent loss of dopaminergic neurons in the posterior protocerebral lateral 1 (PPL1 clusters. This neuronal loss was rescued when the ClkAR mutation was placed in an apoptosis-deficient background. Impairing dopamine synthesis in a single pair of PPL1 neurons that innervate the mushroom bodies accelerated locomotor decline in otherwise wild-type flies. Our results therefore reveal a novel circadian-independent requirement for Clk in brain circadian neurons to maintain a subset of dopaminergic cells and avoid premature locomotor aging in Drosophila.

  7. Drosophila Clock Is Required in Brain Pacemaker Neurons to Prevent Premature Locomotor Aging Independently of Its Circadian Function

    Science.gov (United States)

    Issa, Abdul-Raouf; Seugnet, Laurent; Klarsfeld, André

    2017-01-01

    Circadian clocks control many self-sustained rhythms in physiology and behavior with approximately 24-hour periodicity. In many organisms, oxidative stress and aging negatively impact the circadian system and sleep. Conversely, loss of the clock decreases resistance to oxidative stress, and may reduce lifespan and speed up brain aging and neurodegeneration. Here we examined the effects of clock disruptions on locomotor aging and longevity in Drosophila. We found that lifespan was similarly reduced in three arrhythmic mutants (ClkAR, cyc0 and tim0) and in wild-type flies under constant light, which stops the clock. In contrast, ClkAR mutants showed significantly faster age-related locomotor deficits (as monitored by startle-induced climbing) than cyc0 and tim0, or than control flies under constant light. Reactive oxygen species accumulated more with age in ClkAR mutant brains, but this did not appear to contribute to the accelerated locomotor decline of the mutant. Clk, but not Cyc, inactivation by RNA interference in the pigment-dispersing factor (PDF)-expressing central pacemaker neurons led to similar loss of climbing performance as ClkAR. Conversely, restoring Clk function in these cells was sufficient to rescue the ClkAR locomotor phenotype, independently of behavioral rhythmicity. Accelerated locomotor decline of the ClkAR mutant required expression of the PDF receptor and correlated to an apparent loss of dopaminergic neurons in the posterior protocerebral lateral 1 (PPL1) clusters. This neuronal loss was rescued when the ClkAR mutation was placed in an apoptosis-deficient background. Impairing dopamine synthesis in a single pair of PPL1 neurons that innervate the mushroom bodies accelerated locomotor decline in otherwise wild-type flies. Our results therefore reveal a novel circadian-independent requirement for Clk in brain circadian neurons to maintain a subset of dopaminergic cells and avoid premature locomotor aging in Drosophila. PMID:28072817

  8. [Development deficit risks in the late premature newborn: Evaluation at 48 months using the Ages & Stages Questionnaires®].

    Science.gov (United States)

    Demestre, X; Schonhaut, L; Morillas, J; Martínez-Nadal, S; Vila, C; Raspall, F; Sala, P

    2016-01-01

    Lack of specific monitoring protocols hinders the knowledge of the impact of late prematurity on delayed psychomotor development. The objective of this study is to evaluate this at 48 months and compare it with those born at term. A retrospective cohort study was conducted on 90 late preterm (PT) and 89 term (AT) healthy children at 48 months, assessed by the Ages & Stages Questionnaires® (ASQ-3). Continuous variables described using mean and standard deviation compared with the t Student t test for independent samples. The categorical variables were described as frequencies and proportions, compared with the Chi-square test of independence. A cut-off was determined for the total score of ASQ-3 able to discriminate the risk of developmental deficit by a ROC analysis. A step-wise logistic regression model identified the associated risk factors. The mean scores for each domain and overall ASQ-3 score showed no differences between groups. However, when analyzing the probability density for the ASQ-3 total score of ≤251 points, 15 PT (16.6%) and 4 AT (4.5%) showed risk of psychomotor deficits, and late prematurity and lack of breastfeeding were significantly associated factors. There is an increased prevalence of risk of development deficit in the PT, which justifies considering this population at risk and establishing effective monitoring programs. It should be further investigated whether this risk corresponds to the entire population, or if there are biological factors or perinatal history that makes them more vulnerable. Copyright © 2015 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

  9. No support for premature central nervous system aging in HIV-1 when measured by cerebrospinal fluid phosphorylated tau (p-tau)

    OpenAIRE

    Krut, J. J.; Price, R W; Zetterberg, H; Fuchs, D.; Hagberg, L.; YILMAZ, A.; Cinque, P.; Nilsson, S; Gisslén, M.

    2016-01-01

    BACKGROUND: The prevalence of neurocognitive deficits are reported to be high in HIV-1 positive patients, even with suppressive antiretroviral treatment, and it has been suggested that HIV can cause accelerated aging of the brain. In this study we measured phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) as a potential marker for premature central nervous system (CNS) aging. P-tau increases with normal aging but is not affected by HIV-associated neurocognitive disorders. METHODS: With ...

  10. Premature age-related comorbidities among HIV-infected persons compared with the general population.

    Science.gov (United States)

    Guaraldi, Giovanni; Orlando, Gabriella; Zona, Stefano; Menozzi, Marianna; Carli, Federica; Garlassi, Elisa; Berti, Alessandra; Rossi, Elisa; Roverato, Alberto; Palella, Frank

    2011-12-01

    Human immunodeficiency virus (HIV)-infected patients may have a greater risk of noninfectious comorbidities (NICMs) compared with the general population. We assessed the prevalence and risk factors for NICMs in a large cohort of HIV-infected adults and compared these findings with data from matched control subjects. We performed a case-control study involving antiretroviral therapy (ART)-experienced HIV-infected patients treated at Modena University, Italy, from 2002 through 2009. These patients were compared with age-, sex-, and race-matched adults (control subjects) from the general population included in the CINECA ARNO database. NICMs included cardiovascular disease, hypertension, diabetes mellitus, bone fractures, and renal failure. Polypathology (Pp) was defined as the concurrent presence of ≥2 NICMs. Logistic regression models were constructed to evaluate associated predictors of NICMs and Pp. There were 2854 patients and 8562 control subjects. The mean age was 46 years, and 37% were women. Individual NICM and Pp prevalences in each age stratum were higher among patients than among controls (all P <.001). Pp prevalence among patients aged 41-50 years was similar to that among controls aged 51-60 years (P value was not statistically significant); diabetes mellitus, cardiovascular disease, bone fractures, and renal failure were statistically independent after adjustment for sex, age, and hypertension. Logistic regression models showed that independent predictors of Pp in the overall cohort were (all P < .001) age (odds ratio [OR], 1.11), male sex (OR, 1.77), nadir CD4 cell count <200 cells/μL (OR, 4.46), and ART exposure (OR, 1.01). Specific age-related NICMs and Pp were more common among HIV-infected patients than in the general population. The prevalence of Pp in HIV-infected persons anticipated Pp prevalence observed in the general population among persons who were 10 years older, and HIV-specific cofactors (lower nadir CD4 cell count and more prolonged

  11. Inflammation and Oxidative Stress as Biomarkers of Premature Aging in Persons with Intellectual Disability

    Science.gov (United States)

    Carmeli, Eli; Imam, Bita; Bachar, Asad; Merrick, Joav

    2012-01-01

    The decline in cognitive ability and physical performance in older adults with intellectual disabilities (ID) is accompanied by less participation in social activities and a sedentary lifestyle; however the pathogenesis is not clear yet. It was recently suggested that chronic disease, adverse drug reactions, and aging create a cascade of events…

  12. Premature aging in mice activates a systemic metabolic response involving autophagy induction

    NARCIS (Netherlands)

    G. Mariño (Guillermo); A.P. Ugalde (Alejandro); N. Salvador-Montoliu (Natalia); I. Varela (Ignacio); P.M. Quirós (Pedro); J. Cadiñanos (Juan); I. van der Pluijm (Ingrid); J.M.P. Freije (José); C. López-Otín (Carlos)

    2008-01-01

    textabstractAutophagy is a highly regulated intracellular process involved in the turnover of most cellular constituents and in the maintenance of cellular homeostasis. It is well-established that the basal autophagic activity of living cells decreases with age, thus contributing to the accumulation

  13. Inflammation and Oxidative Stress as Biomarkers of Premature Aging in Persons with Intellectual Disability

    Science.gov (United States)

    Carmeli, Eli; Imam, Bita; Bachar, Asad; Merrick, Joav

    2012-01-01

    The decline in cognitive ability and physical performance in older adults with intellectual disabilities (ID) is accompanied by less participation in social activities and a sedentary lifestyle; however the pathogenesis is not clear yet. It was recently suggested that chronic disease, adverse drug reactions, and aging create a cascade of events…

  14. The transverse diameter of the chest on routine radiographs reliably estimates gestational age and weight in premature infants

    Energy Technology Data Exchange (ETDEWEB)

    Dietz, Kelly R. [University of Minnesota, Department of Radiology, Minneapolis, MN (United States); Zhang, Lei [University of Minnesota, Biostatistical Design and Analysis Center, Minneapolis, MN (United States); Seidel, Frank G. [Lucile Packard Children' s Hospital, Department of Radiology, Stanford, CA (United States)

    2015-08-15

    Prior to digital radiography it was possible for a radiologist to easily estimate the size of a patient on an analog film. Because variable magnification may be applied at the time of processing an image, it is now more difficult to visually estimate an infant's size on the monitor. Since gestational age and weight significantly impact the differential diagnosis of neonatal diseases and determine the expected size of kidneys or appearance of the brain by MRI or US, this information is useful to a pediatric radiologist. Although this information may be present in the electronic medical record, it is frequently not readily available to the pediatric radiologist at the time of image interpretation. To determine if there was a correlation between gestational age and weight of a premature infant with their transverse chest diameter (rib to rib) on admission chest radiographs. This retrospective study was approved by the institutional review board, which waived informed consent. The maximum transverse chest diameter outer rib to outer rib was measured on admission portable chest radiographs of 464 patients admitted to the neonatal intensive care unit (NICU) during the 2010 calendar year. Regression analysis was used to investigate the association between chest diameter and gestational age/birth weight. Quadratic term of chest diameter was used in the regression model. Chest diameter was statistically significantly associated with both gestational age (P < 0.0001) and birth weight (P < 0.0001). An infant's gestational age and birth weight can be reliably estimated by comparing a simple measurement of the transverse chest diameter on digital chest radiograph with the tables and graphs in our study. (orig.)

  15. Targeting isoprenylcysteine methylation ameliorates disease in a mouse model of progeria.

    Science.gov (United States)

    Ibrahim, Mohamed X; Sayin, Volkan I; Akula, Murali K; Liu, Meng; Fong, Loren G; Young, Stephen G; Bergo, Martin O

    2013-06-14

    Several progeroid disorders, including Hutchinson-Gilford progeria syndrome (HGPS) and restrictive dermopathy (ZMPSTE24 deficiency), arise when a farnesylated and methylated form of prelamin A accumulates at the nuclear envelope. Here, we found that a hypomorphic allele of isoprenylcysteine carboxyl methyltransferase (ICMT) increased body weight, normalized grip strength, and prevented bone fractures and death in Zmpste24-deficient mice. The reduced ICMT activity caused prelamin A mislocalization within the nucleus and triggered prelamin A-dependent activation of AKT-mammalian target of rapamycin (mTOR) signaling, which abolished the premature senescence of Zmpste24-deficient fibroblasts. ICMT inhibition increased AKT-mTOR signaling and proliferation and delayed senescence in human HGPS fibroblasts but did not reduce the levels of misshapen nuclei in mouse and human cells. Thus, targeting ICMT might be useful for treating prelamin A-associated progeroid disorders.

  16. Metabolic Damage and Premature Thymus Aging Caused by Stromal Catalase Deficiency.

    Science.gov (United States)

    Griffith, Ann V; Venables, Thomas; Shi, Jianjun; Farr, Andrew; van Remmen, Holly; Szweda, Luke; Fallahi, Mohammad; Rabinovitch, Peter; Petrie, Howard T

    2015-08-18

    T lymphocytes are essential mediators of immunity that are produced by the thymus in proportion to its size. The thymus atrophies rapidly with age, resulting in progressive diminution of new T cell production. This decreased output is compensated by duplication of existing T cells, but it results in gradual dominance by memory T cells and decreased ability to respond to new pathogens or vaccines. Here, we show that accelerated and irreversible thymic atrophy results from stromal deficiency in the reducing enzyme catalase, leading to increased damage by hydrogen peroxide generated by aerobic metabolism. Genetic complementation of catalase in stromal cells diminished atrophy, as did chemical antioxidants, thus providing a mechanistic link between antioxidants, metabolism, and normal immune function. We propose that irreversible thymic atrophy represents a conventional aging process that is accelerated by stromal catalase deficiency in the context of an intensely anabolic (lymphoid) environment.

  17. Effect of Infant Prematurity on Auditory Brainstem Response at Preschool Age

    Directory of Open Access Journals (Sweden)

    Sara Hasani

    2013-03-01

    Full Text Available Introduction: Preterm birth is a risk factor for a number of conditions that requires comprehensive examination. Our study was designed to investigate the impact of preterm birth on the processing of auditory stimuli and brain structures at the brainstem level at a preschool age.   Materials and Methods: An auditory brainstem response (ABR test was performed with low rates of stimuli in 60 children aged 4 to 6 years. Thirty subjects had been born following a very preterm labor or late-preterm labor and 30 control subjects had been born following a full-term labor.   Results: Significant differences in the ABR test result were observed in terms of the inter-peak intervals of the I–III and III–V waves, and the absolute latency of the III wave (P

  18. Autophagy and aging: new lessons from progeroid mice.

    Science.gov (United States)

    Mariño, Guillermo; López-Otín, Carlos

    2008-08-01

    It is widely-assumed that the autophagic activity of living cells decreases with age and probably contributes to the accumulation of damaged macromolecules and organelles during aging. Over the last few years, the study of segmental progeroid syndromes in which certain aspects of aging are manifested precociously or in exacerbated form, has increased our knowledge of the molecular basis of aging. We have recently reported the unexpected finding that distinct progeroid murine models exhibit an extensive basal activation of autophagy instead of the characteristic decline in this process occurring during normal aging. Further studies on Zmpste24-null progeroid mice, which are a reliable model of human Hutchinson-Gilford progeria, have revealed that the observed autophagic increase is associated with a series of metabolic alterations resembling those occurring under calorie restriction or in other situations reported to prolong lifespan. Here, we analyze these unexpected findings and discuss their possible implications for the development of premature aging.

  19. Correlated alterations in genome organization, histone methylation, and DNA–lamin A/C interactions in Hutchinson-Gilford progeria syndrome

    Science.gov (United States)

    McCord, Rachel Patton; Nazario-Toole, Ashley; Zhang, Haoyue; Chines, Peter S.; Zhan, Ye; Erdos, Michael R.; Collins, Francis S.; Dekker, Job; Cao, Kan

    2013-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease that is frequently caused by a de novo point mutation at position 1824 in LMNA. This mutation activates a cryptic splice donor site in exon 11, and leads to an in-frame deletion within the prelamin A mRNA and the production of a dominant-negative lamin A protein, known as progerin. Here we show that primary HGPS skin fibroblasts experience genome-wide correlated alterations in patterns of H3K27me3 deposition, DNA-lamin A/C associations, and, at late passages, genome-wide loss of spatial compartmentalization of active and inactive chromatin domains. We further demonstrate that the H3K27me3 changes associate with gene expression alterations in HGPS cells. Our results support a model that the accumulation of progerin in the nuclear lamina leads to altered H3K27me3 marks in heterochromatin, possibly through the down-regulation of EZH2, and disrupts heterochromatin–lamina interactions. These changes may result in transcriptional misregulation and eventually trigger the global loss of spatial chromatin compartmentalization in late passage HGPS fibroblasts. PMID:23152449

  20. Transgene silencing of the Hutchinson-Gilford progeria syndrome mutation results in a reversible bone phenotype, whereas resveratrol treatment does not show overall beneficial effects.

    Science.gov (United States)

    Strandgren, Charlotte; Nasser, Hasina Abdul; McKenna, Tomás; Koskela, Antti; Tuukkanen, Juha; Ohlsson, Claes; Rozell, Björn; Eriksson, Maria

    2015-08-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder that is most commonly caused by a de novo point mutation in exon 11 of the LMNA gene, c.1824C>T, which results in an increased production of a truncated form of lamin A known as progerin. In this study, we used a mouse model to study the possibility of recovering from HGPS bone disease upon silencing of the HGPS mutation, and the potential benefits from treatment with resveratrol. We show that complete silencing of the transgenic expression of progerin normalized bone morphology and mineralization already after 7 weeks. The improvements included lower frequencies of rib fractures and callus formation, an increased number of osteocytes in remodeled bone, and normalized dentinogenesis. The beneficial effects from resveratrol treatment were less significant and to a large extent similar to mice treated with sucrose alone. However, the reversal of the dental phenotype of overgrown and laterally displaced lower incisors in HGPS mice could be attributed to resveratrol. Our results indicate that the HGPS bone defects were reversible upon suppressed transgenic expression and suggest that treatments targeting aberrant progerin splicing give hope to patients who are affected by HGPS.

  1. Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    McCord, Rachel Patton; Nazario-Toole, Ashley; Zhang, Haoyue; Chines, Peter S; Zhan, Ye; Erdos, Michael R; Collins, Francis S; Dekker, Job; Cao, Kan

    2013-02-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease that is frequently caused by a de novo point mutation at position 1824 in LMNA. This mutation activates a cryptic splice donor site in exon 11, and leads to an in-frame deletion within the prelamin A mRNA and the production of a dominant-negative lamin A protein, known as progerin. Here we show that primary HGPS skin fibroblasts experience genome-wide correlated alterations in patterns of H3K27me3 deposition, DNA-lamin A/C associations, and, at late passages, genome-wide loss of spatial compartmentalization of active and inactive chromatin domains. We further demonstrate that the H3K27me3 changes associate with gene expression alterations in HGPS cells. Our results support a model that the accumulation of progerin in the nuclear lamina leads to altered H3K27me3 marks in heterochromatin, possibly through the down-regulation of EZH2, and disrupts heterochromatin-lamina interactions. These changes may result in transcriptional misregulation and eventually trigger the global loss of spatial chromatin compartmentalization in late passage HGPS fibroblasts.

  2. Unique Preservation of Neural Cells in Hutchinson- Gilford Progeria Syndrome Is Due to the Expression of the Neural-Specific miR-9 MicroRNA

    Directory of Open Access Journals (Sweden)

    Xavier Nissan

    2012-07-01

    Full Text Available One puzzling observation in patients affected with Hutchinson-Gilford progeria syndrome (HGPS, who overall exhibit systemic and dramatic premature aging, is the absence of any conspicuous cognitive impairment. Recent studies based on induced pluripotent stem cells derived from HGPS patient cells have revealed a lack of expression in neural derivatives of lamin A, a major isoform of LMNA that is initially produced as a precursor called prelamin A. In HGPS, defective maturation of a mutated prelamin A induces the accumulation of toxic progerin in patient cells. Here, we show that a microRNA, miR-9, negatively controls lamin A and progerin expression in neural cells. This may bear major functional correlates, as alleviation of nuclear blebbing is observed in nonneural cells after miR-9 overexpression. Our results support the hypothesis, recently proposed from analyses in mice, that protection of neural cells from progerin accumulation in HGPS is due to the physiologically restricted expression of miR-9 to that cell lineage.

  3. Unique preservation of neural cells in Hutchinson- Gilford progeria syndrome is due to the expression of the neural-specific miR-9 microRNA.

    Science.gov (United States)

    Nissan, Xavier; Blondel, Sophie; Navarro, Claire; Maury, Yves; Denis, Cécile; Girard, Mathilde; Martinat, Cécile; De Sandre-Giovannoli, Annachiara; Levy, Nicolas; Peschanski, Marc

    2012-07-26

    One puzzling observation in patients affected with Hutchinson-Gilford progeria syndrome (HGPS), who overall exhibit systemic and dramatic premature aging, is the absence of any conspicuous cognitive impairment. Recent studies based on induced pluripotent stem cells derived from HGPS patient cells have revealed a lack of expression in neural derivatives of lamin A, a major isoform of LMNA that is initially produced as a precursor called prelamin A. In HGPS, defective maturation of a mutated prelamin A induces the accumulation of toxic progerin in patient cells. Here, we show that a microRNA, miR-9, negatively controls lamin A and progerin expression in neural cells. This may bear major functional correlates, as alleviation of nuclear blebbing is observed in nonneural cells after miR-9 overexpression. Our results support the hypothesis, recently proposed from analyses in mice, that protection of neural cells from progerin accumulation in HGPS is due to the physiologically restricted expression of miR-9 to that cell lineage.

  4. Reading, Mathematics and Fine Motor Skills at 5 Years of Age in US Children who were Extremely Premature at Birth.

    Science.gov (United States)

    Lee, Miryoung; Pascoe, John M; McNicholas, Caroline I

    2017-01-01

    Objectives The prevalence of extreme prematurity at birth has increased, but little research has examined its impact on developmental outcomes in large representative samples within the United States. This study examined the association of extreme prematurity with kindergarteners' reading skills, mathematics skills and fine motor skills. Methods The early childhood longitudinal study-birth cohort, a representative sample of the US children born in 2001 was analyzed for this study. Early reading and mathematics skills and fine motor skills were compared among 200 extremely premature children (EPC) (gestational age sampling weights, children's age, race, sex, and general health status, and parental marital status and education among singleton children. Results At age 5 years, EPC were 2.6(95 % CI 1.7-3.8) times more likely to fail build a gate and were 3.1(95 % CI 1.6-5.8) times more likely to fail all four drawing tasks compared to TC (p values gate, 1.3[95 % CI 1.0-1.7]; failed to draw all four shapes, 1.1[95 % CI 0.8-1.6]) was not significantly different from TC. Mean early reading scale score (36.8[SE:1.3]) of EPC was 4.0 points lower than TC (p value sample of infants, the biological risk of extreme prematurity persists after adjusting for other factors related to development.

  5. Vanishing honey bees: Is the dying of adult worker bees a consequence of short telomeres and premature aging?

    Science.gov (United States)

    Stindl, Reinhard; Stindl, Wolfgang

    2010-10-01

    Einstein is often quoted to have said that without the bee, mankind would have but 4years to live. It is highly unlikely that he made this comment, which was even mentioned in a Lancet article on honey bees. However, the current vanishing of the bees can have serious consequences for human health, because 35% of the human diet is thought to benefit from pollination. Colony collapse disorder (CCD) in honey bees is characterized by the rapid decline of the adult bee population, leaving the brood and the queen poorly or completely unattended, with no dead bodies in or around the hive. A large study found no evidence that the presence or amount of any individual pesticide or infectious agent occurred more frequently or abundantly in CCD-affected colonies. The growing consensus is that honey bees are suffering from comprised immune systems, which allow various infectious pathogens to invade. The question remains, what causes immunosuppression in many colonies of Apis mellifera in North America and Europe? Telomeres are protective DNA structures located at eukaryotic chromosome tips that shorten in the somatic tissues of animals with age. Lifelong tissue regeneration takes place in Apis mellifera, and worker bees have been shown to senesce. In humans, a vast amount of literature has accumulated on exhausted telomere reserves causing impaired tissue regeneration and age-associated diseases, specifically cancer and immunosuppression. Therefore, we propose a new causative mechanism for the vanishing of the bees: critically short telomeres in long-lived winter bees. We term this the telomere premature aging syndrome. Copyright 2010 Elsevier Ltd. All rights reserved.

  6. 过氧化氢诱导的人正常和早老细胞中DNA损伤及其修复研究%The Study of Hydrogen Peroxide Induced DNA Damage and Recovery in Normal Aging and Premature Aging Human Cells

    Institute of Scientific and Technical Information of China (English)

    所起凤; 杜文婷; 杨鸣鸣; 范雪娇; 刘戟

    2011-01-01

    目的 研究人早老细胞和正常衰老细胞在氧化应激条件下的DNA损伤和修复.方法 采用免疫荧光技术和彗星电泳技术,分别检测3组不同群体倍增数(PD)的人正常二倍体成纤维细胞BJ(青年组第14代,成年组第30代,衰老组第45代)和2组不同PD的人赫-吉二氏综合征(HGPS)细胞(青年组第8代,衰老组第17代)的DNA基础损伤程度.研究过氧化氢诱导造成以上细胞组DNA损伤及去除致损因素正常培养后的修复水平,采用免疫荧光和彗星电泳技术检测细胞在沉默DNA损伤修复蛋白着色性干皮病蛋白A(XPA)表达前后的修复能力.结果 BJ细胞衰老组DNA损伤程度较高,与成年组相比,对DNA损伤诱导因子更加敏感(P<0.05);成年组与青年组相比,对损伤诱导因子也更敏感(P<0.05).HGPS细胞青年组的DNA基础损伤程度即已达到衰老BJ细胞类似或更高水平,且与BJ细胞具有一致的DNA损伤年龄变化趋势.经siRNA沉默XPA表达后可部分恢复HGPS细胞的修复能力,对BJ细胞则没有影响.随年龄增长无论正常还是早老细胞,DNA损伤程度增加,修复效率降低.结论 XPA功能异常抑制了HGPS细胞的损伤修复.%Objective To study the DNA damage and recovery induced by hydrogen peroxide in normal aging and premature aging human cells. Methods The immunofluorescent assay and comet assay were used to estimate basal DNA damage in normal aging BJ cells and premature aging Hutchinson-Gilford progeria syndrome (HGPS) cells, which were divided into three and two distinct population doubling (PD) number groups (BJ 14· 30, 45 and HGPS 8, 17) respectively. The DNA damage induced by hydrogen peroxide of these cell populations, as well as their repair activity, was also studied. Finally, the recovery capability before and after the xeroderma pigmentosum group A (XPA ) knocked down in these groups was measured. Results Our results indicated that the normal BJ cells of older PD number

  7. Proteomic profiling of adipose tissue from Zmpste24-/- mice, a model of lipodystrophy and premature aging, reveals major changes in mitochondrial function and vimentin processing.

    Science.gov (United States)

    Peinado, Juan R; Quirós, Pedro M; Pulido, Marina R; Mariño, Guillermo; Martínez-Chantar, Maria L; Vázquez-Martínez, Rafael; Freije, José M P; López-Otín, Carlos; Malagón, María M

    2011-11-01

    Lipodystrophy is a major disease involving severe alterations of adipose tissue distribution and metabolism. Mutations in genes encoding the nuclear envelope protein lamin A or its processing enzyme, the metalloproteinase Zmpste24, cause diverse human progeroid syndromes that are commonly characterized by a selective loss of adipose tissue. Similarly to humans, mice deficient in Zmpste24 accumulate prelamin A and display phenotypic features of accelerated aging, including lipodystrophy. Herein, we report the proteome and phosphoproteome of adipose tissue as well as serum metabolome in lipodystrophy by using Zmpste24(-/-) mice as experimental model. We show that Zmpste24 deficiency enhanced lipolysis, fatty acid biogenesis and β-oxidation as well as decreased fatty acid re-esterification, thus pointing to an increased partitioning of fatty acid toward β-oxidation and away from storage that likely underlies the observed size reduction of Zmpste24-null adipocytes. Besides the mitochondrial proteins related to lipid metabolism, other protein networks related to mitochondrial function, including those involved in tricarboxylic acid cycle and oxidative phosphorylation, were up-regulated in Zmpste24(-/-) mice. These results, together with the observation of an increased mitochondrial response to oxidative stress, support the relationship between defective prelamin A processing and mitochondrial dysfunction and highlight the relevance of oxidative damage in lipoatrophy and aging. We also show that absence of Zmpste24 profoundly alters the processing of the cytoskeletal protein vimentin and identify a novel protein dysregulated in lipodystrophy, High-Mobility Group Box-1 Protein. Finally, we found several lipid derivates with important roles in energy balance, such as Lysophosphatidylcholine or 2-arachidonoylglycerol, to be dysregulated in Zmpste24(-/-) serum. Together, our findings in Zmpste24(-/-) mice may be useful to unveil the mechanisms underlying adipose tissue

  8. Impact of Oxidative Stress in Premature Aging and Iron Overload in Hemodialysis Patients

    Science.gov (United States)

    Hernández Vázquez, Wendy Ivett; Solorio-Meza, Sergio; Albarrán-Tamayo, Froylán; Ramos-Rodríguez, Edna; Benítez- Bribiesca, Luis

    2016-01-01

    Background. Increased oxidative stress is a well described feature of patients in hemodialysis. Their need for multiple blood transfusions and supplemental iron causes a significant iron overload that has recently been associated with increased oxidation of polyunsaturated lipids and accelerated aging due to DNA damage caused by telomere shortening. Methods. A total of 70 patients were evaluated concomitantly, 35 volunteers with ferritin levels below 500 ng/mL (Group A) and 35 volunteers with ferritin levels higher than 500 ng/mL (Group B). A sample of venous blood was taken to extract DNA from leukocytes and to measure relative telomere length by real-time PCR. Results. Patients in Group B had significantly higher plasma TBARS (p = 0.008), carbonyls (p = 0.0004), and urea (p = 0.02) compared with those in Group A. Telomeres were significantly shorter in Group B, 0.66 (SD, 0.051), compared with 0.75 (SD, 0.155) in Group A (p = 0.0017). We observed a statistically significant association between relative telomere length and ferritin levels (r = −0.37, p = 0.001). Relative telomere length was inversely related to time on hemodialysis (r = −0.27, p = 0.02). Conclusions. Our findings demonstrate that iron overload was associated with increased levels of oxidative stress and shorter relative telomere length. PMID:27800120

  9. Progeria: Translational insights from cell biology

    Science.gov (United States)

    Gordon, Leslie B.; Cao, Kan

    2012-01-01

    Cell biologists love to think outside the box, pursuing many surprising twists and unexpected turns in their quest to unravel the mysteries of how cells work. But can cell biologists think outside the bench? We are certain that they can, and clearly some already do. To encourage more cell biologists to venture into the realm of translational research on a regular basis, we would like to share a handful of the many lessons that we have learned in our effort to develop experimental treatments for Hutchinson-Gilford progeria syndrome (HGPS), an endeavor that many view as a “poster child” for how basic cell biology can be translated to the clinic. PMID:23027899

  10. Prematurely delivered rats show improved motor coordination during sensory-evoked motor responses compared to age-matched controls.

    Science.gov (United States)

    Roberto, Megan E; Brumley, Michele R

    2014-05-10

    The amount of postnatal experience for perinatal rats was manipulated by delivering pups one day early (postconception day 21; PC21) by cesarean delivery and comparing their motor behavior to age-matched controls on PC22 (the typical day of birth). On PC22, pups were tested on multiple measures of motor coordination: leg extension response (LER), facial wiping, contact righting, and fore- and hindlimb stepping. The LER and facial wiping provided measures of synchronous hind- and forelimb coordination, respectively, and were sensory-evoked. Contact righting also was sensory-evoked and provided a measure of axial coordination. Stepping provided a measure of alternated forelimb and hindlimb coordination and was induced with the serotonin receptor agonist quipazine. Pups that were delivered prematurely and spent an additional day in the postnatal environment showed more bilateral limb coordination during expression of the LER and facial wiping, as well as a more mature righting strategy, compared to controls. These findings suggest that experience around the time of birth shapes motor coordination and the expression of species-typical behavior in the developing rat.

  11. Lamin A-dependent nuclear defects in human aging.

    Science.gov (United States)

    Scaffidi, Paola; Misteli, Tom

    2006-05-19

    Mutations in the nuclear structural protein lamin A cause the premature aging syndrome Hutchinson-Gilford progeria (HGPS). Whether lamin A plays any role in normal aging is unknown. We show that the same molecular mechanism responsible for HGPS is active in healthy cells. Cell nuclei from old individuals acquire defects similar to those of HGPS patient cells, including changes in histone modifications and increased DNA damage. Age-related nuclear defects are caused by sporadic use, in healthy individuals, of the same cryptic splice site in lamin A whose constitutive activation causes HGPS. Inhibition of this splice site reverses the nuclear defects associated with aging. These observations implicate lamin A in physiological aging.

  12. Helicobacter pylori colonization and pregnancies complicated by preeclampsia, spontaneous prematurity, and small for gestational age birth.

    Science.gov (United States)

    den Hollander, Wouter J; Schalekamp-Timmermans, Sarah; Holster, I Lisanne; Jaddoe, Vincent W; Hofman, Albert; Moll, Henriëtte A; Perez-Perez, Guillermo I; Blaser, Martin J; Steegers, Eric A P; Kuipers, Ernst J

    2017-04-01

    Preeclampsia (PE), small for gestational age (SGA), and spontaneous preterm birth (PTB) each may be complications of impaired placental function in pregnancy. Although their exact pathogenesis is still unknown, certain infectious agents seem to play a role. Helicobacter pylori (H. pylori) colonization has been associated with increased risk for PE. Our aim was to assess the association between H. pylori colonization and PE, SGA, and PTB. We measured IgG anti-H. pylori and CagA antibodies in serum of pregnant women (median 20.5 weeks, range 16.5-29.4) who participated in a population-based prospective cohort study. Delivery and medical records were assessed. Information on demographics, education, and maternal risk factors was collected by questionnaire. We used multivariate logistic regression analyses to assess associations between H. pylori colonization and PE, SGA, and PTB. In total, 6348 pregnant women were assessed. H. pylori positivity was found in 2915 (46%) women, of whom 1023 (35%) also were CagA-positive. Pregnancy was complicated by PE, SGA, or PTB in 927 (15%) women. H. pylori colonization was associated with PE (aOR 1.51; 95%CI 1.03-2.25). Differentiation according to CagA status revealed the same risk. H. pylori was positively related with SGA, mainly explained by CagA-positive strains (aOR 1.34; 1.04-1.71). No association was observed between H. pylori and PTB. Our data suggest that H. pylori colonization may be a risk factor for PE and SGA. If these associations are confirmed by future studies and shown to be causal, H. pylori eradication may reduce related perinatal morbidity and mortality. © 2016 John Wiley & Sons Ltd.

  13. NF-κB activation impairs somatic cell reprogramming in ageing.

    Science.gov (United States)

    Soria-Valles, Clara; Osorio, Fernando G; Gutiérrez-Fernández, Ana; De Los Angeles, Alejandro; Bueno, Clara; Menéndez, Pablo; Martín-Subero, José I; Daley, George Q; Freije, José M P; López-Otín, Carlos

    2015-08-01

    Ageing constitutes a critical impediment to somatic cell reprogramming. We have explored the regulatory mechanisms that constitute age-associated barriers, through derivation of induced pluripotent stem cells (iPSCs) from individuals with premature or physiological ageing. We demonstrate that NF-κB activation blocks the generation of iPSCs in ageing. We also show that NF-κB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-κB hyperactivation impairs the generation of iPSCs by eliciting the reprogramming repressor DOT1L, which reinforces senescence signals and downregulates pluripotency genes. Genetic and pharmacological NF-κB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Néstor-Guillermo progeria syndrome and Hutchinson-Gilford progeria syndrome patients, as well as from normal aged donors. Finally, we demonstrate that DOT1L inhibition in vivo extends lifespan and ameliorates the accelerated ageing phenotype of progeroid mice, supporting the interest of studying age-associated molecular impairments to identify targets of rejuvenation strategies.

  14. An Influence of Birth Weight, Gestational Age, and Apgar Score on Pattern Visual Evoked Potentials in Children with History of Prematurity

    Directory of Open Access Journals (Sweden)

    Marta Michalczuk

    2015-01-01

    Full Text Available Purpose. The objective of our study was to examine a possible influence of gestational age, birth weight, and Apgar score on amplitudes and latencies of P100 wave in preterm born school-age children. Materials and Methods. We examined the following group of school-age children: 28 with history of prematurity (mean age 10.56 ± 1.66 years and 25 born at term (mean age 11.2 ± 1.94 years. The monocular PVEP was performed in all children. Results. The P100 wave amplitudes and latencies significantly differ between preterm born school-age children and those born at term. There was an essential positive linear correlation of the P100 wave amplitudes with birth weight, gestational age, and Apgar score. There were the negative linear correlations of P100 latencies in 15-minute stimulation from O1 and Oz electrode with Apgar score and O1 and O2 electrode with gestational age. Conclusions. PVEP responses vary in preterm born children in comparison to term. Low birth weight, early gestational age, and poor baseline output seem to be the predicting factors for the developmental rate of a brain function in children with history of prematurity. Further investigations are necessary to determine perinatal factors that can affect the modified visual system function in preterm born children.

  15. Agreement between grating acuity at age 1 year and Snellen acuity at age 5.5 years in the preterm child. Cryotherapy for Retinopathy of Prematurity Cooperative Group.

    Science.gov (United States)

    Dobson, V; Quinn, G E; Siatkowski, R M; Baker, J D; Hardy, R J; Reynolds, J D; Trese, M T; Tung, B

    1999-02-01

    To examine the relation between grating acuity at age 1 year and Snellen acuity and grating acuity at 5.5 years, in preterm children with birth weights less than 1251 g. Subjects were participants in the multicenter study of Cryotherapy for Retinopathy of Prematurity. The Teller acuity card (TAC; Vistech Consultants, Dayton, OH) procedure was used to measure monocular grating acuity in children at ages 1 and 5.5 years. Early-treatment diabetic retinopathy study (ETDRS) charts were used to measure the childrens' monocular recognition (Snellen) acuity at age 5.5 years. Data are presented for 575 eyes with measurable TAC grating acuity at 1 year and 111 eyes that had no measurable acuity at 1 year. Among eyes with normal acuity at 1 year, 86.8% showed normal Snellen acuity, and 94.3% showed normal grating acuity at 5.5 years. Among eyes that were blind (i.e., had no measurable TAC grating acuity) at 1 year, 96.8% showed no quantifiable Snellen acuity, and 89.2% showed no quantifiable grating acuity at 5.5 years. Only 2.4% of eyes had acuity in the range between normal and blind at 1 year (i.e., measurable grating acuity Snellen and grating acuity at age 5.5 years, and eyes that had no quantifiable acuity at 1 year remained blind at 5.5 years. Relative position of an eye's acuity score within the normal range was not predictive of the relative position of that eye's later acuity score.

  16. Your Premature Baby

    Science.gov (United States)

    ... birth defects, premature birth and infant mortality. Solving premature birth Featured articles Accomplishments and lessons learned since ... Complications & Loss > Preterm labor & premature birth > Premature babies Premature babies E-mail to a friend Please fill ...

  17. Interruption of progerin–lamin A/C binding ameliorates Hutchinson-Gilford progeria syndrome phenotype

    Science.gov (United States)

    Lee, Su-Jin; Jung, Youn-Sang; Yoon, Min-Ho; Kang, So-mi; Oh, Ah-Young; Lee, Jee-Hyun; Jun, So-Young; Woo, Tae-Gyun; Chun, Ho-Young; Kim, Sang Kyum; Chung, Kyu Jin; Lee, Ho-Young; Lee, Kyeong; Jin, Guanghai; Na, Min-Kyun; Ha, Nam Chul; Bárcena, Clea; Freije, José M.P.; López-Otín, Carlos; Song, Gyu Yong

    2016-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant genetic disease that is caused by a silent mutation of the LMNA gene encoding lamins A and C (lamin A/C). The G608G mutation generates a more accessible splicing donor site than does WT and produces an alternatively spliced product of LMNA called progerin, which is also expressed in normal aged cells. In this study, we determined that progerin binds directly to lamin A/C and induces profound nuclear aberrations. Given this observation, we performed a random screening of a chemical library and identified 3 compounds (JH1, JH4, and JH13) that efficiently block progerin–lamin A/C binding. These 3 chemicals, particularly JH4, alleviated nuclear deformation and reversed senescence markers characteristic of HGPS cells, including growth arrest and senescence-associated β-gal (SA–β-gal) activity. We then used microarray-based analysis to demonstrate that JH4 is able to rescue defects of cell-cycle progression in both HGPS and aged cells. Furthermore, administration of JH4 to LmnaG609G/G609G-mutant mice, which phenocopy human HGPS, resulted in a marked improvement of several progeria phenotypes and an extended lifespan. Together, these findings indicate that specific inhibitors with the ability to block pathological progerin–lamin A/C binding may represent a promising strategy for improving lifespan and health in both HGPS and normal aging. PMID:27617860

  18. Interruption of progerin-lamin A/C binding ameliorates Hutchinson-Gilford progeria syndrome phenotype.

    Science.gov (United States)

    Lee, Su-Jin; Jung, Youn-Sang; Yoon, Min-Ho; Kang, So-Mi; Oh, Ah-Young; Lee, Jee-Hyun; Jun, So-Young; Woo, Tae-Gyun; Chun, Ho-Young; Kim, Sang Kyum; Chung, Kyu Jin; Lee, Ho-Young; Lee, Kyeong; Jin, Guanghai; Na, Min-Kyun; Ha, Nam Chul; Bárcena, Clea; Freije, José M P; López-Otín, Carlos; Song, Gyu Yong; Park, Bum-Joon

    2016-10-03

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant genetic disease that is caused by a silent mutation of the LMNA gene encoding lamins A and C (lamin A/C). The G608G mutation generates a more accessible splicing donor site than does WT and produces an alternatively spliced product of LMNA called progerin, which is also expressed in normal aged cells. In this study, we determined that progerin binds directly to lamin A/C and induces profound nuclear aberrations. Given this observation, we performed a random screening of a chemical library and identified 3 compounds (JH1, JH4, and JH13) that efficiently block progerin-lamin A/C binding. These 3 chemicals, particularly JH4, alleviated nuclear deformation and reversed senescence markers characteristic of HGPS cells, including growth arrest and senescence-associated β-gal (SA-β-gal) activity. We then used microarray-based analysis to demonstrate that JH4 is able to rescue defects of cell-cycle progression in both HGPS and aged cells. Furthermore, administration of JH4 to LmnaG609G/G609G-mutant mice, which phenocopy human HGPS, resulted in a marked improvement of several progeria phenotypes and an extended lifespan. Together, these findings indicate that specific inhibitors with the ability to block pathological progerin-lamin A/C binding may represent a promising strategy for improving lifespan and health in both HGPS and normal aging.

  19. Lamin A, farnesylation and aging

    Energy Technology Data Exchange (ETDEWEB)

    Reddy, Sita [Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 (United States); Comai, Lucio, E-mail: comai@usc.edu [Department of Molecular Microbiology and Immunology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 (United States)

    2012-01-01

    Lamin A is a component of the nuclear envelope that is synthesized as a precursor prelamin A molecule and then processed into mature lamin A through sequential steps of posttranslational modifications and proteolytic cleavages. Remarkably, over 400 distinct point mutations have been so far identified throughout the LMNA gene, which result in the development of at least ten distinct human disorders, collectively known as laminopathies, among which is the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). The majority of HGPS cases are associated with a single point mutation in the LMNA gene that causes the production of a permanently farnesylated mutant lamin A protein termed progerin. The mechanism by which progerin leads to premature aging and the classical HGPS disease phenotype as well as the relationship between this disorder and the onset of analogous symptoms during the lifespan of a normal individual are not well understood. Yet, recent studies have provided critical insights on the cellular processes that are affected by accumulation of progerin and have suggested that cellular alterations in the lamin A processing pathway leading to the accumulation of farnesylated prelamin A intermediates may play a role in the aging process in the general population. In this review we provide a short background on lamin A and its maturation pathway and discuss the current knowledge of how progerin or alterations in the prelamin A processing pathway are thought to influence cell function and contribute to human aging.

  20. Osteopenia - premature infants

    Science.gov (United States)

    Neonatal rickets; Brittle bones - premature infants; Weak bones - premature infants; Osteopenia of prematurity ... the baby. This helps the baby grow. A premature infant may not receive the proper amount of ...

  1. Genetics Home Reference: Werner syndrome

    Science.gov (United States)

    ... for This Condition Adult premature aging syndrome Adult Progeria Werner's Syndrome Werners Syndrome WS Related Information How ... BK, Monnat RJ Jr. Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nat ...

  2. Loss of H3K9me3 Correlates with ATM Activation and Histone H2AX Phosphorylation Deficiencies in Hutchinson-Gilford Progeria Syndrome

    Science.gov (United States)

    Zhang, Haoyue; Sun, Linlin; Wang, Kun; Wu, Di; Trappio, Mason; Witting, Celeste; Cao, Kan

    2016-01-01

    Compelling evidence suggests that defective DNA damage response (DDR) plays a key role in the premature aging phenotypes in Hutchinson-Gilford progeria syndrome (HGPS). Studies document widespread alterations in histone modifications in HGPS cells, especially, the global loss of histone H3 trimethylated on lysine 9 (H3K9me3). In this study, we explore the potential connection(s) between H3K9me3 loss and the impaired DDR in HGPS. When cells are exposed to a DNA-damaging agent Doxorubicin (Dox), double strand breaks (DSBs) are generated that result in the phosphorylation of histone H2A variant H2AX (gammaH2AX) within an hour. We find that the intensities of gammaH2AX foci appear significantly weaker in the G0/G1 phase HGPS cells compared to control cells. This reduction is associated with a delay in the recruitment of essential DDR factors. We further demonstrate that ataxia-telangiectasia mutated (ATM) is responsible for the amplification of gammaH2AX signals at DSBs during G0/G1 phase, and its activation is inhibited in the HGPS cells that display significant loss of H3K9me3. Moreover, methylene (MB) blue treatment, which is known to save heterochromatin loss in HGPS, restores H3K9me3, stimulates ATM activity, increases gammaH2AX signals and rescues deficient DDR. In summary, this study demonstrates an early DDR defect of attenuated gammaH2AX signals in G0/G1 phase HGPS cells and provides a plausible connection between H3K9me3 loss and DDR deficiency. PMID:27907109

  3. Oral and maxillofacial surgical considerations for a case of Hutchinson-Gilford progeria.

    Science.gov (United States)

    Batstone, M D; Macleod, A W G

    2002-11-01

    Hutchinson-Guilford progeria is a rare genetic condition showing the stigmata of accelerated ageing combined with severe growth retardation. Patients with this condition show a classical facies and clinical features with an average age of death of 13, usually due to atherosclerotic changes. Craniofacial and dental manifestations include mandibular and maxillary hypoplasia, both vertically and horizontally. Delayed and abnormal tooth eruption and morphology are commonly present. The long-term medical prognosis and eruption potential of individual teeth is important when considering treatment. In addition to this, surgical planning and surgical technique must be modified by the abnormal facial morphology, dermal inelasticity, potential anaesthetic difficulties, and ongoing deterioration in the medical condition. These factors mandate early and definitive intervention for oral surgical conditions. We report the case of a 13-year-old male treated for pericoronitis and oral pain relating to delayed eruption of first permanent molars.

  4. Cardiovascular follow-up at school age after perinatal glucocorticoid exposure in prematurely born children: perinatal glucocorticoid therapy and cardiovascular follow-up.

    Science.gov (United States)

    de Vries, Willem B; Karemaker, Rosa; Mooy, Nicole F; Strengers, Jan L M; Kemperman, Hans; Baerts, Wim; Veen, Sylvia; Visser, Gerard H A; Heijnen, Cobi J; van Bel, Frank

    2008-08-01

    To study whether antenatal or neonatal glucocorticoid therapy to reduce the incidence and severity of chronic lung disease in preterm infants is associated with long-term adverse cardiac effects and hypertension. Retrospective matched-cohort study. Outpatient clinic of a tertiary care hospital. One hundred ninety-three children aged 7 to 10 years who had been born prematurely between December 2, 1993, and September 15, 1997. Main Exposure Neonatal treatment with dexamethasone disodium phosphate(n = 48) or the clinically equally effective glucocorticoid hydrocortisone (n = 51), or only antenatal treatment with betamethasone disodium phosphate and betamethasone acetate (n = 51). These 3 groups were compared with a reference group of prematurely born children who had not been exposed to perinatal glucocorticoid therapy (n = 43). General hemodynamic data (heart rate and blood pressure), cardiovascular function as assessed at echocardiography, intima-media thickness of the carotid arteries, and cardiac biochemical features as early markers of expansion and volume overload of the cardiac left ventricle (B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide). No significant group differences were found for heart rate, blood pressure, biochemical features, intima-media thickness, or systolic or diastolic left ventricular function. Although no differences were found in blood pressure and cardiovascular function at school age in children antenatally or neonatally treated with glucocorticoids, further cardiovascular follow-up may be advisable because cardiovascular dysfunction may become apparent only later in life.

  5. Premature delivery

    Directory of Open Access Journals (Sweden)

    Bernardita Donoso Bernales

    2012-09-01

    Full Text Available Preterm delivery is the single most important cause of perinatal morbidity and mortality. In Chile, preterm births have increased in the past decade, although neonatal morbidity and mortality attributable to it shows a downward trend, thanks to improvements in neonatal care of premature babies, rather than the success of obstetric preventive and therapeutic strategies. This article describes clinical entities, disease processes and conditions that constitute predisposing factors of preterm birth, as well as an outline for the prevention and clinical management of women at risk of preterm birth.

  6. Roles of the nucleoporin Tpr in cancer and aging.

    Science.gov (United States)

    Snow, Chelsi J; Paschal, Bryce M

    2014-01-01

    Tpr is a prominent architectural component of the nuclear pore complex that forms the basket-like structure on the nucleoplasmic side of the pore. Tpr, which stands for translocated promoter region, was originally described in the context of oncogenic fusions with the receptor tyrosine kinases Met, TRK, and Raf. Tpr has been since implicated in a variety of nuclear functions, including nuclear transport, chromatin organization, regulation of transcription, and mitosis. More recently, Tpr function has been linked to events including p53 signaling and premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS). Here we provide an overview of the various processes that involve Tpr, and discuss how the levels and localization of a single protein can affect diverse pathways in the cell.

  7. [The age and sex indicators of mortality of population and years of life lost as a result of premature mortality in the Russian Federation in 2012].

    Science.gov (United States)

    Boiytsov, S A; Samorodskaya, I V

    2014-01-01

    The age-specific mortality coefficients and years of life lost as a result of premature mortality are among important medical demographic characteristics of population health. The study analyzed age and sex indicators of mortality of population in the Russian Federation. The number of years of life lost as a result of premature mortality is calculated. The comparison of values of years of life lost in various subjects of the Russian Federation was carried out. The data of Rosstat concerning population size and number of the deceased in year age groups in the Russian Federation and subjects of the Russian Federation in 2012 was used. The indicator was calculated on the basis of technique included into "The global burden of diseases report" (2010). The minimal indicators of mortality of males are noted at the age of 11 years (25.4 per 100 000 of population) and females at the age of 10 years (18.2 per 100 000 of population). The maximal differences in indicators of mortality of males and females are marked in the age group 20-29 years (314.5 of males and 92.3 of females per 100 000 of population). The percentage of deceased prior 70 years consists 63.2% among males and 29.9% among females. The total number of years of life lost in the Russian Federation consisted 36 864 309 and out of them 24 321 992 (65.9%) as a result of death of males and 12 542 317 (34.1%) as a result of death of females. The maximum percentage of years of life lost among males is marked in the age group of 51-60 years (24.61%) and among females in the age group of 71-80 years (22.38%). The indicator of years of life lost per 100 000 of population consisted 25769 for total population, 36 753 for male population and 16 314 for female population. The highest rate of indicator of years of life lost is marked in the Chukchi Autonomous Okrug and the lowest rate in the Republics of the Northern Caucasus and Moscow. However, in all subjects of the Russian Federation indicator of years of life lost is

  8. Hip pathology in Hutchinson-Gilford progeria syndrome: a report of two children.

    Science.gov (United States)

    Akhbari, Pouya; Jha, Shilpa; James, Kyle D; Hinves, Barry L; Buchanan, Jamie A F

    2012-11-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder. The estimated incidence is one in 4 million births. Orthopaedic manifestations include abnormality of the hips occurring early in the disease process. Severe coxa valga can be apparent by the age of 2 years. We report two cases of HGPS, one in a 7-year-old girl with avascular necrosis of the left hip and the second in a 13-year-old girl with recurrent traumatic hip dislocations. We demonstrate the pathoanatomical changes in the hip with HGPS using a combination of imaging modalities including radiographic, computed tomographic and MRI scans. These include coxa magna, coxa valga and acetabular dysplasia. We also comment on how these would affect the surgical management of this high-risk group of patients.

  9. A hyperoxic lung injury model in premature rabbits: the influence of different gestational ages and oxygen concentrations.

    Directory of Open Access Journals (Sweden)

    Roberta Munhoz Manzano

    Full Text Available BACKGROUND: Many animal models have been developed to study bronchopulmonary dysplasia (BPD. The preterm rabbit is a low-cost, easy-to-handle model, but it has a high mortality rate in response to the high oxygen concentrations used to induce lung injury. The aim of this study was to compare the mortality rates of two models of hyperoxia-induced lung injury in preterm rabbits. METHODS: Pregnant New Zealand white rabbits were subjected to caesarean section on gestational day 28 or 29 (full term  = 31 days. The premature rabbits in the 28-day gestation group were exposed to room air or FiO₂ ≥95%, and the rabbits in the 29-day gestation group were exposed to room air or FiO₂  = 80% for 11 days. The mean linear intercept (Lm, internal surface area (ISA, number of alveoli, septal thickness and proportion of elastic and collagen fibers were quantified. RESULTS: The survival rates in the 29-day groups were improved compared with the 28-day groups. Hyperoxia impaired the normal development of the lung, as demonstrated by an increase in the Lm, the septal thickness and the proportion of elastic fibers. Hyperoxia also decreased the ISA, the number of alveoli and the proportion of collagen fibers in the 28-day oxygen-exposed group compared with the control 28-day group. A reduced number of alveoli was found in the 29-day oxygen exposed animals compared with the control 29-day group. CONCLUSIONS: The 29-day preterm rabbits had a reduced mortality rate compared with the 28-day preterm rabbits and maintained a reduction in the alveoli number, which is comparable to BPD in humans.

  10. Premature Ventricular Contractions (PVCs)

    Science.gov (United States)

    Diseases and Conditions Premature ventricular contractions (PVCs) By Mayo Clinic Staff Premature ventricular contractions (PVCs) are extra, abnormal heartbeats that begin in one of your heart's two ...

  11. Inactivation of RAD52 and HDF1 DNA repair genes leads to premature chronological aging and cellular instability

    Indian Academy of Sciences (India)

    SILVIA MERCADO-SÁENZ; BEATRIZ LÓPEZ-DÍAZ; FRANCISCO SENDRA-PORTERO; MANUEL MARTÍNEZ-MORILLO; MIGUEL J RUIZ-GÓMEZ

    2017-06-01

    The present study aims to investigate the role of radiation sensitive 52 (RAD52) and high-affinity DNA binding factor1 (HDF1) DNA repair genes on the life span of budding yeasts during chronological aging. Wild type (wt) and rad52,hdf1, and rad52 hdf1 mutant Saccharomyces cerevisiae strains were used. Chronological aging and survival assayswere studied by clonogenic assay and drop test. DNA damage was analyzed by electrophoresis after phenol extraction.Mutant analysis, colony forming units and the index of respiratory competence were studied by growing on dextroseand glycerol plates as a carbon source. Rad52 and rad52 hdf1 mutants showed a gradual decrease in surviving fractionin relation to wt and hdf1 mutant during aging. Genomic DNA was spontaneously more degraded during aging,mainly in rad52 mutants. This strain showed an increased percentage of revertant colonies. Moreover, all mutantsshowed a decrease in the index of respiratory competence during aging. The inactivation of RAD52 leads to prematurechronological aging with an increase in DNA degradation and mutation frequency. In addition, RAD52 and HDF1contribute to maintain the metabolic state, in a different way, during chronological aging. The results obtained couldhave important implications in the chronobiology of aging.

  12. Premature ejaculation

    Directory of Open Access Journals (Sweden)

    Chris G McMahon

    2007-01-01

    Full Text Available Premature ejaculation (PE is a common male sexual disorder. Recent normative data suggests that men with an intravaginal ejaculatory latency time (IELT of less than 1 minute have "definite" PE, while men with IELTs between 1 and 1.5 minutes have "probable" PE. Although there is insufficient empirical evidence to identify the etiology of PE, there is limited correlational evidence to suggest that men with PE have high levels of sexual anxiety and inherited altered sensitivity of central 5-HT (5-hydroxytryptamine, serotonin receptors. Pharmacological modulation of the ejaculatory threshold using off-label daily or on-demand selective serotonin re-uptake inhibitors is well tolerated and offers patients a high likelihood of achieving improved ejaculatory control within a few days of initiating treatment, consequential improvements in sexual desire and other sexual domains. Investigational drugs such as the ejaculo-selective serotonin transport inhibitor, dapoxetine represent a major development in sexual medicine. These drugs offer patients the convenience of on-demand dosing, significant improvements in IELT, ejaculatory control and sexual satisfaction with minimal adverse effects.

  13. Premature ejaculation.

    Science.gov (United States)

    McMahon, Chris G

    2007-04-01

    Premature ejaculation (PE) is a common male sexual disorder. Recent normative data suggests that men with an intravaginal ejaculatory latency time (IELT) of less than 1 minute have "definite" PE, while men with IELTs between 1 and 1.5 minutes have "probable" PE. Although there is insufficient empirical evidence to identify the etiology of PE, there is limited correlational evidence to suggest that men with PE have high levels of sexual anxiety and inherited altered sensitivity of central 5-HT (5-hydroxytryptamine, serotonin) receptors. Pharmacological modulation of the ejaculatory threshold using off-label daily or on-demand selective serotonin re-uptake inhibitors is well tolerated and offers patients a high likelihood of achieving improved ejaculatory control within a few days of initiating treatment, consequential improvements in sexual desire and other sexual domains. Investigational drugs such as the ejaculo-selective serotonin transport inhibitor, dapoxetine represent a major development in sexual medicine. These drugs offer patients the convenience of on-demand dosing, significant improvements in IELT, ejaculatory control and sexual satisfaction with minimal adverse effects.

  14. Reversible cell cycle inhibition and premature aging features imposed by conditional expression of p16Ink4a

    Science.gov (United States)

    Boquoi, Amelie; Arora, Sanjeevani; Chen, Tina; Litwin, Sam; Koh, James; Enders, Greg H

    2015-01-01

    The cyclin-dependent kinase (Cdk) inhibitor p16Ink4a (p16) is a canonical mediator of cellular senescence and accumulates in aging tissues, where it constrains proliferation of some progenitor cells. However, whether p16 induction in tissues is sufficient to inhibit cell proliferation, mediate senescence, and/or impose aging features has remained unclear. To address these issues, we generated transgenic mice that permit conditional p16 expression. Broad induction at weaning inhibited proliferation of intestinal transit-amplifying and Lgr5+ stem cells and rapidly imposed features of aging, including hair loss, skin wrinkling, reduced body weight and subcutaneous fat, an increased myeloid fraction in peripheral blood, poor dentition, and cataracts. Aging features were observed with multiple combinations of p16 transgenes and transactivators and were largely abrogated by a germline Cdk4 R24C mutation, confirming that they reflect Cdk inhibition. Senescence markers were not found, and de-induction of p16, even after weeks of sustained expression, allowed rapid recovery of intestinal cell proliferation and reversal of aging features in most mice. These results suggest that p16-mediated inhibition of Cdk activity is sufficient to inhibit cell proliferation and impose aging features in somatic tissues of mammals and that at least some of these aging features are reversible. PMID:25481981

  15. Adult Stem Cells and Diseases of Aging

    Directory of Open Access Journals (Sweden)

    Lisa B. Boyette

    2014-01-01

    Full Text Available Preservation of adult stem cells pools is critical for maintaining tissue homeostasis into old age. Exhaustion of adult stem cell pools as a result of deranged metabolic signaling, premature senescence as a response to oncogenic insults to the somatic genome, and other causes contribute to tissue degeneration with age. Both progeria, an extreme example of early-onset aging, and heritable longevity have provided avenues to study regulation of the aging program and its impact on adult stem cell compartments. In this review, we discuss recent findings concerning the effects of aging on stem cells, contributions of stem cells to age-related pathologies, examples of signaling pathways at work in these processes, and lessons about cellular aging gleaned from the development and refinement of cellular reprogramming technologies. We highlight emerging therapeutic approaches to manipulation of key signaling pathways corrupting or exhausting adult stem cells, as well as other approaches targeted at maintaining robust stem cell pools to extend not only lifespan but healthspan.

  16. Temsirolimus Partially Rescues the Hutchinson-Gilford Progeria Cellular Phenotype

    Science.gov (United States)

    Gabriel, Diana; Gordon, Leslie B.

    2016-01-01

    Hutchinson-Gilford syndrome (HGPS, OMIM 176670, a rare premature aging disorder that leads to death at an average age of 14.7 years due to myocardial infarction or stroke, is caused by mutations in the LMNA gene. Lamins help maintain the shape and stability of the nuclear envelope in addition to regulating DNA replication, DNA transcription, proliferation and differentiation. The LMNA mutation results in the deletion of 50 amino acids from the carboxy-terminal region of prelamin A, producing the truncated, farnesylated protein progerin. The accumulation of progerin in HGPS nuclei causes numerous morphological and functional changes that lead to premature cellular senescence. Attempts to reverse this HGPS phenotype have identified rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), as a drug that is able to rescue the HGPS cellular phenotype by promoting autophagy and reducing progerin accumulation. Rapamycin is an obvious candidate for the treatment of HGPS disease but is difficult to utilize clinically. To further assess rapamycin’s efficacy with regard to proteostasis, mitochondrial function and the degree of DNA damage, we tested temsirolimus, a rapamycin analog with a more favorable pharmacokinetic profile than rapamycin. We report that temsirolimus decreases progerin levels, increases proliferation, reduces misshapen nuclei, and partially ameliorates DNA damage, but does not improve proteasome activity or mitochondrial dysfunction. Our findings suggest that future therapeutic strategies should identify new drug combinations and treatment regimens that target all the dysfunctional hallmarks that characterize HGPS cells. PMID:28033363

  17. Neurodevelopmental sequelae in premature newborns with extremely low weight and with very low weight at two years of age who left the Neonatal Intensive Care Unit of the Hospital Nacional Edgardo Rebagliati Martins 2009-2014

    Directory of Open Access Journals (Sweden)

    Carmen Fernández Sierra

    2017-02-01

    Full Text Available Objective: The purpose of this study is to describe the neurodevelopmental sequelae in premature newborns with extremely low weight and with very low weight at two years of age who left the Neonatal Intensive Care Unit of the Hospital Nacional Edgardo Rebagliati Martins. Materials and methods: A descriptive, retrospective, cross-sectional study in a population of 190 premature newborns with extremely low weight and with very low weight born from January 2009 to June 2014 who left the Neonatal Intensive Care Unit and took part in the follow-up program. The psychomotor development, sensorineural hearing loss, retinopathy of prematurity, presence of cerebral palsy and convulsive syndrome were assessed. Results: The average weight at birth was 1,180.53 ± 212.40 grams with a gestational age of 29.86 ± 2.33 weeks, and 51.58% of the newborns were male. Forty-two point six three percent (42.63% of the premature newborns with very low weight showed retardation of psychomotor development; 25.26%, retinopathy; 13.68%, sensorineural hearing loss; 3.68%, cerebral palsy; and 3.68%, convulsive syndrome. Fifty-two point two seven percent (52.27% of the premature newborns with extremely low weight showed retardation of psychomotor development; 50%, retinopathy; 15.91%, sensorineural hearing loss; and 2.27%, convulsive syndrome. Conclusions: Retardation of psychomotor development and retinopathy were the most important complications shown by premature newborns with extremely low weight and with very low weight at two years of age.

  18. Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model

    Science.gov (United States)

    Lavasani, Mitra; Robinson, Andria R.; Lu, Aiping; Song, Minjung; Feduska, Joseph M.; Ahani, Bahar; Tilstra, Jeremy S.; Feldman, Chelsea H.; Robbins, Paul D.; Niedernhofer, Laura J.; Huard, Johnny

    2012-01-01

    With ageing, there is a loss of adult stem cell function. However, there is no direct evidence that this has a causal role in ageing-related decline. We tested this using muscle-derived stem/progenitor cells (MDSPCs) in a murine progeria model. Here we show that MDSPCs from old and progeroid mice are defective in proliferation and multilineage differentiation. Intraperitoneal administration of MDSPCs, isolated from young wild-type mice, to progeroid mice confer significant lifespan and healthspan extension. The transplanted MDSPCs improve degenerative changes and vascularization in tissues where donor cells are not detected, suggesting that their therapeutic effect may be mediated by secreted factor(s). Indeed, young wild-type-MDSPCs rescue proliferation and differentiation defects of aged MDSPCs when co-cultured. These results establish that adult stem/progenitor cell dysfunction contributes to ageing-related degeneration and suggests a therapeutic potential of post-natal stem cells to extend health. PMID:22215083

  19. News of cognitive cure for age-related brain shrinkage is premature: a comment on Burgmans et al. (2009).

    Science.gov (United States)

    Raz, Naftali; Lindenberger, Ulman

    2010-03-01

    The extant longitudinal literature consistently supports the notion of age-related declines in human brain volume. In a report on a longitudinal cognitive follow-up with cross-sectional brain measurements, Burgmans and colleagues (2009) claim that the extant studies overestimate brain volume declines, presumably due to inclusion of participants with preclinical cognitive pathology. Moreover, the authors of the article assert that such declines are absent among optimally healthy adults who maintain cognitive stability for several years. In this comment accompanied by reanalysis of previously published data, we argue that these claims are incorrect on logical, methodological, and empirical grounds.

  20. Tissue-Specific Suppression of Thyroid Hormone Signaling in Various Mouse Models of Aging.

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    W Edward Visser

    Full Text Available DNA damage contributes to the process of aging, as underscored by premature aging syndromes caused by defective DNA repair. Thyroid state changes during aging, but underlying mechanisms remain elusive. Since thyroid hormone (TH is a key regulator of metabolism, changes in TH signaling have widespread effects. Here, we reveal a significant common transcriptomic signature in livers from hypothyroid mice, DNA repair-deficient mice with severe (Csbm/m/Xpa-/- or intermediate (Ercc1-/Δ-7 progeria and naturally aged mice. A strong induction of TH-inactivating deiodinase D3 and decrease of TH-activating D1 activities are observed in Csbm/m/Xpa-/- livers. Similar findings are noticed in Ercc1-/Δ-7, in naturally aged animals and in wild-type mice exposed to a chronic subtoxic dose of DNA-damaging agents. In contrast, TH signaling in muscle, heart and brain appears unaltered. These data show a strong suppression of TH signaling in specific peripheral organs in premature and normal aging, probably lowering metabolism, while other tissues appear to preserve metabolism. D3-mediated TH inactivation is unexpected, given its expression mainly in fetal tissues. Our studies highlight the importance of DNA damage as the underlying mechanism of changes in thyroid state. Tissue-specific regulation of deiodinase activities, ensuring diminished TH signaling, may contribute importantly to the protective metabolic response in aging.

  1. Inhibition of Mitochondrial Cytochrome c Release and Suppression of Caspases by Gamma-Tocotrienol Prevent Apoptosis and Delay Aging in Stress-Induced Premature Senescence of Skin Fibroblasts

    Directory of Open Access Journals (Sweden)

    Suzana Makpol

    2012-01-01

    Full Text Available In this study, we determined the molecular mechanism of γ-tocotrienol (GTT in preventing cellular aging by focusing on its anti-apoptotic effect in stress-induced premature senescence (SIPS model of human diploid fibroblasts (HDFs. Results obtained showed that SIPS exhibited senescent-phenotypic characteristic, increased expression of senescence-associated β-galactosidase (SA β-gal and promoted G0/G1 cell cycle arrest accompanied by shortening of telomere length with decreased telomerase activity. Both SIPS and senescent HDFs shared similar apoptotic changes such as increased Annexin V-FITC positive cells, increased cytochrome c release and increased activation of caspase-9 and caspase-3 (P<0.05. GTT treatment resulted in a significant reduction of Annexin V-FITC positive cells, inhibited cytochrome c release and decreased activation of caspase-9 and caspase-3 (P<0.05. Gene expression analysis showed that GTT treatment down regulated BAX mRNA, up-regulated BCL2A1 mRNA and decreased the ratio of Bax/Bcl-2 protein expression (P<0.05 in SIPS. These findings suggested that GTT inhibits apoptosis by modulating the upstream apoptosis cascade, causing the inhibition of cytochrome c release from the mitochondria with concomitant suppression of caspase-9 and caspase-3 activation. In conclusion, GTT delays cellular senescence of human diploid fibroblasts through the inhibition of intrinsic mitochondria-mediated pathway which involved the regulation of pro- and anti-apoptotic genes and proteins.

  2. Mutations in EXOSC2 are associated with a novel syndrome characterised by retinitis pigmentosa, progressive hearing loss, premature ageing, short stature, mild intellectual disability and distinctive gestalt.

    Science.gov (United States)

    Di Donato, Nataliya; Neuhann, Teresa; Kahlert, Anne-Karin; Klink, Barbara; Hackmann, Karl; Neuhann, Irmingard; Novotna, Barbora; Schallner, Jens; Krause, Claudia; Glass, Ian A; Parnell, Shawn E; Benet-Pages, Anna; Nissen, Anke M; Berger, Wolfgang; Altmüller, Janine; Thiele, Holger; Weber, Bernhard H F; Schrock, Evelin; Dobyns, William B; Bier, Andrea; Rump, Andreas

    2016-06-01

    Retinitis pigmentosa in combination with hearing loss can be a feature of different Mendelian disorders. We describe a novel syndrome caused by biallelic mutations in the 'exosome component 2' (EXOSC2) gene. Clinical ascertainment of three similar affected patients followed by whole exome sequencing. Three individuals from two unrelated German families presented with a novel Mendelian disorder encompassing childhood myopia, early onset retinitis pigmentosa, progressive sensorineural hearing loss, hypothyroidism, short stature, brachydactyly, recognisable facial gestalt, premature ageing and mild intellectual disability. Whole exome sequencing revealed homozygous or compound heterozygous missense variants in the EXOSC2 gene in all three patients. EXOSC2 encodes the 'ribosomal RNA-processing protein 4' (RRP4)-one of the core components of the RNA exosome. The RNA exosome is a multiprotein complex that plays key roles in RNA processing and degradation. Intriguingly, the EXOSC2-associated phenotype shows only minimal overlap with the previously reported diseases associated with mutations in the RNA exosome core component genes EXOSC3 and EXOSC8. We report a novel condition that is probably caused by altered RNA exosome function and expands the spectrum of clinical consequences of impaired RNA metabolism. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  3. Room temperature housing results in premature cancellous bone loss in growing female mice: implications for the mouse as a preclinical model for age-related bone loss.

    Science.gov (United States)

    Iwaniec, U T; Philbrick, K A; Wong, C P; Gordon, J L; Kahler-Quesada, A M; Olson, D A; Branscum, A J; Sargent, J L; DeMambro, V E; Rosen, C J; Turner, R T

    2016-10-01

    Room temperature housing (22 °C) results in premature cancellous bone loss in female mice. The bone loss was prevented by housing mice at thermoneutral temperature (32 °C). Thermogenesis differs markedly between mice and humans and mild cold stress induced by standard room temperature housing may introduce an unrecognized confounding variable into preclinical studies. Female mice are often used as preclinical models for osteoporosis but, in contrast to humans, mice exhibit cancellous bone loss during growth. Mice are routinely housed at room temperature (18-23 °C), a strategy that exaggerates physiological differences in thermoregulation between mice (obligatory daily heterotherms) and humans (homeotherms). The purpose of this investigation was to assess whether housing female mice at thermoneutral (temperature range where the basal rate of energy production is at equilibrium with heat loss) alters bone growth, turnover and microarchitecture. Growing (4-week-old) female C57BL/6J and C3H/HeJ mice were housed at either 22 or 32 °C for up to 18 weeks. C57BL/6J mice housed at 22 °C experienced a 62 % cancellous bone loss from the distal femur metaphysis during the interval from 8 to 18 weeks of age and lesser bone loss from the distal femur epiphysis, whereas cancellous and cortical bone mass in 32 °C-housed mice were unchanged or increased. The impact of thermoneutral housing on cancellous bone was not limited to C57BL/6J mice as C3H/HeJ mice exhibited a similar skeletal response. The beneficial effects of thermoneutral housing on cancellous bone were associated with decreased Ucp1 gene expression in brown adipose tissue, increased bone marrow adiposity, higher rates of bone formation, higher expression levels of osteogenic genes and locally decreased bone resorption. Housing female mice at 22 °C resulted in premature cancellous bone loss. Failure to account for species differences in thermoregulation may seriously confound interpretation of studies

  4. Low birthweight and premature birth are both associated with type 2 diabetes in a random sample of middle-aged Danes

    DEFF Research Database (Denmark)

    Pilgaard, K; Færch, K; Carstensen, B

    2010-01-01

    We studied the associations of size at birth and prematurity with type 2 diabetes, insulin sensitivity and beta cell function in the Danish population-based Inter99 study (ClinicalTrials.gov NCT00289237)....

  5. Low birthweight and premature birth are both associated with type 2 diabetes in a random sample of middle-aged Danes

    DEFF Research Database (Denmark)

    Pilgaard, K; Færch, K; Carstensen, B;

    2010-01-01

    We studied the associations of size at birth and prematurity with type 2 diabetes, insulin sensitivity and beta cell function in the Danish population-based Inter99 study (ClinicalTrials.gov NCT00289237).......We studied the associations of size at birth and prematurity with type 2 diabetes, insulin sensitivity and beta cell function in the Danish population-based Inter99 study (ClinicalTrials.gov NCT00289237)....

  6. Retinopathy of Prematurity (ROP)

    Science.gov (United States)

    ... of Prematurity (ROP) Facts About Retinopathy of Prematurity (ROP) This information was developed by the National Eye ... blind from ROP. Are there different stages of ROP? Yes. ROP is classified in five stages, ranging ...

  7. Aggrecan expression is substantially and abnormally upregulated in Hutchinson-Gilford Progeria Syndrome dermal fibroblasts.

    Science.gov (United States)

    Lemire, Joan M; Patis, Carrie; Gordon, Leslie B; Sandy, John D; Toole, Bryan P; Weiss, Anthony S

    2006-08-01

    Hutchinson-Gilford Progeria syndrome (HGPS) is a rare genetic disorder that displays features of segmental aging. It is manifested predominantly in connective tissue, with most prominent histological changes occurring in the skin, cartilage, bone and cardiovascular tissues. Detailed quantitative real time reverse-transcription polymerase chain reaction studies confirmed the previous observation that platelet-derived growth factor A-chain transcripts are consistently elevated 11+/-2- to 13+/-2-fold in two HGPS dermal fibroblast lines compared with age-matched controls. Furthermore, we identified two additional genes with substantially altered transcript levels. Nucleotide pyrophosphatase transcription was virtually shut down with decreased expression of 13+/-3- to 59+/-3-fold in HGPS, whereas aggrecan mRNA was elevated to 24+/-5 times to 41+/-4 times that of chronologically age-matched controls. Aggrecan, normally a component of cartilage and not always detectable in normal fibroblasts cultures, was secreted by HGPS fibroblast lines and was produced as a proteoglycan. This demonstrates that elevated aggrecan expression and its secretion are aberrant features of HGPS. We conclude that HGPS cells can display massively altered transcript levels leading to the secretion of inappropriate protein species.

  8. Pharmacotherapy for premature ejaculation

    NARCIS (Netherlands)

    Waldinger, Marcel D

    PURPOSE OF REVIEW: As there are various drugs and different treatment strategies to delay ejaculation, a review of the current drug treatments for premature ejaculation is relevant for daily clinical practice. RECENT FINDINGS: There are four premature ejaculation subtypes: lifelong premature

  9. Pharmacotherapy for premature ejaculation

    NARCIS (Netherlands)

    Waldinger, Marcel D

    2014-01-01

    PURPOSE OF REVIEW: As there are various drugs and different treatment strategies to delay ejaculation, a review of the current drug treatments for premature ejaculation is relevant for daily clinical practice. RECENT FINDINGS: There are four premature ejaculation subtypes: lifelong premature ejacula

  10. Health Issues of Premature Babies

    Science.gov (United States)

    ... Text Size Email Print Share Health Issues of Premature Babies Page Content Because premature babies are born before they are physically ready ... associated with prematurity. Because of these health concerns, premature babies are given extra medical attention and assistance ...

  11. Premature ovarian failure.

    Science.gov (United States)

    Shelling, Andrew N

    2010-11-01

    Premature ovarian failure (POF) is a common cause of infertility in women, and is characterised by amenorrhoea, hypo-oestrogenism and elevated gonadotrophin levels in women under the age of 40. Known causes include iatrogenic agents that cause permanent damage to the ovaries, such as chemotherapy, radiation therapy and surgery, autoimmune conditions, X-chromosome abnormalities and autosomal genetic conditions. However, few genes have been identified that can explain a substantial proportion of cases of POF. Most women with POF are deeply upset by the diagnosis, partly due to the unexpected menopausal symptoms, but also due to infertility. Therefore, early detection would provide better opportunity for early intervention, and furthermore, the identification of specific gene defects will help to direct potential targets for future treatment.

  12. Apnea of prematurity

    Directory of Open Access Journals (Sweden)

    Piermichele Paolillo

    2013-06-01

    Full Text Available Apnea of prematurity (AOP is one of the most frequent pathologies in the Neonatal Intensive Care Unit, with an incidence inversely related to gestational age. Its etiology is often multi factorial and diagnosis of idiopathic forms requires exclusion of other underlying diseases. Despite being a self-limiting condition which regresses with the maturation of the newborn, possible long-term effects of recurring apneas and the degree of desaturation and bradycardia who may lead to abnormal neurological outcome are not yet clarified. Therefore AOP needs careful evaluation of its etiology and adequate therapy that can be both pharmacological and non-pharmacological. Proceedings of the 9th International Workshop on Neonatology · Cagliari (Italy · October 23rd-26th, 2013 · Learned lessons, changing practice and cutting-edge research

  13. Analysis on effects of fetal age and birth weight on prognosis of premature infants%胎龄和出生体重对早产儿预后影响分析

    Institute of Scientific and Technical Information of China (English)

    卫雅蓉; 章恒; 许兵

    2011-01-01

    目的:探讨胎龄及出生体重对早产儿预后的影响.方法:回顾性分析无锡市妇幼保健院2008年1月~2009年12月间分娩的217例早产儿资料.结果:早产儿并发症的发生率和死亡率分别为43.8%和2.3%.早产儿并发症和死亡主要发生于胎龄<32周或出生体重<1 500 g的极低体重儿.缺氧缺血性脑病、窒息、呼吸窘迫综合症发生率和死亡率随胎龄或出生体重增加均呈下降趋势.结论:出生前加强孕期保健,尽可能延长胎龄,促进肺成熟;出生后防止早产儿窒息和加强低出生体重儿监护,将降低早产儿并发症发生率和死亡率.%Objective: To explore the effects of fetal age and birth weight on prognosis of premature infants. Methods: The clinical data of 217 premature infants born in the hospital from January 2008 to December 2009 were analyzed retrospectively. Results: The incidence of complication and mortality of premature infants were 43.8% and 2. 3%, respectively; the premature infants less than 32 gestational weeks or birth weight < 1 500 g had high incidence of complication and high mortality; the incidences of complications ( including hypoxic ischemic encephalopathy, asphyxia and respiratory distress syndrome) and mortality of premature infants showed a decreasing trend with fetal age and the increase of birth weight. Conclusion: Enhancing pregnant health care before delivery, prolonging fetal age as far as possible,promoting fetal lung maturity, preventing neonatal asphyxia and strengthening the monitoring on low birth weight infants may reduce the incidence of complication and mortality of premature infants.

  14. Human milk for the premature infant

    Science.gov (United States)

    Underwood, Mark A.

    2012-01-01

    Synopsis Premature infants are a heterogeneous group with widely differing needs for nutrition and immune protection with risk of growth failure, developmental delays, necrotizing enterocolitis, and late-onset sepsis increasing with decreasing gestational age and birth weight. Human milk from women delivering prematurely has more protein and higher levels of many bioactive molecules compared to milk from women delivering at term. Human milk must be fortified for small premature infants to achieve adequate growth. Mother’s own milk improves growth and neurodevelopment and decreases the risk of necrotizing enterocolitis and late-onset sepsis and should therefore be the primary enteral diet of premature infants. Donor milk is a valuable resource for premature infants whose mothers are unable to provide an adequate supply of milk, but presents significant challenges including the need for pasteurization, nutritional and biochemical deficiencies and a limited supply. PMID:23178065

  15. Size and Composition of the Lexicon in Prematurely Born Very-Low-Birth-Weight and Full-Term Finnish Children at Two Years of Age

    Science.gov (United States)

    Stolt, Suvi; Klippi, Anu; Launonen, Kaisa; Munck, Petriina; Lehtonen, Liisa; Lapinleimu, Helena; Haataja, Leena

    2007-01-01

    This paper focuses on the aspects of the lexicon in 66 prematurely born very-low-birth-weight and 87 full-term Finnish children at 2;0, studied using the Finnish version of the "MacArthur Communicative Developmental Inventory". The groups did not differ in vocabulary size. Furthermore, the female advantage in vocabulary size was not seen…

  16. Premature infants' health at multiple induced pregnancy.

    Directory of Open Access Journals (Sweden)

    Chernenkov Yu.V.

    2015-09-01

    Full Text Available Objective: to define the risk factors adversely influencing prenatal development at premature birth at use of methods of assisted reproductive technology (ART; to estimate premature' infants health from multiple induced pregnancy according to Perinatal Center of Saratov for last 3 years. Material and Methods. Under supervision there were 139 pregnant women with application ART. 202 children (51 twins were born and 5 triplet babies, from them 83 premature infants born from multiple induced pregnancy have been analyzed. Results. The newborns examined by method ART, were distributed as follows: 22-28 weeks — 19 children; 29-32 weeks — 23; 33-36 weeks — 41. Asphyxia at birth was marked at all premature infants. Respiratory insufficiency at birth is revealed in 87,3% of cases. The most frequent pathologies in premature infants are revealed: neurologic infringements and bronchopulmonary pathology occured at all children, developmental anomaly — 33, 8%, retinopathies in premature infants — 26,5%. The mortality causes include: extreme immaturity, cerebral leukomalacia, IVN 3 degrees. Conclusion. The risk factors, premature birth at application of methods ART are revealed: aged primiparas, pharmacological influence, absence of physiological conditions of prenatal development; multifetation. The high percent of birth of children with ELBW and ULBW is revealed. RDCN with further BPD development, retinopathies in premature infants and CNS defeat is more often occured.

  17. Intrauterine infection and prematurity.

    Science.gov (United States)

    Gonçalves, Luís F; Chaiworapongsa, Tinnakorn; Romero, Roberto

    2002-01-01

    Intrauterine infection is a major cause of premature labor with and without intact membranes. Intrauterine infection is present in approximately 25% of all preterm births and the earlier the gestational age at delivery, the higher the frequency of intra-amniotic infection. Microorganisms may also gain access to the fetus before delivery. A fetal inflammatory response syndrome elicited in response to microbial products is associated with the impending onset of preterm labor and also with multi-systemic organ involvement in the human fetus and a higher rate of perinatal morbidity. The most common microorganisms involved in intrauterine infections are Ureaplasma urealyticum, Fusobacterium species and Mycoplasma hominis. The role of Chlamydia trachomatis and viruses in preterm labor remain to be determined. Use of molecular microbiology techniques to diagnose intrauterine infection may uncover the role of fastidious microorganisms that have not yet been discovered. Antibiotic administration to patients with asymptomatic bacteriuria is associated with a significant reduction in the rate of preterm birth. However, such benefit has not been demonstrated for patients with bacterial vaginosis, or women who carry Streptococcus agalactia, Ureaplasma urealyticum or Trichomonas vaginalis. Antibiotic administration to patients with preterm premature rupture of membranes is associated with prolongation of pregnancy and a reduction in the rate of clinical chorioamnionitis and neonatal sepsis. The benefit has not been demonstrated in patients with preterm labor and intact membranes. Major efforts are required to determine why some women develop an ascending intrauterine infection and others do not and also what interventions may reduce the deleterious effect of systemic fetal inflammation. Copyright 2002 Wiley-Liss, Inc.

  18. Longwave UV light induces the aging-associated progerin.

    Science.gov (United States)

    Takeuchi, Hirotaka; Rünger, Thomas M

    2013-07-01

    Premature aging in Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutation of the LMNA gene that activates a cryptic splice site. This results in expression of a truncated form of Lamin A, called progerin. Accumulation of progerin in the nuclei of HGPS cells impairs nuclear functions and causes abnormal nuclear morphology. Progerin accumulation has not only been described in HGPS, but also during normal intrinsic aging. We hypothesized that accumulation of progerin with abnormal nuclear shapes may also be accelerated by UV and with that contribute to photoaging of the skin. We exposed neonatal or aged cultured fibroblasts to single or repeated doses of longwave or shortwave UV (UVA or UVB) and found that UVA, but not UVB, induces progerin expression and HGPS-like abnormal nuclear shapes in all cells, but more in aged cells. The induction of progerin is mediated by UVA-induced oxidative damage and subsequent alternative splicing of the LMNA transcript, as progerin induction was suppressed by the singlet oxygen quencher sodium azide, and as mRNA expression of LMNA was not induced by UVA. These data suggest a previously unreported pathway of photoaging and support the concept that photoaging is at least in part a process of damage-accelerated intrinsic aging.

  19. Increasing incidence of premature thelarche in the Central Region of Denmark - Challenges in differentiating girls less than 7 years of age with premature thelarche from girls with precocious puberty in real-life practice

    DEFF Research Database (Denmark)

    Sømod, Mia Elbek; Vestergaard, Esben Thyssen; Kristensen, Kurt

    2016-01-01

    was the variable which best discriminated PT from PP. Third, stimulated LH in 1-3 years old girls with PT is similar to stimulated LH in 5-7 years old girls with PP. Age, BMISDS, ethnicity, bone age, stimulated gonadotropins and LH/FSH and SHBG are all useful variables for differentiating PP from PT. However...

  20. Acute appendicitis in a premature baby

    Energy Technology Data Exchange (ETDEWEB)

    Beluffi, Giampiero; Alberici, Elisa [Department of Radiodiagnosis, Section of Paediatric Radiology, IRCCS Policlinico S. Matteo, Piazzale Golgi 2, 27100 Pavia PV (Italy)

    2002-07-01

    A case of acute appendicitis in a premature baby in whom diagnosis was suggested on plain films of the abdomen is presented. In this baby air in a hollow viscus suspected of being an enlarged appendix was the clue to diagnosis. The diagnostic dilemma of this rare and life-threatening condition in premature babies and newborns is underlined. The relevance of different imaging modalities and of different findings in this age group is discussed. Awareness of this rare condition and possible differential diagnosis in newborns and premature babies is stressed. (orig.)

  1. [Premature rupture of membranes and chorioamnionitis].

    Science.gov (United States)

    Lopez Garcia, R

    1988-01-01

    , and congenital malformations. Neonatal sepsis occurs in about 5% of live births following premature rupture, but the rate triples after 24 hours, especially in premature infants. The rate of neonatal asphyxia also increases considerable after 24 hours. Congenital malformations, prolapse of the cord, and pelvic presentation are positively associated with premature rupture of membranes. If the decision is made to interrupt the pregnancy, it should be done between 12-24 hours after rupture because the risks of infection and respiratory difficulty are most balanced at that point. Vaginal deliveries should be preferred only if conditions are favorable for a prompt delivery. The gestational age, presence of infection, obstetric condition of the mother, and indication for hysterectomy are the most important points to consider i management of premature rupture.

  2. Progeria with post-streptococcal glomerulonephritis: a rare case report with differential diagnosis.

    Science.gov (United States)

    Sebastian, Alphy A; Ahsan, Auswaf K

    2013-02-01

    Hutchinson-Gilford progeria syndrome is a rare autosomal dominant disorder associated with skin fragility. It is characterized by craniofacial disproportion, delayed dentition, micrognathia, and plucked bird appearance. The genetic defect is mainly de nova mutation in the lamin A gene. This report describes a 16-year-old patient with classical features of progeria along with post-streptococcal glomerulonephritis. The symptoms of hepatomegaly were also present in the patient. The differential diagnoses of this lesion are also discussed in detail in this literature.

  3. Rescue of progeria in trichothiodystrophy by homozygous lethal Xpd alleles.

    Directory of Open Access Journals (Sweden)

    Jaan-Olle Andressoo

    2006-10-01

    Full Text Available Although compound heterozygosity, or the presence of two different mutant alleles of the same gene, is common in human recessive disease, its potential to impact disease outcome has not been well documented. This is most likely because of the inherent difficulty in distinguishing specific biallelic effects from differences in environment or genetic background. We addressed the potential of different recessive alleles to contribute to the enigmatic pleiotropy associated with XPD recessive disorders in compound heterozygous mouse models. Alterations in this essential helicase, with functions in both DNA repair and basal transcription, result in diverse pathologies ranging from elevated UV sensitivity and cancer predisposition to accelerated segmental progeria. We report a variety of biallelic effects on organismal phenotype attributable to combinations of recessive Xpd alleles, including the following: (i the ability of homozygous lethal Xpd alleles to ameliorate a variety of disease symptoms when their essential basal transcription function is supplied by a different disease-causing allele, (ii differential developmental and tissue-specific functions of distinct Xpd allele products, and (iii interallelic complementation, a phenomenon rarely reported at clinically relevant loci in mammals. Our data suggest a re-evaluation of the contribution of "null" alleles to XPD disorders and highlight the potential of combinations of recessive alleles to affect both normal and pathological phenotypic plasticity in mammals.

  4. Outcomes for Extremely Premature Infants

    Science.gov (United States)

    Glass, Hannah C.; Costarino, Andrew T.; Stayer, Stephen A.; Brett, Claire; Cladis, Franklyn; Davis, Peter J.

    2015-01-01

    Premature birth is a significant cause of infant and child morbidity and mortality. In the United States, the premature birth rate, which had steadily increased during the 1990s and early 2000s, has decreased annually for four years and is now approximately 11.5%. Human viability, defined as gestational age at which the chance of survival is 50%, is currently approximately 23–24 weeks in developed countries. Infant girls, on average, have better outcomes than infant boys. A relatively uncomplicated course in the intensive care nursery for an extremely premature infant results in a discharge date close to the prenatal EDC. Despite technological advances and efforts of child health experts during the last generation, the extremely premature infant (less than 28 weeks gestation) and extremely low birth weight infant (ELBW) (premature labor improved neonatal mortality and morbidity in the late 1990s. The recognition that chronic postnatal administration of steroids to infants should be avoided may have improved outcomes in the early 2000s. Evidence from recent trials attempting to define the appropriate target for oxygen saturation in preterm infants suggests arterial oxygen saturation between 91–95% (compared to 85–89%) avoids excess mortality. However, final analyses of data from these trials have not been published, so definitive recommendations are still pending The development of neonatal neurocognitive care visits may improve neurocognitive outcomes in this high-risk group. Long-term follow up to detect and address developmental, learning, behavioral, and social problems is critical for children born at these early gestational ages. The striking similarities in response to extreme prematurity in the lung and brain imply that agents and techniques that benefit one organ are likely to also benefit the other. Finally, since therapy and supportive care continue to change, the outcomes of ELBW infants are ever evolving. Efforts to minimize injury, preserve

  5. Outcomes for extremely premature infants.

    Science.gov (United States)

    Glass, Hannah C; Costarino, Andrew T; Stayer, Stephen A; Brett, Claire M; Cladis, Franklyn; Davis, Peter J

    2015-06-01

    Premature birth is a significant cause of infant and child morbidity and mortality. In the United States, the premature birth rate, which had steadily increased during the 1990s and early 2000s, has decreased annually for 7 years and is now approximately 11.39%. Human viability, defined as gestational age at which the chance of survival is 50%, is currently approximately 23 to 24 weeks in developed countries. Infant girls, on average, have better outcomes than infant boys. A relatively uncomplicated course in the intensive care nursery for an extremely premature infant results in a discharge date close to the prenatal estimated date of confinement. Despite technological advances and efforts of child health experts during the last generation, the extremely premature infant (less than 28 weeks gestation) and extremely low birth weight infant (death and disability with 30% to 50% mortality and, in survivors, at least 20% to 50% risk of morbidity. The introduction of continuous positive airway pressure, mechanical ventilation, and exogenous surfactant increased survival and spurred the development of neonatal intensive care in the 1970s through the early 1990s. Routine administration of antenatal steroids during premature labor improved neonatal mortality and morbidity in the late 1990s. The recognition that chronic postnatal administration of steroids to infants should be avoided may have improved outcomes in the early 2000s. Evidence from recent trials attempting to define the appropriate target for oxygen saturation in preterm infants suggests arterial oxygen saturation between 91% and 95% (compared with 85%-89%) avoids excess mortality; however, final analyses of data from these trials have not been published, so definitive recommendations are still pending. The development of neonatal neurocritical intensive care units may improve neurocognitive outcomes in this high-risk group. Long-term follow-up to detect and address developmental, learning, behavioral, and

  6. Atherosclerosis in ancient humans, accelerated aging syndromes and normal aging: is lamin a protein a common link?

    Science.gov (United States)

    Miyamoto, Michael I; Djabali, Karima; Gordon, Leslie B

    2014-06-01

    Imaging studies of ancient human mummies have demonstrated the presence of vascular calcification that is consistent with the presence of atherosclerosis. These findings have stimulated interest in the underlying biological processes that might impart to humans an inherent predisposition to the development of atherosclerosis. Clues to these processes may possibly be found in accelerated aging syndromes, such as Hutchinson-Gilford progeria syndrome (HGPS), an ultra-rare disorder characterized by premature aging phenotypes, including very aggressive forms of atherosclerosis, occurring in childhood. The genetic defect in HGPS eventuates in the production of a mutant form of the nuclear structural protein lamin A, called progerin, which is thought to interfere with normal nuclear functioning. Progerin appears to be expressed in vascular cells, resulting in vessel wall cell loss and replacement by fibrous tissue, reducing vessel compliance and promoting calcification, leading to the vascular dysfunction and atherosclerosis seen in HGPS. Interestingly, vascular progerin is detectable in lower levels, in an age-related manner, in the general population, providing the basis for further study of the potential role of abnormal forms of lamin A in the atherosclerotic process of normal aging.

  7. Investigation of age-related changes in LMNA splicing and expression of progerin in human skeletal muscles.

    Science.gov (United States)

    Luo, Yue-Bei; Mitrpant, Chalermchai; Johnsen, Russell D; Fabian, Victoria A; Fletcher, Sue; Mastaglia, Frank L; Wilton, Steve D

    2013-01-01

    Age-related changes in splice-forms of LMNA, which encodes the nuclear lamina proteins lamin A/C, have not been investigated in skeletal muscle. In the rare premature ageing disease, Hutchinson-Gilford progeria syndrome (HGPS), de novo point mutations in LMNA activate a cryptic splice site in exon 11, resulting in a 150 base deletion in LMNA mRNA and accumulation of a truncated protein isoform, progerin. The LMNA Δ150 progerin transcript has also been found in trace quantities in tissues of healthy people and its implication in 'natural' ageing has been proposed. We therefore investigated the expression of progerin and lamin A/C in normal human and mouse skeletal muscles of different ages. LMNA Δ150 was detected in most muscle samples from healthy individuals aged 16-71 years, but was not present in any mouse muscle samples up to the age of 18 months. Real time qPCR of human muscle samples showed that there was an age-related increase in both the full length lamin A and LMNA Δ150 transcripts, whereas their protein levels did not change significantly with age. These findings indicate that there is a basal level of mis-splicing during LMNA expression that does not change with ageing in human muscle, but at levels that do not result in increased aberrant protein. The significance of these findings in the pathophysiology of muscle ageing is uncertain and warrants further investigation.

  8. Premature ovarian failure

    Directory of Open Access Journals (Sweden)

    Vujović Svetlana

    2012-01-01

    Full Text Available Premature ovarian failure (POF is the occurrence of hypergonadotropic hypoestrogenic amenorrhea in women under the age of forty years. It is idiopathic in 74-90% patients. Known cases can be divided into primary and secondary POF. In primary POF genetic aberrations can involve the X chromosome (monosomy, trisomy, translocations, deletions or autosomes. Genetic mechanisms include reduced gene dosage and non-specific chromosome effects impairing meiosis, decreasing the pool of primordial follicles and increasing atresia due to apoptosis or failure of follicle maturation. Autoimmune ovarian damage is caused by alteration of T-cell subsets and T-cell mediated injury, increase of autoantibody producing B-cells, a low number of effector/cytotoxic lymphocyte, which decreases the number and activity of natural killer cells. Bilateral oophorectomy, chemotherapy, radiotherapy and infections cause the secondary POF. Symptoms of POF include irritability, nervousness, loss of libido, depression, lack of concentration, hot flushes, weight gaining, dry skin, vaginal dryness, frequent infections etc. The diagnosis is confirmed by the level of FSH of over 40 IU/L and estradiol below 50 pmol/L in women aged below 40 years. Biochemical and other hormonal analysis (free thyroxin, TSH, prolactin, testosterone, karyotype (<30 years of age, ultrasound of the breasts and pelvis are advisable. Optimal therapy is combined estrogen progestagen therapy given in a sequential rhythm, after excluding absolute contraindications. Testosterone can be added to adnexectomized women and those with a low libido. Sequential estrogen progestagen replacement therapy is the first line therapy for ovulation induction in those looking for pregnancy and after that oocyte donation will be advised. Appropriate estro-progestagen therapy improves the quality of life and prevents complications such as cardiovascular diseases, osteoporosis, stroke etc.

  9. Apnea of prematurity: challenges and solutions

    Directory of Open Access Journals (Sweden)

    Picone S

    2014-06-01

    Full Text Available Simonetta Picone, Roberto Aufieri, Piermichele PaolilloDivision of Neonatology and Neonatal Intensive Care, Department of Maternal and Child Health, Casilino General Hospital, Rome, ItalyAbstract: Apnea of prematurity is a developmental disorder that frequently affects preterm infants, especially those with lower gestational age. Even if apnea of prematurity is by definition a self-limiting condition, it can cause serious problems during the hospital stay and can potentially have long-term neurological and cognitive consequences depending on the severity and intensity of the episodes. The diagnosis of apnea of prematurity can be made only after excluding a number of diseases of the preterm infant in which apnea may be an epiphenomenon. Etiological diagnosis is essential for selection of appropriate treatment, which may be nonpharmacological or involve use of drugs.Keywords: apnea of prematurity, idiopathic and secondary apnea, caffeine

  10. Can Hutchinson-Gilford progeria syndrome be cured in the future?

    Science.gov (United States)

    Rehman, Neeha Abdul; Rehman, Aneeqa Abdul; Ashraf, Isra Najib; Ahmed, Shahrukh

    2015-05-01

    Progeria is a rare genetic disease that manifests with progressive symptoms eventually leading to death. The only current treatment protocol of such patients is symptom based. However, recent trials are testing potential and promising drugs to treat the underlying genetic mutation and increase life expectancy of such patients.

  11. Compound heterozygosity for mutations in LMNA causes a progeria syndrome without prelamin A accumulation.

    NARCIS (Netherlands)

    Verstraeten, V.L.; Broers, J.L.; Steensel, M.A.M. van; Zinn-Justin, S.; Ramaekers, F.C.S.; Steijlen, P.M.; Kamps, M.; Kuijpers, H.J.; Merckx, D.; Smeets, H.J.M.; Hennekam, R.C.M.; Marcelis, C.L.M.; Wijngaard, A. van de

    2006-01-01

    LMNA-associated progeroid syndromes have been reported with both recessive and dominant inheritance. We report a 2-year-old boy with an apparently typical Hutchinson-Gilford progeria syndrome (HGPS) due to compound heterozygous missense mutations (p.T528M and p.M540T) in LMNA. Both mutations affect

  12. Compound heterozygosity for mutations in LMNA causes a progeria syndrome without prelamin A accumulation.

    NARCIS (Netherlands)

    Verstraeten, V.L.; Broers, J.L.; Steensel, M.A.M. van; Zinn-Justin, S.; Ramaekers, F.C.S.; Steijlen, P.M.; Kamps, M.; Kuijpers, H.J.; Merckx, D.; Smeets, H.J.M.; Hennekam, R.C.M.; Marcelis, C.L.M.; Wijngaard, A. van de

    2006-01-01

    LMNA-associated progeroid syndromes have been reported with both recessive and dominant inheritance. We report a 2-year-old boy with an apparently typical Hutchinson-Gilford progeria syndrome (HGPS) due to compound heterozygous missense mutations (p.T528M and p.M540T) in LMNA. Both mutations affect

  13. Acetaminophen developmental pharmacokinetics in premature neonates and infants

    DEFF Research Database (Denmark)

    Anderson, Brian J; van Lingen, Richard A; Hansen, Tom G

    2002-01-01

    The aim of this study was to describe acetaminophen developmental pharmacokinetics in premature neonates through infancy to suggest age-appropriate dosing regimens.......The aim of this study was to describe acetaminophen developmental pharmacokinetics in premature neonates through infancy to suggest age-appropriate dosing regimens....

  14. Hutchinson-Gilford progeria syndrome alters nuclear shape and reduces cell motility in three dimensional model substrates.

    Science.gov (United States)

    Booth-Gauthier, Elizabeth A; Du, Vicard; Ghibaudo, Marion; Rape, Andrew D; Dahl, Kris Noel; Ladoux, Benoit

    2013-03-01

    Cell migration through tight interstitial spaces in three dimensional (3D) environments impacts development, wound healing and cancer metastasis and is altered by the aging process. The stiffness of the extracellular matrix (ECM) increases with aging and affects the cells and cytoskeletal processes involved in cell migration. However, the nucleus, which is the largest and densest organelle, has not been widely studied during cell migration through the ECM. Additionally, the nucleus is stiffened during the aging process through the accumulation of a mutant nucleoskeleton protein lamin A, progerin. By using microfabricated substrates to mimic the confined environment of surrounding tissues, we characterized nuclear movements and deformation during cell migration into micropillars where interspacing can be tuned to vary nuclear confinement. Cell motility decreased with decreased micropillar (μP) spacing and correlated with increased dysmorphic shapes of nuclei. We examined the effects of increased nuclear stiffness which correlates with cellular aging by studying Hutchinson-Gilford progeria syndrome cells which are known to accumulate progerin. With the expression of progerin, cells showed a threshold response to decreased μP spacing. Cells became trapped in the close spacing, possibly from visible micro-defects in the nucleoskeleton induced by cell crawling through the μP and from reduced force generation, measured independently. We suggest that ECM changes during aging could be compounded by the increasing stiffness of the nucleus and thus changes in cell migration through 3D tissues.

  15. Otologic and Audiologic Manifestations of Hutchinson-Gilford Progeria Syndrome

    Science.gov (United States)

    Guardiani, Elizabeth; Zalewski, Christopher; Brewer, Carmen; Merideth, Melissa; Introne, Wendy; Smith, Ann C.M; Gordon, Leslie; Gahl, William; Kim, H. Jeffrey

    2013-01-01

    Objectives To define the audiologic and otologic phenotype of Hutchinson-Gilford Progeria syndrome (HGPS). Study Design Prospective case series. Methods Fifteen patients with HGPS were enrolled in a prospective natural history study; fourteen were evaluated in the neurotology clinic and eleven received audiologic evaluations. The physical exam and audiologic findings of these patients were reviewed to define an otologic and audiologic phenotype for HGPS in the largest series of subjects in the literature. Results All patients were noted to have stiff auricular cartilages, small or absent lobules and hypoplasia of the lateral soft tissue portion of the external ear canal leading to a shortened canal. Ten of 14 patients (71%) had dry cerumen impaction and four of 14 patients (29%) reported a history of recurrent otitis media. Nineteen of 22 ears (86.4%) demonstrated low frequency conductive hearing loss in the 250 Hz to 500 Hz range. Sixteen of 22 ears (73%) had type A tympanograms; three of 22 ears (14%) displayed bimodal or "W" peaked tympanograms; two of 22 ears (9%) had type B tympanograms; one of 22 ears (4%) had a type C tympanogram. Nine of 10 patients had distortion product otoacoustic emissions consistent with normal peripheral hearing sensitivity. Conclusions HGPS is caused by a mutation in the LMNA gene resulting in the production of an abnormal nuclear protein; this in turn affects nuclear structure and function. Patients with HGPS have characteristic otologic features due to cartilaginous and subcutaneous tissue abnormalities and typically demonstrate low frequency conductive hearing loss despite largely normal tympanometry. It is important to be aware of these conditions in managing these patients. PMID:21898437

  16. Premature ovarian failure and ovarian autoimmunity

    NARCIS (Netherlands)

    J.A. Schoemaker (Joop); H.A. Drexhage (Hemmo); A. Hoek (Annemieke)

    1997-01-01

    textabstractPremature ovarian failure (POF) is defined as a syndrome characterized by menopause before the age of 40 yr. The patients suffer from anovulation and hypoestrogenism. Approximately 1% of women will experience menopause before the age of 40 yr. POF is a

  17. Premature ovarian failure and ovarian autoimmunity

    NARCIS (Netherlands)

    J.A. Schoemaker (Joop); H.A. Drexhage (Hemmo); A. Hoek (Annemieke)

    1997-01-01

    textabstractPremature ovarian failure (POF) is defined as a syndrome characterized by menopause before the age of 40 yr. The patients suffer from anovulation and hypoestrogenism. Approximately 1% of women will experience menopause before the age of 40 yr. POF is a heter

  18. Premature ovarian failure and ovarian autoimmunity

    NARCIS (Netherlands)

    J.A. Schoemaker (Joop); H.A. Drexhage (Hemmo); A. Hoek (Annemieke)

    1997-01-01

    textabstractPremature ovarian failure (POF) is defined as a syndrome characterized by menopause before the age of 40 yr. The patients suffer from anovulation and hypoestrogenism. Approximately 1% of women will experience menopause before the age of 40 yr. POF is a heter

  19. An Xpd mouse model for the combined xeroderma pigmentosum/Cockayne syndrome exhibiting both cancer predisposition and segmental progeria.

    NARCIS (Netherlands)

    Andressoo, Jaan-Olle; Mitchell, James R; Wit, Jan de; Hoogstraten, Deborah; Volker, Marcel; Toussaint, Wendy; Speksnijder, Ewoud; Beems, Rudolf B; Steeg, Harry van; Jans, Judith; Zeeuw, Chris I de; Jaspers, Nicolaas G J; Raams, Anja; Lehmann, Alan R; Vermeulen, Wim; Hoeijmakers, Jan H J; Horst, Gijsbertus T J van der

    2006-01-01

    Inborn defects in nucleotide excision DNA repair (NER) can paradoxically result in elevated cancer incidence (xeroderma pigmentosum [XP]) or segmental progeria without cancer predisposition (Cockayne syndrome [CS] and trichothiodystrophy [TTD]). We report generation of a knockin mouse model for the

  20. An Xpd mouse model for the combined xeroderma pigmentosum/Cockayne syndrome exhibiting both cancer predisposition and segmental progeria.

    NARCIS (Netherlands)

    Andressoo, Jaan-Olle; Mitchell, James R; Wit, Jan de; Hoogstraten, Deborah; Volker, Marcel; Toussaint, Wendy; Speksnijder, Ewoud; Beems, Rudolf B; Steeg, Harry van; Jans, Judith; Zeeuw, Chris I de; Jaspers, Nicolaas G J; Raams, Anja; Lehmann, Alan R; Vermeulen, Wim; Hoeijmakers, Jan H J; Horst, Gijsbertus T J van der

    2006-01-01

    Inborn defects in nucleotide excision DNA repair (NER) can paradoxically result in elevated cancer incidence (xeroderma pigmentosum [XP]) or segmental progeria without cancer predisposition (Cockayne syndrome [CS] and trichothiodystrophy [TTD]). We report generation of a knockin mouse model for the

  1. 早产儿胎龄和体重对儿童糖尿病的预测作用%Study on the Prediction Function of Gestational Age and Body Weight of Premature Infants on Diabetes in C hildren

    Institute of Scientific and Technical Information of China (English)

    陈召金; 黎见乐; 姚慧梅; 兰红霞

    2014-01-01

    目的:探究并分析早产儿胎龄和体重对儿童糖尿病的预测作用。方法回顾性分析200例早产儿的临床资料。按照早产儿的胎龄分为A1、A2、A3、A4组,根据出生体重分为B1、B2、B3、B4组,根据喂养方式分为C1、C2、C3组。跟踪随访15年后,记录早产儿儿童糖尿病的发病率。结果28~30周胎龄组早产儿儿童糖尿病发病率为80.0%,明显高于其他胎龄组;出生体重≤999 g早产儿发病率为80.0%,较其他组早产儿高;人工喂养组早产儿发病率为60.8%,明显高于其余两组(P均<0.05),具有统计学意义。结论儿童糖尿病的发病率与早产儿胎龄和出生体重密切相关。%Objective To explore and analyze the prediction function of gestational age and body weight of premature infants on diabetes in children .Methods The retrospective analysis of clinical data was taken ,in-cluding 200 cases of premature infants .According to their gestational age ,they were divided into A1,A2,A3, A4 four groups,with B1 ,B2,B3,B4 four groups according to their birth weight ,C1,C2,C3 three groups accord-ing to the feeding patterns .After a follow-up visit for 15 years,records were written down on the incidences of diabetes in these children .Re sults The incidence of diabetes was 80%in group of premature infants with 28~30 weeks'gestational age ,significantly higher than other age groups .So was the morbidity rate of those with birth weight ≤999g,which accounted for 80.0%.The morbidity rate of premature infants ,who were treated with arti-ficial feeding was 60.8%,significantly higher than the other two groups (P<0.05).Besides,the morbidity rate in group of infants with non-nutritive sucking accounted for 50 .9%.Conclusion The incidence of diabetes in children is closely related to the gestational age and birth weight of these premature infants .

  2. The Effects of Fetal Surgery on Retinopathy of Prematurity Development

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    Sudha Nallasamy

    2009-10-01

    Full Text Available Background: Fetal surgery is selectively offered for severe or life-threatening fetal malformations. These infants are often born prematurely and are thus at risk for retinopathy of prematurity (ROP. It is not known whether fetal surgery confers an increased risk of developing severe ROP relative to published rates in standard premature populations ≤37 weeks of age grouped by birth weight (

  3. Micafungin in Premature and Non-premature Infants

    Science.gov (United States)

    Wu, Chunzhang; Tweddle, Lorraine; Roilides, Emmanuel

    2014-01-01

    Background: Invasive fungal infections cause excessive morbidity and mortality in premature neonates and severely ill infants. Methods: Safety and efficacy outcomes of micafungin were compared between prematurely and non-prematurely born infants premature [birth weight (BW) premature, received ≥1 dose of micafungin. Among premature patients, 14.5% were low BW (1500–2499 g), 36.4% very low BW (1000–1499 g) and 49.1% extremely low BW (premature)] died. Significantly more non-premature than premature patients discontinued treatment (P = 0.003). Treatment-related adverse events were recorded in 23% of patients with no difference between groups. More extremely low BW (n = 4, 15%) and very low BW (n = 8, 40%) infants experienced treatment-related adverse events than low BW (n = 0) and there was no relation to micafungin dose or duration. For a subgroup of 30 patients with invasive candidiasis, treatment success was achieved in 73% in both premature and non-premature groups. Prophylaxis was successful in 4/5 non-premature hematopoietic stem cell transplant patients. Conclusion: Micafungin has a safe profile in premature and non-premature infants with substantial efficacy. PMID:24892849

  4. Premature temporal theta (PT theta).

    Science.gov (United States)

    Hughes, J R; Fino, J J; Hart, L A

    1987-07-01

    A distinctive pattern called premature temporal theta (PT theta) was studied in 436 infants, ranging in age from 24 to 46 weeks. The pattern is seen in early prematurity, maximizes at 29-31 weeks and then diminishes and disappears near term. Usually the pattern is found independently on both temporal areas, but with a right-sided preference. Patients without PT theta or with a significantly low amount had either neurological or non-neurological (medical) conditions. With age there is a tendency for an increase in frequency and a decrease in amplitude. Five different peaks in the amount of this pattern are seen at approximately every month. Unilateral PT theta tends to be seen in older babies, more often on the right side and with an abnormal EEG. An abnormal EEG is usually associated with a delay in both the appearance and disappearance of this wave form. PT theta is also associated mainly with REM or active sleep. A polynomial rather than an exponential or power function best describes these data with changes of age. PT theta may arise from the inferior temporal gyrus and/or especially the transverse gyrus.

  5. Predictive factors for neuromotor abnormalities at the corrected age of 12 months in very low birth weight premature infants Fatores preditivos para anormalidades neuromotoras aos 12 meses de idade corrigida em prematuros de muito baixo peso

    Directory of Open Access Journals (Sweden)

    Rosane Reis de Mello

    2009-06-01

    Full Text Available BACKGROUND: The increase in survival of premature newborns has sparked growing interest in the prediction of their long-term neurodevelopment. OBJECTIVE: To estimate the incidence of neuromotor abnormalities at the corrected age of 12 months and to identify the predictive factors associated with altered neuromotor development in very low birth weight premature infants. METHOD: Cohort study. The sample included 100 premature infants. The outcome was neuromotor development at 12 months classified by Bayley Scale (PDI and neurological assessment (tonus, reflexes, posture. A multivariate logistic regression model was constructed. Neonatal variables and neuromotor abnormalities up to 6 months of corrected age were selected by bivariate analysis. RESULTS: Mean birth weight was 1126g (SD: 240. Abnormal neuromotor development was presented in 60 children at 12 months corrected age. CONCLUSION: According to the model, patients with a diagnosis including bronchopulmonary dysplasia, hypertonia of lower extremities, truncal hypotonia showed a 94.0% probability of neuromotor involvement at 12 months.INTRODUÇÃO: O aumento na sobrevida de recém-nascidos prematuros tem suscitado interesse crescente na predição do seu neurodesenvolvimento a longo prazo. OBJETIVO: Estimar a incidência de anormalidades neuromotoras aos 12 meses de idade corrigida e identificar os fatores associados ao desenvolvimento neuromotor alterado em prematuros de muito baixo peso. MÉTODO: Estudo de coorte. A amostra incluiu 100 crianças prematuras.O desfecho foi o desenvolvimento neuromotor aos 12 meses. Modelo de regressão logística multivariado foi construído. Variáveis neonatais e anormalidades neuromotoras até os 6 meses de idade corrigida foram selecionadas por análise bivariada. RESULTADOS: O peso de nascimento médio foi 1126g (DP:240. Aos 12 meses 60% das crianças apresentaram desenvolvimento neuromotor alterado. CONCLUSÃO: De acordo com o modelo, pacientes com diagn

  6. An Upregulation in the Expression of Vanilloid Transient Potential Channels 2 Enhances Hypotonicity-Induced Cytosolic Ca2+ Rise in Human Induced Pluripotent Stem Cell Model of Hutchinson Gillford Progeria

    Science.gov (United States)

    Ho, Jenny Chung-Yee; Siu, Chung-Wah; Cheung, Sin-Ying; Tang, Nelson L.; Yu, Shan; Tse, Hung-Fat; Yao, Xiaoqiang

    2014-01-01

    Hutchinson-Gillford Progeria Syndrome (HGPS) is a fatal genetic disorder characterized by premature aging in multiple organs including the skin, musculoskeletal and cardiovascular systems. It is believed that an increased mechanosensitivity of HGPS cells is a causative factor for vascular cell death and vascular diseases in HGPS patients. However, the exact mechanism is unknown. Transient receptor potential (TRP) channels are cationic channels that can act as cellular sensors for mechanical stimuli. The aim of this present study was to examine the expression and functional role of TRP channels in human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from the patients with HGPS. The mRNA and protein expression of TRP channels in HGPS and control (IMR90) iPSC-ECs were examined by semi-quantitative RT-PCRs and immunoblots, respectively. Hypotonicity-induced cytosolic Ca2+ ([Ca2+]i) rise in iPSC-ECs was measured by confocal microscopy. RT-PCRs and immunoblots showed higher expressional levels of TRPV2 in iPSC-ECs from HGPS patients than those from normal individuals. In functional studies, hypotonicity induced a transient [Ca2+]i rise in iPSC-ECs from normal individuals but a sustained [Ca2+]i elevation in iPSC-ECs from HGPS patients. A nonselective TRPV inhibitor, ruthenium red (RuR, 20 µM), and a specific TRPV2 channel inhibitor, tranilast (100 µM), abolished the sustained phase of hypotonicity-induced [Ca2+]i rise in iPSC-ECs from HGPS patients, and also markedly attenuated the transient phase of the [Ca2+]i rise in these cells. Importantly, a short 10 min hypotonicity treatment caused a substantial increase in caspase 8 activity in iPSC-ECs from HGPS patients but not in cells from normal individuals. Tranilast could also inhibit the hypotonicity-induced increase in caspase 8 activity. Taken together, our data suggest that an up-regulation in TRPV2 expression causes a sustained [Ca2+]i elevation in HGPS-iPSC-ECs under hypotonicity, consequently

  7. An upregulation in the expression of vanilloid transient potential channels 2 enhances hypotonicity-induced cytosolic Ca²⁺ rise in human induced pluripotent stem cell model of Hutchinson-Gillford Progeria.

    Directory of Open Access Journals (Sweden)

    Chun-Yin Lo

    Full Text Available Hutchinson-Gillford Progeria Syndrome (HGPS is a fatal genetic disorder characterized by premature aging in multiple organs including the skin, musculoskeletal and cardiovascular systems. It is believed that an increased mechanosensitivity of HGPS cells is a causative factor for vascular cell death and vascular diseases in HGPS patients. However, the exact mechanism is unknown. Transient receptor potential (TRP channels are cationic channels that can act as cellular sensors for mechanical stimuli. The aim of this present study was to examine the expression and functional role of TRP channels in human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs from the patients with HGPS. The mRNA and protein expression of TRP channels in HGPS and control (IMR90 iPSC-ECs were examined by semi-quantitative RT-PCRs and immunoblots, respectively. Hypotonicity-induced cytosolic Ca²⁺ ([Ca²⁺](i rise in iPSC-ECs was measured by confocal microscopy. RT-PCRs and immunoblots showed higher expressional levels of TRPV2 in iPSC-ECs from HGPS patients than those from normal individuals. In functional studies, hypotonicity induced a transient [Ca²⁺](i rise in iPSC-ECs from normal individuals but a sustained [Ca²⁺](i elevation in iPSC-ECs from HGPS patients. A nonselective TRPV inhibitor, ruthenium red (RuR, 20 µM, and a specific TRPV2 channel inhibitor, tranilast (100 µM, abolished the sustained phase of hypotonicity-induced [Ca²⁺](i rise in iPSC-ECs from HGPS patients, and also markedly attenuated the transient phase of the [Ca²⁺](i rise in these cells. Importantly, a short 10 min hypotonicity treatment caused a substantial increase in caspase 8 activity in iPSC-ECs from HGPS patients but not in cells from normal individuals. Tranilast could also inhibit the hypotonicity-induced increase in caspase 8 activity. Taken together, our data suggest that an up-regulation in TRPV2 expression causes a sustained [Ca²⁺](i elevation in HGPS

  8. An upregulation in the expression of vanilloid transient potential channels 2 enhances hypotonicity-induced cytosolic Ca²⁺ rise in human induced pluripotent stem cell model of Hutchinson-Gillford Progeria.

    Science.gov (United States)

    Lo, Chun-Yin; Tjong, Yung-Wui; Ho, Jenny Chung-Yee; Siu, Chung-Wah; Cheung, Sin-Ying; Tang, Nelson L; Yu, Shan; Tse, Hung-Fat; Yao, Xiaoqiang

    2014-01-01

    Hutchinson-Gillford Progeria Syndrome (HGPS) is a fatal genetic disorder characterized by premature aging in multiple organs including the skin, musculoskeletal and cardiovascular systems. It is believed that an increased mechanosensitivity of HGPS cells is a causative factor for vascular cell death and vascular diseases in HGPS patients. However, the exact mechanism is unknown. Transient receptor potential (TRP) channels are cationic channels that can act as cellular sensors for mechanical stimuli. The aim of this present study was to examine the expression and functional role of TRP channels in human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from the patients with HGPS. The mRNA and protein expression of TRP channels in HGPS and control (IMR90) iPSC-ECs were examined by semi-quantitative RT-PCRs and immunoblots, respectively. Hypotonicity-induced cytosolic Ca²⁺ ([Ca²⁺](i)) rise in iPSC-ECs was measured by confocal microscopy. RT-PCRs and immunoblots showed higher expressional levels of TRPV2 in iPSC-ECs from HGPS patients than those from normal individuals. In functional studies, hypotonicity induced a transient [Ca²⁺](i) rise in iPSC-ECs from normal individuals but a sustained [Ca²⁺](i) elevation in iPSC-ECs from HGPS patients. A nonselective TRPV inhibitor, ruthenium red (RuR, 20 µM), and a specific TRPV2 channel inhibitor, tranilast (100 µM), abolished the sustained phase of hypotonicity-induced [Ca²⁺](i) rise in iPSC-ECs from HGPS patients, and also markedly attenuated the transient phase of the [Ca²⁺](i) rise in these cells. Importantly, a short 10 min hypotonicity treatment caused a substantial increase in caspase 8 activity in iPSC-ECs from HGPS patients but not in cells from normal individuals. Tranilast could also inhibit the hypotonicity-induced increase in caspase 8 activity. Taken together, our data suggest that an up-regulation in TRPV2 expression causes a sustained [Ca²⁺](i) elevation in HGPS

  9. [Application of massage therapy in premature infant nursing care].

    Science.gov (United States)

    Chang, Shu-Min; Sung, Huei-Chuan

    2007-02-01

    Massage therapy has been used in the care of premature infants for many years in western countries, and a significant body of research has already shown the effectiveness of massage therapy in significantly increasing body weight, decreasing infant hospital durations, enhancing bone formation, and improving behavior. Key considerations when applying massage therapy on premature infants include gestational age, bodyweight, and physical condition. Nurses can teach parents to administer massage therapy on their premature infants to enhance parent-child attachment and interaction. This article introduces massage therapy principles and methods, the effectiveness of massage therapy in premature infant care, and an approach to teaching parents how to apply massage therapy on their premature infants. Massage therapy can be included in premature infant care programs in the future.

  10. [Developmental change in facial recognition by premature infants during infancy].

    Science.gov (United States)

    Konishi, Yukihiko; Kusaka, Takashi; Nishida, Tomoko; Isobe, Kenichi; Itoh, Susumu

    2014-09-01

    Premature infants are thought to be at increased risk for developmental disorders. We evaluated facial recognition by premature infants during early infancy, as this ability has been reported to be impaired commonly in developmentally disabled children. In premature infants and full-term infants at the age of 4 months (4 corrected months for premature infants), visual behaviors while performing facial recognition tasks were determined and analyzed using an eye-tracking system (Tobii T60 manufactured by Tobii Technologics, Sweden). Both types of infants had a preference towards normal facial expressions; however, no preference towards the upper face was observed in premature infants. Our study suggests that facial recognition ability in premature infants may develop differently from that in full-term infants.

  11. Lipid profile of women with premature ovarian failure

    NARCIS (Netherlands)

    Knauff, Erik A. H.; Westerveld, Hendrika E.; Goverde, Angelique J.; Eijkemans, Marinus J.; Valkenburg, Olivier; van Santbrink, Evert J. P.; Fauser, Bart C. J. M.; van der Schouw, Yvonne T.

    2008-01-01

    Objective: Earlier menopause is associated with a higher incidence of cardiovascular events later in life. Concurrent with the ages of menopausal transition, a shift in lipid profile takes place. Premature ovarian failure (POF) or premature menopause allows LIS to Study the effect of cessation of

  12. A predictive model for respiratory syncytial virus (RSV hospitalisation of premature infants born at 33–35 weeks of gestational age, based on data from the Spanish FLIP study

    Directory of Open Access Journals (Sweden)

    Figueras-Aloy Jose

    2008-12-01

    Full Text Available Abstract Background The aim of this study, conducted in Europe, was to develop a validated risk factor based model to predict RSV-related hospitalisation in premature infants born 33–35 weeks' gestational age (GA. Methods The predictive model was developed using risk factors captured in the Spanish FLIP dataset, a case-control study of 183 premature infants born between 33–35 weeks' GA who were hospitalised with RSV, and 371 age-matched controls. The model was validated internally by 100-fold bootstrapping. Discriminant function analysis was used to analyse combinations of risk factors to predict RSV hospitalisation. Successive models were chosen that had the highest probability for discriminating between hospitalised and non-hospitalised infants. Receiver operating characteristic (ROC curves were plotted. Results An initial 15 variable model was produced with a discriminant function of 72% and an area under the ROC curve of 0.795. A step-wise reduction exercise, alongside recalculations of some variables, produced a final model consisting of 7 variables: birth ± 10 weeks of start of season, birth weight, breast feeding for ≤ 2 months, siblings ≥ 2 years, family members with atopy, family members with wheeze, and gender. The discrimination of this model was 71% and the area under the ROC curve was 0.791. At the 0.75 sensitivity intercept, the false positive fraction was 0.33. The 100-fold bootstrapping resulted in a mean discriminant function of 72% (standard deviation: 2.18 and a median area under the ROC curve of 0.785 (range: 0.768–0.790, indicating a good internal validation. The calculated NNT for intervention to treat all at risk patients with a 75% level of protection was 11.7 (95% confidence interval: 9.5–13.6. Conclusion A robust model based on seven risk factors was developed, which is able to predict which premature infants born between 33–35 weeks' GA are at highest risk of hospitalisation from RSV. The model could be

  13. Laterality in Prematurely-Born Children.

    Science.gov (United States)

    Segalwitz, Sidney J.; Chapman, Jacqueline S.

    The study examined the relationship between perinatal stress and decreased right handedness and decreased left cerebral dominance for speech with 215 children born prematurely, followed from birth, and tested at age 5. Results indicated that neither hand preference nor hand performance correlated with degree of perinatal stress and that eye…

  14. Premature birth and diseases in premature infants: common genetic background?

    Science.gov (United States)

    Hallman, Mikko

    2012-04-01

    It has been proposed that during human evolution, development of obligate bipedalism, narrow birth canal cross-sectional area and the large brain have forced an adjustment in duration of pregnancy (scaling of gestational age; Plunkett 2011). Children compared to other mammals are born with proportionally small brains (compared to adult brains), suggesting shortening of pregnancy duration during recent evolution. Prevalence of both obstructed delivery and premature birth is still exceptionally high. In near term infants, functional maturity and viability is high, and gene variants predisposing to respiratory distress syndrome (RDS) are rare. Advanced antenatal and neonatal treatment practices during the new era of medicine allowed survival of also very preterm infants (gestation premature birth. Specific genes associating with diseases in preterm infants may also contribute to the susceptibility to preterm birth. Understanding and applying the knowledge of genetic interactions in normal and abnormal perinatal-neonatal development requires large, well-structured population cohorts, studies involving the whole genome and international interdisciplinary collaboration.

  15. Progeria syndrome with characteristic deformation of proximal radius observed on CT

    Energy Technology Data Exchange (ETDEWEB)

    Sood, S.; Rao, R.C.K.; Ragav, B.; Berry, M. (All India Inst. of Medical Sciences, New Delhi (India). Dept. of Radio-Diagnosis)

    1991-01-01

    The progeria syndrome (Hutchinson-Gilford) is an uncommon disease. A peculiar shape of the proximal radial metaphyseal region caused by an infolding of the cortex was observed on CT in 2 brothers suffering from this disorder, a feature not previously reported. A brief review of the radiologic literature was undertaken. This new observation needs to be further evaluated as it may provide a clinching diagnostic feature of this disease. (orig.).

  16. Assessing the efficacy of protein farnesyltransferase inhibitors in mouse models of progeria.

    Science.gov (United States)

    Yang, Shao H; Chang, Sandy Y; Andres, Douglas A; Spielmann, H Peter; Young, Stephen G; Fong, Loren G

    2010-02-01

    Hutchinson-Gilford progeria syndrome (HGPS) is caused by the accumulation of a farnesylated form of prelamin A (progerin). Previously, we showed that blocking protein farnesylation with a farnesyltransferase inhibitor (FTI) ameliorates the disease phenotypes in mouse model of HGPS (Lmna(HG/+)). However, the interpretation of the FTI treatment studies is open to question in light of recent studies showing that mice expressing a nonfarnesylated version of progerin (Lmna(nHG/+)) develop progeria-like disease phenotypes. The fact that Lmna(nHG/+) mice manifest disease raised the possibility that the beneficial effects of an FTI in Lmna(HG/+) mice were not due to the effects of the drug on the farnesylation of progerin, but may have been due to unanticipated secondary effects of the drug on other farnesylated proteins. To address this issue, we compared the ability of an FTI to improve progeria-like disease phenotypes in both Lmna(HG/+) and Lmna(nHG/+) mice. In Lmna(HG/+) mice, the FTI reduced disease phenotypes in a highly significant manner, but the drug had no effect in Lmna(nHG/+) mice. The failure of the FTI to ameliorate disease in Lmna(nHG/+) mice supports the idea that the beneficial effects of an FTI in Lmna(HG/+) mice are due to the effect of drug on the farnesylation of progerin.

  17. Serum fructosamine and retinopathy of prematurity.

    Science.gov (United States)

    Bozdag, Senol; Oguz, Serife Suna; Gokmen, Tulin; Tunay, Zuhal; Tok, Levent; Uras, Nurdan; Erdeve, Omer; Dilmen, Ugur

    2011-12-01

    To determine whether serum fructosamine which is a good marker for detecting hyperglycemia during the previous 2 to 3 wk in infants could predict the development of retinopathy of prematurity in very low birth weight infants. One hundred sixty seven premature infants who had a birth weight of < 1500 g and a gestational age of less than 32 wk were investigated in the present study. Blood glucose was measured at the bedside and infants were recorded as hyperglycemic if their mean blood glucose levels were higher than 150 mg/dL. Serum corrected fructosamine level was obtained from the cord blood at birth and after the first month of life. The infants' eyes were examined by ophthalmologists to detect retinopathy of prematurity at the gestational age of 32 wk or at four wk after birth, whichever came first. Corrected fructosamine was 319.6 ± 59.6 and 272.8 ± 50.6 mmol/l for group 1 on 1(st) and 30(th) day respectively; 320 ± 61.7 and 268.2 ± 47.3 mmol/l for groups 2 + 3 on 1(st) and 30(th) day respectively which did not differ between groups (p = 0.766 and p = 0.665), whereas duration of hyperglycemia was 1.69 ± 1.1 day in group 1 compared with 3.05 ± 2.4 day in groups 2 + 3 which was significantly different (p = 0.019). The multivariate regression analysis indicated that the duration of hyperglycemia in days was significantly correlated with the development of retinopathy of prematurity (OR 3.26; 95% CI 1.09-9.80; p = 0.035). Although the duration of hyperglycemia may contribute to the development of retinopathy of prematurity, serum corrected fructosamine does not have a good predictive value in developing retinopathy of prematurity in very-low-birth-weight (VLBW) infants.

  18. Chemical screening identifies ROCK as a target for recovering mitochondrial function in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Kang, Hyun Tae; Park, Joon Tae; Choi, Kobong; Choi, Hyo Jei Claudia; Jung, Chul Won; Kim, Gyu Ree; Lee, Young-Sam; Park, Sang Chul

    2017-03-19

    Hutchinson-Gilford progeria syndrome (HGPS) constitutes a genetic disease wherein an aging phenotype manifests in childhood. Recent studies indicate that reactive oxygen species (ROS) play important roles in HGPS phenotype progression. Thus, pharmacological reduction in ROS levels has been proposed as a potentially effective treatment for patient with this disorder. In this study, we performed high-throughput screening to find compounds that could reduce ROS levels in HGPS fibroblasts and identified rho-associated protein kinase (ROCK) inhibitor (Y-27632) as an effective agent. To elucidate the underlying mechanism of ROCK in regulating ROS levels, we performed a yeast two-hybrid screen and discovered that ROCK1 interacts with Rac1b. ROCK activation phosphorylated Rac1b at Ser71 and increased ROS levels by facilitating the interaction between Rac1b and cytochrome c. Conversely, ROCK inactivation with Y-27632 abolished their interaction, concomitant with ROS reduction. Additionally, ROCK activation resulted in mitochondrial dysfunction, whereas ROCK inactivation with Y-27632 induced the recovery of mitochondrial function. Furthermore, a reduction in the frequency of abnormal nuclear morphology and DNA double-strand breaks was observed along with decreased ROS levels. Thus, our study reveals a novel mechanism through which alleviation of the HGPS phenotype is mediated by the recovery of mitochondrial function upon ROCK inactivation.

  19. Lifestyle influences on prematurity.

    Science.gov (United States)

    Creasy, R K

    1991-01-01

    It is apparent from this review that the lifestyle of an individual gravida can potentially lead to a premature delivery. Some of these adverse behavioral characteristics may be dealt with by education and motivation, and some with actual medical treatment. However, there also appears to be significant need for public policy reorientation if we are to make a significant impact on the problem of preterm delivery.

  20. Growth in Small-for-Gestational-Age Preterm-Born Children from 0 to 4 Years : The Role of both Prematurity and SGA Status

    NARCIS (Netherlands)

    Bocca-Tjeertes, Inger F. A.; Reijneveld, Sijmen A.; Kerstjens, Jorien M.; de Winter, Andrea F.; Bos, Arend F.

    2013-01-01

    Background: Fullterm small-for-gestational-age children (SGAs) are known for their ability to catch up on growth. Nevertheless, increased risk of growth restriction remains. Evidence on preterm SGA children's growth is lacking. Objective: To determine absolute gains in height and weight, relative gr

  1. The I4895T mutation in the type 1 ryanodine receptor induces fiber-type specific alterations in skeletal muscle that mimic premature aging.

    Science.gov (United States)

    Boncompagni, Simona; Loy, Ryan E; Dirksen, Robert T; Franzini-Armstrong, Clara

    2010-12-01

    The I4898T (IT) mutation in type 1 ryanodine receptor (RyR1), the Ca(2+) release channel of the sarcoplasmic reticulum (SR) is linked to a form of central core disease (CCD) in humans and results in a nonleaky channel and excitation-contraction uncoupling. We characterized age-dependent and fiber-type-dependent alterations in muscle ultrastructure, as well as the magnitude and spatiotemporal properties of evoked Ca(2+) release in heterozygous Ryr1(I4895T/WT) (IT/+) knock-in mice on a mixed genetic background. The results indicate a classical but mild CCD phenotype that includes muscle weakness and the presence of mitochondrial-deficient areas in type I fibers. Electrically evoked Ca(2+) release is significantly reduced in single flexor digitorum brevis (FDB) fibers from young and old IT/+ mice. Structural changes are strongly fiber-type specific, affecting type I and IIB/IIX fibers in very distinct ways, and sparing type IIA fibers. Ultrastructural alterations in our IT/+ mice are also present in wild type, but at a lower frequency and older ages, suggesting that the disease mutation on the mixed background promotes an acceleration of normal age-dependent changes. The observed functional and structural alterations and their similarity to age-associated changes are entirely consistent with the known properties of the mutated channel, which result in reduced calcium release as is also observed in normal aging muscle. In strong contrast to these observations, a subset of patients with the analogous human heterozygous mutation and IT/+ mice on an inbred 129S2/SvPasCrl background exhibit a more severe disease phenotype, which is not directly consistent with the mutated channel properties.

  2. Monitoring antioxidant defenses and free radical production in space-flight, aviation and railway engine operators, for the prevention and treatment of oxidative stress, immunological impairment, and pre-mature cell aging.

    Science.gov (United States)

    De Luca, C; Deeva, I; Mariani, S; Maiani, G; Stancato, A; Korkina, L

    2009-01-01

    Degenerative diseases, immune impairment, and premature ageing commonly affect professional categories exposed to severe environmental and psychological stress. Among these, cosmonauts routinely experience extreme conditions due to microgravity, space radiation, altered oxygen supply, physical and mental fatigue during training, spaceflight, and post-flight. Long route aviation pilots display elevated oncogenic risk, connected with cosmic radiation overexposure, and high mortality rates for cardiovascular causes. Engine drivers, like pilots, are affected by health consequences of psycho-emotional stress, and burnout syndrome. The free radical (FR)/antioxidant (AO) imbalance is a common feature in all these pathological conditions. To assess the effective relevance of oxidative stress, we analyzed blood and urine reliable markers of FR production and AO defenses in 12 Russian cosmonauts, 55 airline pilots, 63 train engine drivers, and 50 age-matched controls by measuring the following: (a) lipophilic/hydrophilic low-molecular weight AO and AO enzyme activities, (b) nitric oxide, superoxide anion, hydroperoxide production, and (c) urinary catecholamine/serotonine metabolites and lipoperoxidation markers. Cosmonauts showed elevated granulocyte superoxide and nitric oxide production, increased erythrocyte superoxide dismutase activity and glutathione oxidation, and drastically decreased plasma/leucocyte lipophilic AO levels (P monitoring of clinical biochemistry laboratory markers of AO/FR status, to tailor individually specific AO supplementation and diet regimen, and monitor treatment outcomes.

  3. Novel Directions In Therapy Against Age-Related Vascular Disease

    NARCIS (Netherlands)

    H. Wu (Haiyan)

    2014-01-01

    markdownabstract__Abstract__ Genomic instability is recognized as one of the primary mechanisms that lead to organismal aging, and leads to progeria when developing in an accelerated pace due to defective genomic maintenance systems, such as nucleotide excision repair, in humans and mouse models of

  4. Novel Directions In Therapy Against Age-Related Vascular Disease

    NARCIS (Netherlands)

    H. Wu (Haiyan)

    2014-01-01

    markdownabstract__Abstract__ Genomic instability is recognized as one of the primary mechanisms that lead to organismal aging, and leads to progeria when developing in an accelerated pace due to defective genomic maintenance systems, such as nucleotide excision repair, in humans and mouse models of

  5. The I4895T Mutation in the Type 1 Ryanodine Receptor Induces Fiber-Type Specific Alterations in Skeletal Muscle that Mimic Premature Aging

    OpenAIRE

    2010-01-01

    The I4898T (IT) mutation in type 1 ryanodine receptor (RyR1), the Ca2+ release channel of the sarcoplasmic reticulum (SR) is linked to a form of central core disease (CCD) in humans and results in a non leaky channel and excitation-contraction uncoupling. We characterized age- and fiber type-dependent alterations in muscle ultrastructure, as well as the magnitude and spatiotemporal properties of evoked Ca2+ release in heterozygous Ryr1I4895T/WT (IT/+) knock-in mice on a mixed genetic backgrou...

  6. DYNAMICS OF DISABILITY ADJUSTED LIFE YEARS (DALY AS A RESULT OF PREMATURE MORTALITY OF CHILDREN AT THE AGE OF 0–17 YEARS IN TOMSK REGION IN 2008–2012

    Directory of Open Access Journals (Sweden)

    О. S. Kobyakova

    2014-01-01

    Full Text Available The DALY indicator (Disability Adjusted Life Years is widely used for the assessment of a contribution of various diseases to losses of the population health and of the analysis of activity efficiency of health care systems. Background: Research objective was to evaluate dynamics of the DALY indicator as a result of premature mortality of the child population of Tomsk region during 2008-2012. Patients and methods: DALY calculation as a result of premature mortality of the child population of the region during the period from 2008 to 2012 is made. While calculating the data of Territorial body of Federal service of state statistics for the Tomsk Region (Rosstat which included a sex of the dead, day, month and year of death, place of residence, cause of death, day, month and year of birth of the dead was used. The number and gender and age structure of the population of the Tomsk Region according to Rosstat data were also considered. Results: The DALY decrease by 16,5% in child population at the age of 0–17 years is observed in the Tomsk region during the period from 2008 to 2012. Following the results of 2012, DALY in studied population made 833.1 (82.3 ± 5.4 years for 10 thousand of corresponding population that is 1,1 times lower than totally in the Russian Federation, and 3.4 times lower than the universal indicator of 2010. Conclusion: The received result reflects the activity of health care system of the region, directed on integration of synthesis of theoretical and practical knowledge. Decrease in DALY among the child population in the territory of the region is promoted by a number of factors: continuous quality improvement of the medical care rendered to children, target programs on motherhood and childhood health protection realized in the territory of the region, and also functioning of the federal scientific and educational institutions promoting introduction of modern techniques of medical care delivery in practical health care

  7. Parent behaviors moderate the relationship between neonatal pain and internalizing behaviors at 18 months corrected age in children born very prematurely.

    Science.gov (United States)

    Vinall, Jillian; Miller, Steven P; Synnes, Anne R; Grunau, Ruth E

    2013-09-01

    Children born very preterm (≤ 32 weeks gestation) exhibit greater internalizing (anxious/depressed) behaviors compared to term-born peers as early as 2 years corrected age (CA); however, the role of early stress in the etiology of internalizing problems in preterm children remains unknown. Therefore, we examined the relationship between neonatal pain and internalizing behavior at 18 months CA in children born very preterm and examined whether parent behavior and stress moderated this relationship. Participants were 145 children (96 very preterm, 49 full term) assessed at 18 months CA. Neonatal data were obtained from medical and nursing chart review. Neonatal pain was defined as the number of skin-breaking procedures. Cognitive ability was measured with the Bayley Scales of Infant Development II. Parents completed the Parenting Stress Index III, Child Behavior Checklist 1.5-5, and participated in a videotaped play session with their child, which was coded using the Emotional Availability Scale IV. Very preterm children displayed greater Internalizing behaviors compared to full-term control children (P=.02). Parent Sensitivity and Nonhostility moderated the relationship between neonatal pain and Internalizing behavior (all Pneonatal medical confounders, gender, and child cognitive ability (all P>.05). Parent Emotional Availability and stress were not associated with Internalizing behaviors in full-term control children. Positive parent interaction and lower stress appears to ameliorate negative effects of neonatal pain on stress-sensitive behaviors in this vulnerable population.

  8. A ceRNA analysis on LMNA gene focusing on the Hutchinson-Gilford progeria syndrome

    Science.gov (United States)

    2013-01-01

    Background Hutchinson-Gilford progeria syndrome is a rare dominant human disease of genetic origin. The average life expectancy is about 20 years, patients’ life quality is still very poor and no efficient therapy has yet been developed. It is caused by mutation of the LMNA gene, which results in accumulation in the nuclear membrane of a particular splicing form of Lamin-A called progerin. The mechanism by which progerin perturbs cellular homeostasis and leads to the symptoms is still under debate. Micro-RNAs are able to negatively regulate transcription by coupling with the 3’ UnTranslated Region of messenger RNAs. Several Micro-RNAs recognize the same 3’ UnTranslated Region and each Micro-RNA can recognize multiple 3’ UnTranslated Regions of different messenger RNAs. When different messenger RNAs are co-regulated via a similar panel of micro-RNAs, these messengers are called Competing Endogenous RNAs, or ceRNAs. The 3’ UnTranslated Region of the longest LMNA transcript was analysed looking for its ceRNAs. The aim of this study was to search for candidate genes and gene ontology functions possibly influenced by LMNA mutations that may exert a role in progeria development. Results 11 miRNAs were isolated as potential LMNA regulators. By computational analysis, the miRNAs pointed to 17 putative LMNA ceRNAs. Gene ontology analysis of isolated ceRNAs showed an enrichment in RNA interference and control of cell cycle functions. Conclusion This study isolated novel genes and functions potentially involved in LMNA network of regulation that could be involved in laminopathies such as the Hutchinson-Gilford progeria syndrome. PMID:23317481

  9. The genetic basis of premature ovarian failure.

    Science.gov (United States)

    Woad, Kathryn J; Watkins, Wendy J; Prendergast, Deborah; Shelling, Andrew N

    2006-06-01

    Premature ovarian failure (POF) is a common condition, affecting approximately 1:100 women. It is characterised by amenorrhea, hypoestrogenism, and elevated gonadotrophin levels in women under the age of 40. It is often an unexpected and distressing diagnosis, which coincides with infertility and menopausal symptoms. There is a well recognised genetic basis to the development of POF. Our laboratory has identified several candidate genes associated with POF.

  10. 小胎龄早产儿支气管肺发育不良发生率和危险因素分析%The incidence and risk factors of bronchopulmonary dysplasia in small gestational age premature infants

    Institute of Scientific and Technical Information of China (English)

    郑国方; 武荣; 刘石; 郝小清

    2012-01-01

    Objective To analyse bronchopulmonary dysplasia (BPD) incidence and high risk factor in the small gestational age premature infants. Methods Retrospective analyse the materials of inpatient infants whose gestational age (GA) were =?2 weeks and survived over 28 days in our neonatal intensive care unite ( NICU). The 28 cases as BPD group met the new diagnostic criteria of BPD. The 56 cases as the control group were randomly selected from all the premature infant with no BPD. Results Total of 197 cases of premature infant were included in this study. The incidence of BPD is about 14.2%. There were statistical significance in each GA period group (x2 =32.269,/* =0.000). The incidence increased when the GA decreased; There were statistical significance in each birth weight group (x2 =30. 244, P =0. 000), the incidence increased when birth weight decreased. From the comparison of the 23 risk factors for BPD, we find thai 12 factors have statistical significance (P < 0. 05), those are GA, body weight, oxygen time, maximum oxygen treatment concentration, hospital days, tracheal intubation mechanical ventilation, replacement therapy with pulmonary surfactant, anemia, application of Meropenem, the ratio of tenth day body weight to birth weight, the first blood gas analysis scores after birth and oxygen index < 300. On the basis of Logistic regression analysis of GA, birth weight, the highest inhaled oxygen volume concentration, tracheal intubation mechanical ventilation, anemia, the ratio of tenth day body weight to birth weight, we find that body weight, the highest inhaled oxygen volume concentration, the ratio of tenth body weight to birth weight are high risk factors for BPD. By compared the 18 factors between mild BPD and moderate or severe BPD, we find that asphyxia, application of diuretic, oxygen time and first blood gas analysis scores after birth have statistical significance ( P < 0.05 ) . Conclusions The birth weight, the highest inhaled oxygen volume

  11. Premature ejaculation: A review

    Directory of Open Access Journals (Sweden)

    Sukumar Reddy Gajjala

    2014-01-01

    Full Text Available Premature ejaculation (PE is a common male sexual disorder. It is defined by the Diagnostic and statistical manual of mental disorders as "ejaculation occurring, without control, on or shortly after penetration and before the person wishes it, causing marked distress or interpersonal difficulty. [1] Although the timing of intravaginal ejaculatory latency time (IELT (i.e., time from penetration to ejaculation is not included in this definition, an IELT of <2 min, or ejaculation occurring before penetration, has been considered consistent with PE. [2] Management involves both the patient and his partner. Therapeutic options should suit both partners and be appropriate to their habit in planning and frequency of intercourse. Follow-up at appropriate intervals to judge efficacy, titrate dosage of pharmacological treatments and ascertain side effects is mandatory.

  12. Apnea of Prematurity (For Parents)

    Science.gov (United States)

    ... other babies. The apnea of prematurity does not cause brain damage. A healthy baby who is apnea free for a week will probably never have AOP again. Although sudden infant death syndrome (SIDS) does happen more often in premature infants, no relationship between AOP and SIDS has ...

  13. Impact of rotavirus vaccine on premature infants.

    Science.gov (United States)

    Roué, Jean-Michel; Nowak, Emmanuel; Le Gal, Grégoire; Lemaitre, Thomas; Oger, Emmanuel; Poulhazan, Elise; Giroux, Jean-Dominique; Garenne, Armelle; Gagneur, Arnaud

    2014-10-01

    Infants born preterm are at a higher risk of complications and hospitalization in cases of rotavirus diarrhea than children born at term. We evaluated the impact of a rotavirus vaccination campaign (May 2007 to May 2010) on hospitalizations for rotavirus gastroenteritis in a population of children under 3 years old born prematurely (before 37 weeks of gestation) in the Brest University Hospital birth zone. Active surveillance from 2002 to 2006 and a prospective collection of hospitalizations for rotavirus diarrhea were initiated in the pediatric units of Brest University Hospital until May 2010. Numbers of hospitalizations for rotavirus diarrhea among the population of children born prematurely, before and after the start of the vaccination program, were compared using a Poisson regression model controlling for epidemic-to-epidemic variation. A total of 217 premature infants were vaccinated from 2007 to 2010. Vaccine coverage for a complete course of three doses was 41.9%. The vaccine safety in premature infants was similar to that in term infants. The vaccination program led to a division by a factor of 2.6 (95% confidence interval [CI], 1.3 to 5.2) in the number of hospitalizations for rotavirus diarrhea during the first two epidemic seasons following vaccine introduction and by a factor of 11 (95% CI, 3.5 to 34.8) during the third season. We observed significant effectiveness of the pentavalent rotavirus vaccine on the number of hospitalizations in a population of prematurely born infants younger than 3 years of age. A multicenter national study would provide better assessment of this impact. (This study [Impact of Systematic Infants Vaccination Against Rotavirus on Gastroenteritis Hospitalization: a Prospective Study in Brest District, France (IVANHOE)] has been registered at ClinicalTrials.gov under registration no. NCT00740935.).

  14. Acute renal failure in premature neonates

    Directory of Open Access Journals (Sweden)

    Doronjski Aleksandra

    2009-01-01

    Full Text Available Background/Aim. Hemodynamic stress is the leading cause of acute renal failure (ARF in premature neonates. Incidence of ARF in this population is between 8 and 24%. The aim of this study was to determine the frequency of presence of ARF in premature neonates, as well as its impact on their survival. Methods. A retrospective study of 114 premature neonates [(gestational age, GA less than 37 gestation weeks (gw] admitted to the Intensive Care Unit (ICU at the Pediatric Clinic, Institute of Child and Youth Healthcare of Vojvodina in 2007 was conducted. Serum creatinine, urea and bilirubine were determined on the 3rd day of life in 65 newborns who met inclusion criteria. ARF was diagnosed in 16 newborns (n=16/65; 25%. Results. The premature neonates with ARF had significantly lower GA [<28 gw - 8/16 (50% vs. 5/49 (10%; p < 0.05], birth weight (BW (1 265 g vs. 1615 g; p < 0.05 and systolic blood pressure (43.37 mm Hg vs. 52.7 mmHg; p < 0.05 than ones without ARF. Non-olyguric ARF was diagnosed in 62% of newborns with ARF (n=10/16, while the rest had the olyguric type (n = 6/16; 38%. Twenty-five percent of premature neonates with ARF (n = 4/16 died in contrast to 10% of premature neonates without ARF (n = 5/49. ARF was treated conservatively in all but 3 cases when peritoneal dialysis was performed. Renal function has recovered completely in all of the survivors. In order to determine their predictivity in relation to ARF, following parameters were analyzed: GA, BW < 1 500 g, presence of concomitant sepsis and intracranial hemorrhage grade III/IV. BW < 1 500 g demonstrated the highest sensitivity (se 0.75, while GA < 28 gw, sepsis and intracranial hemorrhage grade III/IV showed high specificity (sp = 0.90, 0.89 0.88, respectively. Conclusion. Acute renal failure frequently occurs in population of premature neonates and requires meticulous fluid and electrolyte balance, especially in the case of low birth weight and extreme immaturity.

  15. Defective nuclear import of Tpr in Progeria reflects the Ran sensitivity of large cargo transport.

    Science.gov (United States)

    Snow, Chelsi J; Dar, Ashraf; Dutta, Anindya; Kehlenbach, Ralph H; Paschal, Bryce M

    2013-05-13

    The RanGTPase acts as a master regulator of nucleocytoplasmic transport by controlling assembly and disassembly of nuclear transport complexes. RanGTP is required in the nucleus to release nuclear localization signal (NLS)-containing cargo from import receptors, and, under steady-state conditions, Ran is highly concentrated in the nucleus. We previously showed the nuclear/cytoplasmic Ran distribution is disrupted in Hutchinson-Gilford Progeria syndrome (HGPS) fibroblasts that express the Progerin form of lamin A, causing a major defect in nuclear import of the protein, translocated promoter region (Tpr). In this paper, we show that Tpr import was mediated by the most abundant import receptor, KPNA2, which binds the bipartite NLS in Tpr with nanomolar affinity. Analyses including NLS swapping revealed Progerin did not cause global inhibition of nuclear import. Rather, Progerin inhibited Tpr import because transport of large protein cargoes was sensitive to changes in the Ran nuclear/cytoplasmic distribution that occurred in HGPS. We propose that defective import of large protein complexes with important roles in nuclear function may contribute to disease-associated phenotypes in Progeria.

  16. Premature and accelerated aging: HIV or HAART?

    NARCIS (Netherlands)

    Smith, R.L.; de Boer, R.; Brul, S.; Budovskaya, Y.; van der Spek, H.

    2013-01-01

    Highly active antiretroviral therapy (HAART) has significantly increased life expectancy of the human immunodeficiency virus (HIV)-positive population. Nevertheless, the average lifespan of HIV-patients remains shorter compared to uninfected individuals. Immunosenescence, a current explanation for

  17. Prenatal Stress, Prematurity, and Asthma.

    Science.gov (United States)

    Medsker, Brock; Forno, Erick; Simhan, Hyagriv; Celedón, Juan C

    2015-12-01

    Asthma is the most common chronic disease of childhood, affecting millions of children in the United States and worldwide. Prematurity is a risk factor for asthma, and certain ethnic or racial minorities such as Puerto Ricans and non-Hispanic blacks are disproportionately affected by both prematurity and asthma. In this review, we examine current evidence to support maternal psychosocial stress as a putative link between prematurity and asthma, while also focusing on disruption of the hypothalamic-pituitary-adrenal (HPA) axis and immune responses as potential underlying mechanisms for stress-induced "premature asthma." Prenatal stress may cause not only abnormalities in the HPA axis but also epigenetic changes in the fetal glucocorticoid receptor gene (NR3C1), leading to impaired glucocorticoid metabolism. Moreover, maternal stress can alter fetal cytokine balance, favoring TH2 (allergic) immune responses characteristic of atopic asthma: interleukin 6 (IL-6), which has been associated with premature labor, can promote TH2 responses by stimulating production of IL-4 and IL-13. Given a link among stress, prematurity, and asthma, future research should include birth cohorts aimed at confirming and better characterizing "premature asthma." If confirmed, clinical trials of prenatal maternal stress reduction would be warranted to reduce the burden of these common comorbidities. While awaiting the results of such studies, sound policies to prevent domestic and community violence (eg, from firearms) are justified, not only by public safety but also by growing evidence of detrimental effects of violence-induced stress on psychiatric and somatic health.

  18. Discordant gene expression signatures and related phenotypic differences in lamin A- and A/C-related Hutchinson-Gilford progeria syndrome (HGPS.

    Directory of Open Access Journals (Sweden)

    Martina Plasilova

    Full Text Available Hutchinson-Gilford progeria syndrome (HGPS is a genetic disorder displaying features reminiscent of premature senescence caused by germline mutations in the LMNA gene encoding lamin A and C, essential components of the nuclear lamina. By studying a family with homozygous LMNA mutation (K542N, we showed that HGPS can also be caused by mutations affecting both isoforms, lamin A and C. Here, we aimed to elucidate the molecular mechanisms underlying the pathogenesis in both, lamin A- (sporadic and lamin A and C-related (hereditary HGPS. For this, we performed detailed molecular studies on primary fibroblasts of hetero- and homozygous LMNA K542N mutation carriers, accompanied with clinical examinations related to the molecular findings. By assessing global gene expression we found substantial overlap in altered transcription profiles (13.7%; 90/657 in sporadic and hereditary HGPS, with 83.3% (75/90 concordant and 16.7% (15/90 discordant transcriptional changes. Among the concordant ones we observed down-regulation of TWIST2, whose inactivation in mice and humans leads to loss of subcutaneous fat and dermal appendages, and loss of expression in dermal fibroblasts and periadnexial cells from a LMNA(K542N/K542N patient further confirming its pivotal role in skin development. Among the discordant transcriptional profiles we identified two key mediators of vascular calcification and bone metabolism, ENPP1 and OPG, which offer a molecular explanation for the major phenotypic differences in vascular and bone disease in sporadic and hereditary HGPS. Finally, this study correlates reduced TWIST2 and OPG expression with increased osteocalcin levels, thereby linking altered bone remodeling to energy homeostasis in hereditary HGPS.

  19. Discordant Gene Expression Signatures and Related Phenotypic Differences in Lamin A- and A/C-Related Hutchinson-Gilford Progeria Syndrome (HGPS)

    Science.gov (United States)

    Plasilova, Martina; Chattopadhyay, Chandon; Ghosh, Apurba; Wenzel, Friedel; Demougin, Philippe; Noppen, Christoph; Schaub, Nathalie; Szinnai, Gabor; Terracciano, Luigi; Heinimann, Karl

    2011-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disorder displaying features reminiscent of premature senescence caused by germline mutations in the LMNA gene encoding lamin A and C, essential components of the nuclear lamina. By studying a family with homozygous LMNA mutation (K542N), we showed that HGPS can also be caused by mutations affecting both isoforms, lamin A and C. Here, we aimed to elucidate the molecular mechanisms underlying the pathogenesis in both, lamin A- (sporadic) and lamin A and C-related (hereditary) HGPS. For this, we performed detailed molecular studies on primary fibroblasts of hetero- and homozygous LMNA K542N mutation carriers, accompanied with clinical examinations related to the molecular findings. By assessing global gene expression we found substantial overlap in altered transcription profiles (13.7%; 90/657) in sporadic and hereditary HGPS, with 83.3% (75/90) concordant and 16.7% (15/90) discordant transcriptional changes. Among the concordant ones we observed down-regulation of TWIST2, whose inactivation in mice and humans leads to loss of subcutaneous fat and dermal appendages, and loss of expression in dermal fibroblasts and periadnexial cells from a LMNAK542N/K542N patient further confirming its pivotal role in skin development. Among the discordant transcriptional profiles we identified two key mediators of vascular calcification and bone metabolism, ENPP1 and OPG, which offer a molecular explanation for the major phenotypic differences in vascular and bone disease in sporadic and hereditary HGPS. Finally, this study correlates reduced TWIST2 and OPG expression with increased osteocalcin levels, thereby linking altered bone remodeling to energy homeostasis in hereditary HGPS. PMID:21738662

  20. Premature ovarian insufficiency: Pathogenesis and management

    Directory of Open Access Journals (Sweden)

    Anna J Fenton

    2015-01-01

    Full Text Available The term premature ovarian insufficiency (POI describes a continuum of declining ovarian function in a young woman, resulting in an earlier than average menopause. It is a term that reflects the variable nature of the condition and is substantially less emotive than the formerly used "premature ovarian failure" which signaled a single event in time. Contrary to the decline in the age of menarche seen over the last 3-4 decades there has been no similar change in the age of menopause. In developed nations, the average age for cessation of menstrual cycles is 50-52 years. The age is younger among women from developing nations. Much has been written about POI despite a lack of good data on the incidence of this condition. It is believed that 1% of women under the age of 40 years and 0.1% under the age of 30 years will develop POI. Research is increasingly providing information about the pathogenesis and treatments are being developed to better preserve ovarian function during cancer treatment and to improve fertility options. This narrative review summarizes the current literature to provide an approach to best practice management of POI.

  1. 小于2岁婴幼儿乳房早发育临床随访研究%A clinical follow-up study of premature thelarche in infants under two years of age

    Institute of Scientific and Technical Information of China (English)

    王应旻; 梁黎; 方燕兰; 傅君芬; 董关萍; 王春林

    2013-01-01

    目的 了解小于2岁婴幼儿乳房发育的临床现况及转归,分析影响乳房消退的相关因素.方法 分析2009年10月至2010年9月间因乳房早发育来我院内分泌科就诊的863例2岁以下患儿临床及实验诊断资料并进行纵向随访研究.结果 小于2岁单纯乳房早发育患儿中绝大多数(89.3%)在3周岁内消退,乳房消退平均年龄为17±6月龄;小部分(10.7%)反复或持续增大,3岁后仍不消退,极少数转变为中枢性性早熟.初诊时乳房Tanner分期和基础E2值升高与否是影响乳房消退的独立危险因素.结论 小于2岁婴幼儿乳房早发育在临床并不少见,大多呈自限性病程,3周岁内可消退,但对2岁以上乳房增大持续不消退者要定期随访.%Objective To investigate the clinical status and natural course of premature thelarche (PT) in infants under 2 years of age and to analyze the predictive factors for regression of thelarche. Methods The clinical and laboratory data of 863 infants under 2 years of age, who visited the department of endocrinology in our hospital due to PT between October 2009 and September 2010, were analyzed. A a longitudinal follow-up study was performed. Results Of the infants under 2 years of age with isolated PT, 89. 3% showed a regression before the age of 3 years (mean 17 ± 5. 6 months), 10.7% had recurrent or persistent thelarche, with no regression after the age of 3 years, and some even developed into central precocious puberty. The independent predictive factors for regression of thelarche were Tanner stage at the first visit and whether baseline estradiol level had increased. Conclusions PT in infants under 2 years of age is not rare in the clinical setting, and it usually runs a self-limited course, subsiding before the age of 3 years. However, regular follow-ups should be performed for infants aged over 2 years with persistent thelarche.

  2. [Premature newborn: a case presentation].

    Science.gov (United States)

    Pastor Rodríguez, Jesús David; Pastor Bravo, María Del Mar; López García, Visitación; Cotes Teruel, María Isabel; Mellado, Jesús Eulogio; Cárceles, José Jara

    2010-01-01

    A case is presented of a premature newborn of 27 weeks gestation and weighing 420 grams who was delivered as a result of a maternal pre-eclampsia and retarded intra-uterine growth. During the 125 days of hospitalisation, an individual care plan based on the Virginia Henderson model was devised and applied to both the child and her parents using NANDA diagnostics, interventions according to the NIC classification, and the expected results according to the NOC classification. The Marjory Gordon functional patterns were used for the initial assessment. By applying the pre-term newborn (PTNB) plan, all their needs were provided and were modified throughout the hospital stay, with new needs that were added to the established ones. These required a continuous assessment with the subsequent adapting of the care plan. Likewise, the care required by the parents varied from the initial grief due to the possible loss of their child to learning the alarm signs and the home care that their child would need. The child was finally discharged weighing 2900 grams and with normal neurological and psychomotor development, although with a lower weight appropriate to her age. Currently, at 2 years old, the child has a normal neurological and psychomotor development, but with weight and size lower than the P(3) percentile. She requires speech therapy treatment due to paralysis of the right vocal cord.

  3. Premature thelarche: a follow up study of 40 girls. Natural history and endocrine findings.

    Science.gov (United States)

    Pasquino, A M; Tebaldi, L; Cioschi, L; Cives, C; Finocchi, G; Maciocci, M; Mancuso, G; Boscherini, B

    1985-01-01

    Follow up of 40 girls with premature thelarche showed that where this disorder occurred before age 2 years it usually regressed completely, thus representing a transient and isolated phenomenon. Premature thelarche after age 2 years persisted more frequently, however, and represented the first sign of sexual development, generally leading to simple early puberty. PMID:4091585

  4. 早期蛋白质对不同胎龄早产儿营养评估价值的研究进展%Research Progress of Early Protein’s Nutritional Assessment Value to Premature Infants of Different Gestational Ages

    Institute of Scientific and Technical Information of China (English)

    薛军(综述)

    2014-01-01

    Organs of the premature infants develop immaturely, and infants are usualy pre-delivered because of the changes of intrauterine condition, so complications such as feeding difficulties often appear after birth; protein deficiency and lipid metabolism disorder may easily come along. So the early nutritional status not only decides the survival of the premature infants but also has lasting effects on their future living quality. According to the research findings, the shorter the gestational age of a premature infant is, the lower his ALB, PAB and TP wil be. PAB is the most sensitive index to evaluate the maturity and nutritional status of premature infants so far. Therefore, monitoring the SP level of premature infants has great guiding significance to the clinical reasonable nutritional treatment and disease prevention.%早产儿各脏器发育不成熟,且多因宫内生存条件变化而致早产,生后常有喂养困难等合并症,易发生蛋白质缺乏及血脂代谢紊乱,其早期的营养状况不但决定早产儿存活与否,而且对早产儿远期生活质量也有持久的影响。研究发现,早产儿胎龄越小,白蛋白、前白蛋白、总蛋白水平越低,前白蛋白是目前评价早产儿成熟度及营养状况最敏感的指标。监测早产儿血清蛋白水平变化,对临床合理营养支持治疗及预防疾病具有指导意义。

  5. Premature atherosclerosis: Sounds familial?

    NARCIS (Netherlands)

    Mulders, T.A.

    2013-01-01

    The prevention of cardiovascular disease is an important challenge in current medical practice. Despite higher event rates and cardiovascular burden in individuals at a more advanced age, it represents a greater challenge in individuals who develop cardiovascular disease at a very young age. In

  6. Preterm labor and premature birth: Are you at risk?

    Science.gov (United States)

    ... labor and premature birth: Are you at risk? Preterm labor and premature birth: Are you at risk? ... for preterm labor and premature birth. What are preterm labor and premature birth? Preterm and premature mean ...

  7. Naïve adult stem cells from patients with Hutchinson-Gilford progeria syndrome express low levels of progerin in vivo

    Science.gov (United States)

    Wenzel, Vera; Roedl, Daniela; Gabriel, Diana; Gordon, Leslie B.; Herlyn, Meenhard; Schneider, Reinhard; Ring, Johannes; Djabali, Karima

    2012-01-01

    Summary Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare disorder characterized by segmental accelerated aging and early death from coronary artery disease or stroke. Nearly 90% of HGPS sufferers carry a G608G mutation within exon 11 of LMNA, producing a truncated form of prelamin A, referred to as “progerin”. Here, we report the isolation of naïve multipotent skin-derived precursor (SKP) cells from dermal fibroblast cultures from HGPS donors. These cells form spheres and express the neural crest marker, nestin, in addition to the multipotent markers, OCT4, Sox2, Nanog and TG30; these cells can self-renew and differentiate into smooth muscle cells (SMCs) and fibroblasts. The SMCs derived from the HGPS-SKPs accumulate nuclear progerin with increasing passages. A subset of the HGPS-naïve SKPs express progerin in vitro and in situ in HGPS skin sections. This is the first in vivo evidence that progerin is produced in adult stem cells, and implies that this protein could induce stem cells exhaustion as a mechanism contributing to aging. Our study provides a basis on which to explore therapeutic applications for HGPS stem cells and opens avenues for investigating the pathogenesis of other genetic diseases. PMID:23213444

  8. Coronary Artery Disease in a Werner Syndrome-Like Form of Progeria Characterized by Low Levels of Progerin, a Splice Variant of Lamin A

    Science.gov (United States)

    Hisama, Fuki M.; Lessel, Davor; Leistritz, Dru; Friedrich, Katrin; McBride, Kim L.; Pastore, Matthew T.; Gottesman, Gary S.; Saha, Bidisha; Martin, George M.; Kubisch, Christian; Oshima, Junko

    2015-01-01

    Classical Hutchinson–Gilford progeria syndrome (HGPS) is caused by LMNA mutations that generate an alternatively spliced form of lamin A, termed progerin. HGPS patients present in early childhood with atherosclerosis and striking features of accelerated aging. We report on two pedigrees of adult-onset coronary artery disease with progeroid features, who were referred to our International Registry of Werner Syndrome (WS) because of clinical features consistent with the diagnosis. No mutations were identified in the WRN gene that is responsible for WS, among these patients. Instead, we found two novel heterozygous mutations at the junction of exon 10 and intron 11 of the LMNA gene. These mutations resulted in the production of progerin at a level substantially lower than that of HGPS. Our findings indicate that LMNA mutations may result in coronary artery disease presenting in the fourth to sixth decades along with short stature and a progeroid appearance resembling WS. The absence of early-onset cataracts in this setting should suggest the diagnosis of progeroid laminopathy. This study illustrates the evolving genotype–phenotype relationship between the amount of progerin produced and the age of onset among the spectrum of restrictive dermopathy, HGPS, and atypical forms of WS. PMID:22065502

  9. Naïve adult stem cells from patients with Hutchinson-Gilford progeria syndrome express low levels of progerin in vivo

    Directory of Open Access Journals (Sweden)

    Vera Wenzel

    2012-04-01

    Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670 is a rare disorder characterized by segmental accelerated aging and early death from coronary artery disease or stroke. Nearly 90% of HGPS sufferers carry a G608G mutation within exon 11 of LMNA, producing a truncated form of prelamin A, referred to as “progerin”. Here, we report the isolation of naïve multipotent skin-derived precursor (SKP cells from dermal fibroblast cultures from HGPS donors. These cells form spheres and express the neural crest marker, nestin, in addition to the multipotent markers, OCT4, Sox2, Nanog and TG30; these cells can self-renew and differentiate into smooth muscle cells (SMCs and fibroblasts. The SMCs derived from the HGPS-SKPs accumulate nuclear progerin with increasing passages. A subset of the HGPS-naïve SKPs express progerin in vitro and in situ in HGPS skin sections. This is the first in vivo evidence that progerin is produced in adult stem cells, and implies that this protein could induce stem cells exhaustion as a mechanism contributing to aging. Our study provides a basis on which to explore therapeutic applications for HGPS stem cells and opens avenues for investigating the pathogenesis of other genetic diseases.

  10. Coronary artery disease in a Werner syndrome-like form of progeria characterized by low levels of progerin, a splice variant of lamin A.

    Science.gov (United States)

    Hisama, Fuki M; Lessel, Davor; Leistritz, Dru; Friedrich, Katrin; McBride, Kim L; Pastore, Matthew T; Gottesman, Gary S; Saha, Bidisha; Martin, George M; Kubisch, Christian; Oshima, Junko

    2011-12-01

    Classical Hutchinson-Gilford progeria syndrome (HGPS) is caused by LMNA mutations that generate an alternatively spliced form of lamin A, termed progerin. HGPS patients present in early childhood with atherosclerosis and striking features of accelerated aging. We report on two pedigrees of adult-onset coronary artery disease with progeroid features, who were referred to our International Registry of Werner Syndrome (WS) because of clinical features consistent with the diagnosis. No mutations were identified in the WRN gene that is responsible for WS, among these patients. Instead, we found two novel heterozygous mutations at the junction of exon 10 and intron 11 of the LMNA gene. These mutations resulted in the production of progerin at a level substantially lower than that of HGPS. Our findings indicate that LMNA mutations may result in coronary artery disease presenting in the fourth to sixth decades along with short stature and a progeroid appearance resembling WS. The absence of early-onset cataracts in this setting should suggest the diagnosis of progeroid laminopathy. This study illustrates the evolving genotype-phenotype relationship between the amount of progerin produced and the age of onset among the spectrum of restrictive dermopathy, HGPS, and atypical forms of WS.

  11. Premature menopause linked to CVD and osteoporosis.

    Science.gov (United States)

    Park, Claire; Overton, Caroline

    2010-03-01

    Premature menopause affects 1% of women under the age of 40, the usual age of the menopause is 51. Most women will present with irregular periods or no periods at all with or without climacteric symptoms. Around 10% of women present with primary amenorrhoea. A careful history and examination are required. It is important to ask specifically about previous chemotherapy or radiotherapy and to look for signs of androgen excess e.g. polycystic ovarian syndrome, adrenal problems e.g. galactorrhoea and thyroid goitres. Once pregnancy has been excluded, a progestagen challenge test can be performed in primary care. Norethisterone 5 mg tds po for ten days or alternatively medroxyprogesterone acetate 10 mg daily for ten days is prescribed. A withdrawal bleed within a few days of stopping the norethisterone indicates the presence of oestrogen and bleeding more than a few drops is considered a positive withdrawal bleed. The absence of a bleed indicates low levels of oestrogen, putting the woman at risk of CVD and osteoporosis. FSH levels above 30 IU/l are an indicator that the ovaries are failing and the menopause is approaching or has occurred. It should be remembered that FSH levels fluctuate during the month and from one month to the next, so a minimum of two measurements should be made at least four to six weeks apart. The presence of a bleed should not exclude premature menopause as part of the differential diagnosis as there can be varying and unpredictable ovarian function remaining. The progestagen challenge test should not be used alone, but in conjunction with FSH, LH and oestradiol. There is no treatment for premature menopause. Women desiring pregnancy should be referred to a fertility clinic and discussion of egg donation. Women not wishing to become pregnant should be prescribed HRT until the age of 50 to control symptoms of oestrogen deficiency and reduce the risks of osteoporosis and CVD.

  12. Reactivation of latently infected HIV-1 viral reservoirs and correction of aberrant alternative splicing in the LMNA gene via AMPK activation: Common mechanism of action linking HIV-1 latency and Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Finley, Jahahreeh

    2015-09-01

    Although the use of antiretroviral therapy (ART) has proven highly effective in controlling and suppressing HIV-1 replication, the persistence of latent but replication-competent proviruses in a small subset of CD4(+) memory T cells presents significant challenges to viral eradication from infected individuals. Attempts to eliminate latent reservoirs are epitomized by the 'shock and kill' approach, a strategy involving the combinatorial usage of compounds that influence epigenetic modulation and initiation of proviral transcription. However, efficient regulation of viral pre-mRNA splicing through manipulation of host cell splicing machinery is also indispensible for HIV-1 replication. Interestingly, aberrant alternative splicing of the LMNA gene via the usage of a cryptic splice site has been shown to be the cause of most cases of Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic condition characterized by an accelerated aging phenotype due to the accumulation of a truncated form of lamin A known as progerin. Recent evidence has shown that inhibition of the splicing factors ASF/SF2 (or SRSF1) and SRp55 (or SRSF6) leads to a reduction or an increase in progerin at both the mRNA and protein levels, respectively, thus altering the LMNA pre-mRNA splicing ratio. It is also well-established that during the latter stages of HIV-1 infection, an increase in the production and nuclear export of unspliced viral mRNA is indispensible for efficient HIV-1 replication and that the presence of ASF/SF2 leads to excessive viral pre-mRNA splicing and a reduction of unspliced mRNA, while the presence of SRp55 inhibits viral pre-mRNA splicing and aids in the generation and translation of unspliced HIV-1 mRNAs. The splicing-factor associated protein and putative mitochondrial chaperone p32 has also been shown to inhibit ASF/SF2, increase unspliced HIV-1 viral mRNA, and enhance mitochondrial DNA replication and oxidative phosphorylation. It is our hypothesis that activation of

  13. Resveratrol rescues SIRT1-dependent adult stem cell decline and alleviates progeroid features in laminopathy-based progeria.

    Science.gov (United States)

    Liu, Baohua; Ghosh, Shrestha; Yang, Xi; Zheng, Huiling; Liu, Xinguang; Wang, Zimei; Jin, Guoxiang; Zheng, Bojian; Kennedy, Brian K; Suh, Yousin; Kaeberlein, Matt; Tryggvason, Karl; Zhou, Zhongjun

    2012-12-05

    Abnormal splicing of LMNA gene or aberrant processing of prelamin A results in progeroid syndrome. Here we show that lamin A interacts with and activates SIRT1. SIRT1 exhibits reduced association with nuclear matrix (NM) and decreased deacetylase activity in the presence of progerin or prelamin A, leading to rapid depletion of adult stem cells (ASCs) in Zmpste24(-/-) mice. Resveratrol enhances the binding between SIRT1 and A-type lamins to increases its deacetylase activity. Resveratrol treatment rescues ASC decline, slows down body weight loss, improves trabecular bone structure and mineral density, and significantly extends the life span in Zmpste24(-/-) mice. Our data demonstrate lamin A as an activator of SIRT1 and provide a mechanistic explanation for the activation of SIRT1 by resveratrol. The link between conserved SIRT1 longevity pathway and progeria suggests a stem cell-based and SIRT1 pathway-dependent therapeutic strategy for progeria.

  14. 早老症的分子机制%Molecular mechanism of Hutchinson-Gilford Progeria Syndrome

    Institute of Scientific and Technical Information of China (English)

    刘新光; 赵炜; 周中军

    2010-01-01

    @@ 儿童早老症(Hutchinson Giford Progeria Syn-drome,HGPS)是由于基因突变导致的疾病,它的发病率很低,大概是八百万分之一,患者出生的早期就开始出现衰老的容貌"[1]. 这种疾病最早由Hutchins于1886年报道"[2],1904年Gilford报道了第二例,他在文章中使用了progeria(早老)这个词[3].1962年,DeBusk总结了60例病例,其中包括4例他本人报道的病人,他将这种疾病命名为Hutchinson-Giford Progefia Syndrome,HGPS.

  15. Cost-effectiveness of early treatment for retinopathy of prematurity.

    Science.gov (United States)

    Kamholz, Karen L; Cole, Cynthia H; Gray, James E; Zupancic, John A F

    2009-01-01

    The Early Treatment for Retinopathy of Prematurity trial demonstrated that peripheral retinal ablation of eyes with high-risk prethreshold retinopathy of prematurity (early treatment) is associated with improved visual outcomes at 9 months' corrected gestational age compared with treatment at threshold disease (conventional management). However, early treatment increased the frequency of laser therapy, anesthesia with intubation, treatment-related systemic complications, and the need for repeat treatments. To determine the cost-effectiveness of an early treatment strategy for retinopathy of prematurity compared with conventional management. We developed a stochastic decision analytic model to assess the incremental cost of early treatment per eye with severe visual impairment prevented. We derived resource-use and efficacy estimates from the Early Treatment for Retinopathy of Prematurity trial's published outcome data. We used a third-party payer perspective. Our primary analysis focused on outcomes from birth through 9 months' corrected gestational age. A secondary analysis used a lifetime horizon. Parameter uncertainty was quantified by using probabilistic and deterministic sensitivity analyses. The incremental cost-effectiveness of early treatment was $14,200 per eye with severe visual impairment prevented. There was a 90% probability that the cost-effectiveness of early treatment would be less than $40,000 per eye with severe visual impairment prevented and a 0.5% probability that early treatment would be cost-saving (less costly and more effective). Limiting early treatment to more severely affected eyes (eyes with "type 1 retinopathy of prematurity" as defined by the Early Treatment for Retinopathy of Prematurity trial) had a cost-effectiveness of $6,200 per eye with severe visual impairment prevented. Analyses that considered long-term costs and outcomes found that early treatment was cost-saving. Early treatment of retinopathy of prematurity is both

  16. Neurosensory outcome of prematurely born children following intracranial hemorrhage

    Directory of Open Access Journals (Sweden)

    Velisavljev-Filipović Gordana

    2011-01-01

    Full Text Available Introduction. More and more survival of newborns with small or extremely small body mass at birth, as well as increasing percent of prematurely born babies, have emphasized the significance of intracranial haemorrhage problem. Prematurely born infants are under increased risk for strabismus, amblyopia, blinding and hearing loss. Objective. Establishing the frequency of sensory damages (damage of sight and hearing in prematurely born infants with various degrees of intracranial haemorrhage. Methods. The study is prospective, controlled and included 120 prematurely born infants with diagnosed four different grade intracranial haemorrhage on ultrasonic examination of the central nervous system. The study excluded prematurely born children from twin pregnancies with congenital malformations and stoppage of intrauterine growth. Ophthalmological examination was done at 9, 12, and 36 months of postnatal age. Audilogical examination was done after delivery, at 2 months of age. Results. There are statistically significant differences (p<0.01 related to the presence of strabismus among groups of examinees with vairious hemorrhage degrees. Strabismus was present only in one premature infant with 1st and in 10 children (33.3% with the 4th degree. Amblyopia occurred only among examinees with 4th degree hemorrhage. There were statistically significant differences (p<0.01 related to the finding of transitory otoacoustic emission of the left ear and the right ear among the groups. The finding of the right ear was not usual in 7 examinees from the 4th degree hemorrhage. The finding of the left ear was not usual in 1 examinee from the third and in 7 examinees from the fourth group. Conclusion. Prematurely born children with a higher degree intracranial hemorrhage have a greater risk for the loss of hearing and development of visual handicap.

  17. Insight on pathogenesis of lifelong premature ejaculation: inverse relationship between lifelong premature ejaculation and obesity.

    Science.gov (United States)

    Gökçe, A; Ekmekcioglu, O

    2010-01-01

    Although both biological and psychological factors are important in the etiology, the exact pathogenesis of lifelong premature ejaculation (PE) remains to be clarified. Obesity is a worldwide epidemic that contributes to many chronic diseases. Obesity is associated with erectile dysfunction, but the relationship between obesity and PE has not yet been specifically investigated. The aim of this study was to evaluate the relationships of these two conditions. Between January 2008 and December 2009, we evaluated consecutive patients with lifelong PE in the urology outpatient clinic. Control cases without lifelong PE were selected randomly among cases attending the department of internal medicine for a checkup procedure. The age and sex of control group were matched with that of the study group. Body mass index (BMI) of each case was calculated using the World Health Organization criteria by the measurements of the physician instead of relying on verbal expressions. The mean (+/-s.d.) age of the premature ejaculators was 31.7+/-5.7 (range 21-51) years and in the control cases it was 32.3+/-6.7 (range 22-54) years. The comparison of the mean (+/-s.d.) weight between the study (74.1+/-11.2 kg) and control groups (81.9+/-6.4 kg) revealed a significant difference (Pobese cases in the control group (n=26, 24.1%) was three times greater than the obese premature ejaculators (Pobesity, and we found that patients with lifelong PE were leaner than the healthy control cases.

  18. Defective DSB repair correlates with abnormal nuclear morphology and is improved with FTI treatment in Hutchinson-Gilford progeria syndrome fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Constantinescu, Dan [Department of Cell Biology-Physiology, University of Pittsburgh, Pittsburgh, PA 15260 (United States); Pittsburgh Development Center, Magee-Women' s Research Institute, University of Pittsburgh, Pittsburgh, PA 15260 (United States); Csoka, Antonei B. [Division of Geriatrics, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15260 (United States); Navara, Christopher S. [Division of Developmental and Regenerative Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15260 (United States); Pittsburgh Development Center, Magee-Women' s Research Institute, University of Pittsburgh, Pittsburgh, PA 15260 (United States); Schatten, Gerald P., E-mail: schattengp@upmc.edu [Division of Developmental and Regenerative Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15260 (United States); Department of Cell Biology-Physiology, University of Pittsburgh, Pittsburgh, PA 15260 (United States); Pittsburgh Development Center, Magee-Women' s Research Institute, University of Pittsburgh, Pittsburgh, PA 15260 (United States)

    2010-10-15

    Impaired DSB repair has been implicated as a molecular mechanism contributing to the accelerating aging phenotype in Hutchinson-Gilford progeria syndrome (HGPS), but neither the extent nor the cause of the repair deficiency has been fully elucidated. Here we perform a quantitative analysis of the steady-state number of DSBs and the repair kinetics of ionizing radiation (IR)-induced DSBs in HGPS cells. We report an elevated steady-state number of DSBs and impaired repair of IR-induced DSBs, both of which correlated strongly with abnormal nuclear morphology. We recreated the HGPS cellular phenotype in human coronary artery endothelial cells for the first time by lentiviral transduction of GFP-progerin, which also resulted in impaired repair of IR-induced DSBs, and which correlated with abnormal nuclear morphology. Farnesyl transferase inhibitor (FTI) treatment improved the repair of IR-induced DSBs, but only in HGPS cells whose nuclear morphology was also normalized. Interestingly, FTI treatment did not result in a statistically significant reduction in the higher steady-state number of DSBs. We also report a delay in localization of phospho-NBS1 and MRE11, MRN complex repair factors necessary for homologous recombination (HR) repair, to DSBs in HGPS cells. Our results demonstrate a correlation between nuclear structural abnormalities and the DSB repair defect, suggesting a mechanistic link that may involve delayed repair factor localization to DNA damage. Further, our results show that similar to other HGPS phenotypes, FTI treatment has a beneficial effect on DSB repair.

  19. Blocking protein farnesylation improves nuclear shape abnormalities in keratinocytes of mice expressing the prelamin A variant in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Wang, Yuexia; Ostlund, Cecilia; Worman, Howard J

    2010-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is an accelerated aging disorder caused by mutations in LMNA leading to expression of a truncated prelamin A variant termed progerin. Whereas a farnesylated polypeptide is normally removed from the carboxyl-terminus of prelamin A during endoproteolytic processing to lamin A, progerin lacks the cleavage site and remains farnesylated. Cultured cells from human subjects with HGPS and genetically modified mice expressing progerin have nuclear morphological abnormalities, which are reversed by inhibitors of protein farnesylation. In addition, treatment with protein farnesyltransferase inhibitors improves whole animal phenotypes in mouse models of HGPS. However, improvement in nuclear morphology in tissues after treatment of animals has not been demonstrated. We therefore treated transgenic mice that express progerin in epidermis with the protein farnesyltransferase inhibitor FTI-276 or a combination of pravastatin and zoledronate to determine if they reversed nuclear morphological abnormalities in tissue. Immunofluorescence microscopy and "blinded" electron microscopic analysis demonstrated that systemic administration of FTI-276 or pravastatin plus zoledronate significantly improved nuclear morphological abnormalities in keratinocytes of transgenic mice. These results show that pharmacological blockade of protein prenylation reverses nuclear morphological abnormalities that occur in HGPS in vivo. They further suggest that skin biopsy may be useful to determine if protein farnesylation inhibitors are exerting effects in subjects with HGPS in clinical trials.

  20. Defective DSB repair correlates with abnormal nuclear morphology and is improved with FTI treatment in Hutchinson-Gilford progeria syndrome fibroblasts.

    Science.gov (United States)

    Constantinescu, Dan; Csoka, Antonei B; Navara, Christopher S; Schatten, Gerald P

    2010-10-15

    Impaired DSB repair has been implicated as a molecular mechanism contributing to the accelerating aging phenotype in Hutchinson-Gilford progeria syndrome (HGPS), but neither the extent nor the cause of the repair deficiency has been fully elucidated. Here we perform a quantitative analysis of the steady-state number of DSBs and the repair kinetics of ionizing radiation (IR)-induced DSBs in HGPS cells. We report an elevated steady-state number of DSBs and impaired repair of IR-induced DSBs, both of which correlated strongly with abnormal nuclear morphology. We recreated the HGPS cellular phenotype in human coronary artery endothelial cells for the first time by lentiviral transduction of GFP-progerin, which also resulted in impaired repair of IR-induced DSBs, and which correlated with abnormal nuclear morphology. Farnesyl transferase inhibitor (FTI) treatment improved the repair of IR-induced DSBs, but only in HGPS cells whose nuclear morphology was also normalized. Interestingly, FTI treatment did not result in a statistically significant reduction in the higher steady-state number of DSBs. We also report a delay in localization of phospho-NBS1 and MRE11, MRN complex repair factors necessary for homologous recombination (HR) repair, to DSBs in HGPS cells. Our results demonstrate a correlation between nuclear structural abnormalities and the DSB repair defect, suggesting a mechanistic link that may involve delayed repair factor localization to DNA damage. Further, our results show that similar to other HGPS phenotypes, FTI treatment has a beneficial effect on DSB repair.

  1. Breastfeeding maintenance of very low weight premature babies: experience of mothers

    Directory of Open Access Journals (Sweden)

    Beatriz de Carvalho Ciaciare

    2015-09-01

    Full Text Available The objectives of this study were to comprehend the breastfeeding process from reports of mothers of premature babies and identify factors facilitating or complicating this process. A descriptive qualitative study regarding the family centered care. We conducted 12 interviews with mothers of six months premature babies of chronological age and we submitted data to content analysis. Four categories emerged: The previous breastfeeding experience in the process of breastfeeding the premature baby; Emotional context versus the breastfeeding process; The ability to manage breastfeeding the premature baby and, Successes and failures. We concluded that family and professional support, adequate management and the welcoming of individualized services in the prematurity context were majorly responsible for the breastfeeding success, being even able to surpass the previous maternal desire. Breastfeeding accompaniment after discharge is indispensable for its success with premature babies.

  2. Your Premature Baby: Low Birthweight

    Science.gov (United States)

    ... many low-birthweight babies are born prematurely, many risk factors for having a low-birthweight baby are the same for preterm labor and ... risk for having a low-birthweight baby. Medical risk factors for having a low-birthweight baby Preterm labor . This is labor that starts ...

  3. Music Therapy with Premature Infants

    Science.gov (United States)

    Standley, Jayne

    2003-01-01

    Over 20 years of research and clinical practice in music therapy with premature infants has been compiled into this text designed for Board Certified Music Therapists specializing in Neonatal Intensive Care clinical services, for NICU medical staff incorporating research-based music therapy into developmental care plans, and for parents of…

  4. Music Therapy with Premature Infants

    Science.gov (United States)

    Standley, Jayne

    2003-01-01

    Over 20 years of research and clinical practice in music therapy with premature infants has been compiled into this text designed for Board Certified Music Therapists specializing in Neonatal Intensive Care clinical services, for NICU medical staff incorporating research-based music therapy into developmental care plans, and for parents of…

  5. Influence of Perinatal Risk Factors on Premature Labor Outcome

    Directory of Open Access Journals (Sweden)

    Agamurad A. Orazmuradov

    2016-09-01

    Full Text Available In this article, for the first time, the problem of premature labor (PL is considered from the standpoint of the concept of perinatal obstetric risk. The obtained results show that the optimal choice of the mode of delivery must be based on gestational age and perinatal risk (PR factors with calculation of their intrapartum gain (IG.

  6. Similar phenotype characteristics comparing familial and sporadic premature ovarian failure.

    NARCIS (Netherlands)

    Janse, F.; Knauff, E.A.; Niermeijer, M.F.; Eijkemans, M.J.; Laven, J.S.E.; Lambalk, C.B.; Fauser, B.C.J.M.; Goverde, A.J.

    2010-01-01

    OBJECTIVE: Premature ovarian failure (POF) is characterized by secondary amenorrhea before the age of 40 years, along with repeated increased follicle-stimulating hormone and low estrogen concentrations. POF is considered a complex genetic disease with a familial presentation in 12% to 50% of cases.

  7. Similar phenotype characteristics comparing familial and sporadic premature ovarian failure

    NARCIS (Netherlands)

    Janse, Femi; Knauff, Erik A. H.; Niermeijer, Martinus F.; Eijkemans, Marinus J.; Laven, Joop S. E.; Lambalk, Cornelius B.; Fauser, Bart C. J. M.; Goverde, Angelique J.; Hoek, Annemieke

    2010-01-01

    Objective: Premature ovarian failure (POF) is characterized by secondary amenorrhea before the age of 40 years, along with repeated increased follicle-stimulating hormone and low estrogen concentrations. POF is considered a complex genetic disease with a familial presentation in 12% to 50% of cases.

  8. Early repolarization as a predictor of premature ventricular beats.

    Science.gov (United States)

    Matoshvili, Z T; Petriashvili, Sh G; Archadze, A T; Azaladze, I G

    2015-02-01

    Early repolarization pattern (ERP) is a common ECG variant, characterized by J point elevation manifested either as terminal QRS slurring (the transition from the QRS segment to the ST segment) or notching (a positive deflection inscribed on terminal QRS complex) associated with concave upward ST-segment elevation and prominent T waves in at least two contiguous leads. Aim of this observational study was to compare number of premature ventricular beats in the different groups of patients with early repolarization. The result of this observational study shows that there are: 1,74 fold higher number of premature ventricular beats in 41-74 year subgroup VS 19-40 year subgroup; 1,31 fold higher number of premature ventricular beats in male subgroup VS female subgroup (But this difference is not statistically significant, because t=1,49, p=0,141); 2,85 fold higher number of premature ventricular beats in CAD+ERP subgroup VS ERP without CAD subgroup; 1,74 fold higher number of premature ventricular beats in HF+ERP subgroup VS ERP without HF subgroup; 1,81 fold higher number of premature ventricular beats in CAD+ERP subgroup VS CAD without ERP subgroup; 1,58 fold higher number of premature ventricular beats in HF+ERP subgroup VS HF without ERP subgroup; So, CAD+ERP is very arrhythmogenic condition, after this is HF+ERP, Then Age. This study shows that ERP independently increase number of PVB in different groups (CAD, HF). This is principally new and very important result. Also the number of patients is enough to make this conclusion.

  9. MODERN PRODUCTS FOR FEEDING PREMATURE BABIES

    National Research Council Canada - National Science Library

    A. V. Surzhik

    2012-01-01

    .... Adequate feeding is one of the fundamental factors of premature babies nursing. To ensure a premature baby with all necessary components for power saving in breast milk intake, breast milk fortifiers...

  10. Modern Approach in Premature Ovarian Failure

    Directory of Open Access Journals (Sweden)

    Pacu Irina

    2014-09-01

    Full Text Available Premature ovarian failure (POF is a condition affecting 1-2% of women younger than 40 years of age, characterized by amenorrhea, hypoestrogenism and elevated gonadotropin levels. In the last years it became a problem of social health interest as the frequency increased due to environmental factors and new, efficient methods for cancer treatment in young women. Few genes have beed identified to explain cases of POF but there are also autoimmune associated conditions and an increasing number of iatrogenic cases (chemotherapy, surgery, radiotherapy. Modern approach in POF means not only a precise etiological diagnosis, but also a correct counseling for these patients who often want to become parents, and a chance for a healthy life without the long term consequences of estrogen deprivation from an early age. In vitro fertilization (IVF techniques can be useful for certain cases but research is needed on strategies to improve fertility for women who have follicles remaining in the ovaries.

  11. Premature birth as a risk factor for autism spectrum disorder.

    Science.gov (United States)

    Goldin, Rachel L; Matson, Johnny L

    2016-06-01

    Autism spectrum disorder (ASD) is common, life-long in nature, and can be very debilitating. Thus, an intensive search is on to identify the potential risk factors for the disorder. Premature birth has been identified as one potential factor that could influence potential symptoms of ASD. The sample for this study consisted of 1655 at risk children for developmental delays who were 17-37 months of age. Participants were divided into those diagnosed with ASD (n = 916) and children with atypical development only (n = 739). Premature births were almost twice as common for the atypical development group versus the ASD group. Implications of these data are discussed.

  12. The relationship between premature birth and caregiver first concern in toddlers with autism spectrum disorder: A brief report.

    Science.gov (United States)

    Goldin, Rachel L; Matson, Johnny L; Matheis, Maya; Jang, Jina

    2017-05-01

    The current study examines the relationship between premature birth and the age at which caregivers first become concerned with their child's development in a sample of 84 toddlers with autism spectrum disorder (ASD). The participants were split into two groups: those born prematurely and those born full term. The results indicate that the age of caregiver first concern is significantly younger for those born prematurely than those born full term. The average age caregivers reported first becoming concerned about their child's development was around 7 months for participants born prematurely and around 13 months for participants born full term. Possible explanations for the results and their implications are discussed.

  13. New insights into roles of intermediate filament phosphorylation and progeria pathogenesis.

    Science.gov (United States)

    Goto, Hidemasa; Inagaki, Masaki

    2014-03-23

    Intermediate filaments (IFs) form one of the major cytoskeletal systems in the cytoplasm or beneath the nuclear membrane. Because of their insoluble nature, cellular IFs had been considered to be stable for a long time. The discovery that a purified protein kinase phosphorylated a purified IF protein and in turn induced the disassembly of IF structure in vitro led to the novel concept of dynamic IF regulation. Since then, a variety of protein kinases have been identified to phosphorylate IF proteins such as vimentin in a spatiotemporal regulated manner. A series of studies using cultured cells have demonstrated that preventing IF phosphorylation during mitosis inhibits cytokinesis by the retention of an IF bridge-like structure (IF-bridge) connecting the two daughter cells. Knock-in mice expressing phosphodeficient vimentin variants developed binucleation/aneuploidy in lens epithelial cells, which promoted microophthalmia and lens cataract. Therefore, mitotic phosphorylation of vimentin is of great importance in the completion of cytokinesis, the impairment of which promotes chromosomal instability and premature aging. © 2014 IUBMB Life, 2014.

  14. [Preterm premature rupture of membranes: active or expectant management?].

    Science.gov (United States)

    Kayem, G; Maillard, F

    2009-04-01

    Preterm premature rupture of membranes (PPROM) occurs in 3% of pregnancies and is responsible for 30% of preterm births. The management is discussed between active and expectant management. French recommendations let open both possibilities. The risks described in the case of PPROM are those of prematurity, maternofetal infection, acute procidence of the umbilical cord and abruptio placentae. Before 32 weeks of gestation (WG) and even 34 WG, a prolongation of one week of gestational age significantly decreases neonatal mortality and morbidity. Therefore, most of the authors choose expectant management in case of PPROM. Between 34 and 37 WG, the risk of rare severe morbidity associated with prematurity has to be balanced with risks of an acute maternofetal infection and of abruptio placentae. Further randomized trials are required to choose a type of management with a sufficient level of evidence.

  15. Ability to Keep Milk-Ejecting Activity after Premature Birth

    Directory of Open Access Journals (Sweden)

    S. G. Gribakin

    2015-01-01

    Full Text Available The article examines the modern data on the importance of breast milk in nursing premature babies. It is shown that the amount of breast milk in women, who gave birth prematurely, decreases rapidly, especially when it is impossible to get a baby latched on to the breast. There is a negative correlation between gestational age and duration of lactation. According to the opinion of both doctors and the majority of mothers, pumping out breast milk and using it in feeding a premature baby is an important psychological and physiological factor linking a mother and a child at the intensive care unit. Individual breast milk banks are a new safe and effective method for long-term keeping of breast milk.

  16. Risk factors of intracranial hemorrhage in premature neonates.

    Directory of Open Access Journals (Sweden)

    Nasrin Khalessi

    2014-09-01

    Full Text Available Intraventricular hemorrhage (IVH is an important cause of brain injury in premature neonates. Current study tries to define associated risk factors of IVH in preterm neonates in Aliasghar Children Hospital during 2008 to 2011. In this study, the risk factors have been evaluated in premature neonates with IVH, who had at least one brain sonography since their admission in NICU. A total of 63 premature neonates with IVH were assessed. Mean gestational age was 29.81 (24-34 weeks and mean birth weight was 1290.83±382.96 gr. Other risk factors such as sex, mode of delivery, history of using infertility drugs, maternal disease, maternal hypertension and preeclampsia, lumbar puncture, ventilator therapy and pneumothorax were considered. Because no absolute treatment for IVH is available, identifying risk factors is important in prevention and management of IVH.

  17. Evaluation and Treatment of Anemia in Premature Infants

    Science.gov (United States)

    Hasanbegovic, Edo; Cengic, Nermana; Hasanbegovic, Snijezana; Heljic, Jasmina; Lutolli, Ismail; Begic, Edin

    2016-01-01

    Introduction: Anemia in preterm infants is the pathophysiological process with greater and more rapid decline in hemoglobin compared to the physiological anemia in infants. There is a need for transfusions and administration of human recombinant erythropoietin. Aim: To determine the frequency of anemia in premature infants at the Pediatric Clinic, University Clinical Center Sarajevo, as well as parameter values in the blood count of premature infants and to explore a relationship between blood transfusions with the advent of intraventricular hemorrhage (determine treatment outcome in preterm infants). Patients and methods: Research is retrospective study and it included the period of six months in year 2014. Research included 100 patients, gestational age < 37 weeks (premature infants). Data were collected by examining the medical records of patients at the Pediatric Clinic, UCCS. Results: The first group of patients were premature infants of gestational age ≤ 32 weeks (62/100) and the second group were premature infants of gestational age 33-37 weeks (38/100). Among the patients, 5% were boys and 46% girls. There was significant difference in birth weight and APGAR score among the groups. In the first group, there were 27.42% of deaths, while in the second group, there were only 10.53% of deaths. There was a significant difference in the length of treatment. There was a statistically significant difference in the need for transfusion among the groups. 18 patients in the first group required a transfusion, while in the second group only 3 patients. Conclusions: Preterm infants of gestational age ≤ 32 weeks are likely candidates for blood transfusion during treatment. Preterm infants of gestational age ≤ 32 weeks have the risk of intracranial bleeding associated with the application of blood transfusion in the first week of life. PMID:28210010

  18. Premature: growth and its relation to oral skills.

    Science.gov (United States)

    Vargas, Camila Lehnhart; Berwig, Luana Cristina; Steidl, Eduardo Matias dos Santos; Prade, Leila Sauer; Bolzan, Geovana; Keske-Soares, Márcia; Weinmann, Angela Regina Maciel

    2015-01-01

    To evaluate the influence of oral motor skills of premature infants on their oral feeding performance and growth, during neonatal hospitalization. Fifty-one newborns hospitalized in the neonatal intensive care unit of a hospital in Southern Brazil, between July 2012 and March 2013, were evaluated. The evaluation of oral feeding skills, according to Lau and Smith, was applied after prescription for starting oral feeding. The oral feeding performance was analyzed using the following variables: days taken to start independent oral feeding and hospital discharge. Growth was measured by weight, length, and head circumference, using the curves of Fenton, at birth, first and independent oral feeding, and hospital discharge. At birth, 71% preterm infants were proper for gestational age, most of them were males (53%), with average of 33.6 (±1.5) weeks of gestational age. The gestational age in the assessment did not influence the oral feeding performance of the premature infant and did not differ between levels. Time of transition from tube feeding to oral feeding and hospital stay was shorter when the oral skills were higher. At birth, there was a tendency of low weight and low oral feeding performance. Level IV premature infants in the release of oral feeding presented higher weights. The level of oral skills of the premature infant interfered positively on time of feeding transition from tube to independent oral feeding and hospital stay. Growth, represented by weight gain, was not affected by the level of oral skill.

  19. Retinopathy of prematurity and risk factors: a prospective cohort study

    Directory of Open Access Journals (Sweden)

    Angell Linda

    2005-06-01

    Full Text Available Abstract Background Increased survival of extremely low birth infants due to advances in antenatal and neonatal care has resulted in a population of infants at high risk of developing retinopathy of prematurity (ROP. Therapeutic interventions include the use of antenatal and postnatal steroids however, their effects on the severity of ROP is in dispute. In addition, it has not been investigated whether severe ROP is due to therapeutic interventions or due to the severity of illness. The aim of the present study was to assess the association between the incidence of severe retinopathy of prematurity (greater than stage 2 – International classification of ROP and mechanical ventilation, oxygen therapy, gestational age, antenatal and postnatal steroids in extremely low birth weight infants. Methods Neonates admitted to the neonatal intensive care unit in Lansing, Michigan, during 1993–2000 were followed to determine factors influencing the development of severe retinopathy of prematurity. Ophthalmologic examinations were started at 6 weeks and followed until resolution. We used logistic regression to estimate the relative risk (odds ratio associated with risk factors of ROP. Results Of the neonates with ≤ 1500 g birth weight, admitted to the neonatal intensive care unit, 85% (616/725 survived. Severe retinopathy of prematurity was detected in 7.8% of 576 neonates who had eye examinations. Neonates of lower gestational age (≤ 25 weeks and 26–28 weeks had an increased odds ratio of 8.49 and 3.19 for the development of severe retinopathy of prematurity, respectively, compared to those 29 weeks and older. Late postnatal steroid treatment starting after 3 weeks of life showed 2.9-fold increased odds ratio, in particular administration for two weeks and more (OR: 4.09, 95% CI: 1.52–11.03. With increasing antenatal steroids courses the risk of severe retinopathy of prematurity decreased, however, it was not significant. Lower gestational age

  20. Prematurity stereotyping and mothers' interactions with their premature and full-term infants during the first year.

    Science.gov (United States)

    Stern, Marilyn; Karraker, Katherine; McIntosh, Bonnie; Moritzen, Sara; Olexa, Michelle

    2006-07-01

    To longitudinally assess stability and correlates of prematurity stereotyping and perceptions of infant vulnerability in mothers of premature (N = 56) and full-term (N = 59) infants. At 5, 9, and 12 months, mothers rated videotapes of unfamiliar infants with a full-term label (FTL) or a preterm label (PL), interacted with their own infant, and completed other questionnaires. A subgroup of infants were administered a developmental assessment at 32 months. Mothers rated PL infants more negatively than FTL infants at each age. Individual differences in stereotyping were not stable. Mothers who negatively rated infants labeled with the same birth status of their own infants exhibited more negative interactive behaviors with their infants. Mothers who viewed their own infant as more vulnerable and who showed more prematurity stereotyping at 5 months had infants with lower 32-month mental scores. The results suggest an association between early maternal cognitions and both contemporaneous maternal behavior and later child developmental outcomes.

  1. MODERN PRODUCTS FOR FEEDING PREMATURE BABIES

    Directory of Open Access Journals (Sweden)

    A. V. Surzhik

    2012-01-01

    Full Text Available In recent decades there has been substantial progress in the technology of premature infants nursing, especially with extremely low birth weight. Adequate feeding is one of the fundamental factors of premature babies nursing. To ensure a premature baby with all necessary components for power saving in breast milk intake, breast milk fortifiers — specifically developed additives that adjust the composition of food for premature babies, are used for more than 20 years (for premature babies receiving breast milk. On the one hand, to preserve all benefits of breastfeeding, on the other — to prevent the deficit development of necessary elements for adequate growth and development of nutrients.

  2. [Forensic importance of premature craniosynostosis].

    Science.gov (United States)

    Fehlow, P

    1991-01-01

    In agreement with Canabis craniosynostosis as a little known organic partial factor of sociopathy is demonstrated. A psychic syndrome of the frontal lobe with increased susceptibility in environmental damages is assumed to be basic disorder. In the criminals of the material sexual offenders were preponderating. Associated craniofacial dysplasias are a risk for psychic maldevelopment. The importance of premature craniosynostocis as a biological risk factor, incidence, diagnostic, indication for an operation, also in the meaning of a neurosurgical "Konflikttherapie" (cosmetical indication) are discussed.

  3. A pathway linking oxidative stress and the Ran GTPase system in progeria.

    Science.gov (United States)

    Datta, Sutirtha; Snow, Chelsi J; Paschal, Bryce M

    2014-04-01

    Maintaining the Ran GTPase at a proper concentration in the nucleus is important for nucleocytoplasmic transport. Previously we found that nuclear levels of Ran are reduced in cells from patients with Hutchinson-Gilford progeria syndrome (HGPS), a disease caused by constitutive attachment of a mutant form of lamin A (termed progerin) to the nuclear membrane. Here we explore the relationship between progerin, the Ran GTPase, and oxidative stress. Stable attachment of progerin to the nuclear membrane disrupts the Ran gradient and results in cytoplasmic localization of Ubc9, a Ran-dependent import cargo. Ran and Ubc9 disruption can be induced reversibly with H2O2. CHO cells preadapted to oxidative stress resist the effects of progerin on Ran and Ubc9. Given that HGPS-patient fibroblasts display elevated ROS, these data suggest that progerin inhibits nuclear transport via oxidative stress. A drug that inhibits pre-lamin A cleavage mimics the effects of progerin by disrupting the Ran gradient, but the effects on Ran are observed before a substantial ROS increase. Moreover, reducing the nuclear concentration of Ran is sufficient to induce ROS irrespective of progerin. We speculate that oxidative stress caused by progerin may occur upstream or downstream of Ran, depending on the cell type and physiological setting.

  4. Different prelamin A forms accumulate in human fibroblasts: a study in experimental models and progeria

    Directory of Open Access Journals (Sweden)

    S Dominici

    2009-08-01

    Full Text Available Lamin A is a component of the nuclear lamina mutated in a group of human inherited disorders known as laminopathies. Among laminopathies, progeroid syndromes and lipodystrophies feature accumulation of prelamin A, the precursor protein which, in normal cells, undergoes a multi-step processing to yield mature lamin A. It is of utmost importance to characterize the prelamin A form accumulated in each laminopathy, since existing evidence shows that drugs acting on protein processing can improve some pathological aspects.We report that two antibodies raised against differently modified prelamin A peptides show a clear specificity to full-length prelamin A or carboxymethylated farnesylated prelamin A, respectively. Using these antibodies, we demonstrated that inhibition of the prelamin A endoprotease ZMPSTE24 mostly elicits accumulation of full-length prelamin A in its farnesylated form, while loss of the prelamin A cleavage site causes accumulation of carboxymethylated prelamin A in progeria cells. These results suggest a major role of ZMPSTE24 in the first prelamin A cleavage step.

  5. Different prelamin A forms accumulate in human fibroblasts: a study in experimental models and progeria

    Directory of Open Access Journals (Sweden)

    G Lattanzi

    2009-03-01

    Full Text Available Lamin A is a component of the nuclear lamina mutated in a group of human inherited disorders known as laminopathies. Among laminopathies, progeroid syndromes and lipodystrophies feature accumulation of prelamin A, the precursor protein which, in normal cells, undergoes a multi-step processing to yield mature lamin A. It is of utmost importance to characterize the prelamin A form accumulated in each laminopathy, since existing evidence shows that drugs acting on protein processing can improve some pathological aspects.We report that two antibodies raised against differently modified prelamin A peptides show a clear specificity to full-length prelamin A or carboxymethylated farnesylated prelamin A, respectively. Using these antibodies, we demonstrated that inhibition of the prelamin A endoprotease ZMPSTE24 mostly elicits accumulation of full-length prelamin A in its farnesylated form, while loss of the prelamin A cleavage site causes accumulation of carboxymethylated prelamin A in progeria cells. These results suggest a major role of ZMPSTE24 in the first prelamin A cleavage step.

  6. The influence of premature extractions of primary molars on the ultimate root length of their permanent successors.

    Science.gov (United States)

    Brin, I; Koyoumdijsky-Kaye, E

    1981-06-01

    Final root length of lower premolars which succeed prematurely--extracted primary molars is shortened. The proposed explanation focuses on a possible accelerated movement of the permanent tooth bud and undue environmental stress following the premature extraction of its deciduous predecessor. The degree of shortening is different in both sexes and depends on the age at which the premature extraction is performed. Girls are more affected than boys, especially in cases in which the premature extractions are performed before the age of eight yr.

  7. Modeling premature brain injury and recovery

    Science.gov (United States)

    Scafidi, Joey; Fagel, Devon M.; Ment, Laura R.; Vaccarino, Flora M.

    2009-01-01

    Premature birth is a growing and significant public health problem because of the large number of infants that survive with neurodevelopmental sequelae from brain injury. Recent advances in neuroimaging have shown that although some neuroanatomical structures are altered, others improve over time. This review outlines recent insights into brain structure and function in these preterm infants at school age and relevant animal models. These animal models have provided scientists with an opportunity to explore in depth the molecular and cellular mechanisms of injury as well as the potential of the brain for recovery. The endogenous potential that the brain has for neurogenesis and gliogenesis, and how environment contributes to recovery, are also outlined. These preclinical models will provide important insights into the genetic and epigenetic mechanisms responsible for variable degrees of injury and recovery, permitting the exploration of targeted therapies to facilitate recovery in the developing preterm brain. PMID:19482072

  8. Periodic heart rate decelerations in premature infants.

    Science.gov (United States)

    Flower, Abigail A; Moorman, J Randall; Lake, Douglas E; Delos, John B

    2010-04-01

    The pacemaking system of the heart is complex; a healthy heart constantly integrates and responds to extracardiac signals, resulting in highly complex heart rate patterns with a great deal of variability. In the laboratory and in some pathological or age-related states, however, dynamics can show reduced complexity that is more readily described and modeled. Reduced heart rate complexity has both clinical and dynamical significance - it may provide warning of impending illness or clues about the dynamics of the heart's pacemaking system. In this paper, we describe simple and interesting heart rate dynamics that we have observed in premature human infants - reversible transitions to large-amplitude periodic oscillations - and we show that the appearance and disappearance of these periodic oscillations can be described by a simple mathematical model, a Hopf bifurcation.

  9. NEONATAL COMPLICATIONS OF PREMATURE RUPTURE OF MEMBRANES

    Directory of Open Access Journals (Sweden)

    F. Nili AA. Shams Ansari

    2003-07-01

    Full Text Available Premature rupture of membranes (PROM is one of the most common complications of pregnancy that has a major impact on neonatal outcomes. With respect to racial, nutritional and cultural differences between developed and developing countries, this study was conducted to detect the prevalence of neonatal complications following PROM and the role of the duration of rupture of membranes in producing morbidities and mortalities in these neonates in our hospital. Among 2357 pregnant women, we found 163 (6.91% cases of premature rupture of the fetal membranes in Tehran Vali-e-Asr Hospital during April 2001 to April 2002. Route of delivery was cesarean section in 65.6% of women. Urinary tract infection occured in 1.8%, maternal leukocytosis and fever in 20.2% and 5.5%, chorioamnionitis in 6.1%, fetal tachycardia in 1.2% and olygohydramnios in 4.9%. Gestational age in 138 (86% of neonates was less than 37 completed weeks. Thirty five infants (21.47% had respiratory distress syndrome and 33 (20.245% had clinical sepsis. Pneumonia in 6 (3.7% and skeletal deformity in 7 (4.294% were seen. Rupture of membrane of more than 24 hours duration occurred in 71 (43.6% of the patients. Comparison of morbidities between two groups of neonates and their mothers according to the duration of PROM (less and more than 24 hours showed significant differences in NICU admission, olygohydramnios, maternal fever, leukocytosis and chorioamnionitis rates (p24 hr of PROM with an odds ratio of 2.68 and 2.73, respectively. Positive blood and eye cultures were detected in 16 cases during 72 hours of age. Staphylococcus species, klebsiella, E.coli and streptococcus were the predominant organisms among positive blood cultures. Mortality was seen in 18 (11% of neonates because of respiratory failure, disseminated intravascular coagulation, septic shock, and a single case of congenital toxoplasmosis. In this study, the prevalence of prematurity, sepsis and prolonged rupture of membrane

  10. Effects of prematurity on language acquisition and auditory maturation: a systematic review.

    Science.gov (United States)

    Rechia, Inaê Costa; Oliveira, Luciéle Dias; Crestani, Anelise Henrich; Biaggio, Eliara Pinto Vieira; Souza, Ana Paula Ramos de

    2016-01-01

    To verify which damages prematurity causes to hearing and language. We used the decriptors language/linguagem, hearing/audição, prematurity/prematuridade in databases LILACS, MEDLINE, Cochrane Library and Scielo. randomized controlled trials, non-randomized intervention studies and descriptive studies (cross-sectional, cohort, case-control projects). The articles were assessed independently by two authors according to the selection criteria. Twenty-six studies were selected, of which seven were published in Brazil and 19 in international literature. Nineteen studies comparing full-term and preterm infants. Two of the studies made comparisons between premature infants small for gestational age and appropriate for gestational age. In four studies, the sample consisted of children with extreme prematurity, while other studies have been conducted in children with severe and moderate prematurity. To assess hearing, these studies used otoacoustic emissions, brainstem evoked potentials, tympanometry, auditory steady-state response and visual reinforcement audiometry. For language assessment, most of the articles used the Bayley Scale of Infant and Toddler Development. Most studies reviewed observed that prematurity is directly or indirectly related to the acquisition of auditory and language abilities early in life. Thus, it could be seen that prematurity, as well as aspects related to it (gestational age, low weight at birth and complications at birth), affect maturation of the central auditory pathway and may cause negative effects on language acquisition.

  11. [Premature ejaculation: pills or sexology?].

    Science.gov (United States)

    Wisard, M; Audette, N

    2008-03-26

    Premature ejaculation (PE) is a frequent male sexual complaint that affects 20 to 30% of men. The exact aetiology is unknown: psychological/behavioristic and biogenic etiologies have been proposed. The introduction of selective serotonin reuptake inhibitors (SSRI) was revolutionary in the medical treatment of PE. However precautions should be taken because of potential adverse side effects. There is no clear consensus as to whether SSRI may represent an eventual cure of PE or will be required for life. The sexocorporal approach is an other treatment of PE, but convincing scientific treatment data are also lacking.

  12. Positional moulding in premature hydrocephalics.

    Directory of Open Access Journals (Sweden)

    Kumar R

    2002-04-01

    Full Text Available Seven premature hydrocephalics presenting with lambdoid positional moulding (LPM were reviewed. All were treated for hydrocephalus secondary to aqueductal stenosis, Dandy Walker Syndrome and infection. Parenchymal hemorrhage, intraventricular bleed, cortical atrophy, septal agenesis, cortical anomalies and subdural hygroma were the other common associations. These children did not show expected improvement in their higher mental functions at 6 months to 5.4 years of follow-up, following the management of hydrocephalus. It was not the LPM but associated intracranial anomalies, which were most probably responsible for their poor outcome. The differentiation from posterior plagiocephaly is also highlighted.

  13. Metabolic bone disease of prematurity

    Directory of Open Access Journals (Sweden)

    Stacy E. Rustico, MD

    2014-09-01

    Full Text Available Metabolic bone disease (MBD of prematurity remains a significant problem for preterm, chronically ill neonates. The definition and recommendations for screening and treatment of MBD vary in the literature. A recent American Academy of Pediatrics Consensus Statement may help close the gap in institutional variation, but evidence based practice guidelines remain obscure due to lack of normative data and clinical trials for preterm infants. This review highlights mineral homeostasis physiology, current recommendations in screening and monitoring, prevention and treatment strategies, and an added perspective of a bone health team serving a high volume referral neonatal intensive care center.

  14. Current therapies for premature ejaculation.

    Science.gov (United States)

    Gur, Serap; Kadowitz, Philip J; Sikka, Suresh C

    2016-07-01

    Premature ejaculation (PE) subjectively affects 20-30% of men globally. Until recently, understanding of PE was hampered by the absence of a widely accepted definition, paucity of evidence-based clinical studies, and the absence of an appropriate animal model. Here, we elaborate on the current definition of PE, its pathogenesis, currently available therapies, and future treatment prospects. Most treatments for PE are 'off-label' and include selective serotonin reuptake inhibitors (SSRIs), topical anesthetics, tramadol, and phosphodiesterase type 5 (PDE5) inhibitors. Such knowledge of the benefit and limitations of each treatment will help to direct future drug design and formulations.

  15. The burden of premature mortality in Spain using standard expected years of life lost: a population-based study

    OpenAIRE

    Álvarez-Martín Elena; de Larrea-Baz Nerea; Catalá-López Ferrán; Gènova-Maleras Ricard; Morant-Ginestar Consuelo

    2011-01-01

    Abstract Background Measures of premature mortality have been used to guide debates on future health priorities and to monitor the population health status. Standard expected years of life lost (SEYLL) is one of the methods used to assess the time lost due to premature death. This article affords an overview of premature mortality in Spain for the year 2008. Methods A population-based study was conducted estimating SEYLL by sex and age groups. SEYLL, a key component of the disability-adjusted...

  16. Premature ventricular contractions associated with isotretinoin use.

    Science.gov (United States)

    Alan, Sevil; Ünal, Betül; Yildirim, Aytül

    2016-01-01

    Isotretinoin has been considered a unique drug for acne treatment. However, it is associated with numerous adverse effects. Isotretinoin can trigger premature ventricular contractions. This report describes a 33-year-old-woman who presented with palpitations for 1 week while undergoing 1-month isotretinoin treatment for mild-moderate facial acne. An electrocardiogram and Holter monitoring showed premature ventricular contractions during isotretinoin (Roaccutane, Roche) treatment. Isotretinoin-related premature ventricular contractions were strongly suggested in this case due to the existence of documented premature ventricular contractions on electrocardiograms and the disappearance of these premature ventricular contractions two weeks after termination of the treatment To the authors' knowledge, there has been 1 reported case of premature ventricular contractions linked to isotretinoin use; this report describes a second such case.

  17. Premature ventricular contractions associated with isotretinoin use*

    Science.gov (United States)

    Alan, Sevil; Ünal, Betül; Yildirim, Aytül

    2016-01-01

    Isotretinoin has been considered a unique drug for acne treatment. However, it is associated with numerous adverse effects. Isotretinoin can trigger premature ventricular contractions. This report describes a 33-year-old-woman who presented with palpitations for 1 week while undergoing 1-month isotretinoin treatment for mild-moderate facial acne. An electrocardiogram and Holter monitoring showed premature ventricular contractions during isotretinoin (Roaccutane, Roche) treatment. Isotretinoin-related premature ventricular contractions were strongly suggested in this case due to the existence of documented premature ventricular contractions on electrocardiograms and the disappearance of these premature ventricular contractions two weeks after termination of the treatment To the authors' knowledge, there has been 1 reported case of premature ventricular contractions linked to isotretinoin use; this report describes a second such case. PMID:28099609

  18. Comparative study of visual functions in premature pre-school children with and without retinopathy of prematurity

    Directory of Open Access Journals (Sweden)

    Lígia Beatriz Bonotto

    2014-01-01

    Full Text Available Purpose: Observe whether there are differences in visual functions among premature infants with treated retinopathy of prematurity (ROP in relation to preterm infants with ROP and spontaneous regression; and among these two groups with ROP and the control group without ROP. Methods: Crosssectional observational no blind study. Premature infants were born between 06/199206/2006 and were exam between 06/200912/2010; registered in data of Hospital de Olhos Sandalla Amin Ghanem; with gestational age less than or equal to 32 weeks and 1,599 g born weigh; without ROP and ROP stages II or III, in one of the eyes, with spontaneous regression or with treatment; at least three visits during the selection period at maximum 6 months in the first exam and minimum 4 years of age in reassessment (chronological age were include. Premature that did not respond or were not located for reassessment and those that did not have conditions to do the exams were exclude. Study's groups: G1 ROP posttreatment; G2ROP postspontaneous regression; G3 without ROP (control. Visual function evaluated with visual acuity (VA, contrast sensitivity test (CST, color test (CT, eye movement, stereopsis. Results: Overall, there were 24 premature infants and 48 eyes. Normal VA: 64.28% (G1, 87.5% (G2 and 100% (G3; Normal CST: 66.67% (G1, 100% (G2 and 55.56% (G3; Normal Ishihara CT: 100% (G1 and G2 and 86% (G3; Normal Farnsworth CT: 20% (G1, 75% (G2 and 50% (G3. Normal stereoacuity: 0.00% (G1; 25% (G2 and 3.5% (G3. Strabismus: 37% (G2, 0.00% (G1 and G3. The prevalent tendency for lower response in CST and CT between the premature children in group G3 and Farnsworth color test in G1 is a curious result of this work and more study is necessary about these visual functions in older premature children. Conclusion: The visual functions showed no statistically significant difference among the groups studied.

  19. p.Pro4Arg mutation in LMNA gene: a new atypical progeria phenotype without metabolism abnormalities.

    Science.gov (United States)

    Guo, Hong; Luo, Na; Hao, Fei; Bai, Yun

    2014-08-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a typical presenile disorder, with mutation in the LMNA gene. Besides HGPS, mutations in LMNA gene have also been reported in atypical progeroid syndrome (APS). The objective of the study was to investigate the phenotype and molecular basis of APS in a Chinese family. LMNA gene mutations were also reviewed to identify the phenotypic and pathogenic differences among APS. Two siblings in a non-consanguineous Chinese family with atypical progeria were reported. The clinical features were observed, including presenile manifestations such as bird-like facial appearance, generalized lipodystrophy involving the extremities and mottled hyperpigmentation on the trunk and extremities. A heterozygous mutation c.11C>G (p.Pro4Arg) of the LMNA gene was detected in the two patients. 28 different variants of the LMNA gene have been reported in APS families, spreading over almost all the 12 exons of the LMNA gene with some hot-spot regions. This is the first detailed description of an APS family without metabolism abnormalities. APS patients share most of the clinical features, but there may be some distinct features in different ethnic groups.

  20. Respiratory Failure in Premature Babies Born from Multiple Pregnancy

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    S. A. Perepelitsa

    2010-01-01

    Full Text Available Objective: to reveal the factors that are responsible for the development of respiratory distress syndrome (RDS and the specific features of its course in preterm twin neonates. Subjects and methods. Twenty-three patients who had had twin pregnancy, including 9 (39.1% and 14 (60% with monochorial and bichorial biamniotic twin pregnancies, respectively, were examined. Their mean age was 28.5±5.4 years. Obstetric and gynecologic histories, conditions at conception, the course of pregnancy, the type of pla-centation, and fetal presentation were considered. The placentas were morphologically examined. In all the patients, pregnancy ended in birth of 46 premature neonates, of them there were 19 (41.3% boys and 27 (58.7% girls. The gestational age of the neonates averaged 31.7±2.3 weeks. The evaluation of the efficiency of performed therapy used clinical assessment of the status of the premature neonates; measurement of partial oxygen tension (pO2 and calculation of alveolar-arterial oxygen gradient (A-a DO2, respiratory index (RI, and oxygenation index (OI; death rates were analyzed. Results. The main cause of respiratory failure (RF was RDS in premature twins. Neonatal blood aspiration-caused pneumonia occurred in one case. The course of RDS was variable. Most neonatal infants needed exogenous surfactant replacement therapy and mechanical ventilation (MV. No signs of RF were present in 7 (15.2% premature neonates. Conclusion. Premature twins are a high RDS risk group. The unfavorable factors that contribute to the development of the disease are multiple pregnancy, a past maternal obstetric history, in-vitro fertilization-induced pregnancy, severe gestosis in the second half of pregnancy, and preterm delivery. The type of placentation affects the fetal status after birth. Fatal outcome occurred in infants from the monochorial bioamniotic twins. In multiple pregnancies, there are pathological changes in the placenta, its membranes, and umbilical

  1. PERINATAL AND MATERNAL OUTCOME IN PREMATURE RUPTURE OF MEMBRANES

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    Mercy Rodrigo

    2016-06-01

    Full Text Available BACKGROUND The objectives of this study are 1 To find out the incidence of premature rupture of membranes, 2 To evaluate the aetiology of premature rupture of membranes, 3 To assess foetal and maternal outcome in premature rupture of membranes. MATERIAL AND METHODS This prospective case control study was conducted in Govt. RSRM Lying In Hospital, Chennai, over a period of 6 months and 100 cases of spontaneous rupture of membranes attending the Department of Obstetrics and Gynaecology were studied. Maternal and neonatal outcome were compared with controls. RESULTS Incidence of PROM was 9.06%. Most of them belonged to low socioeconomic class and in the age group 20-29 years, commonly seen primi gravida and in unbooked cases. Aetiological analysis revealed infection in 15% of cases, which is evident by positive amniotic fluid culture, h/o recent coitus in 20%, mal-presentation in 7%. Cause is unknown in most of the cases. The caesarean section rate is 24% when compared to 12% in control group. The PROM group had higher morbidities like postpartum haemorrhage, postpartum fever, wound infection, neonatal sepsis. CONCLUSION This study showed significantly increased morbidity for both mother and baby. PROM causes major increase in the incidence of prematurity, hence careful screening of high risk factors and treatment of infection promptly is needed to decrease the perinatal morbidity and mortality.

  2. Effect of vocal stimulation on responses of premature infants

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    Zahra Alipour

    2014-03-01

    Full Text Available Background and Objectives: There are studies that support music and singing as appropriate developmental care for premature infants, thus, we conducted this study to investigate the physiological and behavioral responses of premature infants to Quran recitation, lullaby music and silence. Methods: In a randomized controlled trial (2011-2012,120 premature infants in the Neonatal Unit (NNU at Izadi Hospital, were randomly assigned to experimental (holy Quran recitation, lullaby music and silence and control groups. The four groups were surveyed for physiological responses including, oxygen saturation, respiratory rate and heart rate and behavioral states. The data were analyzed using SPSS-PC software and quantitative tests. Results: 66females and 54 male infants with gestational age 28- 36 weeks entered into the study. The fourgroupswere not significantly different in terms of demographic variables (P>0.05. The comparisonofchangesinthe infant’s responsesintheendof the intervention comparedtothebase lines, showedno statistically significant differencesbetweengroups(P>0.05. Repeated measures ANOVA and Friedman test did notindicate any significant differences in the mean ofresponseswithinanyof the four groups during the courseof study (P>0.05. Conclusion: Although fluctuations were observed in the mean of physiological responses and behavioral states in premature infants who listened to the recitation of the holy Quran and lullaby music, but these fluctuations were not significant. Findings of this study demonstrated that the preterm infants did not display any adverse reactions to the carefully designed acoustic intervention.

  3. Delayed umbilical cord clamping in premature neonates.

    Science.gov (United States)

    Kaempf, Joseph W; Tomlinson, Mark W; Kaempf, Andrew J; Wu, YingXing; Wang, Lian; Tipping, Nicole; Grunkemeier, Gary

    2012-08-01

    Delayed umbilical cord clamping is reported to increase neonatal blood volume. We estimated the clinical outcomes in premature neonates who had delayed umbilical cord clamping compared with a similar group who had early umbilical cord clamping. This was a before-after investigation comparing early umbilical cord clamping with delayed umbilical cord clamping (45 seconds) in two groups of singleton neonates, very low birth weight (VLBW) (401-1,500 g) and low birth weight (LBW) (greater than 1,500 g but less than 35 weeks gestation). Neonates were excluded from delayed umbilical cord clamping if they needed immediate major resuscitation. Primary outcomes were provision of delivery room resuscitation, hematocrit, red cell transfusions, and the principle Vermont Oxford Network outcomes. In VLBW neonates (77 delayed umbilical cord clamping, birth weight [mean±standard deviation] 1,099±266 g; 77 early umbilical cord clamping 1,058±289 g), delayed umbilical cord clamping was associated with less delivery room resuscitation, higher Apgar scores at 1 minute, and higher hematocrit. Delayed umbilical cord clamping was not associated with significant differences in the overall transfusion rate, peak bilirubin, any of the principle Vermont Oxford Network outcomes, or mortality. In LBW neonates (172 delayed umbilical cord clamping, birth weight [mean±standard deviation] 2,159±384 g; 172 early umbilical cord clamping 2,203±447 g), delayed umbilical cord clamping was associated with higher hematocrit and was not associated with a change in delivery room resuscitation or Apgar scores or with changes in the transfusion rate or peak bilirubin. Regression analysis showed increasing gestational age and birth weight and delayed umbilical cord clamping were the best predictors of higher hematocrit and less delivery room resuscitation. Delayed umbilical cord clamping can safely be performed in singleton premature neonates and is associated with a higher hematocrit, less delivery room

  4. Temperament analysis of children combined with retinopathy of prematurity aged 3 years old%合并早产儿视网膜病变的儿童学龄前期气质特点

    Institute of Scientific and Technical Information of China (English)

    夏宁; 尹同进; 叶巍岭; 杨代秀

    2014-01-01

    目的 探讨合并不同程度早产儿视网膜病变(retinopathy of prematurity,ROP)幼儿期的气质特征,为临床早期干预提供理论依据.方法 采用Carry儿童气质问卷对46例合并不同程度ROP的早产儿在36月龄时进行测试,并与对照组46例进行比较.结果 合并ROP组患儿气质类型以抚养困难型与中间偏难型为主,在适应性、持久性、反应阈方面分值与对照组比较差异有统计学意义.结论 合并ROP的儿童有其自身的气质特点.

  5. Maternal panic disorder: Infant prematurity and low birth weight.

    Science.gov (United States)

    Warren, Susan L; Racu, Camellia; Gregg, Vanessa; Simmens, Samuel J

    2006-01-01

    The aim of this pilot research was to investigate whether infants of mothers with panic disorder (PD) would be at higher risk for prematurity and low birth weight (corrected for gestational age) than controls. Medical records were reviewed for 25 mothers with PD and 33 mothers without a lifetime history of anxiety disorders or other major psychopathology as determined by diagnostic interview. Mothers also completed questionnaires concerning demographic information and life stresses. Compared to controls, infants with PD mothers were not significantly more likely to be born prematurely or earlier than controls but did show smaller birth weight corrected for gestational age, even after accounting for possible confounding influences. Additional research is needed to confirm these preliminary findings. Studying PD mothers during pregnancy could provide insight concerning mechanisms for the development of low birth weight and psychopathology.

  6. The genetics of premature ovarian failure: current perspectives

    OpenAIRE

    2015-01-01

    Chevy Chapman, Lynsey Cree, Andrew N Shelling Department of Obstetrics and Gynecology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand Abstract: Premature ovarian failure (POF) is a common cause of infertility in women, characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels in women under the age of 40. Many genes have been identified over the past few years that contribute to the development of POF. However, few genes have been ...

  7. Psychosocial determinants of premature cardiovascular mortality differences within Hungary

    Science.gov (United States)

    Kopp, Maria; Skrabski, Árpád; Szántó, Zsuzsa; Siegrist, Johannes

    2006-01-01

    Objectives The life expectancy gap between Central‐Eastern European (CEE) countries, including Hungary, and Western Europe (WE) is mainly attributable to excess cardiovascular (CV) mortality in midlife. This study explores the contribution of socioeconomic, work related, psychosocial, and behavioural variables to explaining variations of middle aged male and female CV mortality across 150 sub‐regions in Hungary. Design Cross sectional, ecological analyses. Setting 150 sub‐regions of Hungary. Participants and methods 12 643 people were interviewed in Hungarostudy 2002 survey, representing the Hungarian population according to sex, age, and sub‐regions. Independent variables were income, education, control in work, job insecurity, weekend working hours, social support, depression, hostility, anomie, smoking, body mass index, and alcohol misuse. Main outcome measures Gender specific standardised premature (45–64 years) total CV, ischaemic heart disease, and cerebrovascular mortality rates in 150 sub‐regions of Hungary. Results Low education and income were the most important determinants of mid‐aged CV mortality differences across sub‐regions. High weekend workload, low social support at work, and low control at work account for a large part of variation in male premature CV mortality rates, whereas job insecurity, high weekend workload, and low control at work contribute most noticeably to variations in premature CV mortality rates among women. Low social support from friends, depression, anomie, hostility, alcohol misuse and cigarette smoking can also explain a considerable part of variations of premature CV mortality differences. Conclusion Variations in middle aged CV mortality rates in a rapidly changing society in CEE are largely accounted for by distinct unfavourable working and other psychosocial stress conditions. PMID:16905723

  8. Adolescent Premature Ovarian Insufficiency Following Human Papillomavirus Vaccination

    OpenAIRE

    Deirdre Therese Little MBBS, DRANZCOG, FACRRM; Harvey Rodrick Grenville Ward Bsc(Med), MBChB, DMCOG, FCOG(SA), MMed (O&G), FRANZCOG

    2014-01-01

    Three young women who developed premature ovarian insufficiency following quadrivalent human papillomavirus (HPV) vaccination presented to a general practitioner in rural New South Wales, Australia. The unrelated girls were aged 16, 16, and 18 years at diagnosis. Each had received HPV vaccinations prior to the onset of ovarian decline. Vaccinations had been administered in different regions of the state of New South Wales and the 3 girls lived in different towns in that state. Each had been p...

  9. Long Latency Auditory Evoked Potential in Term and Premature Infants

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    Didoné, Dayane Domeneghini

    2014-01-01

    Full Text Available Introduction The research in long latency auditory evokes potentials (LLAEP in newborns is recent because of the cortical structure maturation, but studies note that these potentials may be evidenced at this age and could be considered as indicators of cognitive development. Purpose To research the exogenous potentials in term and premature infants during their first month of life. Materials and Methods The sample consisted of 25 newborns, 15 term and 10 premature infants. The infants with gestational age under 37 weeks were considered premature. To evaluate the cortical potentials, the infants remained in natural sleep. The LLAEPs were researched binaurally, through insertion earphones, with frequent /ba/ and rare /ga/ speech stimuli in the intensity of 80 dB HL (decibel hearing level. The frequent stimuli presented a total of 80% of the presentations, and the rare, 20%. The data were statistically analyzed. Results The average gestational age of the term infants was 38.9 weeks (± 1.3 and for the premature group, 33.9 weeks (± 1.6. It was possible to observe only the potentials P1 and N1 in both groups, but there was no statistically significant difference for the latencies of the components P1 and N1 (p > 0.05 between the groups. Conclusion It was possible to observe the exogenous components P1 and N1 of the cortical potentials in both term and preterm newborns of no more than 1 month of age. However, there was no difference between the groups.

  10. Economic evaluation of caffeine for apnea of prematurity.

    Science.gov (United States)

    Dukhovny, Dmitry; Lorch, Scott A; Schmidt, Barbara; Doyle, Lex W; Kok, Joke H; Roberts, Robin S; Kamholz, Karen L; Wang, Na; Mao, Wenyang; Zupancic, John A F

    2011-01-01

    To determine the cost-effectiveness of treatment with caffeine compared with placebo for apnea of prematurity in infants with birth weights less than 1250 g, from birth through 18 to 21 months' corrected age. We undertook a retrospective economic evaluation of the cost per survivor without neurodevelopmental impairment by using individual-patient data from the Caffeine for Apnea of Prematurity clinical trial (N = 1869). We included direct medical costs either to the insurance payer or the hospital but excluded costs to parents and society, such as lost productivity. We used a price of $0.21/mg of generic caffeine citrate for our base-case analysis. All costs were expressed in 2008 Canadian dollars and discounted at 3%. The time horizon for this analysis extended through 18 to 21 months' corrected age to match the clinical trial. The mean cost per infant was $124 466 in the caffeine group and $133 505 in the placebo group (difference: $9039 [-14 749 to -3375]; adjusted P = .014). Cost-effectiveness analysis showed caffeine to be a dominant or "win-win" therapy: in >99% of 1000 bootstrap replications of the analysis, caffeine-treated infants had simultaneously better outcomes and lower mean costs. These results were robust to a 1000% increase in the individual resource items, including the price of caffeine citrate. In comparison with placebo, caffeine therapy for apnea of prematurity in infants weighing less than 1250 g is economically appealing for infants up to 18 to 21 months' corrected age.

  11. The relation between oxygen saturation level and retionopathy of prematurity

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    Mohammad Gharavi Fard

    2016-03-01

    Full Text Available Introduction: Oxygen therapy used for preterm infant disease might be associated with oxygen toxicity or oxidative stress. The exact oxygen concentration to control and maintain the arterial oxygen saturation balance is not certainly clear. We aimed to compare the efficacy of higher or lower oxygen saturations on the development of severe retinopathy of prematurity which is a major cause of blindness in preterm neonates. Methods: PubMed was searched for obtaining the relevant articles. A total of seven articles were included after studying the titles, abstracts, and the full text of retrieved articles at initial search. Inclusion criteria were all the English language human clinical randomized controlled trials with no time limitation, which studied the efficacy of low versus high oxygen saturation measured by pulse oximetry in preterm infants.Result: It can be suggested that lower limits of oxygen saturations have higher efficacy at postmesetural age of ≤28 weeks in preterm neonates. This relation has been demonstrated in five large clinical trials including three Boost trials, COT, and Support.Discussion: Applying higher concentrations of oxygen supplementations at mesentural age ≥32 weeks reduced the development of retinopathy of prematurity. Lower concentrations of oxygen saturation decreased the incidence and the development of retinopathy of prematurity in preterm neonates while applied soon after the birth.Conclusions: Targeting levels of oxygen saturation in the low or high range should be performed cautiously with attention to the postmesentural age in preterm infants at the time of starting the procedures.

  12. Study on the relationship between retinopathy of prematurity and maternal age,smoking during pregnancy,drugs and pregnancy complications%早产儿视网膜病变与孕妇年龄、孕期吸烟、药物、妊娠并发症的关系研究

    Institute of Scientific and Technical Information of China (English)

    熊永强; 刘生荣; 陈立宇; 吕月娥; 陈美玲; 周俊楠

    2011-01-01

    Objective: To explore the relationship between the occurrence of retinopathy of prematurity (ROP) and hazard factorsduring pregnancy including maternal age, smoking during pregnancy, drugs and pregnancy complications. Methods: 829 premature infants visiting the hospital from January 2008 to April 2010 received fundus examination regularly. International staging system of ROP was used for diagnosis and staging of ROP. The related clinical data of pregnant women were collected. Results: Among 829 premature infants, 97 infants were diagnosed as ROP, the incidence was 11.7%. There was no significant difference in maternal age and drug use during pregnancy, there was significant difference in smoking during pregnancy and pregnancy complicationa, multivariate logistic analysis showed that there was a significant correlation between smoking, pregnancy complications and the occurrence of ROP. Conclusion: Smoking and pregnancy complications are important risk factors of ROP during pregnancy.%目的:探讨早产儿视网膜病变(ROP)的发生与孕妇年龄、孕期吸烟、药物、妊娠并发症等孕期危害因素的关系.方法:对2008年1月~2010年4月在厦门市妇幼保健院收治的829例早产儿定期进行眼底检查,根据ROP国际分期标准进行ROP的诊断和分期,并收集孕妇孕期相关临床资料.结果,829例早产儿中ROP的患儿为97例,患病率为11.70%.孕妇年龄、孕期服用药物无明显差异,而孕期吸烟和妊娠期并发症差异有统计学意义,经进一步多因素Logistic回归分析显示吸烟、妊娠并发症与ROP发生有显著相关性.结论:吸烟和妊娠并发症是孕期导致ROP发病的高危因素.

  13. Developmental Outcomes of Premature and Low Birth Weight Infants

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    Reza Saeidi

    2016-03-01

    Full Text Available Background: Prematurity is the most common cause of death and disability And Preterm infants, are prone to developmental complications. For this reason this study was designed for follow up of these babies until 2 years by modified DDST-2. Methods: This study was a prospective longitudinal descriptive study from March 2009 to March 2011 in clinic of sheikh and Imam Reza Hospitals, mashhad, Iran. Sample size with Confidence coefficient of 95% and power 80%, was determined 100 hundred babies. Infants were seen by a pediatrician at a follow up clinic at 1, 3, 6, 9,12,15,18, 24, months.The developmental assessment was done using Denver-2 Developmental Screening Test. Results: mean age for smiling was 4/6 ± 2/1  months which significantly differed with appropriate age (p = 0.000, mean age for telling two syllables words 11/7±  1/9 months, without significant difference of appropriate age.(p = 0.139. Average age for understanding NO was 10/4±  2/0 months that significantly differed with appropriate age(p = 0.000. The average age for telling 6 word was 17/8±  3/0, without significant difference with appropriate age (p = 0.510. Conclusion: Children with history of prematurity and low birth weight have more disability and developmental delay so they need to developmental screening tests.

  14. Sexual function of premature ejaculation patients assayed with Chinese Index of Premature Ejaculation

    Institute of Scientific and Technical Information of China (English)

    Yi-MingYuan; Zhong-ChengXin; HuiJiang; Yan-JieGuo; Wu-JiangLiu; LongTian; Ji-ChuanZhu

    2004-01-01

    Aim: To assess the psychometric properties of the Chinese Index of Premature Ejaculation (CIPE).Methods: The sexual function of 167 patients with and 114 normal controls without premature ejaculation (PE) were evaluated with CIPE. All subjects were married and had regular sexual activity. The CIPE has 10 questions, focusing on libido, erectile function, ejaculatory latency, sexual satisfaction and difficulty in delaying ejaculation, self-confidence and depression. Each question was responded to on a 5 point Likert-type scale. The individual question score and the total scale score were analyzed between the two groups. Results: There were no significant differences between the age, duration of marriage and educational level (P>0.05) of patients with and without PE and normal controls. The mean latency of patients with PE and normal controls were 1.6±1.2 and 10.2±9.5 minutes,respectively. Significant differences between patients with (26.7±4.6) PE and normal controls (41.9±4.0) were observed on the total score of CIPE (P15 point) 19.8%, moderate (10~14 point) 62.8% and severe (<9point) 16.7%. Conclusion:The CIPE-5 is a useful method for the evaluation of sexual function of patients with PE and can be used as a clinical endpoint for clinical trials studying the efficacy of pharmacological intervention.

  15. 7 CFR 29.2290 - Premature primings.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 2 2010-01-01 2010-01-01 false Premature primings. 29.2290 Section 29.2290 Agriculture Regulations of the Department of Agriculture AGRICULTURAL MARKETING SERVICE (Standards... 21) § 29.2290 Premature primings. Ground leaves harvested before reaching complete growth and...

  16. 28 CFR 51.22 - Premature submissions.

    Science.gov (United States)

    2010-07-01

    ... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Premature submissions. 51.22 Section 51.22 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED) PROCEDURES FOR THE ADMINISTRATION OF... § 51.22 Premature submissions. The Attorney General will not consider on the merits: (a) Any proposal...

  17. Serbia within the European context: An analysis of premature mortality.

    Science.gov (United States)

    Santric Milicevic, Milena; Bjegovic, Vesna; Terzic, Zorica; Vukovic, Dejana; Kocev, Nikola; Marinkovic, Jelena; Vasic, Vladimir

    2009-08-05

    Based on the global predictions majority of deaths will be collectively caused by cancer, cardiovascular diseases, and traffic accidents over the coming 25 years. In planning future national health policy actions, inter - regional assessments play an important role. The purpose of the study was to analyze similarities and differences in premature mortality between Serbia, EURO A, EURO B, and EURO C regions in 2000. Mortality and premature mortality patterns were analysed according to cause of death, by gender and seven age intervals. The study results are presented in relative (%) and absolute terms (age-specific and age-standardized death rates per 100,000 population, and age-standardized rates of years of life lost - YLL per 1,000). Direct standardization of rates was undertaken using the standard population of Europe. The inter-regional comparison was based on a calculation of differences in YLL structures and with a ratio of age-standardized YLL rates per 1,000. A multivariate generalized linear model was used to explore mortality of Serbia and Europe sub-regions with ln age-specific death rates. The dissimilarity was achieved with a p death case. YLL patterns indicated similarities between Serbia and EURO A, while SRR YLL had similarities between Serbia and EURO B. Compared to all Europe sub-regions, Serbia had a major excess of premature mortality in neoplasms and diabetes mellitus. Serbia had lost more years of life than EURO A due to cardiovascular, genitourinary diseases, and intentional injuries. Yet, Serbia was not as burdened with communicable diseases and injuries as were EURO B and EURO C. With a premature mortality pattern, Serbia is placed in the middle position of the Europe triangle. The main excess of YLL in Serbia was due to cardiovascular, malignant diseases, and diabetes mellitus. The results may be used for assessment of unacceptable social risks resulting from health inequalities. Within intentions to reduce an unfavourable premature

  18. Serbia within the European context: An analysis of premature mortality

    Directory of Open Access Journals (Sweden)

    Marinkovic Jelena

    2009-08-01

    Full Text Available Abstract Background Based on the global predictions majority of deaths will be collectively caused by cancer, cardiovascular diseases, and traffic accidents over the coming 25 years. In planning future national health policy actions, inter – regional assessments play an important role. The purpose of the study was to analyze similarities and differences in premature mortality between Serbia, EURO A, EURO B, and EURO C regions in 2000. Methods Mortality and premature mortality patterns were analysed according to cause of death, by gender and seven age intervals. The study results are presented in relative (% and absolute terms (age-specific and age-standardized death rates per 100,000 population, and age-standardized rates of years of life lost – YLL per 1,000. Direct standardization of rates was undertaken using the standard population of Europe. The inter-regional comparison was based on a calculation of differences in YLL structures and with a ratio of age-standardized YLL rates per 1,000. A multivariate generalized linear model was used to explore mortality of Serbia and Europe sub-regions with ln age-specific death rates. The dissimilarity was achieved with a p ≤ 0.05. Results According to the mortality pattern, Serbia was similar to EURO B, but with a lower average YLL per death case. YLL patterns indicated similarities between Serbia and EURO A, while SRR YLL had similarities between Serbia and EURO B. Compared to all Europe sub-regions, Serbia had a major excess of premature mortality in neoplasms and diabetes mellitus. Serbia had lost more years of life than EURO A due to cardiovascular, genitourinary diseases, and intentional injuries. Yet, Serbia was not as burdened with communicable diseases and injuries as were EURO B and EURO C. Conclusion With a premature mortality pattern, Serbia is placed in the middle position of the Europe triangle. The main excess of YLL in Serbia was due to cardiovascular, malignant diseases, and

  19. Telomeres, telomerase and premature ovarian failure

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    Renata Košir Pogačnik

    2011-11-01

    Full Text Available Telomeres are specialized structures at the ends of chromosomes, consisting of six repeated nucleotides in TTAGGG sequence. Genome stability is partly maintained by the architecture of telomeres and is gradually lost as telomeres progressively shorten with each cell replication. Critically shortened telomeres are recognized by DNA repair mechanisms as DNA damage and the cell replication cycle stops. The cell eventually dies or undergoes cell apoptosis. Telomere represents a cellular marker of biological age and are therefore also called cell mitotic clock. The enzyme that counteracts telomere shortening by adding nucleotides to the 3’ end of DNA strand is called telomerase. It is composed of the RNA subunit (TR, which is special type of messenger RNA (mRNA, the catalytic protein subunit (TERT, which works as a reverse transcriptase and numerous additional proteins. Telomerase is active in some germline, epithelial and haemopoietic cells, but in most somatic cells the activity is undetectable. In literature, the length of telomeres is closely connected with premature ovarian failure (POF. POF is generally defined as the onset of menopause before the age of 40. The causes of disease are genetical, autoimmune, iatrogenic or if we cannot establish the cause – idiopathic. A lot of studies examined correlation between idiopathic POF, length of telomeres and telomerase activity. The studies mostly show that women with POF have shortened telomeres and decreased activity of telomerase as compared to healthy women.

  20. Could Metabolic Syndrome, Lipodystrophy, and Aging Be Mesenchymal Stem Cell Exhaustion Syndromes?

    Directory of Open Access Journals (Sweden)

    Eduardo Mansilla

    2011-01-01

    Full Text Available One of the most important and complex diseases of modern society is metabolic syndrome. This syndrome has not been completely understood, and therefore an effective treatment is not available yet. We propose a possible stem cell mechanism involved in the development of metabolic syndrome. This way of thinking lets us consider also other significant pathologies that could have similar etiopathogenic pathways, like lipodystrophic syndromes, progeria, and aging. All these clinical situations could be the consequence of a progressive and persistent stem cell exhaustion syndrome (SCES. The main outcome of this SCES would be an irreversible loss of the effective regenerative mesenchymal stem cells (MSCs pools. In this way, the normal repairing capacities of the organism could become inefficient. Our point of view could open the possibility for a new strategy of treatment in metabolic syndrome, lipodystrophic syndromes, progeria, and even aging: stem cell therapies.