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Sample records for abnormalities drug-induced

  1. Drug-induced Inhibition and Trafficking Disruption of ion Channels: Pathogenesis of QT Abnormalities and Drug-induced Fatal Arrhythmias.

    Cubeddu, Luigi X

    2016-01-01

    Risk of severe and fatal ventricular arrhythmias, presenting as Torsade de Pointes (TdP), is increased in congenital and acquired forms of long QT syndromes (LQTS). Drug-induced inhibition of K+ currents, IKs, IKr, IK1, and/or Ito, delay repolarization, prolong QT, and increase the risk of TdP. Drug-induced interference with IKr is the most common cause of acquired LQTS/TdP. Multiple drugs bind to KNCH2-hERG-K+ channels affecting IKr, including antiarrythmics, antibiotics, antivirals, azole-antifungals, antimalarials, anticancer, antiemetics, prokinetics, antipsychotics, and antidepressants. Azithromycin has been recently added to this list. In addition to direct channel inhibition, some drugs interfere with the traffic of channels from the endoplasmic reticulum to the cell membrane, decreasing mature channel membrane density; e.g., pentamidine, geldalamicin, arsenic trioxide, digoxin, and probucol. Other drugs, such as ketoconazole, fluoxetine, norfluoxetine, citalopram, escitalopram, donepezil, tamoxifen, endoxifen, atazanavir, and roxitromycin, induce both direct channel inhibition and impaired channel trafficking. Although many drugs prolong the QT interval, TdP is a rare event. The following conditions increase the risk of drug-induced TdP: a) Disease states/electrolyte levels (heart failure, structural cardiac disease, bradycardia, hypokalemia); b) Pharmacogenomic variables (presence of congenital LQTS, subclinical ion-channel mutations, history of or having a relative with history of drug-induced long QT/TdP); c) Pharmacodynamic and kinetic factors (high doses, women, elderly, metabolism inhibitors, combining two or more QT prolonging drugs, drugs that prolong the QT and increase QT dispersion, and drugs with multiple actions on ion channels). Because most of these conditions are preventable, careful evaluation of risk factors and increased knowledge of drug use associated with repolarization abnormalities are strongly recommended.

  2. Identifying drug-induced repolarization abnormalities from distinct ECG patterns in congenital long QT syndrome: a study of sotalol effects on T-wave morphology

    Graff, Claus; Andersen, Mads P; Xue, Joel Q

    2009-01-01

    BACKGROUND: The electrocardiographic QT interval is used to identify drugs with potential harmful effects on cardiac repolarization in drug trials, but the variability of the measurement can mask drug-induced ECG changes. The use of complementary electrocardiographic indices of abnormal repolariz......BACKGROUND: The electrocardiographic QT interval is used to identify drugs with potential harmful effects on cardiac repolarization in drug trials, but the variability of the measurement can mask drug-induced ECG changes. The use of complementary electrocardiographic indices of abnormal...... are typical ECG patterns in LQT2. Blinded to labels, the new morphology measures were tested in a third group of 39 healthy subjects receiving sotalol. Over 3 days the sotalol group received 0, 160 and 320 mg doses, respectively, and a 12-lead Holter ECG was recorded for 22.5 hours each day. Drug...... with QTcF, p ECG patterns in LQT2 carriers effectively quantified repolarization changes induced by sotalol. Further studies are needed to validate whether this measure has...

  3. 畸形子宫早孕药物流产的临床观察%Clinical Observation on Drug Induced Abortion in Abnormal Uterine Pregnancy

    赵童; 张立红

    2016-01-01

    Objective:To investigate the clinical effect of drug induced abortion in abnormal uterine preg-nancy (the uterine septum,uterus bicornis,bicorbate uterus and uterus unicornis).Methods:37 patients with abnormal uterine pregnancy received drug induced abortion (mifepristone combined with misoprostol) termination of pregnancy.Results:Among the 37 patients,28 patients were complete abortion,8 patients were incomplete abortion,1 case was abortion failure.Incomplete abortion and abortion failure patients un-derwent curettage,the postoperative course was uneventful,no accidents such as uterine perforation or suc-tion leaks occurred.The complete abortion rate was 75.7%,the curettage rate was 24.3%.Conclusion:The success rate of drug induced abortion in abnormal uterine pregnancy is high,and for incomplete abortion and medical abortion failure patients,because early drug effects enable embryo stripping,uterine contraction ex-trusion blastocyst and uterine luminal contents of depression or partial discharge,it can effectively reduce the risk of abortion.%目的::针对药物流产终止畸形子宫(子宫纵隔、双角子宫及鞍状子宫、单角子宫)早孕的临床效果展开探讨。方法:37名畸形子宫早孕患者用药物流产(米非司酮联合米索前列醇口服)终止妊娠。结果:37名患者中完全流产28名,未完全流产8名,流产失败1名。而后为不全流产及流产失败患者均行清宫术,手术过程顺利,未产生子宫穿孔、漏吸等情况。完全流产率为75.7%,清宫率为24.3%。结论:畸形子宫早孕应用药物流产成功概率较高,对不全流产及药流失败者因前期药物作用使胚胎剥离,子宫收缩挤压胚囊及宫腔内容物下移或部分排出,可有效降低清宫术的风险。

  4. Drug-induced lupus.

    Rubin, Robert L

    2005-04-15

    Autoantibodies and, less commonly, systemic rheumatic symptoms are associated with treatment with numerous medications and other types of ingested compounds. Distinct syndromes can be distinguished, based on clinical and laboratory features, as well as exposure history. Drug-induced lupus has been reported as a side-effect of long-term therapy with over 40 medications. Its clinical and laboratory features are similar to systemic lupus erythematosus, except that patients fully recover after the offending medication is discontinued. This syndrome differs from typical drug hypersensitivity reactions in that drug-specific T-cells or antibodies are not involved in induction of autoimmunity, it usually requires many months to years of drug exposure, is drug dose-dependent and generally does not result in immune sensitization to the drug. Circumstantial evidence strongly suggests that oxidative metabolites of the parent compound trigger autoimmunity. Several mechanisms for induction of autoimmunity will be discussed, including bystander activation of autoreactive lymphocytes due to drug-specific immunity or to non-specific activation of lymphocytes, direct cytotoxicity with release of autoantigens and disruption of central T-cell tolerance. The latter hypothesis will be supported by a mouse model in which a reactive metabolite of procainamide introduced into the thymus results in lupus-like autoantibody induction. These findings, as well as evidence for thymic function in drug-induced lupus patients, support the concept that abnormalities during T-cell selection in the thymus initiate autoimmunity.

  5. Vitiligo, drug induced (image)

    ... this person's face have resulted from drug-induced vitiligo. Loss of melanin, the primary skin pigment, occasionally ... is the case with this individual. The typical vitiligo lesion is flat and depigmented, but maintains the ...

  6. Drug-induced hepatitis

    Toxic hepatitis ... to get liver damage. Some drugs can cause hepatitis with small doses, even if the liver breakdown ... liver. Many different drugs can cause drug-induced hepatitis. Painkillers and fever reducers that contain acetaminophen are ...

  7. Drug-induced catatonia.

    Duggal, Harpreet S; Singh, Ira

    2005-09-01

    Catatonia is a heterogeneous syndrome that varies in etiology, presentation, course and sequelae. Initially conceptualized as a subtype of schizophrenia, catatonia is now recognized to occur not only with other psychiatric conditions but also with medical conditions and drug-induced and toxic states. While drug-induced catatonia is now a recognized entity, most studies club it with catatonia due to general medical conditions or organic catatonia, thus precluding any meaningful interpretation of such cases. The literature on drug-induced catatonia mostly draws from scattered case reports. This article attempts to review the available literature in this realm and integrate the information in an attempt to explore the epidemiology, etiology, mechanism and treatment of drug-induced catatonia.

  8. Drug-induced hyperkalemia.

    Ben Salem, Chaker; Badreddine, Atef; Fathallah, Neila; Slim, Raoudha; Hmouda, Houssem

    2014-09-01

    Hyperkalemia is a common clinical condition that can be defined as a serum potassium concentration exceeding 5.0 mmol/L. Drug-induced hyperkalemia is the most important cause of increased potassium levels in everyday clinical practice. Drug-induced hyperkalemia may be asymptomatic. However, it may be dramatic and life threatening, posing diagnostic and management problems. A wide range of drugs can cause hyperkalemia by a variety of mechanisms. Drugs can interfere with potassium homoeostasis either by promoting transcellular potassium shift or by impairing renal potassium excretion. Drugs may also increase potassium supply. The reduction in renal potassium excretion due to inhibition of the renin-angiotensin-aldosterone system represents the most important mechanism by which drugs are known to cause hyperkalemia. Medications that alter transmembrane potassium movement include amino acids, beta-blockers, calcium channel blockers, suxamethonium, and mannitol. Drugs that impair renal potassium excretion are mainly represented by angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, direct renin inhibitors, nonsteroidal anti-inflammatory drugs, calcineurin inhibitors, heparin and derivatives, aldosterone antagonists, potassium-sparing diuretics, trimethoprim, and pentamidine. Potassium-containing agents represent another group of medications causing hyperkalemia. Increased awareness of drugs that can induce hyperkalemia, and monitoring and prevention are key elements for reducing the number of hospital admissions, morbidity, and mortality related to drug-induced hyperkalemia.

  9. Drug-induced diarrhoea.

    Chassany, O; Michaux, A; Bergmann, J F

    2000-01-01

    Diarrhoea is a relatively frequent adverse event, accounting for about 7% of all drug adverse effects. More than 700 drugs have been implicated in causing diarrhoea; those most frequently involved are antimicrobials, laxatives, magnesium-containing antacids, lactose- or sorbitol-containing products, nonsteroidal anti-inflammatory drugs, prostaglandins, colchicine, antineoplastics, antiarrhythmic drugs and cholinergic agents. Certain new drugs are likely to induce diarrhoea because of their pharmacodynamic properties; examples include anthraquinone-related agents, alpha-glucosidase inhibitors, lipase inhibitors and cholinesterase inhibitors. Antimicrobials are responsible for 25% of drug-induced diarrhoea. The disease spectrum of antimicrobial-associated diarrhoea ranges from benign diarrhoea to pseudomembranous colitis. Several pathophysiological mechanisms are involved in drug-induced diarrhoea: osmotic diarrhoea, secretory diarrhoea, shortened transit time, exudative diarrhoea and protein-losing enteropathy, and malabsorption or maldigestion of fat and carbohydrates. Often 2 or more mechanisms are present simultaneously. In clinical practice, 2 major types of diarrhoea are seen: acute diarrhoea, which usually appears during the first few days of treatment, and chronic diarrhoea, lasting more than 3 or 4 weeks and which can appear a long time after the start of drug therapy. Both can be severe and poorly tolerated. In a patient presenting with diarrhoea, the medical history is very important, especially the drug history, as it can suggest a diagnosis of drug-induced diarrhoea and thereby avoid multiple diagnostic tests. The clinical examination should cover severity criteria such as fever, rectal emission of blood and mucus, dehydration and bodyweight loss. Establishing a relationship between drug consumption and diarrhoea or colitis can be difficult when the time elapsed between the start of the drug and the onset of symptoms is long, sometimes up to several

  10. Drug-induced gynecomastia.

    Eckman, Ari; Dobs, Adrian

    2008-11-01

    Gynecomastia is caused by drugs in 10 - 25% of all cases. The pathophysiologic mechanism for some drugs includes exogenous estrogens exposure, medications that cause hypogonadism, anti-androgenic effects and hyperprolactinemia. This manuscript reviews common examples of drug-induced gynecomastia, discussing the mechanisms and possible treatments. Discontinuing the medication is always the best choice; however, if this is not possible, then testosterone replacement therapy may be needed for hypogonadism. When a man is euogonadal, a trial of the anti-estrogen, tamoxifen or an aromatase inhibitor may be an option.

  11. [Risk factors and subjective symptoms of drug-induced leucopenia].

    Hayashi, Kyoko; Ohtsu, Fumiko; Yano, Reiko; Sakakibara, Jinsaku; Goto, Nobuyuki

    2011-01-01

    The present study investigated risk factors and subjective symptoms associated with drug-induced leucopenia. We selected 248 patients with drug-induced leucopenia from the Case Reports of Adverse Drug Reactions and Poisoning Information System (CARPIS) database of over 47000 case reports of adverse drug reactions and assigned them to a case group. We also randomly selected 743 cases of adverse drug reactions not associated with leucopenia as a control group. A comparison of patient characteristic data between the two groups using logistic-regression analysis revealed that female sex, autoimmune disease and renal damage were background risk factors for drug-induced leucopenia. In addition, thiamazole, ritodrine, propylthiouracil, ticlopidine, allopurinol, minocycline and captopril administration significantly increased the risk of drug-induced leucopenia. A significant association was also found for fever, chills and pharyngeal abnormalities. Based on these findings, we developed two estimated regression equations to help prevent drug-induced leucopenia in the community pharmacy setting.

  12. Drug induced lung disease - amiodarone in focus

    Vasić Nada R.

    2014-01-01

    Full Text Available More than 380 medications are known to cause pulmonary toxicity. Selected drugs that are important causes of pulmonary toxicity fall into the following classes: cytotoxic, cardiovascular, anti-inflammatory, antimicrobial, illicit drugs, miscellaneous. The adverse reactions can involve the pulmonary parenchyma, pleura, the airways, pulmonary vascular system, and mediastinum. Drug-induced lung diseases have no pathognomonic clinical, laboratory, physical, radiographic or histological findings. A drug-induced lung disease is usually considered a diagnosis of exclusion of other diseases. The diagnosis of drug-mediated pulmonary toxicity is usually made based on clinical findings. In general, laboratory analyses do not help in establishing the diagnosis. High-resolution computed tomography scanning is more sensitive than chest radiography for defining radiographic abnormalities. The treatment of drug-induced lung disease consists of immediate discontinuation of the offending drug and appropriate management of the pulmonary symptoms. Glucocorticoids have been associated with rapid improvement in gas exchange and reversal of radiographic abnormalities. Before starting any medication, patients should be educated about the potential adverse effects of the drug. Amiodarone is an antiarrhythmic agent used in the treatment of many types of tachyarrhythmia. Amiodarone-caused pulmonary toxicity is a well-known side effect (complication of this medication. The incidence of amiodarone-induced lung disease is approximately 5-7%.

  13. An update on risk factors for drug-induced arrhythmias.

    Vlachos, Konstantinos; Georgopoulos, Stamatis; Efremidis, Michael; Sideris, Antonios; Letsas, Konstantinos P

    2016-01-01

    A variety of drugs, either anti-arrhythmics or non-antiarrhythmics, have been associated with drug-induced arrhythmias. Drug-induced arrhythmias are usually observed in the presence of long QT interval or Brugada electrocardiographic pattern. Clinical risk factors, such as female gender, structural heart disease, metabolic and electrolyte abnormalities, bradycardia and conduction disease, increased drug bioavailability, and silent channelopathies act as ''effect amplifiers'' which can make an otherwise relatively safe drug dangerous with regard to risk for polymorphic ventricular tachycardia in the setting of QT interval prolongation. A drug-induced type 1 electrocardiographic pattern of Brugada syndrome is considered highly proarrhythmic. Specific electrocardiographic markers including the corrected QT interval, QRS duration, Tpeak-Tend/QT ratio, and others may predict the risk of arrhythmias in both situations. The present review highlights on the current clinical and electrocardiographic risk factors for prediction of drug-induced arrhythmias.

  14. Drug-induced lupus erythematosus

    M. Carrabba

    2011-09-01

    Full Text Available Drug-induced lupus is a syndrome which share symptoms and laboratory characteristics with the idiopathic systemic lupus erythematosus (SLE. The list of medications implicated as etiologic agents in drug-induced lupus continues to grow. The terms used for this condition are lupus-like syndrome, drug-induced lupus erythematosus (DILE and drug related lupus. More than 80 drugs have been associated with DILE. The first case of DILE was reported in 1945 and associated with sulfadiazin. In 1953 it was reported that DILE was related to the use of hydralazine. Drugs responsible for the development of DILE can divided into three groups, but the list of these drugs is quite long because new drugs are included yearly in the list. The syndrome is characterised by arthralgia, myalgia, pleurisy, rash and fever in association with antinuclear antibodies in the serum. Recognition of DILE is important because it usually reverts within a few weeks after stopping the drug.

  15. Drug-Induced Metabolic Acidosis.

    Pham, Amy Quynh Trang; Xu, Li Hao Richie; Moe, Orson W

    2015-01-01

    Metabolic acidosis could emerge from diseases disrupting acid-base equilibrium or from drugs that induce similar derangements. Occurrences are usually accompanied by comorbid conditions of drug-induced metabolic acidosis, and clinical outcomes may range from mild to fatal. It is imperative that clinicians not only are fully aware of the list of drugs that may lead to metabolic acidosis but also understand the underlying pathogenic mechanisms. In this review, we categorized drug-induced metabolic acidosis in terms of pathophysiological mechanisms, as well as individual drugs' characteristics.

  16. Drug-induced renal disease.

    Curtis, J R

    1979-11-01

    The clinical manifestations of drug-induced renal disease may include all the manifestations attributed to natural or spontaneous renal diseases such as acute renal failure, chronic renal failure, acute nephritic syndrome, renal colic, haematuria, selective tubular defects, obstructive nephropathy, etc. It is therefore vital in any patient with renal disease whatever the clinical manifestations might be, to obtain a meticulous drug and toxin inventory. Withdrawal of the offending drug may result in amelioration or cure of the renal disorder although in the case of severe renal failure it may be necessary to utilise haemodialysis or peritoneal dialysis to tide the patient over the period of acute renal failure. Analgesic nephropathy is an important cause of terminal chronic renal failure and it is therefore vital to make the diagnosis as early as possible. The pathogenesis of some drug-induced renal disorders appears to be immunologically mediated. There are many other pathogenetic mechanisms involved in drug-induced renal disorders and some drugs may under appropriate circumstances be responsible for a variety of different nephrotoxic effects. For example, the sulphonamides have been incriminated in examples of crystalluria, acute interstitial nephritis, acute tubular necrosis, generalised hypersensitivity reactions, polyarteritis nodosa and drug-induced lupus erythematosus.

  17. Drug-induced cutaneous vasculitides.

    Antiga, E; Verdelli, A; Bonciani, D; Bonciolini, V; Quintarelli, L; Volpi, W; Fabbri, P; Caproni, M

    2015-04-01

    Cutaneous vasculitides (CV) can be idiopathic or secondary to several triggers, including drugs, which account for up to 30% of all the cases of CV. Several drugs can induce CV, including some medications commonly used in dermatology, including minocycline, and several new drugs, such as anti-TNF agents. Different pathomecanisms are involved in the development of drug-induced CV, including the formation and deposition of immune complexes, the induction of neutrophil apoptosis, the formation of neoantigens between the drugs and proteins from the host, the shift of the immune response, and others. Although the diagnosis is difficult, because the clinical picture of drug-induced CV is in general indistinguishable from that of other forms of CV, it is important to recognize such entities in order to correctly manage the patient. Anamnesis, diagnostic algorithms to assess the likelihood of the association between a drug and a cutaneous reaction, skin biopsy and laboratory testing (including the search for antineutrophil cytoplasmic antibodies) are useful tools to make a diagnosis of drug-induced CV. About the therapy, while in idiopathic vasculitides the treatment is usually more aggressive and long-lasting, very often requiring a maintenance therapy with immunosuppressive drugs, in drug-induced CV the discontinuation of the suspected drug alone is usually enough to achieve complete remission, making the prognosis usually very good.

  18. Drug-Induced Sleep Endoscopy.

    Charakorn, Natamon; Kezirian, Eric J

    2016-12-01

    Drug-induced sleep endoscopy (DISE) is an upper airway evaluation technique in which fiberoptic examination is performed under conditions of unconscious sedation. Unique information obtained from this 3-dimensional examination of the airway potentially provides additive benefits to other evaluation methods to guide treatment selection. This article presents recommendations regarding DISE technique and the VOTE Classification system for reporting DISE findings and reviews the evidence concerning DISE test characteristics and the association between DISE findings and treatment outcomes.

  19. Drug-induced hepatic injury

    Friis, Henrik; Andreasen, P B

    1992-01-01

    The Danish Committee on Adverse Drug Reactions received 1100 reports of suspected drug-induced hepatic injury during the decade 1978-1987. The causal relationship between drug and hepatic injury was classified as definite in 57 (5.2%) reports, probable in 989 (89.9%) reports, possible in 50 (4...... during the last 2 years of the decade. Based on consumption data, the incidence of hepatic injury due to sulindac was estimated to be 18-fold higher than that due to ibuprofen. Paracetamol was reported to induce acute cytotoxic as well as cholestatic reactions in non-alcoholic subjects taking therapeutic...

  20. Drug-induced hair loss.

    2016-05-01

    Hair loss can have major psychological consequences. It can be due to a wide variety of causes, including hormonal disorders, dietary factors, infections, inflammation, trauma, emotional factors, and cancer. Drugs can also induce hair loss, by interacting with the hair growth cycle. Drug-induced hair loss may be immediate or delayed, sudden or gradual, and diffuse or localised. It is usually reversible after drug discontinuation. The drugs most often implicated in hair loss are anticancer agents, interferon, azole antifungals, lithium, immunosuppressants, and many other drugs belonging to a variety of pharmacological classes.

  1. Drug-induced peripheral neuropathy

    Vilholm, Ole Jakob; Christensen, Alex Alban; Zedan, Ahmed;

    2014-01-01

    Peripheral neuropathy can be caused by medication, and various descriptions have been applied for this condition. In this MiniReview, the term 'drug-induced peripheral neuropathy' (DIPN) is used with the suggested definition: Damage to nerves of the peripheral nervous system caused by a chemical...... substance used in the treatment, cure, prevention or diagnosis of a disease. Optic neuropathy is included in this definition. A distinction between DIPN and other aetiologies of peripheral neuropathy is often quite difficult and thus, the aim of this MiniReview is to discuss the major agents associated...

  2. Drug-induced liver injury

    Nielsen, Mille Bækdal; Ytting, Henriette; Skalshøi Kjær, Mette

    2017-01-01

    biochemical findings included bilirubin elevated to above 3.2 × ULN, ALT elevated to above 9 × ULN in 86%, INR above 1.4 in 70%. Twenty two patients needed treatment in the liver intensive care unit. Fifteen patients developed acute liver failure with a severe outcome. Six patients were liver transplanted......OBJECTIVE: The idiosyncratic subtype of drug-induced liver injury (DILI) is a rare reaction to medical treatment that in severe cases can lead to acute liver failure and death. The aim of this study was to describe the presentation and outcome of DILI and to identify potential predictive factors...... and outcome. RESULTS: Of 43 patients, 25 (58%) were female with a mean age of 54 years. The two most frequent causes of DILI were Disulfiram (30%) and antibiotics (19%). The most common symptoms were jaundice, nausea, fatigue and gastrointestinal discomfort. At the time of admission, the most frequent...

  3. Drug-induced sexual dysfunction.

    Aldridge, S A

    1982-01-01

    Commonly used drugs that may cause sexual dysfunction are reviewed. The anatomy and physiology of the normal sexual response are reviewed. The influence of drugs on neurogenic, hormonal, and vascular mechanisms may result in diminished libido, impotence, ejaculatory and orgasmic difficulties, inhibited vaginal lubrication, menstrual irregularities, and gynecomastia in men or painful breast enlargement in women. Parasympatholytic agents, which interfere with cholinergic transmission, may affect erectile potency, while adrenergic inhibiting agents may interfere with ejaculatory control. Central nervous system depressants or sedating drugs, drugs producing hyperprolactinemia, and antiandrogenic drugs also may affect the normal sexual response. Drugs such as antihypertensive and antipsychotic agents may induce sexual dysfunction that can result in patient noncompliance. Usually, drug-induced side effects are reversible with discontinuation of the offending agent.

  4. Drug-induced status epilepticus.

    Cock, Hannah R

    2015-08-01

    Drug-induced status epilepticus (SE) is a relatively uncommon phenomenon, probably accounting for less than 5% of all SE cases, although limitations in case ascertainment and establishing causation substantially weaken epidemiological estimates. Some antiepileptic drugs, particularly those with sodium channel or GABA(γ-aminobutyric acid)-ergic properties, frequently exacerbate seizures and may lead to SE if used inadvertently in generalized epilepsies or less frequently in other epilepsies. Tiagabine seems to have a particular propensity for triggering nonconvulsive SE sometimes in patients with no prior history of seizures. In therapeutic practice, SE is most commonly seen in association with antibiotics (cephalosporins, quinolones, and some others) and immunotherapies/chemotherapies, the latter often in the context of a reversible encephalopathy syndrome. Status epilepticus following accidental or intentional overdoses, particularly of antidepressants or other psychotropic medications, has also featured prominently in the literature: whilst there are sometimes fatal consequences, this is more commonly because of cardiorespiratory or metabolic complications than as a result of seizure activity. A high index of suspicion is required in identifying those at risk and in recognizing potential clues from the presentation, but even with a careful analysis of patient and drug factors, establishing causation can be difficult. In addition to eliminating the potential trigger, management should be as for SE in any other circumstances, with the exception that phenobarbitone is recommended as a second-line treatment for suspected toxicity-related SE where the risk of cardiovascular complications is higher anyways and may be exacerbated by phenytoin. There are also specific recommendations/antidotes in some situations. The outcome of drug-induced status epilepticus is mostly good when promptly identified and treated, though less so in the context of overdoses. This article is

  5. Drug-induced liver injury: Is it somehow foreseeable?

    Giovanni Tarantino; Matteo Nicola Dario Di Minno; Domenico Capone

    2009-01-01

    The classic view on the pathogenesis of drug-induced liver injury is that the so-called parent compounds are made hepatotoxic by metabolism (formation of neosubstances that react abnormally), mainly by cytochromes -450 (CYP), with further pathways, such as mitochondrial dysfunction and apoptosis, also playing a role. Risk factors for drug-induced liver injury include concomitant hepatic diseases, age and genetic polymorphisms of CYP. However, some susceptibility can today be predicted before drug administration, working on the common substrate, by phenotyping and genotyping studies and by taking in consideration patients' health status. Physicians should always think of this adverse effect in the absence of other clear hepatic disease. Ethical and legal problems towards operators in the health care system are always matters to consider.

  6. Drug-induced fulminant hepatic failure in pregnancy.

    Firoz, Tabassum; Webber, Douglas; Rowe, Hilary

    2015-12-01

    Liver disease in pregnancy can be classified as predating, co-incidental or unique to pregnancy. Medications are often overlooked as a significant cause of liver disease. We present the case of a 39-year-old patient who presented at 20 weeks with jaundice, elevated liver enzymes, and abnormal liver function progressing eventually to fulminant hepatic failure. The patient was on methyldopa and labetalol from 12 weeks' gestational age. Liver biopsy was consistent with drug-induced liver injury. Both methyldopa and labetalol have been associated with hepatotoxicity including liver failure. This case highlights the importance of including medications as a cause of liver failure in pregnant patients.

  7. Drug Induced Hearing Loss: What Is Ototoxicity?

    ... page please turn JavaScript on. Feature: Drug-Induced Hearing Loss What Is Ototoxicity? Past Issues / Spring 2016 Table ... of patients taking these drugs." "Antibiotics Caused My Hearing Loss..." Gulab Lalwani Photo Courtesy of: Gulab Lalwani When ...

  8. Pharmacogenetics of drug-induced arrhythmias

    De Bruin, Marie L; van Puijenbroek, Eugene P; Bracke, Madelon

    2006-01-01

    of a spontaneous reporting system for ADRs, using drug-induced arrhythmias as an example. METHODS: Reports of drug-induced arrhythmias to proarrhythmic drugs were selected from the database of the Netherlands Pharmacovigilance Centre (1996-2003). Information on the patient's general practitioner (GP) was obtained...... were screened for 10 missense mutations in 5 genes associated with the congenital long-QT (LQT) syndrome (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2). RESULTS: We identified 45 eligible cases, 29 GPs could be contacted of which seven were willing to participate. Four cases and five matched controls could...

  9. Drug-induced hyperthermia in Huntington's disease.

    Gaasbeek, D.; Naarding, P.; Stor, T.; Kremer, H.P.H.

    2004-01-01

    Until now, only three patients with Huntington's disease (HD) and a neuroleptic malignant syndrome (NMS) have been reported in the literature. We describe four cases with advanced stage Huntington's disease who within a period of one year developed drug-induced hyperthermia, either the neuroleptic m

  10. Treatment of drug-induced seizures.

    Chen, Hsien-Yi; Albertson, Timothy E; Olson, Kent R

    2016-03-01

    Seizures are a common complication of drug intoxication, and up to 9% of status epilepticus cases are caused by a drug or poison. While the specific drugs associated with drug-induced seizures may vary by geography and change over time, common reported causes include antidepressants, stimulants and antihistamines. Seizures occur generally as a result of inadequate inhibitory influences (e.g., gamma aminobutyric acid, GABA) or excessive excitatory stimulation (e.g. glutamate) although many other neurotransmitters play a role. Most drug-induced seizures are self-limited. However, status epilepticus occurs in up to 10% of cases. Prolonged or recurrent seizures can lead to serious complications and require vigorous supportive care and anticonvulsant drugs. Benzodiazepines are generally accepted as the first line anticonvulsant therapy for drug-induced seizures. If benzodiazepines fail to halt seizures promptly, second line drugs include barbiturates and propofol. If isoniazid poisoning is a possibility, pyridoxine is given. Continuous infusion of one or more anticonvulsants may be required in refractory status epilepticus. There is no role for phenytoin in the treatment of drug-induced seizures. The potential role of ketamine and levetiracetam is promising but not established.

  11. Drug-induced arrhythmias, quantifying the problem

    Bruin, M.L. de

    2004-01-01

    Cardiac arrhythmias as an adverse reaction to the use of non-antiarrhythmic drugs have attracted much attention during recent years. It has become the single most common reason for regulatory action regarding the marketing of drugs. Although drug-induced arrhythmias are very rare (approximately 1 pe

  12. Drug-induced regulation of target expression

    Iskar, Murat; Campillos, Monica; Kuhn, Michael;

    2010-01-01

    further newly identified drug-induced differential regulation of Lanosterol 14-alpha demethylase, Endoplasmin, DNA topoisomerase 2-alpha and Calmodulin 1. The feedback regulation in these and other targets is likely to be relevant for the success or failure of the molecular intervention....

  13. Serious drug-induced liver disease secondary to ezetimibe

    José Castellote; Javier Adza; Rosa Rota; Anna Girbau; Xavier Xiol

    2008-01-01

    Ezetimibe is the first member of a new family of lipidlowering drugs that inhibits uptake of dietary and biliary cholesterol. It was approved by the FDA in 2002for hypercholesterolemia alone or in combination with statins. Its use has been spreading over the last years.Ezetimibe was considered a safe drug. We report a case of a woman who developed a serious hepatocellular drug-induced liver disease after 4 mo therapy with 10 mg daily of ezetimibe. After withdrawal of the drug, the patient recovered slowly. Ezetimibe may produce serious toxic hepatitis and prompt withdrawal is mandatory in case of a significant abnormality in liver testing after beginning or during treatment with ezetimibe.

  14. Mechanistic Review of Drug-Induced Steatohepatitis

    Schumacher, Justin; Guo, Grace

    2015-01-01

    Drug-induced steatohepatitis is a rare form of liver injury known to be caused by only a handful of compounds. These compounds stimulate the development of steatohepatitis through their toxicity to hepatocyte mitochondria; inhibition of beta-oxidation, mitochondrial respiration, and/or oxidative phosphorylation. Other mechanisms discussed include the disruption of phospholipid metabolism in lysosomes, prevention of lipid egress from hepatocytes, targeting mitochondrial DNA and topoisomerase, decreasing intestinal barrier function, activation of the adenosine pathway, increasing fatty acid synthesis, and sequestration of coenzyme A. It has been found that the majority of compounds that induce steatohepatitis have cationic amphiphilic structures; a lipophilic ring structure with a side chain containing a cationic secondary or tertiary amine. Within the last decade, the ability of many chemotherapeutics to cause steatohepatitis has become more evident coining the term chemotherapy-associated steatohepatitis (CASH). The mechanisms behind drug-induced steatohepatitis are discussed with a focus on cationic amphiphilic drugs and chemotherapeutic agents. PMID:26344000

  15. Recent Advances in Drug-Induced Angioedema

    Naoko Inomata

    2012-01-01

    Full Text Available Angioedema is the end result of deep dermal, subcutaneous and/or mucosal swelling, and is potentially a life- threatening condition in cases where the pharynx or larynx is involved. Drug-induced angioedema has been reported to occur in response to a wide range of drugs and vaccines. Drug-induced angioedema, like other cutaneous drug reactions, has been reported to be most frequently elicited by beta-lactam antibiotics and nonsteroidal anti-inflammatory drugs, although reliable data from epidemiologic studies are scarce. Recent reports suggested an increasing role of angiotensin-converting enzyme inhibitors (ACEIs in the causation of life- threatening angioedema. ACEI-related angioedema is never accompanied by urticaria and occurs via a kinin- dependent mechanism. ACEI-related angioedema not only can start years after beginning the treatment, but it can then recur irregularly while under that treatment. Furthermore, allergy tests are unreliable for the diagnosis of ACEI-related angioedema, and so the relationship between angioedema and ACEIs is often missed and consequently quite underestimated. Accordingly, better understanding of the kinin-dependent mechanism, which is particular to angioedema, is necessary for the appropriate management of drug-induced angioedema.

  16. [DRUGS-INDUCED URTICARIA AND ANGIOEDEMA].

    Braire-Bourrel, Marion; Augey, Frédéric; Doutre, Marie-Sylvie

    2015-09-01

    Drug-induced urticaria and/or angioedema is a frequent issue encountered in family medicine. A specific collection of the anamnesis and of the general context is very important to appreciate the involved mechanism, allergic or not, and potential cofactors. If in doubt about an allergic mechanism, tests will be conducted, mostly under a hospital setting. Bradykinin-mediated angioedema, so much rare than histamine-mediated one, has to be known, because it is potentially lethal. It is often iatrogenic (ACE inhibitors especially). At the end of the allergology work-up, a course of action is proposed to the patient and his family practitioner as far as the rechallenge of the drug is concerned, In case of non-allergic urticaria, much more frequent than allergy, taking the drug is possible with a premedication with antihistamines.

  17. Pathogenesis of drug induced acneform eruptions

    Lobo Audrey

    1992-01-01

    Full Text Available To determine the pathogenesis of drug induced acneform eruption (DAE, 44 patients were evaluated clinically and representative samples histologically. INAH and corticosteroids were the main offenders in 38.6 percent and 36.4 percent patients respectively. Chloroquin precipitated lesions in 9.1 percent of the patients. There were significant differences in the duration of drug-intake before onset, morphology and severity of lesions. Histological differences with different drugs were also noted. Based on clinical and histological findings, pathogenesis of lesions caused by different drugs could be suggested. Keratinization of follicular epithelium was the main effect with corticosteroids and INAH. Suppuration of follicular epithelium was an additional early event with corticosteroids. Type III allergic reaction was responsible for iodine lesions and delayed hypersensitivity for chlorpromazine and chloroquine induced lesions.

  18. Drug-induced cutaneous lupus erythematosus

    Laurinaviciene, Rasa; Sandholdt, Linda Holm; Bygum, Anette

    2017-01-01

    BACKGROUND: An increasing number of drugs have been linked to drug-induced subacute cutaneous lupus erythematosus (DI-SCLE). The recognition and management of DI-SCLE can be challenging, as the condition may be triggered by different classes of drugs after variable lengths of time. OBJECTIVES......: To determine the proportion of patients with cutaneous lupus erythematosus (CLE) whose drugs are an inducing or aggravating factor. MATERIALS & METHODS: We conducted a retrospective chart review of patients diagnosed with CLE at a dermatological department over a 21-year period. We registered clinical......, serological, and histological data with a focus on drug intake. RESULTS: Of 775 consecutive patients with a diagnosis of lupus erythematosus (LE) or suspected LE, a diagnosis of CLE could be confirmed in 448 patients. A total of 130 patients had a drug intake that could suggest DI-SCLE. In 88 cases, a drug...

  19. The discovery of drug-induced illness.

    Jick, H

    1977-03-01

    The increased use of drugs (and the concurrent increased risks of drug-induced illness) require definition of relevant research areas and strategy. For established marketed drugs, research needs depend on the magnitudes of risk of an illness from a drug and the base-line risk. With the drug risk high and the base-line risk low, the problem surfaces in premarketing studies or through the epidemic that develops after marketing. If the drug adds slightly to a high base-line risk, the effect is undetectable. When both risks are low, adverse effects can be discovered by chance, but systematic case-referent studies can speed discovery. If both risks are high, clinical trials and nonexperimental studies may be used. With both risks intermediate, systematic evaluations, especially case-referent studies are needed. Newly marketed drugs should be routinely evaluated through compulsory registration and follow-up study of the earliest users.

  20. Drug-Induced Oxidative Stress and Toxicity

    Damian G. Deavall

    2012-01-01

    Full Text Available Reactive oxygen species (ROS are a byproduct of normal metabolism and have roles in cell signaling and homeostasis. Species include oxygen radicals and reactive nonradicals. Mechanisms exist that regulate cellular levels of ROS, as their reactive nature may otherwise cause damage to key cellular components including DNA, protein, and lipid. When the cellular antioxidant capacity is exceeded, oxidative stress can result. Pleiotropic deleterious effects of oxidative stress are observed in numerous disease states and are also implicated in a variety of drug-induced toxicities. In this paper, we examine the nature of ROS-induced damage on key cellular targets of oxidative stress. We also review evidence implicating ROS in clinically relevant, drug-related side effects including doxorubicin-induced cardiac damage, azidothymidine-induced myopathy, and cisplatin-induced ototoxicity.

  1. Melatonin modulates drug-induced acute porphyria

    Sandra M. Lelli

    2016-01-01

    Full Text Available This work investigated the modulation by melatonin (Mel of the effects of the porphyrinogenic drugs 2-allyl-2-isopropylacetamide (AIA and 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-collidine (DDC on oxidative environment, glucose biosynthesis and heme pathway parameters. Administration of Mel before rat intoxication with AIA/DDC showed a clear beneficial effect in all cases. Mel induced decreases of 42% and 35% in the excretion of the hemeprecursors 5-aminolevulinic acid (ALA and porphobilinogen (PBG, respectively, and a 33% decrease in the induction of the heme regulatory enzyme 5-aminolevulinic acid-synthase (ALA-S. The activity of the glucose metabolism enzyme phosphoenolpyruvate carboxykinase (PEPCK, which had been diminished by the porphyrinogenic treatment, was restored by 45% when animals were pre-treated with Mel. Mel abolished the modest decrease in glucose 6-phospatase (G6Pase activity caused by AIA/DDC treatment. The oxidative status of lipids was attenuated by Mel treatment in homogenates by 47%, whereas no statistically significant AIA/DDC-induced increase in thiobarbituric acid reactive substances (TBARS was observed in microsomes after Mel pre-treatment. We hypothesize that Mel may be scavenging reactive species of oxygen (ROS that could be damaging lipids, PEPCK, G6Pase and ferrochelatase (FQ. Additionally, Mel administration resulted in the repression of the key enzyme ALA-S, and this could be due to an increase in glucose levels, which is known to inhibit ALA-S induction. The consequent decrease in levels of the heme precursors ALA and PBG had a beneficial effect on the drug-induced porphyria. The results obtained open the possibility of further research on the use of melatonin as a co-treatment option in acute porphyria.

  2. Drug-induced parkinsonism: diagnosis and management

    Blanchet PJ

    2016-09-01

    Full Text Available Pierre J Blanchet,1–3 Veronika Kivenko1–3 1Department of Stomatology, Faculty of Dental Medicine, University of Montreal, 2Andre-Barbeau Movement Disorders Unit, University of Montreal Hospital Center (CHU Montreal, 3Montreal Mental Health University Institute, Montreal, QC, Canada Abstract: Drug-induced parkinsonism (DIP has been known for >60 years. It is the second leading cause of parkinsonism, but still underdiagnosis is likely to influence reported incidence figures. Since DIP is clinically undistinguishable from Lewy-body Parkinson’s disease, any new case of parkinsonism should prompt the search for an offending antipsychotic, hidden neuroleptic, or nonneuroleptic agent that may produce DIP. DIP is reversible upon drug withdrawal in most cases. There is no consensus regarding the duration of the recovery period to allow motor signs to fully remit in order to confirm the diagnosis of DIP following removal of the causative agent, but a drug-free interval of at least 6 months is generally recommended. Interestingly, up to 30% of DIP cases may show persisting or worsening motor signs beyond 6 months following drug withdrawal or adjustment, due to complex postsynaptic and presynaptic factors that may variably interact to negatively influence nigrostriatal dopamine transmission in a so-called “double-hit” hypothesis. The condition significantly impacts on quality of life and increases the risks of morbidity and mortality. Management is challenging in psychiatric patients and requires a team approach to achieve the best outcome. Keywords: neuroleptic drugs, extrapyramidal side effects, second generation antipsychotics, calcium channel blockers, valproic acid, tetrabenazine 

  3. Drug-induced angioedema without urticaria.

    Agostoni, A; Cicardi, M

    2001-01-01

    probability that such an agent could be the cause. The most important action to take in a patient with suspected drug-induced angioedema is to discontinue the pharmacological agent. Epinephrine (adrenaline), diphenydramine and intravenous methylprednisolone have been proposed for the medical management of airway obstruction, but so far no controlled studies have demonstrated their efficacy. If the acute airway obstruction leads to life-threatening respiratory compromise an emergency cricothyroidotomy must be performed.

  4. Prevalence and Complications of Drug-induced Seizures in Baharloo Hospital, Tehran, Iran

    Behnam Behnoush

    2012-05-01

    Full Text Available Background: Seizure is a frequent and important finding in the field of clinical toxicology. Almost all poisons and drugs can produce seizure. We have evaluated frequency and complications of drug-induced seizure in present study. Methods: The present descriptive cross-sectional study was done on patients who were referred to Baharloo Hospital, Tehran, Iran, that had developed seizure before or after hospitalization following intoxication between 20 March 2010 and 20 March 2011. The exclusion criteria were a positive history of epilepsy, head trauma, or abnormal findings in EEG or brain CT scan. Results: Tramadol and tricyclic antidepressants were the most common causes of drug-induced seizure (31.5% and 14.7% of the cases, respectively. Overall, 6 patients (4.2% had developed persistent vegetative state in consequence of brain hypoxia, 16 patients (11.2% had died due to complications of seizure or the poisoning itself. Tramadol was the leading cause of drug-induced seizure and its morbidity and mortality. Tonic-colonic seizure was the most common type of drug-induced seizure. Seizure had occurred once in 58% of the patients, twice in 37.1% of the patients, and had been revolutionized to status epilepticus in 4.9% of them. Among the 7 patients who had developed status epilepticus, 3 cases had died. Conclusion: Appropriate measures for treatment of seizure and prevention of its complications should be taken when patients with drug poisoning are admitted into hospital, especially when the offending drug(s has a higher likelihood to induce seizure.

  5. Drug Induced Hearing Loss: Researchers Study Strategies to Preserve Hearing

    ... of this page please turn JavaScript on. Feature: Drug-Induced Hearing Loss Researchers Study Strategies to Preserve ... brain there was a sound. What are ototoxic drugs and why are they important? Ototoxic drugs are ...

  6. Phenotypes and Pathology of Drug-Induced Liver Disease.

    Goodman, Zachary D

    2017-02-01

    Drug hepatotoxicity can simulate nearly any clinical syndrome or pathologic lesion that may occur in the liver, so clinical and histopathologic diagnosis of drug-induced liver injury may be difficult. Nevertheless, most drugs that are known to idiosyncratic liver injury tend to cause patterns of injury that produce characteristic phenotypes. Recognition of these patterns or phenotypes in liver biopsy material is helpful in evaluation of clinical cases of suspected drug-induced liver injury.

  7. Acute and subacute drug-induced movement disorders.

    Burkhard, Pierre R

    2014-01-01

    Many pharmacological agents may induce a variety of movement disorders, including dystonia, tremor, parkinsonism, myoclonus and dyskinesia, with an acute, subacute or more chronic time course. Motor symptoms may be isolated or part of a more extensive cerebral or systemic condition, such as the neuroleptic malignant syndrome or the serotonin syndrome. Drug-induced movement disorders share a number of features that should make them easy to identify, including a clear temporal relationship between medication initiation and symptom onset, a dose-effect, and, with the exception of tardive syndromes, complete resolution after discontinuation of the offending agent. Diagnosis relies on a thorough medication history. Medications commonly involved include dopamine receptor blockers, antidepressants and anti-epileptics, among many others. Mechanisms underlying drug-induced movement disorders involve blockade, facilitation or imbalance of dopamine, serotonin, noradrenaline and cholinergic neurotransmission in the basal ganglia. The present review focuses on drug-induced movement disorders that typically develop as an acute (hours to days) or subacute (days to weeks) event, including acute dystonic reactions, akathisia, drug-induced parkinsonism, neuroleptic malignant syndrome, serotonin syndrome, parkinsonism-hyperpyrexia syndrome, drug-induced tremor, drug-induced hyperkinesias and movement disorders associated with the use of recreational drugs.

  8. Contemporary review of drug-induced pancreatitis: A different perspective

    Whitney; Y; Hung; Odaliz; Abreu; Lanfranco

    2014-01-01

    Although gallstone and alcohol use have been consid-ered the most common causes of acute pancreatitis, hundreds of frequently prescribed medications are as-sociated with this disease state. The true incidence is unknown since there are few population based studies available. The knowledge of drug induced acute pan-creatitis is limited by the availability and the quality of the evidence as the majority of data is extrapolated from case reports. Establishing a definitive causal rela-tionship between a drug and acute pancreatitis poses a challenge to clinicians. Several causative agent classifi-cation systems are often used to identify the suspected agents. They require regular updates since new drug induced acute pancreatitis cases are reported continu-ously. In addition, infrequently prescribed medications and herbal medications are often omitted. Furthermore, identification of drug induced acute pancreatitis with new medications often requires accumulation of post market case reports. The unrealistic expectation for a comprehensive list of medications and the multifacto-rial nature of acute pancreatitis call for a different ap-proach. In this article, we review the potential mecha-nisms of drug induced acute pancreatitis and providethe perspective of deductive reasoning in order to allow clinicians to identify potential drug induced acute pan-creatitis with limited data.

  9. Visual contrast sensitivity in drug-induced Parkinsonism.

    Bulens, C; Meerwaldt, J D; van der Wildt, G J; Keemink, C J

    1989-03-01

    The influence of stimulus orientation on contrast sensitivity function was studied in 10 patients with drug-induced Parkinsonism. Nine of the 10 patients had at least one eye with contrast sensitivity deficit for vertical and/or horizontal stimuli. Only generalised contrast sensitivity loss, observed in two eyes, was stimulus orientation independent. All spatial frequency-selective contrast deficits in 15 eyes were orientation dependent. The striking similarity between the pattern of contrast sensitivity loss in drug-induced Parkinsonism and that in idiopathic Parkinson's disease, suggests that generalised dopaminergic deficiency, from whatever cause, affects visual function in an analogous way.

  10. [THREE CASES OF DRUG-INDUCED PNEUMONIA CAUSED BY MESALAZINE].

    Akiyama, Norimichi; Yokomura, Koshi; Nozue, Tsuyoshi; Abe, Takefumi; Matsui, Takashi; Suda, Takafumi

    2015-12-01

    We report three cases of drug-induced pneumonia caused by mesalazine. They were all diagnosed as ulcerative colitis and treated with mesalazine orally. Our three cases and literature review revealed that mesalazine-induced pneumonia resemble like eosinophilic pneumonia or organizing pneumonia and that have good prognosis with drug cessation or administration of corticosteroid. The patient of ulcerative colitis is increasing every year and it is anticipated that the patient with mesalazine-induced pneumonia may also increase. In the treatment of ulcerative colitis with mesalazine, we should pay attention with patient's cough or fever for early detection of drug-induced pneumonia.

  11. Visual contrast sensitivity in drug-induced Parkinsonism.

    Bulens, C; Meerwaldt, J D; van der Wildt, G J; Keemink, C J

    1989-01-01

    The influence of stimulus orientation on contrast sensitivity function was studied in 10 patients with drug-induced Parkinsonism. Nine of the 10 patients had at least one eye with contrast sensitivity deficit for vertical and/or horizontal stimuli. Only generalised contrast sensitivity loss, observed in two eyes, was stimulus orientation independent. All spatial frequency-selective contrast deficits in 15 eyes were orientation dependent. The striking similarity between the pattern of contrast sensitivity loss in drug-induced Parkinsonism and that in idiopathic Parkinson's disease, suggests that generalised dopaminergic deficiency, from whatever cause, affects visual function in an analogous way. PMID:2926418

  12. Drug-Induced Metabolic Acidosis [version 1; referees: 3 approved

    Amy Quynh Trang Pham

    2015-12-01

    Full Text Available Metabolic acidosis could emerge from diseases disrupting acid-base equilibrium or from drugs that induce similar derangements. Occurrences are usually accompanied by comorbid conditions of drug-induced metabolic acidosis, and clinical outcomes may range from mild to fatal. It is imperative that clinicians not only are fully aware of the list of drugs that may lead to metabolic acidosis but also understand the underlying pathogenic mechanisms. In this review, we categorized drug-induced metabolic acidosis in terms of pathophysiological mechanisms, as well as individual drugs’ characteristics.

  13. Prolonged drug-induced hypothermia in experimental stroke

    Johansen, Flemming Fryd; Jørgensen, Henrik Stig; Reith, Jakob

    2007-01-01

    In experimental and human stroke, hypothermia is strongly related to a favorable outcome. Previous attempts to manipulate the core temperature in focal cerebral ischemia have been based on mechanical cooling. The purpose of the study is to establish a model for long-term drug-induced hypothermia...

  14. A rare cause of drug-induced hepatitis in an immunocompromised patient and the role of glutathione.

    Senadhi, Viplove; Arora, Deepika; Arora, Manish; Marsh, Franklin

    2012-08-27

    The Food and Drug Administration (FDA) has issued a warning on numerous herbal drugs, including many popular products at General Nutrition Centers (GNC), regarding unstudied hepatotoxicity. There have been recent reports of GNC products such as hydroxycut and herbalife, causing drug-induced hepatitis. Herbal medications are over-the-counter products and are not investigated thoroughly by the FDA. Given that the most common outpatient laboratory abnormality is elevated liver transaminases, a sign of hepatocellular toxicity; it is not surprising that some of these products end up causing hepatic dysfunction, especially when taken in large volume. There are numerous herbal supplements that are hepatotoxic, however, these medications have a much more significant effect in human immunodeficiency virus (HIV)/ acquired immune deficiency syndrome patients, which is secondary to depleted glutathione. We present a rare case of drug induced hepatitis secondary to herbal medications used to treat HIV and elucidate the role of glutathione depletion in immunocompromised patients.

  15. 药源性血栓栓塞症%Drug-induced thromboembolism

    杨文君; 徐翔

    2014-01-01

    药源性血栓栓塞症是指因某些药物使血管内血栓形成和/或栓塞并导致组织和器官功能受损的疾病.药源性血栓栓塞症的发病机制主要为血管内皮细胞损伤、血液成分改变和血流动力学异常.导致血栓栓塞症的常见药物有造影剂、化疗药、免疫抑制剂、免疫增强剂、环氧化酶2抑制剂、抗精神病药和激素等.药源性血栓栓塞症以门静脉、脾静脉、肾静脉或脑静脉窦等深静脉血栓形成较常见,动脉血栓较为少见.药源性血栓栓塞症可应用普通肝素、低分子肝素、磺达肝癸钠、华法林、尿激酶、阿替普酶、阿加曲班、重组水蛭素或达那肝素钠治疗.%The term of drug-induced thromboembolism refers to intravascular thrombosis and/or thromboembolism due to drugs and resulting in impaired tissue and organ function.The main mechanisms of drug-induced thromboembolism involve injury of endothelial cells,the change of blood components and hemodynamic abnormality.Drugs which cause thrombosis mainly include contrast media,chemotherapeutic agents,immunosuppressive agents,immunopotentiators,cyclooxygenase-2 inhibitors,antipsychotic agents,and hormones.The most common drug-induced thrombosis is deep vein thrombosis such as portal vein,splenic vein,renal vein,or cerebral venous sinus.Arterial thrombosis is less common.Drug-induced thrombosis could be treated with unfractionated heparin,low molecular weight heparin,fondaparinux sodium,warfarin,urokinase,alteplase,argatroban,recombinant hirudin or danaparoid sodium.

  16. Clinical Features Indicating Nigrostriatal Dopaminergic Degeneration in Drug-Induced Parkinsonism

    Seung Ha Lee

    2017-01-01

    Full Text Available Objective Patients with drug-induced parkinsonism (DIP may have nigrostriatal dopaminergic degeneration. We studied the clinical features that may indicate nigrostriatal dopaminergic degeneration in patients with DIP. Methods Forty-one DIP patients were classified into normal and abnormal [18F] FP-CIT scan groups. Differences in 32 clinical features and drug withdrawal effects were studied. Results Twenty-eight patients had normal (Group I and 13 patients had abnormal (Group II scans. Eight patients of Group I, but none of Group II, had taken calcium channel blockers (p = 0.040. Three patients of Group I and six of Group II had hyposmia (p = 0.018. After drug withdrawal, Group I showed greater improvement in Unified Parkinson’s Disease Rating Scale total motor scores and subscores for bradykinesia and tremors than Group II. Only hyposmia was an independent factor associated with abnormal scans, but it had suboptimal sensitivity. Conclusion None of the clinical features were practical indicators of nigrostriatal dopaminergic degeneration in patients with DIP.

  17. Imaging of Drug-induced Complications in the Gastrointestinal System.

    McGettigan, Melissa J; Menias, Christine O; Gao, Zhenqiang J; Mellnick, Vincent M; Hara, Amy K

    2016-01-01

    Drug-induced injury commonly affects the gastrointestinal and hepatobiliary systems because of the mechanisms of absorption and metabolism. In pill esophagitis, injury is frequently related to direct contact with the esophageal mucosa, resulting in small superficial ulcers in the mid esophagus. Nonsteroidal anti-inflammatory drugs can lead to gastrointestinal tract ulcers and small bowel mucosal diaphragms (thin weblike strictures). Injury to the pancreatic and hepatobiliary systems can manifest as pancreatitis, acute or chronic hepatitis, cholestasis, or steatosis and steatohepatitis (which may progress to cirrhosis). Various drugs may also insult the hepatic vasculature, resulting in Budd-Chiari and sinusoidal obstructive syndromes. Focal lesions such as hepatic adenomas may develop after use of oral contraceptives or anabolic steroids. Ultrasonography, computed tomography, and magnetic resonance imaging can aid in diagnosis of drug-induced injuries and often are necessary to exclude other causes.

  18. A diagnostic dilemma: drug-induced aseptic meningitis in a 45-year-old HIV-positive man.

    Rowley, D

    2014-03-01

    We describe a case of aseptic meningitis following the administration of moxifloxacin in a 45-year-old man with human immunodeficiency virus (HIV). At presentation he was receiving tuberculosis treatment on a modified regimen following severe hepatotoxicity; this included moxifloxacin, started 8 days previously. Initial cerebrospinal fluid (CSF) analysis was grossly abnormal. Anti-viral and -bacterial treatments were started. All microbiological tests proved negative and his moxifloxacin was withheld resulting in a complete normalisation of CSF. Drug-induced aseptic meningitis is a diagnosis of exclusion and presents a serious diagnostic dilemma. The decision to withhold medication cannot be taken lightly.

  19. In silico modeling to predict drug-induced phospholipidosis

    Choi, Sydney S.; Kim, Jae S.; Valerio, Luis G., E-mail: luis.valerio@fda.hhs.gov; Sadrieh, Nakissa

    2013-06-01

    Drug-induced phospholipidosis (DIPL) is a preclinical finding during pharmaceutical drug development that has implications on the course of drug development and regulatory safety review. A principal characteristic of drugs inducing DIPL is known to be a cationic amphiphilic structure. This provides evidence for a structure-based explanation and opportunity to analyze properties and structures of drugs with the histopathologic findings for DIPL. In previous work from the FDA, in silico quantitative structure–activity relationship (QSAR) modeling using machine learning approaches has shown promise with a large dataset of drugs but included unconfirmed data as well. In this study, we report the construction and validation of a battery of complementary in silico QSAR models using the FDA's updated database on phospholipidosis, new algorithms and predictive technologies, and in particular, we address high performance with a high-confidence dataset. The results of our modeling for DIPL include rigorous external validation tests showing 80–81% concordance. Furthermore, the predictive performance characteristics include models with high sensitivity and specificity, in most cases above ≥ 80% leading to desired high negative and positive predictivity. These models are intended to be utilized for regulatory toxicology applied science needs in screening new drugs for DIPL. - Highlights: • New in silico models for predicting drug-induced phospholipidosis (DIPL) are described. • The training set data in the models is derived from the FDA's phospholipidosis database. • We find excellent predictivity values of the models based on external validation. • The models can support drug screening and regulatory decision-making on DIPL.

  20. Meiotic abnormalities

    NONE

    1993-12-31

    Chapter 19, describes meiotic abnormalities. These include nondisjunction of autosomes and sex chromosomes, genetic and environmental causes of nondisjunction, misdivision of the centromere, chromosomally abnormal human sperm, male infertility, parental age, and origin of diploid gametes. 57 refs., 2 figs., 1 tab.

  1. Drug-Induced Ocular Hypertension and Angle-Closure Glaucoma.

    Badhu, Badri P; Bhattarai, Balkrishna; Sangraula, Himal P

    2013-01-01

    The objective of this study was to review the available literature on the drugs causing ocular hypertension and glaucoma. Electronic literature search was carried out using the Web sites www.pubmed.gov and www.google.com published through the year 2011. The search words were "drug induced ocular hypertension" and "drug induced glaucoma" used in combination. The articles published or translated into English were studied. Quite a significant number of drugs commonly prescribed by various physicians of different specialties can induce ocular hypertension or glaucoma. A brief account of various drugs that can induce ocular hypertension has been given in this article. Those drugs are parasympatholytics; steroids; anticholinergics, adrenergics, and antidepressants; cholinomimetics; antineoplastic agents; antipsychotic and antiparkinsonism agents; H1 and H2 receptor blockers; botulinum toxin, cardiac agents, and anticoagulants; silicone oil; sulfa drugs; and anesthetic agents. Rational use of these drugs and knowledge of their potential adverse effects can help prevent the devastating complications resulting in loss of vision and compromised quality of life.

  2. Diagnosis and classification of drug-induced autoimmunity (DIA).

    Xiao, Xiao; Chang, Christopher

    2014-01-01

    Since sulfadiazine associated lupus-like symptoms were first described in 1945, certain drugs have been reported to interfere with the immune system and induce a series of autoimmune diseases (named drug-induced autoimmunity, DIA), exemplified by systemic lupus erythematosus (SLE). Among the drugs, procainamide and hydralazine are considered to be associated with the highest risk for developing lupus, while quinidine has a moderate risk, and all other drugs have low or very low risk. More recently, drug-induced lupus has been associated with the use of newer biological modulators, such as tumor necrosis factor (TNF)-alpha inhibitors and cytokines. In addition to lupus, other major autoimmune diseases, including vasculitis and arthritis, have also been associated with drugs. Because resolution of symptoms generally occurs after cessation of the offending drugs, early diagnosis is crucial for treatment strategy and improvement of prognosis. Unfortunately, it is difficult to establish standardized criteria for DIA diagnosis. Diagnosis of DIA requires identification of a temporal relationship between drug administration and the onset of symptoms, but the relative risk with respect to dose and duration for each drug has rarely been determined. DIA is affected by multiple genetic and environmental factors, leading to difficulties in establishing a list of global clinical features that are characteristic of most or all DIA patients. Moreover, the distinction between authentic DIA and unmasking of a latent autoimmune disease also poses challenges. In this review, we summarize the highly variable clinical features and laboratory findings of DIA, with an emphasis on the diagnostic criteria.

  3. Drug-induced linear IgA bullous dermatosis.

    Navi, Daniel; Michael, Daniel J; Fazel, Nasim

    2006-09-08

    A 73-year-old man was admitted to the University of California Davis Medical Center for treatment of a pleural effusion and congestive heart failure. His hospital course was complicated by asymptomatic sustained ventricular tachycardia requiring placement of an implantable cardiac defibrillator. The patient was treated with vancomycin and cefazolin during the procedure. After 3 days he developed tense vesicles over the dorsal aspect of the hands. Perilesional skin biopsy showed subepidermal cleavage with a neutrophilic infiltrate. Direct immunofluorescence revealed granular IgA and C3 deposition along the dermal epidermal junction. A diagnosis of drug-induced linear IgA bullous dermatosis secondary to vancomycin was established. Linear IgA bullous dermatosis is a rare autoimmune blistering disorder with clinical features that can overlap with bullous pemphigoid and dermatitis herpetiformis. Drug-induced linear IgA bullous dermatosis is a less common variant that is correspondingly less well characterized. Although a variety of medications have been implicated, vancomycin is the most common associated drug.

  4. The Possible Potential Therapeutic Targets for Drug Induced Gingival Overgrowth

    Tamilselvan Subramani

    2013-01-01

    Full Text Available Gingival overgrowth is a side effect of certain medications. The most fibrotic drug-induced lesions develop in response to therapy with phenytoin, the least fibrotic lesions are caused by cyclosporin A, and the intermediate fibrosis occurs in nifedipine-induced gingival overgrowth. Fibrosis is one of the largest groups of diseases for which there is no therapy but is believed to occur because of a persistent tissue repair program. During connective tissue repair, activated gingival fibroblasts synthesize and remodel newly created extracellular matrix. Proteins such as transforming growth factor (TGF, endothelin-1 (ET-1, angiotensin II (Ang II, connective tissue growth factor (CCN2/CTGF, insulin-like growth factor (IGF, and platelet-derived growth factor (PDGF appear to act in a network that contributes to the development of gingival fibrosis. Since inflammation is the prerequisite for gingival overgrowth, mast cells and its protease enzymes also play a vital role in the pathogenesis of gingival fibrosis. Drugs targeting these proteins are currently under consideration as antifibrotic treatments. This review summarizes recent observations concerning the contribution of TGF-β, CTGF, IGF, PDGF, ET-1, Ang II, and mast cell chymase and tryptase enzymes to fibroblast activation in gingival fibrosis and the potential utility of agents blocking these proteins in affecting the outcome of drug-induced gingival overgrowth.

  5. [The general practitioner and abnormal liver function tests].

    Hallez, R

    1997-09-01

    In case of abnormal liver function tests, it's necessary to distinguish different situations, starting from this first data. We will successively consider: the high and moderate acute increases of aminotransferase, the chronic increases of aminotransferase, the isolated cholestase picture and the isolated increases of gamma GT or of bilirubine. We will finish with a partial survey about drug-induced liver diseases.

  6. Lupus in a patient with cystinosis: is it drug induced?

    Eroglu, F K; Besbas, N; Ozaltin, F; Topaloglu, R; Ozen, S

    2015-11-01

    A 9-year-old girl with a diagnosis of cystinosis since 2 years of age, on cysteamine therapy, presented with complaints of serositis and arthritis, and laboratory tests revealed high antinuclear antibody titers with hypocomplementemia. Kidney biopsy was not consistent with lupus nephritis. With prednisolone treatment her complaints resolved and creatinine level decreased, but on follow-up, serological features of systemic lupus erythematosus (SLE) continued. Six years after cessation of prednisolone, lupus features were reactivated, with positive antihistone antibodies and ANCA. Coincidence of cystinosis and SLE is very rare, and to the best of our knowledge this is the fourth case reported in the literature. Physicians should be aware that cystinosis patients may have some autoimmune manifestations with features of true or drug-induced lupus. In the light of this case, pathophysiology and treatment are discussed.

  7. Possibly drug-induced palpable migratory arciform erythema*

    Dantas, Fernando Luiz Teixeira; Valente, Neusa Yuriko Sakai; Veronez, Isis Suga; Kakizaki, Priscila; Leitão, Juliana Ribeiro; Fraga, Rafael Cavanellas

    2015-01-01

    Palpable migratory arciform erythema is an entity of unknown etiology, with few published cases in the literature. The clinical and histopathological features of this disease are difficult to be distinguished from those of Jessner’s lymphocytic infiltration of the skin, lupus erythematous tumidus and the deep erythema annulare centrifugum. We describe here the first two Brazilian cases of palpable migratory arciform erythema. The patients presented with infiltrated annular plaques and erythematous arcs without scales. These showed centrifugal growth before disappearing without scarring or residual lesions after a few days. They had a chronic course with repeated episodes for years. In addition, these cases provide evidence of a drug-induced etiology. PMID:26312680

  8. Role of dermatology in pharmacogenomics: drug-induced skin injury.

    Borroni, Riccardo G

    2015-01-01

    Different individuals may respond diversely to the same drug, in terms of efficacy and toxicity. Adverse drug reactions cause about 6% of all hospital admissions and account for up to 9% of hospitalization costs. Drug-induced skin injury (DISI) is the most common presentation of adverse drug reactions, ranging from maculopapular eruptions to severe adverse cutaneous drug reactions (SCARs) with mortality of up to 40%. Specific genetic polymorphisms confer susceptibility to different types of DISI. Identifying patients genetically at risk for SCARs is one of the goals of pharmacogenomics. In this article, the aspects of clinical dermatology relevant to the pharmacogenetics of DISI are reviewed. Many SCARs are now preventable, with consequent reduction of morbidity, mortality and healthcare costs.

  9. Pattern analysis of drug-induced skin diseases.

    Justiniano, Hildamari; Berlingeri-Ramos, Alma C; Sánchez, Jorge L

    2008-08-01

    Drug eruptions are common adverse reactions to drug therapy and are a frequent reason for consultation in clinical practice. Even though any medication can potentially cause an adverse cutaneous reaction, some drugs are implicated more commonly than others. Histologically, drugs can elicit a variety of inflammatory disease patterns in the skin and panniculus, no pattern being specific for a particular drug. The most common pattern elicited by systemically administered medications is the perivascular pattern. Psoriasiform or granulomatous patterns are rarely caused by medications. The usual histologic patterns of drug eruptions are discussed in this review using the basic patterns of inflammatory diseases. Clinicopathologic correlation is established for relevant patterns. However, the changes of drug-induced skin disease must be made considering clinical presentation, histopathological analysis, and course of the disease.

  10. Genetic association studies in drug-induced liver injury.

    Daly, Ann K; Day, Chris P

    2009-11-01

    Genetic studies on drug-induced liver injury (DILI) have proved challenging, both because of their rarity and their difficulty in replicating observed effects. However, significant progress has now been achieved by both candidate-gene and genome-wide association studies. These two approaches are considered in detail, together with examples of DILI due to specific drugs where consistent associations have been reported. Particular consideration is given to associations between antituberculosis drug-related liver injury and the "slow acetylator" genotype for N-acetyltransferase 2, amoxicillin/clavulanate-related liver injury, and the human leukocyte antigen (HLA) class II DRB1*1501 allele and flucloxacillin-related injury and the HLA class I B*5701 allele. Although these associations are drug-specific, the possibility that additional, more general susceptibility genes for DILI exist requires further investigation, ideally by genome-wide association studies involving international collaboration. The possibility of interethnic variation in susceptibility to DILI also requires further study.

  11. PTTG1 attenuates drug-induced cellular senescence.

    Yunguang Tong

    Full Text Available As PTTG1 (pituitary tumor transforming gene abundance correlates with adverse outcomes in cancer treatment, we determined mechanisms underlying this observation by assessing the role of PTTG1 in regulating cell response to anti-neoplastic drugs. HCT116 cells devoid of PTTG1 (PTTG1(-/- exhibited enhanced drug sensitivity as assessed by measuring BrdU incorporation in vitro. Apoptosis, mitosis catastrophe or DNA damage were not detected, but features of senescence were observed using low doses of doxorubicin and TSA. The number of drug-induced PTTG1(-/- senescent cells increased ∼4 fold as compared to WT PTTG1-replete cells (p<0.001. p21, an important regulator of cell senescence, was induced ∼3 fold in HCT116 PTTG1(-/- cells upon doxorubicin or Trichostatin A treatment. Binding of Sp1, p53 and p300 to the p21 promoter was enhanced in PTTG1(-/- cells after treatment, suggesting transcriptional regulation of p21. p21 knock down abrogated the observed senescent effects of these drugs, indicating that PTTG1 likely suppresses p21 to regulate drug-induced senescence. PTTG1 also regulated SW620 colon cancer cells response to doxorubicin and TSA mediated by p21. Subcutaneously xenografted PTTG1(-/- HCT116 cells developed smaller tumors and exhibited enhanced responses to doxorubicin. PTTG1(-/- tumor tissue derived from excised tumors exhibited increased doxorubicin-induced senescence. As senescence is a determinant of cell responses to anti-neoplastic treatments, these findings suggest PTTG1 as a tumor cell marker to predict anti-neoplastic treatment outcomes.

  12. 13.5.Toxic and drug-induced liver disease

    1992-01-01

    920133 Measurement of human plasma abnormal prothrombin by biotin-avidin (BA)ELISA in the diagnosis of hepatocellularcarcinoma.HU Dachun (胡大春),et al.DeptChem,Basic Med Sci,Shanhai Med Univ,200032.Chin J Cancer 1991; 10 (4): 283-285.After the removal of fibrinogen and prothrom-bin by bentoite and barium citrate,the abnormal

  13. Drug-induced hepatitis superimposed on the presence of anti-SLA antibody: a case report

    Etxagibel Aitziber

    2008-01-01

    Full Text Available Abstract Introduction Autoimmune hepatitis is a necroinflammatory disorder of unknown etiology characterized by the presence of circulating antibodies, hypergammaglobulinemia, and response to immunosuppression. It has the histological features of chronic hepatitis. The onset is usually insidious, but in some patients the presentation may be acute and occasionally severe. Certain drugs can induce chronic hepatitis mimicking autoimmune hepatitis. Different autoantibodies have been associated with this process but they are not detectable after drug withdrawal and clinical resolution. Case presentation We describe a case of drug-induced acute hepatitis associated with antinuclear, antisoluble liver-pancreas and anti-smooth muscle autoantibodies in a 66-year-old woman. Abnormal clinical and biochemical parameters resolved after drug withdrawal, but six months later anti-soluble liver-pancreas antibodies remained positive and liver biopsy showed chronic hepatitis and septal fibrosis. Furthermore, our patient has a HLA genotype associated with autoimmune hepatitis. Conclusion Patient follow-up will disclose whether our patient suffers from an autoimmune disease and if the presence of anti-soluble liver antigens could precede the development of an autoimmune hepatitis, as the presence of antimitochondrial antibodies can precede primary biliary cirrhosis.

  14. Case Characterization, Clinical Features and Risk Factors in Drug-Induced Liver Injury

    Aida Ortega-Alonso

    2016-05-01

    Full Text Available Idiosyncratic drug-induced liver injury (DILI caused by xenobiotics (drugs, herbals and dietary supplements presents with a range of both phenotypes and severity, from acute hepatitis indistinguishable of viral hepatitis to autoimmune syndromes, steatosis or rare chronic vascular syndromes, and from asymptomatic liver test abnormalities to acute liver failure. DILI pathogenesis is complex, depending on the interaction of drug physicochemical properties and host factors. The awareness of risk factors for DILI is arising from the analysis of large databases of DILI cases included in Registries and Consortia networks around the world. These networks are also enabling in-depth phenotyping with the identification of predictors for severe outcome, including acute liver failure and mortality/liver transplantation. Genome wide association studies taking advantage of these large cohorts have identified several alleles from the major histocompatibility complex system indicating a fundamental role of the adaptive immune system in DILI pathogenesis. Correct case definition and characterization is crucial for appropriate phenotyping, which in turn will strengthen sample collection for genotypic and future biomarkers studies.

  15. Leukocyte abnormalities.

    Gabig, T G

    1980-07-01

    Certain qualitative abnormalities in neutrophils and blood monocytes are associated with frequent, severe, and recurrent bacterial infections leading to fatal sepsis, while other qualitative defects demonstrated in vitro may have few or no clinical sequelae. These qualitative defects are discussed in terms of the specific functions of locomotion, phagocytosis, degranulation, and bacterial killing.

  16. In vitro validation of drug-induced phospholipidosis.

    Park, Sora; Choi, You-Jin; Lee, Byung-Hoon

    2012-01-01

    Intracellular accumulation of phospholipids with lamellar bodies is a hallmark of drug-induced phospholipidosis (PLD) which is caused by impaired phospholipid metabolism of the lysosome. Although it remains uncertain whether PLD is associated with the adverse effects, sponsors generally terminate the development of a candidate drug when PLD is observed in an organ. For drugs that are used without serious adverse events, there should be labels indicating that the drug can induce PLD. We conducted LipidTox and NBD-PE assays for detecting PLD to compare and validate the methods. In the case of contrary results in both assays, electron microscopy was performed to confirm the data. We selected 12 chemicals and divided them into 4 categories: P+S+, PLD and steatosis positive; P+/S-, PLD positive and steatosis negative; P-S+, PLD negative and steatosis positive; P-/S-, PLD and steatosis negative. In general, results showed very good agreement with the known information with some minor discrepancies. LipidTox assay is proven to be a very sensitive method. Considering the contrary results of acetaminophen and menadione in LipidTox and the NBD-PE assay, the combination of two methods using different phospholipids is advantageous to reduce false positives. The finding that acetaminophen was positive in LipidTos assay and increased the frequency of lamellar body implies that acetaminophen is a weak inducer of PLD.

  17. Drug-induced proarrhythmia: risk factors and electrophysiological mechanisms.

    Frommeyer, Gerrit; Eckardt, Lars

    2016-01-01

    Drug-induced ventricular tachyarrhythmias can be caused by cardiovascular drugs, noncardiovascular drugs, and even nonprescription agents. They can result in arrhythmic emergencies and sudden cardiac death. If a new arrhythmia or aggravation of an existing arrhythmia develops during therapy with a drug at a concentration usually considered not to be toxic, the situation can be defined as proarrhythmia. Various cardiovascular and noncardiovascular drugs can increase the occurrence of polymorphic ventricular tachycardia of the 'torsade de pointes' type. Antiarrhythmic drugs, antimicrobial agents, and antipsychotic and antidepressant drugs are the most important groups. Age, female sex, and structural heart disease are important risk factors for the occurrence of torsade de pointes. Genetic predisposition and individual pharmacodynamic and pharmacokinetic sensitivity also have important roles in the generation of arrhythmias. An increase in spatial or temporal dispersion of repolarization and a triangular action-potential configuration have been identified as crucial predictors of proarrhythmia in experimental models. These studies emphasized that sole consideration of the QT interval is not sufficient to assess the proarrhythmic risk. In this Review, we focus on important triggers of proarrhythmia and the underlying electrophysiological mechanisms that can enhance or prevent the development of torsade de pointes.

  18. Drug-induced pulmonary arterial hypertension: a recent outbreak

    Gérald Simonneau

    2013-09-01

    Full Text Available Pulmonary arterial hypertension (PAH is a rare disorder characterised by progressive obliteration of the pulmonary microvasculature resulting in elevated pulmonary vascular resistance and premature death. According to the current classification PAH can be associated with exposure to certain drugs or toxins, particularly to appetite suppressant intake drugs, such as aminorex, fenfluramine derivatives and benfluorex. These drugs have been confirmed to be risk factors for PAH and were withdrawn from the market. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary artery smooth muscle cells. Amphetamines, phentermine and mazindol were less frequently used, but are considered possible risk factors, for PAH. Dasatinib, dual Src/Abl kinase inhibitor, used in the treatment of chronic myelogenous leukaemia was associated with cases of severe PAH, potentially in part reversible after dasatinib withdrawal. Recently, several studies have raised the issue of potential endothelial dysfunction that could be induced by interferon, and a few cases of PAH have been reported with interferon therapy. PAH remains a rare complication of these drugs, suggesting possible individual susceptibility, and further studies are needed to identify patients at risk of drug-induced PAH.

  19. First report of drug-induced esophagitis by deferasirox.

    Yoshikawa, Takeshi; Hara, Takeshi; Araki, Hiroshi; Tsurumi, Hisashi; Oyama, Masami; Moriwaki, Hisataka

    2012-06-01

    Deferasirox is a new oral iron chelator used to treat transfusional iron overload. We describe a case of a 79-year-old man with myelodysplastic syndrome (MDS) who developed esophagitis induced by deferasirox. He repeatedly received multiple red blood cell transfusions after a diagnosis of MDS. Two years after starting red blood cell transfusions, he was diagnosed with iron overload, and was then started on deferasirox at 1 g/day with about 400 ml of water. He was admitted to our institution because he was unable to swallow his own saliva 1 month after starting deferasirox. Esophagogastroendoscopy revealed white-coated mucosa covering the entire esophagus. A component analysis of biopsy specimens using high-performance liquid chromatography identified deferasirox. Symptoms resolved within about 2 weeks after discontinuing deferasirox, and repeated endoscopy showed marked improvement of esophagitis after 1 month. Re-administration of deferasirox was not attempted. Unfortunately, the patient died due to pneumonia 6 months after administration of deferasirox was started. This is the first report of drug-induced esophagitis associated with deferasirox.

  20. Drug-induced secretory diarrhea: A role for CFTR.

    Moon, Changsuk; Zhang, Weiqiang; Sundaram, Nambirajan; Yarlagadda, Sunitha; Reddy, Vadde Sudhakar; Arora, Kavisha; Helmrath, Michael A; Naren, Anjaparavanda P

    2015-12-01

    Many medications induce diarrhea as a side effect, which can be a major obstacle to therapeutic efficacy and also a life-threatening condition. Secretory diarrhea can be caused by excessive fluid secretion in the intestine under pathological conditions. The cAMP/cGMP-regulated cystic fibrosis transmembrane conductance regulator (CFTR) is the primary chloride channel at the apical membrane of intestinal epithelial cells and plays a major role in intestinal fluid secretion and homeostasis. CFTR forms macromolecular complexes at discreet microdomains at the plasma membrane, and its chloride channel function is regulated spatiotemporally through protein-protein interactions and cAMP/cGMP-mediated signaling. Drugs that perturb CFTR-containing macromolecular complexes in the intestinal epithelium and upregulate intracellular cAMP and/or cGMP levels can hyperactivate the CFTR channel, causing excessive fluid secretion and secretory diarrhea. Inhibition of CFTR chloride-channel activity may represent a novel approach to the management of drug-induced secretory diarrhea.

  1. Cytomorphological Effects of Mitomycin C on Urothelial Cells: Eosinophils May Be Clue to The Drug-Induced Changes

    Gulcin Guler Simsek

    2014-04-01

    Full Text Available Cytomorphological changes of mitomycin C on urothelial cells may be misinterpreted as a neoplastic process. A 60-year old male patient who was given an eight-week course of intravesical mitomycin C due to non-invasive low grade transitional cell carcinoma. During his follow-up care, the findings of a urine cytology exam were as follows: nuclear enlargement of cells, wrinkled nuclear membranes, little hyperchromasia, pleomorphism, abnormal nuclear morphology and disordered orientation of the urothelium. Furthermore, there were eosinophils nearby the atypical cells. This report aimed at reminding the cytomorphologic changes of mitomycin C may be misinterpreted as carcinoma, so the presence of eosinophils is required to predict the drug-induced changes.

  2. Drug-Induced Gingival Overgrowth: The Genetic Dimension

    Charles, Noronha Shyam Curtis; Chavan, Rahul; Moon, Ninad Joshirao; Nalla, Srinivas; Mali, Jaydeepchandra; Prajapati, Anchal

    2014-01-01

    Background: Currently, the etiology of drug-induced gingival overgrowth is not entirely understood but is clearly multifactorial. Phenytoin, one of the common drugs implicated in gingival enlargement, is metabolized mainly by cytochrome P450 (CYP)2C9 and partly by CYP2C19. The CYP2C9 and CYP2C19 genes are polymorphically expressed and most of the variants result in decreased metabolism of the respective substrates. Aims: The present study was undertaken to investigate the influence of the CYP2C9*2 and *3 variant genotypes on phenytoin hydroxylation in subjects diagnosed with epilepsy from South India, thus establishing the genetic polymorphisms leading to its defective hydroxylation process. Materials and Methods: Fifteen epileptic subjects, age 9 to 60 years were included in the study. Among the study subjects, 8 were males and 7 were females. Genomic DNA was extracted from patients’ blood using Phenol-chloroform method and genotyping was done for CYP2C9 using customized TaqMan genotyping assays on a real time thermocycler, by allelic discrimination method. The genetic polymorphisms *1, *2 and *3 on CYP2C9 were selected based on their function and respective allele frequencies in Asian subcontinent among the Asian populations. Results: CYP2C9*1*2 and CYP2C9*3/*3 were identified with equal frequency in the study population. There were seven subjects with CYP2C9*1/*2 genotype (heterozygous mutant), one subject with CYP2C9*1/*1 (wild type) and seven study subjects with CYP2C9*3/*3 (homozygous mutant). Conclusion: The results obtained in the present study will be helpful in the medical prescription purposes of phenytoin, and a more personalized patient approach with its administration can be advocated. PMID:25317394

  3. Drug-induced liver injury and drug development: industry perspective.

    Regev, Arie

    2014-05-01

    Despite intensive ongoing research, drug-induced live injury (DILI) remains a serious issue for care providers and patients, and has been a major cause of drug withdrawal and non-approval by regulatory authorities in the past 50 years. Consequently, DILI remains a major concern for the pharmaceutical industry and a leading cause for attrition during drug development. In most instances, severe DILI is an uncommon idiosyncratic reaction, which typically does not present during preclinical phases or early clinical phases of drug development. In the majority of cases, drugs that caused severe DILI in humans have not shown clear and consistent hepatotoxic signals in preclinical assessment including animal studies, cell cultures, or other methods. Despite intensive efforts to develop better biomarkers that would help in predicting DILI risk in earlier phases of drug development, such biomarkers are currently not supported by sufficient evidence and are not yet available for routine use by drug makers. Due to the lack of effective and accurate methods for prediction of idiosyncratic DILI during preclinical phases of drug development, different drug makers have adopted different approaches, which are often not supported by strong systematic evidence. Based on growing experience, it is becoming increasingly evident that milder forms of liver injury occurring during clinical development, when assessed correctly, may significantly enhance our ability to predict the drug's potential to cause more severe liver injury postmarketing. Strategies based on this concept have been adopted by many drug makers, and are being increasingly implemented during drug development. Meticulous causality assessment of individual hepatic cases and adherence to strict hepatic discontinuation rules are critical components of this approach and have to rely on thorough clinical evaluation and occasionally on assessment by liver experts experienced with DILI and drug development.

  4. Unusual case of drug-induced cholestasis due to glucosamine and chondroitin sulfate

    Stephen; Ip; Rachel; Jeong; David; F; Schaeffer; Eric; M; Yoshida

    2015-01-01

    Glucosamine(GS) and chondroitin sulfate(CS) are common over-the-counter(OTC) supplements used in the treatment of osteoarthritis. These medications are seemingly safe, but there are increasing reports of hepatotoxicity with these supplements. We reported a unique case of drug-induced cholestasis caused by GS and CS in a combination tablet. The etiology of the jaundice was overlooked despite extensive investigations over a three-month period. Unlike drug-induced hepatocellular injury, drug-induced cholestatic jaundice with GS and CS has only been reported twice before. This case emphasizes the importance of a complete medication history, especially OTC supplements, in the assessment of cholestasis.

  5. ECG-Based Measurements of Drug-induced Repolarization Changes

    Bhuiyan, Tanveer Ahmed

    The purpose of this thesis is to investigate the abnormal repolarization both in the cellular and the surface ECG along with their relationship. It has been identified that the certain morphological changes of the monophasic action potential are predictor of TdP arrhythmia. Therefore the proporti......The purpose of this thesis is to investigate the abnormal repolarization both in the cellular and the surface ECG along with their relationship. It has been identified that the certain morphological changes of the monophasic action potential are predictor of TdP arrhythmia. Therefore...... the proportional changes of the surface ECG which corresponds to the arrhythmia-triggering MAP morphology is warranted to increase the confidence of determining cardiotoxicity of drugs....

  6. 药源性干眼症%Drug-induced dry eye

    杨永升; 张守康; 谢立科

    2012-01-01

    Drug-induced dry eye is gradually recognized by ophthalmologists in recent years.It has been found that more than 10 categories and hundreds of drugs can induce dry eye,which include anti-cholinergic receptor drugs,antihistamines,antidepressant drugs,anti-psychotic drugs,hormone drugs,antiglaucoma drugs,and so on.The main mechanisms include the influence of drugs on the parasympathetic/sympathetic system so that the secretion pathway of lacrimal gland blocked,or tear film instability and ocular surface abnormalities caused by eye drops or ointments. Preventions and treatments are mainly to stop or change the drugs,etiological treatment and symptomatic treatment.%药源性干眼症是近年来逐渐被认识的一类药源性眼病,引起此病的药物有十余类上百种,其中常见的有抗胆碱能受体药、抗组胺药、抗抑郁症类药、抗精神病类药、激素类药、抗青光眼类药等.主要机制是药物影响副交感或交感神经系统,支配腺体分泌的通路受到阻断;或药物局部使用引起泪膜不稳定及眼表面异常.防治此类干眼症主要采用停药或换药,对因治疗以及对症处理.

  7. Drug-induced lupus: simvastatin or amiodarone? A case report in elderly

    Mauro Turrin

    2013-03-01

    Full Text Available Reports of systemic lupus erythematosus (SLE seen during treatment with amiodarone are rare in the literature. SLE or immunological abnormalities induced by treatment with statins are more frequent. In this issue we report a case of a 81-year-old male who, after a 2-year therapy with amiodarone, developed a clinical and serologic picture of drug-induced SLE (DILE. He was admitted for congestive heart failure in mechanical aortic valve prosthesis, permanent atrial fibrillation (anticoagulation with warfarin, hypercholesterolaemia, and hypothyroidism. Amiodarone was started two years earlier for polymorphic ventricular tachycardia, statin and L-thyroxine the following year. At admission he presented pleuro-pericardical effusion detected by CT-scan (also indicative of interstitial lung involvement and echocardiography. Serological main indicative findings were: elevation of inflammatory markers, ANA (Anti-Nuclear Antibodies titers = 1:320 (indirect immune-fluorescence – IIF – assay on HEp-2, homogeneous/fine speckled pattern, anti-dsDNA titers = 1:80 (IIF on Crithidia luciliae, negative ENA (Extractable Nuclear Antigens and antibodies anti-citrulline, rheumatoid factor = 253 KU/l, normal C3-C4, negative HbsAg and anti-HCV, negative anticardiolipin antibodies IgG and IgM, negative anti-beta2GPI IgG and IgM. Amiodarone was discontinued and methylprednisolone was started, since the patient was severely ill. At discharge, after a month, the patient was better and pleuro-pericardical effusion was reduced. Readmitted few weeks later for bradyarithmia and worsening of dyspnoea, pericardial effusion was further reduced but he died for refractory congestive heart failure and pneumonia. Clinical picture (sierositis, neither skin nor kidney involvement, other typical side effects of amiodarone (hypothyroidism and lung interstitial pathology and serological findings are suggestive of amiodarone-induced SLE.

  8. [Analysis of risk factors of drug-induced lung injury in patients receiving gemcitabine treatment].

    Nakamichi, Hidenori; Fujita, Tetsuo; Tsuji, Daiki; Atsumi, Ichiko; Totsuka, Kasumi; Suzuki, Rina; Miki, Yoshihiro; Tomita, Kazuhiro; Nakamura, Hidenori; Shiokawa, Mitsuru

    2012-05-01

    Gemcitabine hydrochloride is a very safe medicine that even outpatients can be administered, and the bone marrow depression that is the dose limiting factor remains moderate and does not need special treatment, although it is confirmed in most cases. Meanwhile, caution is required because there is a possibility of drug-induced lung injury and death due to high frequency, compared with the appearance rate described in the packaging insertion. We investigated the clinical background of a patient in whom drug-induced lung injury appeared, and clarified the risk factor by administering gemcitabine hydrochloride. Males, people aged 65 or over, those with a smoking history and those undergoing first-line chemotherapy treatment are at risk of drug-induced lung injury. Attention must be paid to the occurrence of drug-induced lung injury, to examining the clinical course, the chest image, and the blood test, and to do earlier detection, the offending medicine discontinuance, and beginning of the treatment.

  9. Immunoelectron microscopy study of superficial skin nerves in drug-induced acute urticaria

    Criado, Paulo Ricardo; CRIADO, Roberta Fachini Jardim; TAKAKURA, CLEUSA F.H.; Pagliari, Carla; SOTTO, Mirian Nacagami; Cidia VASCONCELLOS

    2012-01-01

    BACKGROUND: Few studies have evaluated the ultrastructure of the superficial skin nerves in urticaria. OBJECTIVE: The objective of this study was to describe findings in superficial skin nerves in cases of drug-induced acute urticaria. METHODS: Seven patients with drug-induced acute urticaria were included in the study. Skin biopsies were obtained from the urticarial lesion and from the apparently normal skin. The 14 fragments collected were processed for immunogold electron microscopy using ...

  10. Comparison of clinical features between primary and drug-induced sleep-related eating disorder

    Komada Y

    2016-05-01

    Full Text Available Yoko Komada,1 Yoshikazu Takaesu,2 Kentaro Matsui,3 Masaki Nakamura,3 Shingo Nishida,3 Meri Kanno,3,† Akira Usui,3 Yuichi Inoue1,3 1Department of Somnology, 2Department of Psychiatry, Tokyo Medical University, 3Japan Somnology Center, Institute of Neuropsychiatry, Tokyo, Japan †Meri Kanno passed away on March 1, 2016 Purpose: The aim of this study was to ascertain the clinical characteristics of drug-induced sleep-related eating disorder (SRED. Patients and methods: We retrospectively reviewed the medical records of 30 patients with primary SRED (without any comorbid sleep disorders and who were not taking any possible causative medications, and ten patients with drug-induced SRED (occurrence of SRED episodes after starting nightly medication of sedative drugs, which completely resolved after dose reduction or discontinuation of the sedatives. Results: All patients with drug-induced SRED took multiple types of sedatives, such as benzodiazepines or benzodiazepine receptor agonists. Clinical features of drug-induced SRED compared with primary SRED were as follows: higher mean age of onset (40 years old in drug-induced SRED vs 26 years old in primary SRED, significantly higher rate of patients who had total amnesia during most of their SRED episodes (75.0% vs 31.8%, significantly lower rate of comorbidity of night eating syndrome (0% vs 63.3%, and significantly lower rate of history of sleepwalking (10.0% vs 46.7%. Increased doses of benzodiazepine receptor agonists may be responsible for drug-induced SRED. Conclusion: The clinical features of drug-induced SRED were different from those of primary SRED, possibly reflecting differences in the underlying mechanisms between these two categories of SREDs. Keywords: nocturnal eating syndrome, night eating, eating disorder, hypnotics, amnesia, sleepwalking, benzodiazepine

  11. Prevalence and risk factors of liver biochemical abnormalities in patients with systemic lupus erythematosus

    Reem Ismail El Shazly

    2014-01-01

    Conclusion The prevalence of elevated liver enzymes among SLE patients attending the Rheumatology and Rehabilitation Department during the time of the study was 6.5%. The most common liver abnormality was found to be fatty liver, affecting 38.5% of the patients, followed by drug-induced hepatotoxicity (30.8%, and then HCV infection, AIH, and SLE (each 15.4%.

  12. Screening system for drug-induced arrhythmogenic risk combining a patch clamp and heart simulator

    Okada, Jun-ichi; Yoshinaga, Takashi; Kurokawa, Junko; Washio, Takumi; Furukawa, Tetsushi; Sawada, Kohei; Sugiura, Seiryo; Hisada, Toshiaki

    2015-01-01

    To save time and cost for drug discovery, a paradigm shift in cardiotoxicity testing is required. We introduce a novel screening system for drug-induced arrhythmogenic risk that combines in vitro pharmacological assays and a multiscale heart simulator. For 12 drugs reported to have varying cardiotoxicity risks, dose-inhibition curves were determined for six ion channels using automated patch clamp systems. By manipulating the channel models implemented in a heart simulator consisting of more than 20 million myocyte models, we simulated a standard electrocardiogram (ECG) under various doses of drugs. When the drug concentrations were increased from therapeutic levels, each drug induced a concentration-dependent characteristic type of ventricular arrhythmia, whereas no arrhythmias were observed at any dose with drugs known to be safe. We have shown that our system combining in vitro and in silico technologies can predict drug-induced arrhythmogenic risk reliably and efficiently. PMID:26601174

  13. Hepatocyte-based in vitro model for assessment of drug-induced cholestasis

    Chatterjee, Sagnik, E-mail: Sagnik.Chatterjee@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium); Richert, Lysiane, E-mail: l.richert@kaly-cell.com [KaLy-Cell, 20A rue du Général Leclerc, 67115 Plobsheim (France); Augustijns, Patrick, E-mail: Patrick.Augustijns@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium); Annaert, Pieter, E-mail: Pieter.Annaert@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium)

    2014-01-01

    Early detection of drug-induced cholestasis remains a challenge during drug development. We have developed and validated a biorelevant sandwich-cultured hepatocytes- (SCH) based model that can identify compounds causing cholestasis by altering bile acid disposition. Human and rat SCH were exposed (24–48 h) to known cholestatic and/or hepatotoxic compounds, in the presence or in the absence of a concentrated mixture of bile acids (BAs). Urea assay was used to assess (compromised) hepatocyte functionality at the end of the incubations. The cholestatic potential of the compounds was expressed by calculating a drug-induced cholestasis index (DICI), reflecting the relative residual urea formation by hepatocytes co-incubated with BAs and test compound as compared to hepatocytes treated with test compound alone. Compounds with clinical reports of cholestasis, including cyclosporin A, troglitazone, chlorpromazine, bosentan, ticlopidine, ritonavir, and midecamycin showed enhanced toxicity in the presence of BAs (DICI ≤ 0.8) for at least one of the tested concentrations. In contrast, the in vitro toxicity of compounds causing hepatotoxicity by other mechanisms (including diclofenac, valproic acid, amiodarone and acetaminophen), remained unchanged in the presence of BAs. A safety margin (SM) for drug-induced cholestasis was calculated as the ratio of lowest in vitro concentration for which was DICI ≤ 0.8, to the reported mean peak therapeutic plasma concentration. SM values obtained in human SCH correlated well with reported % incidence of clinical drug-induced cholestasis, while no correlation was observed in rat SCH. This in vitro model enables early identification of drug candidates causing cholestasis by disturbed BA handling. - Highlights: • Novel in vitro assay to detect drug-induced cholestasis • Rat and human sandwich-cultured hepatocytes (SCH) as in vitro models • Cholestatic compounds sensitize SCH to toxic effects of accumulating bile acids • Drug-induced

  14. Drug-induced Fanconi syndrome associated with fumaric acid esters treatment for psoriasis: A case series

    D.M.W. Balak (Deepak); J.N.B. Bavinck (Jan Nico Bouwes); De Vries, A.P.J. (Aiko P. J.); Hartman, J. (Jenny); Martino Neumann, H.A. (Hendrik A.); R. Zietse (Bob); H.B. Thio (Bing)

    2016-01-01

    textabstractBackground: Fumaric acid esters (FAEs), an oral immunomodulating treatment for psoriasis and multiple sclerosis, have been anecdotally associated with proximal renal tubular dysfunction due to a drug-induced Fanconi syndrome. Few data are available on clinical outcomes of FAE-induced Fan

  15. Drug-induced liver toxicity and prevention by herbal antioxidants: an overview

    Divya eSingh

    2016-01-01

    Full Text Available The liver is the center for drug and xenobiotic metabolism, which is influenced most with medication/xenobiotic-mediated toxic activity. Drug-induced hepatotoxicity is common and its actual frequency is hard to determine due to underreporting, difficulties in detection or diagnosis, and incomplete observation of exposure. The death rate is high, up to about 10% for medication instigated liver danger. Endorsed medications (counting acetaminophen represented >50% of instances of intense liver failure in a study from the Acute Liver Failure Study Group (ALFSG of the patients admitted in 17 US healing facilities. Albeit different studies are accessible uncovering the mechanistic aspects of medication prompted hepatotoxicity, we are in the dilemma about the virtual story. The expanding prevalence and effectiveness of Ayurveda and herbal products in the treatment of various disorders led the investigators to look into their potential in countering drug-induced liver toxicity. Several plant products have been reported to date to mitigate the drug-induced toxicity. The dietary nature and less side reactions of the herbs provide them an extra edge over other candidates of supplementary medication. In this paper, we have discussed on the mechanism involved in drug-induced liver toxicity and the potential of herbal antioxidants as supplementary medication.

  16. Topical drug-induced subacute cutaneous lupus erythematosus isolated to the hands

    Ramachandran, Sarika M; Leventhal, Jonathan S; Franco, Loren G; Mir, Adnan; Walters, Ruth F; Franks, Andrew G

    2017-01-01

    Subacute cutaneous lupus erythematosus (SCLE) is a well-defined subtype of lupus erythematosus, characterised by photosensitivity, annular and/or psoriasiform lesions, variable systemic involvement and presence of circulating SSA/anti-Ro antibodies. SCLE may be idiopathic or drug-induced. Both the idiopathic and drug-induced forms of SCLE are analogous in their clinical, serological and histological features. Drug-induced SCLE has been reported with various oral agents, but to our knowledge this is the first reported case due to a topical medication. A 34-year-old female foot masseuse presented with a 2-month history of scaly, erythematous lesions isolated to the dorsal hands and interdigital spaces. She had used topical terbinafine, a topical antifungal cream, to her clients’ feet for a number of years. ANA and anti-SSA/Ro antibodies were positive. Physical examination, serology and histopathology were consistent with SCLE. We propose that our patient's unique presentation of SCLE may be explained by a prolonged occupational exposure to topical terbinafine as a foot masseuse. While oral terbinafine is a drug known to cause drug-induced SCLE, to our knowledge, this is the first topically induced form of the disease. PMID:28331627

  17. Drug-Induced Hypersensitivity Syndrome Caused by Carbamazepine Used for the Treatment of Trigeminal Neuralgia

    Yuko Ono

    2016-01-01

    Full Text Available An 88-year-old man was diagnosed with trigeminal neuralgia, and treatment of carbamazepine 200 mg/day was initiated. About 6 weeks later, the patient developed a skin rash accompanied by fever. He was admitted to hospital and diagnosed with drug-induced hypersensitivity syndrome (DIHS caused by carbamazepine. Oral carbamazepine treatment was stopped, but blood tests showed acute liver and acute renal failure. Drug-induced lymphocyte stimulation test (DLST for carbamazepine, human herpes virus-6 (HHV-6 IgG, and CMV-HRP were negative. Oral prednisolone therapy was begun 18 days later. The titer of HHV-6 IgG antibodies was then detected (640 times. Following treatment, liver and renal function improved and the erythema disappeared.

  18. Drug-induced systemic lupus erythematosus in a child after 3 years of treatment with carbamazepine.

    Molina-Ruiz, Ana María; Lasanta, Begoña; Barcia, Ana; Pérez-Vega, Elisa; Requena, Luis

    2017-02-01

    Drug-induced lupus erythematosus (DILE) is a less severe variant of systemic lupus erythematosus (SLE) that generally resolves within weeks or months after the withdrawal of the implicated drug. DILE is unusual during childhood, with the most frequent age of presentation being at 50-70 years of age. Among different drugs, most commonly procainamide and hydralazine have been implicated as a cause of DILE. However carbamazepine (CBZ) is considered a low-risk drug and very few cases have been reported in children. We describe the case of CBZ-induced SLE in a 9-year-old girl following 3 years of CBZ therapy. This case report shows that drug-induced SLE is an important side-effect to be considered, even after long-term treatment with CBZ, and also during childhood.

  19. Drug-induced subacute cutaneous lupus erythematosus associated with nab-paclitaxel therapy.

    Lamond, N W D; Younis, T; Purdy, K; Dorreen, M S

    2013-10-01

    Drug-induced lupus erythematosus (dile) syndromes are documented complications of chemotherapeutic agents, including paclitaxel. Subacute cutaneous lupus erythematosus (scle) is a distinct dile syndrome presenting with characteristic annular or papulosquamous skin lesions in a photosensitive distribution with associated high anti-ssa titres. Previously, dile syndromes complicating paclitaxel therapy have been attributed to polyethoxylated castor oil (Kolliphor EL: BASF, Ludwigshafen, Germany), the biologic solvent included in the drug's original formulation (Taxol: Bristol-Myers Squibb, Montreal, QC), rather than the parent chemotherapy molecule. Here, we report a characteristic case of drug-induced scle complicating treatment with nanoparticle albumin bound (nab)-paclitaxel (Abraxane: Celgene, Summit, NJ, U.S.A.), a solvent-free taxane formulation. The pertinent English-language literature is also discussed. This case report is the first to link solvent-free paclitaxel with scle, and it suggests that the parent molecule is responsible for the reaction.

  20. Drug-induced long QT syndrome increases the risk of drowning.

    Vincenzi, Frank F

    2016-02-01

    There is strong evidence linking inherited long QT syndromes with an increased risk of drowning due to fatal arrhythmias in the water. Drug-induced long QT syndrome (DILQTS) is hypothesized to increase the risk of drowning by similar mechanisms. It is suggested that QT prolongation caused by a drug or drugs, when combined with the autonomic conflict associated with the mammalian dive reflex and/or the cold shock reflex, sets up conditions that may result in a sudden fatal arrhythmia while in water - thus an increased risk of drowning related to a drug-induced prolongation of the QT interval. Many widely used drugs prolong the QT interval thus raising a drug safety issue that needs confirmation or refutation.

  1. Acute fulminant drug induced necrotizing pancreatitis in a patient with ankylosing spondylitis

    Pablo Miramontes

    2015-03-01

    Full Text Available Drug-induced acute necrotizing pancreatitis is a rare adverse event, although it has been reported in association with different drugs, including non-steroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, and analgesic agents commonly used in rheumatology. In different reviews of the pancreotoxicity of drugs, infliximab and etanercept are mentioned among all medications implicated in drug-induced pancreatitis, but clinical cases of acute pancreatitis complicating treatment with these anti-TNF-α agents have been exceptionally reported. We describe a patient with ankylosing spondylitis treated with etanercept, who developed an acute fulminant necrotizing pancreatitis that resulted in death. Doctors should pay close attention to patients taking biologic drugs in which a complaint of abdominal pain lasting for several days with no apparent cause may require a prompt referral for medical consultation.

  2. Drug-Induced Myocardial Infarction Secondary to Coronary Artery Spasm in Teenagers and Young Adults

    Menyar Ayman

    2006-01-01

    Full Text Available There is no published registry for drug-induced acute myocardial infarction (AMI with subsequent patent coronary angiogram in teenagers. To highlight the mechanism and impact of drug-induced MI with patent coronary arteries among teenagers who have relatively few coronary risk factors in comparison with older patients, we conducted a review of the literature. In this review most of the pertinent published (English and non-English articles through the Medline, Scopus, Cochrane Database of Systematic Reviews, and EBSCO Host research databases from 1970 to 2005 have been revised. Teenagers and young adults with AMI and subsequent patent coronary angiogram were included. In those cases drug-induced coronary spasm was highlighted. Among 220 articles (>12000 cases related with AMI with normal coronary angiogram, 50 articles (~100 cases reported the role of drug in AMI secondary to coronary artery spasm (CAS. There is no well-conducted trial for AMI secondary to CAS in young adults but only a series of case reports, and the diagnosis in most of cases was based on the clinical and laboratory findings without provocation. CAS was associated with 12 illicit substances in teenagers (i.e., cocaine, marijuana, alcohol, butane, and amphetamine. Smoking is not only the initiative but also might harbor other illicit substances that increase the risk for CAS. Cocaine-associated AMI is the most frequent in various research papers. CAS was reported with 19 types of medications (i.e., over-the-counter, chemotherapy, antimigraine, and antibiotics without strong relation to age. Despite drug-induced AMI being not a common event, attention to smoking and drugs in teenagers and young adults will have major therapeutic and prognostic implications.

  3. Is periodontal health a predictor of drug-induced gingival overgrowth? A cross-sectional study

    Ruchi Banthia; Santosh Gupta; Priyank Banthia; Pallavi Singh; Sapna Raje; Navkiran Kaur

    2014-01-01

    Background: Gingival overgrowth is a common side-effect of amlodipine regimen on the oral cavity. There is controversy regarding the cause and effect relationship of periodontal health and drug induced gingival overgrowth. Therefore, this study was conducted to investigate and to assess the relationship between the periodontal health and the onset and severity of gingival overgrowth in hypertensive patients receiving amlodipine. Materials and Methods: A total of 99 known hypertensive pati...

  4. Proteomics Investigations of Drug-Induced Hepatotoxicity in HepG2 Cells

    Van Summeren, Anke; Renes, Johan; Bouwman, Freek G.; Noben, Jean-Paul; van Delft, Joost H. M.; Kleinjans, Jos C.S.; Mariman, Edwin C. M.

    2011-01-01

    Unexpected hepatotoxicity is one of the major reasons of drugs failing in clinical trials. This emphasizes the need for new screening methods that address toxicological hazards early in the drug discovery process. Here, proteomics techniques were used to gain further insight into the mechanistic processes of the hepatotoxic compounds. Drug-induced hepatotoxicity is mainly divided in hepatic steatosis, cholestasis, or necrosis. For each class, a compound was selected, respectively amiodarone, ...

  5. Interdisciplinary management of a patient with a drug-induced gingival hyperplasia

    Raghu Devanna

    2010-01-01

    Full Text Available Interdisciplinary treatment is becoming an ever-increasing part of modern-day orthodontic practice. This case report details the successful orthodontic-periodontal management of an epileptic patient with a significant drug-induced gingival hyperplasia. The problems that such patient′s present are discussed before considering the specific orthodontic techniques employed. Recommendations are made for practitioners managing such cases.

  6. Clinical analysis of 275 cases of acute drug-induced liver disease

    LI Lei; JIANG Wei; WANG Jiyao

    2007-01-01

    In order to analyze the causative drugs,clinical manifestation and pathological characteristics of the patients with acute drug-induced liver disease,from January 2000 to December 2005,275 cases diagnosed as acute druginduced liver diseases according to Maria Criterion and hospitalized in Zhongshan Hospital of Fudan University were retrospectively reviewed.Each was determined by drug history,clinical symptoms and signs,laboratory tests and therapeutic effects.In 41 cases,the diagnosis was confirmed by liver biopsy.The proportion of acute drug-induced liver disease among all of the acute liver injuries was annually increased.The most common drugs which induced acute liver injuries were traditional Chinese herb medicine (23.3 %,64/275 cases),antineoplastics (15.3%,42/275),hormones and other immunosuppressant agents (13.8%,38/275),antihypertensive drugs and other cardiovascular drugs (10.2 %,28/275),NSAIDs (8.7%,24/275) respectively.Hepatocellular injury was the predominant type in these cases (132 cases,48%).The principal clinical manifestation included nausea (54.8%),fatigue (50.2%),jaundice (35.6%).27.9% patients were asymptomatic.Most patients were cured with good prognosis.The total effective rate was 94.2% after treatment.The clinicians should pay attention to the prevention,diagnosis and therapy of drug-induced liver disease.

  7. Immunoexpression of interleukin-6 in drug-induced gingival overgrowth patients

    P R Ganesh

    2016-01-01

    Full Text Available Background: To analyze the role of proinflammatory cytokines in drug-induced gingival enlargement in Indian population. Aim: To evaluate for the presence of interleukin-6 (IL-6 in drug-induced gingival enlargement and to compare it with healthy control in the absence of enlargement. Materials and Methods: Thirty-five patients selected for the study and divided into control group (10 and study group (25 consisting of phenytoin (10; cyclosporin (10 and nifedipine (5 induced gingival enlargement. Gingival overgrowth index of Seymour was used to assess overgrowth and allot groups. Under LA, incisional biopsy done, tissue sample fixed in 10% formalin and immunohistochemically evaluated for the presence of IL-6 using LAB-SA method, Labeled- Streptavidin-Biotin Method (LAB-SA kit from Zymed- 2nd generation LAB-SA detection system, Zymed Laboratories, CA. The results of immunohistochemistry were statistically analyzed using Kruskaal–Wallis and Mann–Whitney test. Results: The data obtained from immunohistochemistry assessment shows that drug-induced gingival overgrowth (DIGO samples express more IL-6 than control group and cyclosporin expresses more IL-6 followed by phenytoin and nifedipine. Conclusion: Increased IL-6 expression was noticed in all three DIGO groups in comparison with control group. Among the study group, cyclosporin expressed maximum IL-6 expression followed by phenytoin and nifedipine.

  8. An Overview on the Proposed Mechanisms of Antithyroid Drugs-Induced Liver Injury

    Reza Heidari

    2015-03-01

    Full Text Available Drug-induced liver injury (DILI is a major problem for pharmaceutical industry and drug development. Mechanisms of DILI are many and varied. Elucidating the mechanisms of DILI will allow clinicians to prevent liver failure, need for liver transplantation, and death induced by drugs. Methimazole and propylthiouracil (PTU are two convenient antithyroid agents which their administration is accompanied by hepatotoxicity as a deleterious side effect. Although several cases of antithyroid drugs-induced liver injury are reported, there is no clear idea about the mechanism(s of hepatotoxicity induced by these medications. Different mechanisms such as reactive metabolites formation, oxidative stress induction, intracellular targets dysfunction, and immune-mediated toxicity are postulated to be involved in antithyroid agents-induced hepatic damage. Due to the idiosyncratic nature of antithyroid drugs-induced hepatotoxicity, it is impossible to draw a specific conclusion about the mechanisms of liver injury. However, it seems that reactive metabolite formation and immune-mediated toxicity have a great role in antithyroids liver toxicity, especially those caused by methimazole. This review attempted to discuss different mechanisms proposed to be involved in the hepatic injury induced by antithyroid drugs.

  9. Urine - abnormal color

    ... medlineplus.gov/ency/article/003139.htm Urine - abnormal color To use the sharing features on this page, please enable JavaScript. The usual color of urine is straw-yellow. Abnormally colored urine ...

  10. Using saliva nitrite and nitrate levels as a biomarker for drug induced gingival overgrowth

    Erkan eSukuroglu

    2015-12-01

    Full Text Available Aim: Drug-induced gingival overgrowth has a multifactorial nature and the pathogenesis is still uncertain. It has been suggested that Nitric Oxide (NO might play a role in the pathogenesis of drug-induced gingival overgrowth due to the contribution of NO to immune response and matrix degradation. NO levels in biological fluids have been used as a diagnostic biomarker in many diseases. The aim of this study is to determine whether NO levels in plasma, saliva and gingival crevicular fluid (GCF can serve as a potential biomarker for the evaluation of drug-induced gingival overgrowth risk. Material and Methods: A total of 104 patients, receiving cyclosporine A (n=35, phenytoin (n=25, nifedipine (n=26 or diltiazem (n=18 participated in the study. The amount of gingival overgrowth was evaluated with two indices and was given as percentage. Periodontal clinical parameters including plaque index (PI, gingival index (GI, gingival bleeding time index (GBTI and probing depth (PD were also assessed. Saliva, GCF and plasma samples were obtained from each participants. Nitrite and nitrate levels in saliva, GCF and plasma were analyzed by Griess reagent. Results: Salivary nitrite and nitrate levels in responders were significantly higher than those in non-responders in only phenytoin group (p˂0.05. Nitrite and nitrate levels of gingival crevicular fluid and plasma did not significantly differ between responders and non-responders in all study groups (p˃0.05. Salivary nitrite levels exhibited a significant correlation with PD, GBTI, severity of gingival overgrowth (%GO and GCF volume (p˂0.05. Additionally, a strong positive correlation was detected between saliva and plasma nitrate levels (p˂0.005. However, both nitrite and nitrate levels in GCF and plasma demonstrated no significant correlation with clinical parameters, GO severity and GCF volume (p˃0.05.Conclusion: Salivary nitrite and nitrate levels could be used as periodontal disease biomarkers in

  11. A prediction model of drug-induced ototoxicity developed by an optimal support vector machine (SVM) method.

    Zhou, Shu; Li, Guo-Bo; Huang, Lu-Yi; Xie, Huan-Zhang; Zhao, Ying-Lan; Chen, Yu-Zong; Li, Lin-Li; Yang, Sheng-Yong

    2014-08-01

    Drug-induced ototoxicity, as a toxic side effect, is an important issue needed to be considered in drug discovery. Nevertheless, current experimental methods used to evaluate drug-induced ototoxicity are often time-consuming and expensive, indicating that they are not suitable for a large-scale evaluation of drug-induced ototoxicity in the early stage of drug discovery. We thus, in this investigation, established an effective computational prediction model of drug-induced ototoxicity using an optimal support vector machine (SVM) method, GA-CG-SVM. Three GA-CG-SVM models were developed based on three training sets containing agents bearing different risk levels of drug-induced ototoxicity. For comparison, models based on naïve Bayesian (NB) and recursive partitioning (RP) methods were also used on the same training sets. Among all the prediction models, the GA-CG-SVM model II showed the best performance, which offered prediction accuracies of 85.33% and 83.05% for two independent test sets, respectively. Overall, the good performance of the GA-CG-SVM model II indicates that it could be used for the prediction of drug-induced ototoxicity in the early stage of drug discovery.

  12. Drug-induced autoimmune liver disease: A diagnostic dilemma of an increasingly reported disease.

    Castiella, Agustin; Zapata, Eva; Lucena, M Isabel; Andrade, Raúl J

    2014-04-27

    The aetiology of autoimmune hepatitis (AIH) is uncertain but the disease can be triggered in susceptible patients by external factors such as viruses or drugs. AIH usually develops in individuals with a genetic background mainly consisting of some risk alleles of the major histocompatibility complex (HLA). Many drugs have been linked to AIH phenotypes, which sometimes persist after drug discontinuation, suggesting that they awaken latent autoimmunity. At least three clinical scenarios have been proposed that refers to drug- induced autoimmune liver disease (DIAILD): AIH with drug-induced liver injury (DILI); drug induced-AIH (DI-AIH); and immune mediated DILI (IM-DILI). In addition, there are instances showing mixed features of DI-AIH and IM-DILI, as well as DILI cases with positive autoantibodies. Histologically distinguishing DILI from AIH remains a challenge. Even more challenging is the differentiation of AIH from DI-AIH mainly relying in histological features; however, a detailed standardised histologic evaluation of large cohorts of AIH and DI-AIH patients would probably render more subtle features that could be of help in the differential diagnosis between both entities. Growing information on the relationship of drugs and AIH is being available, being drugs like statins and biologic agents more frequently involved in cases of DIAILD. In addition, there is some evidence on the fact that patients diagnosed with DIAILD may have had a previous episode of hepatotoxicity. Further collaborative studies in DIAILD will strengthen the knowledge and understanding of this intriguing and complex disorder which might represent different phenotypes across the spectrum of disease.

  13. Drug-induced interstitial lung diseases%药源性间质性肺疾病

    王晓芳; 张运剑; 夏国光

    2012-01-01

    Drug-induced interstitial lung disease is the most common type of drug-induced respiratory diseases. It is known that a lot of drugs can cause interstitial lung diseases. The underlying mechanism may be associated with allergy and the direct cellular toxicity. Its clinical symptoms, imaging, and histopathology were untypical. Clinical diagnosis of the disease was based on the medical history ( medication history), clinical features, chest imaging, hi sto pathological changes, and response to treatment. If interstitial lung diseases were suspected to be; drug-induced, the drug should be discontinued immediately and glucocorticoid could be given. The prognosis is good if intervention is rapid.%药源性间质性肺疾病(DI-ILD)是最常见的药源性肺部疾病,目前已知多种药物可导致间质性肺疾病,其发病机制与药物引起的变态反应和直接细胞毒性作用有关.此类疾病临床症状、影像学及组织病理学表现均无特异性,临床诊断DI-ILD需根据病史(用药史)、临床特点、胸部影像学、组织病理学改变及治疗效果.临床疑诊DI-ILD时应立刻停药并应用糖皮质激素.若及时干预,预后良好.

  14. Drug-induced premature chromosome condensation (PCC) protocols: cytogenetic approaches in mitotic chromosome and interphase chromatin.

    Gotoh, Eisuke

    2015-01-01

    Chromosome analysis is a fundamental technique which is used in wide areas of cytogenetic study including karyotyping species, hereditary diseases diagnosis, or chromosome biology study. Chromosomes are usually prepared from mitotic cells arrested by colcemid block protocol. However, obtaining mitotic chromosomes is often hampered under several circumstances. As a result, cytogenetic analysis will be sometimes difficult or even impossible in such cases. Premature chromosome condensation (PCC) (see Note 1) is an alternative method that has proved to be a unique and useful way in chromosome analysis. Former, PCC has been achieved following cell fusion method (cell-fusion PCC) mediated either by fusogenic viruses (e.g., Sendai virus) or cell fusion chemicals (e.g., polyethylene glycol), but the cell fusion PCC has several drawbacks. The novel drug-induced PCC using protein phosphatase inhibitors was introduced about 20 years ago. This method is much simpler and easier even than the conventional mitotic chromosome preparation protocol use with colcemid block and furthermore obtained PCC index (equivalent to mitotic index for metaphase chromosome) is usually much higher than colcemid block method. Moreover, this method allows the interphase chromatin to be condensed to visualize like mitotic chromosomes. Therefore drug-induced PCC has opened the way for chromosome analysis not only in metaphase chromosomes but also in interphase chromatin. The drug-induced PCC has thus proven the usefulness in cytogenetics and other cell biology fields. For this second edition version, updated modifications/changes are supplemented in Subheadings 2, 3, and 4, and a new section describing the application of PCC in chromosome science fields is added with citation of updated references.

  15. Organization and logistics of drug-induced sleep endoscopy in a training hospital.

    Benoist, L B L; de Vries, N

    2015-09-01

    Drug-induced sleep endoscopy (DISE) is a rapidly growing method to evaluate airway collapse in patients receiving non-CPAP therapies for sleep-disordered breathing (SDB). The growing number of DISEs has consequences for the organization of clinical protocols. In this paper we present our recent experiences with DISE, performed by an ENT resident, with sedation given by a nurse anesthetist, in an outpatient endoscopy setting, while the staff member/sleep surgeon discusses the findings and the recommended treatment proposal on the same day.

  16. Subjective cognitive dysfunction associated with drug-induced parkinsonism in schizophrenia.

    Kim, Jong-Hoon; Kim, Seong-Youn; Byun, Hee-Jung

    2008-01-01

    The authors investigated the subjective cognitive dysfunction associated with drug-induced parkinsonism (DIP) among 58 stabilized schizophrenic outpatients. Subjective cognitive dysfunction was comprehensively assessed using the Frankfurt Complaint Questionnaire (FCQ). Multivariate analysis revealed that the DIP group scored significantly higher on the total FCQ score than the non-DIP group. In phenomenological subscale scores, the DIP group had significantly higher scores on "deterioration of discrimination", "psychomotor disorder", and "perceptual disorder" than the non-DIP group. These results suggest that DIP is significantly associated with subjective cognitive-perceptual dysfunction, reflecting the complex nature of DIP that includes motor and cognitive aspects.

  17. Drug-induced acute pancreatitis: A rare manifestation of an incomplete "dapsone syndrome"

    Anup K Das

    2014-01-01

    Full Text Available Drug-induced acute pancreatitis (AP is under-reported, and a large number of drugs are listed as offenders, but are often overlooked. Knowledge about the possible association of medications in causing AP is important, and needs a high index of suspicion, especially with drugs that have been reported to be the etiology only rarely. Dapsone, a commonly used drug, can cause various hypersensitivity reactions including AP collectively called "dapsone syndrome." Here, we report dapsone-induced AP in a young man. Our case shows certain dissimilarities like associated acute renal failure and acute hemolysis not previously described.

  18. Treatment with diazepam of children with drug-induced extrapyramidal symptoms.

    Rainier-Pope, C R

    1979-03-03

    Thirteen patients with acute dystonia and extrapyramidal symptoms as a result of drug intoxication are reported. In a number of instances, the symptoms were due to more than one drug being given to the patient, among which were phenothiazine derivatives, non-phenothiazine tranquilizers and metoclopramide. Diazepam (Valium) given intravenously caused the patients to fall asleep immediately and to wake within an hour, free from all symptoms. It is felt that in patients with drug-induced extrapyramidal symptoms, diazepam should be considered as the possible drug of choice.

  19. Episcleritis Related to Drug-Induced Lupus Erythematosus following Infliximab Therapy: A Case Report

    Irini P. Chatziralli

    2011-01-01

    Full Text Available Drug-induced lupus erythematosus is defined as a lupus-like syndrome temporally related to continuous drug exposure which resolves after discontinuation of the offending drug. Herein, we describe a patient with distinct clinical manifestations of anti-TNF-associated DILE related to infliximab therapy. The patient exhibited clinical and laboratory findings of lupus-like illnesses as well as ocular disorders, such as episcleritis. The main message is that the symptoms of DILE should not be overlooked, although sometimes other systematic conditions may underlie them. As a result, it is very important for the clinicians to evaluate the symptoms of DILE and manage appropriately these cases.

  20. Pharmaco-epidemiological, clinical and laboratory characteristics of drug-induced liver injury in tuberculosis

    M. V. Koroleva

    2015-01-01

    Full Text Available Objective: improving the efficiency of pharmacotherapy of drug-induced liver injury in tuberculosis by clarifying pharmaco-epidemiological, clinical and laboratory features.Materials and Methods: A retrospective analysis of primary medical records of 250 patients with pulmonary tuberculosis, patients «Volgograd Regional Clinical TB Dispensary № 1». We evaluated the dynamics of biochemical parameters characterizing the development of hepatic cytolytic syndrome, examined the impact of gender and age on the incidence of liver damage, we investigated the relationship of clinical tuberculosis and chemotherapy regimen with the incidence of drug-induced liver injury, examined the clinical manifestations of liver disease.Results: Drug-induced liver injury as a complication of a specific anti-TB treatment was diagnosed in 67 patients (26,8%. In 170 patients (68,0% showed increase in alanine aminotransferase and asparaginaminotrasferazy. Hepatotoxicity significantly more common in patients with disseminated tuberculosis with the collapse of the lung tissue, smear, and a high degree of disease severity. Risk factors for drug liver damage were female gender and age older than 50 years. Women develop liver disease at an earlier date, and displays it harder than men. The earliest and most informative routine biochemical tests, reflecting the state of the liver in the dynamics are ALT and AST. It was found that the mode of the standard anti-TB treatment determines the type of liver injury: the first, 2a and 3rd modes prevails cytolytic hepatocellular type, with 2b mode – combined (mixed type 4th – type of cholestatic liver damage. It was found that repeated, after the development of hepatotoxic reactions, the appointment of anti-TB drugs without gepatoprotektsii in 94% of patients leads to repeated drug-induced liver damage. Cancel specific therapy against the background of cytolytic syndrome promotes the formation of

  1. A Novel SCN5A Mutation Associated with Drug Induced Brugada Type ECG

    Isik, Turker; Takeru, Makiyama; Matteo, Vatta; Hideki, Itoh; Takeshi, Ueyama; Akihiko, Shimizu; Tomohiko, Ai; Minoru, Horie

    2016-01-01

    Background: Class IC antiarrhythmic agents may induce acquired forms of Brugada Syndrome. We have identified a novel mutation in SCN5A, the gene that encodes the α-subunit of the human cardiac sodium channel (hNav1.5), in a patient who exhibited Brugada- type ECG changes during pharmacotherapy of atrial arrhythmias. Objective: To assess whether the novel mutation p.V1328M can cause drug induced Brugada Syndrome. Methods: Administration of pilsicainide, a class IC antiarrhythmic agent, caused ...

  2. Drug-induced immune hemolytic anemia associated with albumin-bound paclitaxel.

    Thomas, Roby; Shillingburg, Alexandra

    2015-08-01

    Drug-induced immune hemolytic anemia (DIIHA) is rare, with only 1 patient in 1 million affected by the condition.1 Garratty identified 125 drugs indicated in DIIHA of which 11% were antineoplastic agents, and neither paclitaxel nor albumin-bound paclitaxel were included.2 In addition, we did not find any reports in our own search of the literature. Taxanes are known to cause anemia as a result of their myelosuppressive effects, but an immune hemolysis is rare. To our knowledge, we present here the first case of DIIHA with nab-paclitaxel.

  3. Mechanism of drug-induced gingival overgrowth revisited: a unifying hypothesis

    Brown, RS; Arany, PR

    2015-01-01

    Drug-induced gingival overgrowth (DIGO) is a disfiguring side effect of anti-convulsants, calcineurin inhibitors, and calcium channel blocking agents. A unifying hypothesis has been constructed which begins with cation flux inhibition induced by all three of these drug categories. Decreased cation influx of folic acid active transport within gingival fibroblasts leads to decreased cellular folate uptake, which in turn leads to changes in matrix metalloproteinases metabolism and the failure to activate collagenase. Decreased availability of activated collagenase results in decreased degradation of accumulated connective tissue which presents as DIGO. Studies supporting this hypothesis are discussed. PMID:24893951

  4. Comparison of clinical features between primary and drug-induced sleep-related eating disorder

    Komada Y; Takaesu Y; Matsui K.; Nakamura M; Nishida S; Kanno M; Usui A; Inoue Y

    2016-01-01

    Yoko Komada,1 Yoshikazu Takaesu,2 Kentaro Matsui,3 Masaki Nakamura,3 Shingo Nishida,3 Meri Kanno,3,† Akira Usui,3 Yuichi Inoue1,3 1Department of Somnology, 2Department of Psychiatry, Tokyo Medical University, 3Japan Somnology Center, Institute of Neuropsychiatry, Tokyo, Japan †Meri Kanno passed away on March 1, 2016 Purpose: The aim of this study was to ascertain the clinical characteristics of drug-induced sleep-related eating disorder (SRED). Patients and me...

  5. 药源性自身免疫性疾病%Drug-induced Autoimmunity

    李洪波; 林玲

    2016-01-01

    自从1945年首次报道磺胺嘧啶引起狼疮样症状至今,越来越多的药物被报道能影响人体免疫系统从而诱发自身免疫性疾病,药源性自身免疫性疾病(drug-induced autoimmunity, DIA)的关注度越来越高,但目前DIA的致病机制尚未完全阐明,尚未制定一个合适的诊断标准,治疗和预防也缺乏系统的循证医学证据。本文就 DIA的一般临床特征、致病机制、实验室检查特点、诊断、预防和治疗进行综合。%Since sulfadiazine associated lupus-like symptoms were first described in 1945, more and more drugs have been reported to interfere with the immune system and induce a series of autoimmune diseases ( named drug-induced autoimmunity, DIA ) . However, the pathogenesis of DIA has not been fully clarified, and the standardized criteria for DIA diagnosis has not been established, and it is also lack of systematic research on its treatment and prevention. In this review, we summarize the clinical features, pathogenesis, laboratory findings, diagnosis, prevention and treatment of DIA.

  6. [DRUG-INDUCED LUPUS CAUSED BY LONG TERM MINOCYCLINE TREATMENT FOR ACNE VULGARIS].

    Hanai, Shunichiro; Sato, Takeo; Takeda, Koichi; Nagatani, Katsuya; Iwamoto, Masahiro; Minota, Seiji

    2015-09-01

    An 18-year-old Japanese girl had received oral minocycline 200mg daily for treatment of acne vulgaris since 16 years old. She had a fever three months before admission, followed by joint pains in her knees, elbows and several proximal interphalangeal joints one month before admission. She was referred to our hospital because of a high serum level of anti-DNA antibody. She had already discontinued oral minocycline five weeks before admission, because she missed her medication refilled. On admission, the arthralgia and fever spontaneously resolved, and there were no laboratory evidence of hypocomplementemia and cytopenia. She had neither erythema nor internal organ involvements. Because her symptoms subsided spontaneously after the cessation of minocycline, she was considered to have drug-induced lupus. Both the arthralgia and fever did not relapse, and anti-ds DNA antibody returned to normal during a follow-up period without treatment. There are few reports of drug-induced lupus caused by minocycline in Japan. This case highlights the importance of considering minocycline-induced lupus.

  7. Glucuronidation of drugs and drug-induced toxicity in humanized UDP-glucuronosyltransferase 1 mice.

    Kutsuno, Yuki; Itoh, Tomoo; Tukey, Robert H; Fujiwara, Ryoichi

    2014-07-01

    UDP-glucuronosyltransferases (UGTs) are phase II drug-metabolizing enzymes that catalyze glucuronidation of various drugs. Although experimental rodents are used in preclinical studies to predict glucuronidation and toxicity of drugs in humans, species differences in glucuronidation and drug-induced toxicity have been reported. Humanized UGT1 mice in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus (hUGT1 mice) were recently developed. In this study, acyl-glucuronidations of etodolac, diclofenac, and ibuprofen in liver microsomes of hUGT1 mice were examined and compared with those of humans and regular mice. The kinetics of etodolac, diclofenac, and ibuprofen acyl-glucuronidation in hUGT1 mice were almost comparable to those in humans, rather than in mice. We further investigated the hepatotoxicity of ibuprofen in hUGT1 mice and regular mice by measuring serum alanine amino transferase (ALT) levels. Because ALT levels were increased at 6 hours after dosing in hUGT1 mice and at 24 hours after dosing in regular mice, the onset pattern of ibuprofen-induced liver toxicity in hUGT1 mice was different from that in regular mice. These data suggest that hUGT1 mice can be valuable tools for understanding glucuronidations of drugs and drug-induced toxicity in humans.

  8. Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

    Ignazio Grattagliano; Leonilde Bonfrate; Catia V Diogo; Helen H Wang; David QH Wang; Piero Portincasa

    2009-01-01

    Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local O_2 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca~(2+)-dependent ATPase, reduced capability to sequester Ca~(2+) within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.

  9. Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death

    De Bruin, M L; Pettersson, M; Meyboom, R H B;

    2005-01-01

    AIMS: Drug-induced QTc-prolongation, resulting from inhibition of HERG potassium channels may lead to serious ventricular arrhythmias and sudden death. We studied the quantitative anti-HERG activity of pro-arrhythmic drugs as a risk factor for this outcome in day-to-day practice. METHODS AND RESU......AIMS: Drug-induced QTc-prolongation, resulting from inhibition of HERG potassium channels may lead to serious ventricular arrhythmias and sudden death. We studied the quantitative anti-HERG activity of pro-arrhythmic drugs as a risk factor for this outcome in day-to-day practice. METHODS...... AND RESULTS: All 284,426 case reports of suspected adverse drug reactions of drugs with known anti-HERG activity received by the International Drug Monitoring Program of the World Health Organization (WHO-UMC) up to the first quarter of 2003, were used to calculate reporting odds ratios (RORs). Cases were...... defined as reports of cardiac arrest, sudden death, torsade de pointes, ventricular fibrillation, and ventricular tachycardia (n = 5591), and compared with non-cases regarding the anti-HERG activity, defined as the effective therapeutic plasma concentration (ETCPunbound) divided by the HERG IC50 value...

  10. Complement-fixing properties of antinuclear antibodies distinguish drug-induced lupus from systemic lupus erythematosus.

    Rubin, R L; Teodorescu, M; Beutner, E H; Plunkett, R W

    2004-01-01

    The immunofluorescence antinuclear antibody (ANA) test has been widely used to monitor autoimmune disease, but its value for diagnostic purposes is compromised by low specificity and high prevalence in disease-free individuals. The capacity of autoantibodies to fix serum complement proteins when bound to antigen is an important effector function because this property is associated with acute and chronic inflammatory processes. The current study evaluates the complement-fixing properties of antinuclear antibodies (CANA) in three well-defined and clinically-related patient groups: systemic lupus erythematosus (SLE), drug-induced lupus (DIL) and drug-induced autoimmunity (DIA). Of 20 patients diagnosed with SLE, 90% displayed complement-fixing ANA while this feature was present in only two of 18 patients with DIL and no patients with DIA without associated disease even though the mean ANA titres were similar among these patient groups. CANA was significantly correlated with anti-Sm activity. Because SLE but not DIL or DIA can be a life-threatening disease associated with complement consumption in vivo, these results demonstrate that measurement of CANA is a diagnostically useful tool and may have immunopathologic implications.

  11. Hereditary urea cycle abnormality

    ... vitro so the specific genetic cause is known. Teamwork between parents, the affected child, and doctors can help prevent severe illness. Alternative Names Abnormality of the urea cycle - hereditary; Urea cycle - hereditary abnormality Images Male urinary system Urea cycle References Lichter-Konecki ...

  12. Detecting drug-induced prolongation of the QRS complex: New insights for cardiac safety assessment

    Cros, C., E-mail: caroline.cros@hotmail.co.uk [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Skinner, M., E-mail: Matthew.Skinner@astrazeneca.com [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Moors, J. [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Lainee, P. [Sanofi-Aventis R and D, 371, rue du Pr Joseph Blayac, 34184 Montpellier Cedex 04 (France); Valentin, J.P. [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom)

    2012-12-01

    Background: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I{sub Na}) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I{sub Na}, this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation. Methods: Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1 h period from 1 h pre-dose to 5 h post-dose. Results: Compared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (E{sub max} 13% and 20% respectively, P < 0.01–0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of + 0.7 ± 0.5 ms (quinidine, NS), + 1.8 ± 0.8 ms (mexiletine, P < 0.05) and + 2.8 ± 0.8 ms (flecainide, P < 0.01) (calculated as QRS at basal HR-QRS at high HR). Conclusion: Electrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function. -- Highlights: ► We aimed to improve detection of drug-induced QRS prolongation in safety screening. ► We used telemetered dogs to test class I antiarrhythmics at low and high heart rate. ► At low heart rate only quinidine and flecainide induced an increase in QRS duration. ► At high heart rate the effects of two

  13. "Jeopardy" in Abnormal Psychology.

    Keutzer, Carolin S.

    1993-01-01

    Describes the use of the board game, Jeopardy, in a college level abnormal psychology course. Finds increased student interaction and improved application of information. Reports generally favorable student evaluation of the technique. (CFR)

  14. Chromosomal Abnormalities in ADHD

    J Gordon Millichap

    2002-07-01

    Full Text Available The prevalence of fragile X syndrome, velocardiofacial syndrome (VCFS, and other cytogenetic abnormalities among 100 children (64 boys with combined type ADHD and normal intelligence was assessed at the NIMH and Georgetown University Medical Center.

  15. Abnormal menstrual periods (image)

    ... may have a variety of causes, such as endometrial hyperplasia, endometrial polyps, uterine fibroids, and abnormal thyroid or ... the endometrium becomes unusually thick it is called endometrial ... Hyperplasia may cause profuse or extended menstrual bleeding.

  16. Chromosomal abnormalities and autism

    Farida El-Baz

    2016-01-01

    Conclusion: Chromosomal abnormalities were not detected in the studied autistic children, and so the relation between the genetics and autism still needs further work up with different study methods and techniques.

  17. Drug-induced liver injury: Advances in mechanistic understanding that will inform risk management.

    Mosedale, M; Watkins, P B

    2016-11-09

    Drug-induced liver injury (DILI) is a major public health problem. Intrinsic (dose-dependent) DILI associated with acetaminophen overdose is the number one cause of acute liver failure in the US. However, the most problematic type of DILI impacting drug development is idiosyncratic, occurring only very rarely among treated patients and often only after several weeks or months of treatment with the offending drug. Recent advances in our understanding of the pathogenesis of DILI suggest that three mechanisms may underlie most hepatocyte effects in response to both intrinsic and idiosyncratic DILI drugs: mitochondrial dysfunction, oxidative stress, and alterations in bile acid homeostasis. However, in some cases hepatocyte stress promotes an immune response that results in clinically important idiosyncratic DILI. This review discusses recent advances in our understanding of the pathogenesis of both intrinsic and idiosyncratic DILI as well as emerging tools and techniques that will likely improve DILI risk identification and management.

  18. Caenorhabditis elegans as a Model System for Studying Drug Induced Mitochondrial Toxicity.

    Richard de Boer

    Full Text Available Today HIV-1 infection is recognized as a chronic disease with obligatory lifelong treatment to keep viral titers below detectable levels. The continuous intake of antiretroviral drugs however, leads to severe and even life-threatening side effects, supposedly by the deleterious impact of nucleoside-analogue type compounds on the functioning of the mitochondrial DNA polymerase. For detailed investigation of the yet partially understood underlying mechanisms, the availability of a versatile model system is crucial. We therefore set out to develop the use of Caenorhabditis elegans to study drug induced mitochondrial toxicity. Using a combination of molecular-biological and functional assays, combined with a quantitative analysis of mitochondrial network morphology, we conclude that anti-retroviral drugs with similar working mechanisms can be classified into distinct groups based on their effects on mitochondrial morphology and biochemistry. Additionally we show that mitochondrial toxicity of antiretroviral drugs cannot be exclusively attributed to interference with the mitochondrial DNA polymerase.

  19. Drug-induced mitochondrial neuropathy in children: a conceptual framework for critical windows of development.

    Wallace, Kendall B

    2014-09-01

    Mitochondrial disease arises from genetic or nongenetic events that interfere either directly or indirectly with the bioenergetic function of the mitochondrion and manifest clinically in some form of metabolic disorder. In primary mitochondrial disease, the critical molecular target is one or more of the individual subunits of the respiratory complexes or their assembly and incorporation into the inner mitochondrial membrane, whereas with secondary mitochondrial disease the bioenergetic deficits are secondary to effects on targets other than the electron transport chain and oxidative phosphorylation. Primary genetic events include mutations to or altered expression of proteins targeted to the mitochondrial compartment, whether they are encoded by the nuclear or mitochondrial genome. In this review, we emphasize the occurrence of nongenetic mitochondrial disease resulting from therapeutic drug administration, review the broad scope of drugs implicated in affecting specific primary mitochondrial targets, and describe evidence demonstrating critical windows of risk for the developing neonate to drug-induced mitochondrial disease and neuropathy.

  20. Recurrent drug-induced liver injury (DILI) with ciprofloxacin and amoxicillin/clavulanic.

    Moreno, Luís; Sánchez-Delgado, Jordi; Vergara, Mercedes; Casas, Meritxell; Miquel, Mireia; Dalmau, Blai

    2015-12-01

    Ciprofloxacin and amoxicillin/clavulanic are two widely used antibiotics due to their high efficacy and few side effects. While the percentage of hepatotoxicity of these antibiotics is low, their frequent use has led to a progressive increase in the number of cases. Both antibiotics have been associated with a wide variety of hepatotoxic reactions, from a slight rise of transaminases to fulminant hepatitis. Once hepatotoxicity secondary to a drug appears, the first step is to discontinue the drug. Physicians may opt to administer an alternative treatment with a different chemical structure. It should be borne in mind, however, that different chemical structures may also cause recurrent drug-induced liver injuries (DILI). We present the case of a patient who consecutively developed DILI due to ciprofloxacin and amoxicillin/clavulanic.

  1. Radiation- and drug-induced DNA repair in mammalian oocytes and embryos

    Pedersen, R A; Brandriff, B

    1979-01-01

    A review of studies showing ultraviolet- or drug-induced unscheduled DNA synthesis in mammalian oocytes and embryos suggests that the female gamete has an excision repair capacity from the earliest stages of oocyte growth. The oocyte's demonstrable excision repair capacity decreases at the time of meiotic maturation for unknown reasons, but the fully mature oocyte maintans a repair capacity, in contrast to the mature sperm, and contributes this to the zygote. Early embryo cells maintain relatively constant levels of excision repair until late fetal stages, when they lose their capacity for excision repair. These apparent changes in excision repair capacity do not have a simple relationship to known differences in radiation sensitivity of germ cells and embryos.

  2. Drug-Induced Liver Injury Network Causality Assessment: Criteria and Experience in the United States

    Paul H. Hayashi

    2016-02-01

    Full Text Available Hepatotoxicity due to drugs, herbal or dietary supplements remains largely a clinical diagnosis based on meticulous history taking and exclusion of other causes of liver injury. In 2004, the U.S. Drug-Induced Liver Injury Network (DILIN was created under the auspices of the U.S. National Institute of Diabetes and Digestive and Kidney Diseases with the aims of establishing a large registry of cases for clinical, epidemiological and mechanistic study. From inception, the DILIN has used an expert opinion process that incorporates consensus amongst three different DILIN hepatologists assigned to each case. It is the most well-established, well-described and vigorous expert opinion process for DILI to date, and yet it is an imperfect standard. This review will discuss the DILIN expert opinion process, its strengths and weaknesses, psychometric performance and future.

  3. Abnormal protein aggregationand neurodegenerativediseases

    2001-01-01

    Abnormal protein aggregation or amyloid is the major cause ofmany neurodegenerative disorders. The present review focuses on the correlation between sequence and structure features of proteins related to the diseases and abnormal protein aggregation. Recent progress has improved our knowledge on understand-ing the mechanism of amyloid formation. We suggest a nucleation model for ordered protein aggregation, which can also explain pathogenesis mechanisms of these neurodegenerative diseases in vivo.

  4. Nucleoside drugs induce cellular differentiation by caspase-dependent degradation of stem cell factors.

    Tanja Musch

    Full Text Available BACKGROUND: Stem cell characteristics are an important feature of human cancer cells and play a major role in the therapy resistance of tumours. Strategies to target cancer stem cells are thus of major importance for cancer therapy. Differentiation therapy by nucleoside drugs represents an attractive approach for the elimination of cancer stem cells. However, even if it is generally assumed that the activity of these drugs is mediated by their ability to modulate epigenetic pathways, their precise mode of action remains to be established. We therefore analysed the potential of three nucleoside analogues to induce differentiation of the embryonic cancer stem cell line NTERA 2 D1 and compared their effect to the natural ligand retinoic acid. METHODOLOGY/PRINCIPAL FINDINGS: All nucleoside analogues analyzed, but not retinoic acid, triggered proteolytic degradation of the Polycomb group protein EZH2. Two of them, 3-Deazaneplanocin A (DZNep and 2'-deoxy-5-azacytidine (decitabine, also induced a decrease in global DNA methylation. Nevertheless, only decitabine and 1beta-arabinofuranosylcytosine (cytarabine effectively triggered neuronal differentiation of NT2 cells. We show that drug-induced differentiation, in contrast to retinoic acid induction, is caused by caspase activation, which mediates depletion of the stem cell factors NANOG and OCT4. Consistent with this observation, protein degradation and differentiation could be counteracted by co-treatment with caspase inhibitors or by depletion of CASPASE-3 and CASPASE-7 through dsRNA interference. In agreement with this, OCT4 was found to be a direct in-vitro-target of CASPASE-7. CONCLUSIONS/SIGNIFICANCE: We show that drug-induced differentiation is not a consequence of pharmacologic epigenetic modulation, but is induced by the degradation of stem-cell-specific proteins by caspases. Our results thus uncover a novel pathway that induces differentiation of embryonic cancer stem cells and is triggered by

  5. Serotonergic Hyperactivity as a Potential Factor in Developmental, Acquired and Drug-Induced Synesthesia

    Berit eBrogaard

    2013-10-01

    Full Text Available Though synesthesia research has seen a huge growth in recent decades, and tremendous progress has been made in terms of understanding the mechanism and cause of synesthesia, we are still left mostly in the dark when it comes to the mechanistic commonalities (if any among developmental, acquired and drug-induced synesthesia. We know that many forms of synesthesia involve aberrant structural or functional brain connectivity. Proposed mechanisms include direct projection and disinhibited feedback mechanisms, in which information from two otherwise structurally or functionally separate brain regions mix. We also know that synesthesia sometimes runs in families. However, it is unclear what causes its onset. Studies of psychedelic drugs, such as psilocybin, LSD and mescaline, reveal that exposure to these drugs can induce synesthesia. One neurotransmitter suspected to be central to the perceptual changes is serotonin. Excessive serotonin in the brain may cause many of the characteristics of psychedelic intoxication. Excessive serotonin levels may also play a role in synesthesia acquired after brain injury. In brain injury sudden cell death floods local brain regions with serotonin and glutamate. This neurotransmitter flooding could perhaps result in unusual feature binding. Finally, developmental synesthesia that occurs in individuals with autism may be a result of alterations in the serotonergic system, leading to a blockage of regular gating mechanisms. I conclude on these grounds that one commonality among at least some cases of acquired, developmental and drug-induced synesthesia may be the presence of excessive levels of serotonin, which increases the excitability and connectedness of sensory brain regions.

  6. Drug-induced anaphylactic reactions in Indian population: A systematic review

    Tejas K Patel

    2014-01-01

    Full Text Available Background: Epidemiological data on drug-induced anaphylactic reactions are limited in India and are largely depending on studies from developed countries. Aim: The aim was to analyze the published studies of drug-induced anaphylaxis reported from India in relation with causative drugs and other clinical characteristics. Materials and Methods: The electronic databases were searched for Indian publications from 1998 to 2013 describing anaphylactic reactions. The information was collected for demographics, set up in which anaphylaxis occurred, causative drugs, incubation period, clinical features, associated allergic conditions, past reactions, co-morbid conditions, skin testing, IgE assays, therapeutic intervention and mortality. Reactions were analyzed for severity, causality, and preventability. Data were extracted and summarized by absolute numbers, mean (95% confidence interval [CI], percentages and odds ratio (OR (95% CI. Results: From 3839 retrieved references, 52 references describing 54 reactions were included. The mean age was 35.31 (95% CI: 30.52-40.10 years. Total female patients were 61.11%. Majority reactions were developed in perioperative conditions (53.70%, ward (20.37% and home (11.11%. The major incriminated groups were antimicrobials (18.52%, nonsteroidal antiinflammatory drugs-(NSAIDs (12.96% and neuromuscular blockers (12.96%. Common causative drugs were diclofenac (11.11%, atracurium (7.41% and β-lactams (5.96%. Cardiovascular (98.15% and respiratory (81.48% symptoms dominated the presentation. Skin tests and IgE assays were performed in 37.03% and 18.52% cases, respectively. The fatal cases were associated with complications (OR =5.04; 95% CI: 1.41-17.92, cerebral hypoxic damage (OR =6.80; 95% CI: 2.14-21.58 and preventable reactions (OR =14.33; 95% CI: 2.33-87.97. Conclusion: Antimicrobials, NSAIDs, and neuromuscular blockers are common causative groups. The most fatal cases can be prevented by avoiding allergen drugs.

  7. Drug-Induced Liver Injury Is a Major Risk for New Drugs.

    Seeff, Leonard B

    2015-01-01

    Drug-induced liver injury (DILI), a relatively rare condition, is nevertheless a major reason for not approving a drug in development or for removing one already marketed. With a specific diagnostic biomarker lacking, finding elevated serum enzyme [alanine aminotransferase (ALT), aspartate aminotransferase and alkaline phosphatase] activities remains an initial signal for incipient liver injury. Enzyme elevations alone may not be harmful, but if caused by a drug and followed by jaundice (called 'Hy's law') there is a high possibility of serious DILI. In 1997 several drugs were approved by the Food and Drug Administration (FDA) of the USA that were later withdrawn from the market for serious liver toxicity. New drugs in development are now required to be monitored for liver injury, and the data is to be considered in the approval decision. A program called e-DISH (evaluation of drug-induced serious hepatotoxicity) was introduced in 2004 to aid medical reviewers to select from all subjects studied those few who show nontrivial liver injury and estimate the most likely cause. The threshold of enzyme elevation comprising a warning for possibly serious DILI is uncertain, although generally accepted as 3-5 times the 'upper limit of normal'. The new direct-acting antiviral agents for treating chronic hepatitis C virus, which often lead to a reduction of elevated ALTs, mandate that a later increase without viral breakthrough be compared to the new on-treatment level of values. The drug may be discontinued or interrupted for evaluation to exclude other possible causes of liver injury. The FDA has approved no drug since 1997 that has been withdrawn later because of serious hepatotoxicity.

  8. Assessment of drug-induced hepatotoxicity in clinical practice: A challenge for gastroenterologists

    Raúl J Andrade; Mercedes Robles; Alejandra Fernández-Casta(n)er; Susana López-Ortega; M Carmen López-Vega; M Isabel Lucena

    2007-01-01

    Currently, pharmaceutical preparations are serious contributors to liver disease; hepatotoxicity ranking as the most frequent cause for acute liver failure and postcommercialization regulatory decisions. The diagnosis of hepatotoxicity remains a difficult task because of the lack of reliable markers for use in general clinical practice.To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug's hepatotoxic potential, the exclusion of alternative causes of liver damage and the ability to detect the presence of subtle data that favors a toxic etiology. This process is time-consuming and the final result is frequently inaccurate. Diagnostic algorithms may add consistency to the diagnostic process by translating the suspicion into a quantitative score. Such scales are useful since they provide a framework that emphasizes the features that merit attention in cases of suspected hepatic adverse reaction as well. Current efforts in collecting bona fide cases of drug-induced hepatotoxicity will make refinements of existing scales feasible. It is now relatively easy to accommodate relevant data within the scoring system and to delete low-impact items. Efforts should also be directed toward the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be made. The instrument chosen would enable a confident diagnosis to be made on admission of the patient and treatment to be finetuned as further information is collected.

  9. Clinical features and {sup 123}I-FP-CIT SPECT imaging in drug-induced parkinsonism and Parkinson's disease

    Diaz-Corrales, Francisco J.; Escobar-Delgado, Teresa [Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Unidad de Trastornos del Movimiento, Servicio de Neurologia, Instituto de Biomedicina de Sevilla, Seville (Spain); Sanz-Viedma, Salome [Hospital Universitario Virgen del Rocio, Unidad Diagnostica de Medicina Nuclear, Seville (Spain); Garcia-Solis, David [Hospital Universitario Virgen del Rocio, Unidad Diagnostica de Medicina Nuclear, Seville (Spain); Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Seville (Spain); Mir, Pablo [Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Unidad de Trastornos del Movimiento, Servicio de Neurologia, Instituto de Biomedicina de Sevilla, Seville (Spain); Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Seville (Spain); Hospital Universitario Virgen del Rocio, Unidad de Trastornos del Movimiento. Servicio de Neurologia, Seville (Spain)

    2010-03-15

    To determine clinical predictors and accuracy of {sup 123}I-FP-CIT SPECT imaging in the differentiation of drug-induced parkinsonism (DIP) and Parkinson's disease (PD). Several clinical features and {sup 123}I-FP-CIT SPECT images in 32 patients with DIP, 25 patients with PD unmasked by antidopaminergic drugs (PDu) and 22 patients with PD without a previous history of antidopaminergic treatment (PDc) were retrospectively evaluated. DIP and PD shared all clinical features except symmetry of parkinsonian signs which was more frequently observed in patients with DIP (46.9%) than in patients with PDu (16.0%, p<0.05) or PDc (4.5%, p<0.01). Qualitatively {sup 123}I-FP-CIT SPECT images were normal in 29 patients with DIP (90.6%) and abnormal in all patients with PD, and this imaging technique showed high levels of accuracy. DIP and PD are difficult to differentiate based on clinical signs. The precision of clinical diagnosis could be reliably enhanced by {sup 123}I-FP-CIT SPECT imaging. (orig.)

  10. Common Variation in the NOS1AP Gene Is Associated With Drug-Induced QT Prolongation and Ventricular Arrhythmia

    Jamshidi, Yalda; Nolte, Ilja M.; Dalageorgou, Chrysoula; Zheng, Dongling; Johnson, Toby; Bastiaenen, Rachel; Ruddy, Suzanne; Talbott, Daniel; Norris, Kris J.; Snieder, Harold; George, Alfred L.; Marshall, Vanessa; Shakir, Saad; Kannankeril, Prince J.; Munroe, Patricia B.; Camm, A. John; Jeffery, Steve; Roden, Dan M.; Behr, Elijah R.

    2012-01-01

    Objectives This study sought to determine whether variations in NOS1AP affect drug-induced long QT syndrome (LQTS). Background Use of antiarrhythmic drugs is limited by the high incidence of serious adverse events including QT prolongation and torsades de pointes. NOS1AP gene variants play a role in

  11. 药源性青光眼的防治%Prevention & treatment of drug-induced glaucoma

    马红利; 李世洋

    2015-01-01

    药源性青光眼系局部或全身用药而诱发的继发性开角或闭角青光眼。为提高临床医师对该病的认识,注意药物的不良反应,预防药源性青光眼的发生,本文就临床上可能诱发该病的常见药物、作用机制及防治作了综述。%Drug-induced glaucoma include secondary open-angle glaucoma or angle-closure glaucoma which were induced by patient's administering drugs locally or systematisally. In order to enhance physician's understanding this eye disease,and notice them to pay attention to the adverse-reaction of drugs,so that prevent drug-induced glaucoma occurence,authors review the related issures about common drugs inducing glaucoma,their action mechanism,as well as the prevention & treatment of drug-induced glaucoma in this paper.

  12. [Hair shaft abnormalities].

    Itin, P H; Düggelin, M

    2002-05-01

    Hair shaft disorders may lead to brittleness and uncombable hair. In general the hair feels dry and lusterless. Hair shaft abnormalities may occur as localized or generalized disorders. Genetic predisposition or exogenous factors are able to produce and maintain hair shaft abnormalities. In addition to an extensive history and physical examination the most important diagnostic examination to analyze a hair shaft problem is light microscopy. Therapy of hair shaft disorders should focus to the cause. In addition, minimizing traumatic influences to hair shafts, such as dry hair with an electric dryer, permanent waves and dyes is important. A short hair style is more suitable for such patients with hair shaft disorders.

  13. Drug-induced interstitial lung diseases. Often forgotten; Medikamenteninduzierte interstitielle Lungenerkrankungen. Haeufig vergessen

    Poschenrieder, F.; Stroszczynski, C. [Universitaetsklinikum Regensburg, Institut fuer Roentgendiagnostik, Regensburg (Germany); Hamer, O.W. [Universitaetsklinikum Regensburg, Institut fuer Roentgendiagnostik, Regensburg (Germany); Lungenfachklinik Donaustauf, Donaustauf (Germany)

    2014-12-15

    Drug-induced interstitial lung diseases (DILD) are probably more common than diagnosed. Due to their potential reversibility, increased vigilance towards DILD is appropriate also from the radiologist's point of view, particularly as these diseases regularly exhibit radiological correlates in high-resolution computed tomography (HRCT) of the lungs. Based on personal experience typical relatively common manifestations of DILD are diffuse alveolar damage (DAD), eosinophilic pneumonia (EP), hypersensitivity pneumonitis (HP), organizing pneumonia (OP), non-specific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP). These patterns are presented based on case studies, whereby emphasis is placed on the clinical context. This is to highlight the relevance of interdisciplinary communication and discussion in the diagnostic field of DILD as it is a diagnosis of exclusion or of probability in most cases. Helpful differential diagnostic indications for the presence of DILD, such as an accompanying eosinophilia or increased attenuation of pulmonary consolidations in amiodarone-induced pneumopathy are mentioned and the freely available online database http://www.pneumotox.com is presented. (orig.) [German] Medikamenteninduzierte interstitielle Lungenerkrankungen (engl. ''drug-induced interstitial lung diseases'', DILD) sind wahrscheinlich haeufiger, als sie diagnostiziert werden. Aufgrund ihrer potenziellen Reversibilitaet ist eine erhoehte Vigilanz gegenueber DILD auch seitens der Radiologie angebracht, da diese regelmaessig ein radiomorphologisches Korrelat in der hochaufloesenden Computertomographie (''high-resolution CT'', HRCT) der Lunge aufweisen. Typische, nach eigener Erfahrung relativ haeufige Manifestationsformen von DILD sind der diffuse Alveolarschaden (engl. ''diffuse alveolar damage'', DAD), die eosinophile Pneumonie (EP), die Hypersensitivitaetspneumonitis (HP), die organisierende

  14. MicroRNA changes in rat mesentery and serum associated with drug-induced vascular injury

    Thomas, Roberta A., E-mail: Roberta.A.Thomas@gsk.com; Scicchitano, Marshall S.; Mirabile, Rosanna C.; Chau, Nancy T.; Frazier, Kendall S.; Thomas, Heath C.

    2012-08-01

    Regulatory miRNAs play a role in vascular biology and are involved in biochemical and molecular pathways dysregulated during vascular injury. Collection and integration of functional miRNA data into these pathways can provide insight into pathogenesis at the site of injury; the same technologies applied to biofluids may provide diagnostic or surrogate biomarkers. miRNA was analyzed from mesentery and serum from rats given vasculotoxic compounds for 4 days. Fenoldopam, dopamine and midodrine each alter hemodynamics and are associated with histologic evidence of vascular injury, while yohimbine is vasoactive but does not cause histologic evidence of vascular injury in rat. There were 38 and 35 miRNAs altered in a statistically significant manner with a fold change of 2 or greater in mesenteries of fenoldopam- and dopamine-dosed rats, respectively, with 9 of these miRNAs shared. 10 miRNAs were altered in rats given midodrine; 6 were shared with either fenoldopam or dopamine. In situ hybridization demonstrated strong expression and co-localization of miR-134 in affected but not in adjacent unaffected vessels. Mesenteric miRNA expression may provide clarity or avenues of research into mechanisms involved in vascular injury once the functional role of specific miRNAs becomes better characterized. 102 miRNAs were altered in serum from rats with drug-induced vascular injury. 10 miRNAs were commonly altered in serum from dopamine and either fenoldopam or midodrine dosed rats; 18 of these 102 were also altered in mesenteries from rats with drug-induced vascular injury, suggesting their possible utility as peripheral biomarkers. -- Highlights: ► Mesentery and serum were examined from rats given vasoactive compounds for 4 days. ► 72 miRNAs were altered in mesenteries from rats with vascular injury. ► miR-134 was localized to affected but not adjacent unaffected vessels. ► 102 miRNAs were changed in serum from rats with vascular injury. ► 18 miRNAs changed in both

  15. Abnormalities of gonadal differentiation.

    Berkovitz, G D; Seeherunvong, T

    1998-04-01

    Gonadal differentiation involves a complex interplay of developmental pathways. The sex determining region Y (SRY) gene plays a key role in testis determination, but its interaction with other genes is less well understood. Abnormalities of gonadal differentiation result in a range of clinical problems. 46,XY complete gonadal dysgenesis is defined by an absence of testis determination. Subjects have female external genitalia and come to clinical attention because of delayed puberty. Individuals with 46,XY partial gonadal dysgenesis usually present in the newborn period for the valuation of ambiguous genitalia. Gonadal histology always shows an abnormality of seminiferous tubule formation. A diagnosis of 46,XY true hermaphroditism is made if the gonads contain well-formed testicular and ovarian elements. Despite the pivotal role of the SRY gene in testis development, mutations of SRY are unusual in subjects with a 46,XY karyotype and abnormal gonadal development. 46,XX maleness is defined by testis determination in an individual with a 46,XX karyotype. Most affected individuals have a phenotype similar to that of Klinefelter syndrome. In contrast, subjects with 46,XX true hermaphroditism usually present with ambiguous genitalia. The majority of subjects with 46,XX maleness have Y sequences including SRY in genomic DNA. However, only rare subjects with 46,XX true hermaphroditism have translocated sequences encoding SRY. Mosaicism and chimaerism involving the Y chromosome can also be associated with abnormal gonadal development. However, the vast majority of subjects with 45,X/46,XY mosaicism have normal testes and normal male external genitalia.

  16. Cortical Abnormalities in ADHD

    J Gordon Millichap

    2003-12-01

    Full Text Available Grey-matter abnormalities at the cortical surface and regional brain size were mapped by high-resolution MRI and surface-based, computational image analytical techniques in a group of 27 children and adolescents with attention deficit hyperactivity disorder (ADHD and 46 controls, matched by age and sex, at the University of California at Los Angeles.

  17. Neurological abnormalities predict disability

    Poggesi, Anna; Gouw, Alida; van der Flier, Wiesje

    2014-01-01

    To investigate the role of neurological abnormalities and magnetic resonance imaging (MRI) lesions in predicting global functional decline in a cohort of initially independent-living elderly subjects. The Leukoaraiosis And DISability (LADIS) Study, involving 11 European centres, was primarily aimed...

  18. Lacrimal system abnormalities.

    Moore, B D

    1994-03-01

    This report outlines several of the more important abnormalities of the lacrimal system in infants and young children. Although rare, alacrima can be a very difficult clinical problem to treat. The most common cause of alacrima is the Riley-Day syndrome. Nasolacrimal duct obstruction is a very common anomaly in children. The clinical appearance and treatment of this disorder are discussed.

  19. Periodic Lateralized Epileptiform Discharges can Survive Anesthesia and Result in Asymmetric Drug-induced Burst Suppression

    Mader, Edward C.; Cannizzaro, Louis A.; Williams, Frank J.; Lalan, Saurabh; Olejniczak, Piotr W.

    2017-01-01

    Drug-induced burst suppression (DIBS) is bihemispheric and bisymmetric in adults and older children. However, asymmetric DIBS may occur if a pathological process is affecting one hemisphere only or both hemispheres disproportionately. The usual suspect is a destructive lesion; an irritative or epileptogenic lesion is usually not invoked to explain DIBS asymmetry. We report the case of a 66-year-old woman with new-onset seizures who was found to have a hemorrhagic cavernoma and periodic lateralized epileptiform discharges (PLEDs) in the right temporal region. After levetiracetam and before anesthetic antiepileptic drugs (AEDs) were administered, the electroencephalogram (EEG) showed continuous PLEDs over the right hemisphere with maximum voltage in the posterior temporal region. Focal electrographic seizures also occurred occasionally in the same location. Propofol resulted in bihemispheric, but not in bisymmetric, DIBS. Remnants or fragments of PLEDs that survived anesthesia increased the amplitude and complexity of the bursts in the right hemisphere leading to asymmetric DIBS. Phenytoin, lacosamide, ketamine, midazolam, and topiramate were administered at various times in the course of EEG monitoring, resulting in suppression of seizures but not of PLEDs. Ketamine and midazolam reduced the rate, amplitude, and complexity of PLEDs but only after producing substantial attenuation of all burst components. When all anesthetics were discontinued, the EEG reverted to the original preanesthesia pattern with continuous non-fragmented PLEDs. The fact that PLEDs can survive anesthesia and affect DIBS symmetry is a testament to the robustness of the neurodynamic processes underlying PLEDs. PMID:28286626

  20. Psychobiology of drug-induced religious experience: from the brain "locus of religion" to cognitive unbinding.

    Nencini, Paolo; Grant, Kathleen A

    2010-11-01

    The recent interest in the psychopharmacological underpinnings of religious experiences has led to both the laboratory characterizations of drug-induced mystical events and psychobiological models of religious experiences rooted in evolution and fitness. Our examination of this literature suggests that these theories may be congruent only within more modern religious and cultural settings and are not generalizable to all historical beliefs, as would be expected from an evolutionarily conserved biological mechanism. The strong influence of culture on the subjective effects of drugs as well as religious thoughts argues against the concept of a common pathway in the brain uniquely responsible for these experiences. Rather, the role of personal beliefs, expectations and experiences may interject bias into the interpretation of psychoactive drug action as a reflection of biologically based religious thought. Thus, psychobiological research proposing specific brain mechanisms should consider anthropological and historical data to address alternative explanations to the "fitness" of religious thought. A psychobiological model of the religious experience based on the concept of cognitive unbinding seems to accommodate these data better than that of a specific brain locus of religion.

  1. Generation of Pig Induced Pluripotent Stem Cells with a Drug-Inducible System

    Zhao Wu; Jijun Chen; Jiangtao Ren; Lei Bao; Jing Liao; Chun Cui; Linjun Rao; Hui Li; Yijun Gu; Huiming Dai; Hui Zhu; Xiaokun Teng; Lu Cheng; Lei Xiao

    2009-01-01

    Domesticated ungulate pluripotent embryonic stem (ES) cell lines would be useful for generating precise gene-modified animals. To date, many efforts have been made to establish domesticated ungulate pluripotent ES cells from early embryos without success.Here, we report the generation of porcine-induced pluripotent stem (iPS) cells using drug-inducible expression of defined factors.We showed that porcine iPS cells expressed alkaline phosphatase, SSEA3, SSEA4, Tra-1-60, Tra-1-81, Oct3/4, Nanog, Sox2, Rex1 and CDH1. Pig iPS cells expressed high levels of telomerase activity and showed normal karyotypes. These cells could differentiate into cell types of all three germ layers in vitro and in teratomas. Our study reveals properties of porcine pluripotent stem cells that may facilitate the eventual establishment of porcine ES cells. Moreover, the porcine iPS cells produced may be directly useful for the generation of precise gene-modified pigs.

  2. Correlation of pretreatment drug induced apoptosis in ovarian cancer cells with patient survival and clinical response

    Salom Emery

    2012-08-01

    Full Text Available Abstract Background This study was performed to determine if a chemotherapy-induced apoptosis assay (MiCK could predict the best therapy for patients with ovarian cancer. Methods A prospective, multi-institutional and blinded trial of the assay was conducted in 104 evaluable ovarian cancer patients treated with chemotherapy. The MiCK assay was performed prior to therapy, but treating physicians were not told of the results and selected treatment only on clinical criteria. Outcomes (response, time to relapse, and survival were compared to the drug-induced apoptosis observed in the assay. Results Overall survival in primary therapy, chemotherapy naïve patients with Stage III or IV disease was longer if patients received a chemotherapy which was best in the MiCK assay, compared to shorter survival in patients who received a chemotherapy that was not the best. (p  Conclusion The MiCK assay can predict the chemotherapy associated with better outcomes in ovarian cancer patients. This study quantifies outcome benefits on which a prospective randomized trial can be developed.

  3. Drug-induced sleep endoscopy changes snoring management plan very significantly compared to standard clinical evaluation.

    Pilaete, Karen; De Medts, Joris; Delsupehe, Kathelijne Godelieve

    2014-05-01

    Drug-induced sleep endoscopy (DISE) is a new tool in the work-up of patients with sleep-disordered breathing (SDB). We assessed the impact of DISE on the treatment plan of snoring patients. This is a single institution prospective longitudinal clinical trial. The setting is a private teaching hospital. A consecutive series of 100 snoring patients prospectively underwent a standardised questionnaire, clinical examination, rhinomanometry, allergy skin prick testing, DISE and polysomnography. Management plan before and after DISE evaluation was compared. In 61 patients (excluding 16 patients sent for continuous positive airway pressure, three patients refused sleep endoscopy and 20 were lost to follow-up), we compared the treatment plans. DISE showed single level airway collapse in 13 and multilevel collapse in 48 patients. The site of flutter did not add additional information as compared to the pattern and the location of the collapse. After DISE, the initial management plan changed in 41% of patients irrespective of the type of initial management plan. The only somewhat accurate initial treatment plan was uvulopalatopharyngoplasty (unchanged in 11/13 patients). Excluding moderate to severe obstructive sleep apnea patients DISE is an indispensable tool in treatment decision in all SDB patients. We suggest to simplify the protocol for DISE reporting.

  4. The role of drug-induced sleep endoscopy in surgical planning for obstructive sleep apnea syndrome.

    Aktas, Ozturk; Erdur, Omer; Cirik, Ahmet Adnan; Kayhan, Fatma Tulin

    2015-08-01

    This study investigated the role of drug-induced sleep endoscopy (DISE) in the surgical treatment planning of patients with obstructive sleep apnea syndrome (OSAS). This study was conducted using patients diagnosed with OSAS between January 2007 and March 2009, who were scheduled for surgical treatment. DISE was performed using propofol in patients considered to have upper respiratory tract obstruction as indicated by Muller's maneuver. After completing the sleep endoscopy, the patient was intubated and surgery was performed (tonsillectomy and uvulopalatopharyngoplasty). A successful operation was defined as a decrease in the respiratory disturbance index to below 5 or a decrease of ≥50 % following the operation. The study included 20 patients (4 female and 16 male) aged 19-57 years. No statistically significant correlation between modified Mallampati class and operation success or between the polysomnographic stage of disease and operation success was identified. A significantly high operation success rate was found in the group with obstruction of the upper airway according to DISE (p DISE (p DISE may be used to identify the localization of obstruction for diagnostic purposes, and it can be helpful in selecting the treatment method.

  5. Drug-induced sleep endoscopy in the obstructive sleep apnea: comparison between NOHL and VOTE classifications.

    da Cunha Viana, Alonço; Mendes, Daniella Leitão; de Andrade Lemes, Lucas Neves; Thuler, Luiz Claudio Santos; Neves, Denise Duprat; de Araújo-Melo, Maria Helena

    2017-02-01

    Obstructive sleep apnea (OSA) is characterized by recurrent episodes of partial or complete collapse of the pharynx that result in a decrease in oxyhemoglobin saturation. Nasofibrolaryngoscopy under induced sleep is a promising alternative for identifying sites of upper airway obstruction in patients with OSA. This study aimed to compare the obstruction sites screened by drug-induced sleep endoscopy (DISE) using the Nose oropharynx hypopharynx and larynx (NOHL) and Velum oropharynx tongue base epiglottis (VOTE) classifications. We also determined the relationship between OSA severity and the number of obstruction sites and compared the minimum SaO2 levels between DISE and polysomnography (PSG). This was a prospective study in 45 patients with moderate and severe OSA using DISE with target-controlled infusion of propofol bispectral index (BIS) monitoring. The retropalatal region was the most frequent obstruction site, followed by the retrolingual region. Forty-two percent of patients had obstruction in the epiglottis. Concentrically shaped obstructions were more prevalent in both ratings. The relationship between OSA severity and number of obstruction sites was significant for the VOTE classification. Similar minimum SaO2 values were observed in DISE and PSG. The VOTE classification was more comprehensive in the analysis of the epiglottis and pharynx by DISE and the relationship between OSA severity and number of affected sites was also established by VOTE. The use of BIS associated with DISE is a reliable tool for the assessment of OSA patients.

  6. Drug-Induced Sleep Endoscopy Changes the Treatment Concept in Patients with Obstructive Sleep Apnoea.

    Hybášková, Jaroslava; Jor, Ondřej; Novák, Vilém; Zeleník, Karol; Matoušek, Petr; Komínek, Pavel

    2016-01-01

    The present study evaluated whether drug-induced sleep endoscopy (DISE) helps identify the site of obstruction in patients with obstructive sleep apnoea (OSA). A total of 51 consecutive patients with polysomnography-confirmed OSA were enrolled in this prospective study. The presumed site of obstruction was determined according to history, otorhinolaryngologic examination, and polysomnography and a therapeutic plan designed before DISE. In 11 patients with severe OSA and/or previously failed continuous positive airway pressure (CPAP) treatment, DISE with simultaneous CPAP was performed. Multilevel collapse was noted in 49 patients (96.1%). The most frequent multilevel collapse was palatal, oropharyngeal, and tongue base collapse (n = 17, 33.3%), followed by palatal and oropharyngeal collapse (n = 12, 23.5%). Pathology of the larynx (epiglottis) was observed in 16 patients (31.4%). The laryngeal obstruction as a reason for intolerance of CPAP was observed in 3/11 (27.3%) patients. After DISE, the surgical plan was changed in 31 patients (60.8%). The results indicate that DISE helps identify the site of obstruction in the upper airways in patients with OSA more accurately and that the larynx plays an important role in OSA.

  7. Ice water submersion for rapid cooling in severe drug-induced hyperthermia

    Laskowski, Larissa K.; Landry, Adaira; Vassallo, Susi U.; Hoffman, Robert S.

    2015-01-01

    Context The optimal method of cooling hyperthermic patients is controversial. Although controlled data support ice water submersion, many authorities recommend a mist and fan technique. We report two patients with drug-induced hyperthermia, to demonstrate the rapid cooing rates of ice water submersion. Case details Case 1. A 27-year-old man presented with a sympathomimetic toxic syndrome and a core temperature of 41.4°C after ingesting 4-fluoroamphetamine. He was submerged in ice water and his core temperature fell to 38°C within 18 minutes (a mean cooling rate of 0.18°C/min). His vital signs stabilized, his mental status improved and he left on hospital day 2. Case 2. A 32-year-old man with a sympathomimetic toxic syndrome after cocaine use was transported in a body bag and arrived with a core temperature of 44.4°C. He was intubated, sedated with IV benzodiazepines, and submerged in ice water. After 20 minutes his temperature fell to 38.8°C (a cooling rate of 0.28°C/min). He was extubated the following day, and discharged on day 10. Discussion In these two cases, cooling rates exceeded those reported for mist and fan technique. Since the priority in hyperthermia is rapid cooling, clinical data need to be collected to reaffirm the optimal approach. PMID:25695144

  8. Drug-Induced Sleep Endoscopy Changes the Treatment Concept in Patients with Obstructive Sleep Apnoea

    Jaroslava Hybášková

    2016-01-01

    Full Text Available The present study evaluated whether drug-induced sleep endoscopy (DISE helps identify the site of obstruction in patients with obstructive sleep apnoea (OSA. A total of 51 consecutive patients with polysomnography-confirmed OSA were enrolled in this prospective study. The presumed site of obstruction was determined according to history, otorhinolaryngologic examination, and polysomnography and a therapeutic plan designed before DISE. In 11 patients with severe OSA and/or previously failed continuous positive airway pressure (CPAP treatment, DISE with simultaneous CPAP was performed. Multilevel collapse was noted in 49 patients (96.1%. The most frequent multilevel collapse was palatal, oropharyngeal, and tongue base collapse (n=17, 33.3%, followed by palatal and oropharyngeal collapse (n=12, 23.5%. Pathology of the larynx (epiglottis was observed in 16 patients (31.4%. The laryngeal obstruction as a reason for intolerance of CPAP was observed in 3/11 (27.3% patients. After DISE, the surgical plan was changed in 31 patients (60.8%. The results indicate that DISE helps identify the site of obstruction in the upper airways in patients with OSA more accurately and that the larynx plays an important role in OSA.

  9. Drug-induced interstitial nephritis in a child with idiopathic nephrotic syndrome

    Printza Nikoleta

    2009-01-01

    Full Text Available Acute renal failure (ARF is a rare but severe complication of active idiopathic nephrotic syndrome (INS in children. It may be due to several causes with different outcomes. Both the clinical picture of the patient as well as laboratory, imaging and histopathological findings may help in the diagnosis. We present a case of drug-induced acute interstitial nephritis (AIN, complicated with ARF, in a 2½ -year-old girl with active INS. The child was referred to the Hippokration General Hospital, Thessaloniki, Greece hospital with steroid-resistant NS; renal biopsy was performed, which did not show any remarkable findings and cyclosporine was admi-nistered in addition to steroid therapy. The first day after biopsy, the child developed gross hematuria and abdominal pain and an antibiotic was added to her treatment. In the following days, fever, vomiting, hypertension and ARF occurred. Ultrasound study revealed enlarged kidneys with increased echogenity and loss of corticomedullary differentiation. The antibiotic and cyclos-porine were stopped and the child was managed with furosemide, nifedipine and steroids. A second renal biopsy was performed, which confirmed the diagnosis of acute interstitial nephritis. The child did not require dialysis therapy. Her urine output improved gradually and the serum creatinine normalized one month after the initial episode. Our case re-emphasizes the need for investigation of factors precipitating ARF in children with idiopathic NS.

  10. Predicting drug-induced liver injury in human with Naïve Bayes classifier approach

    Zhang, Hui; Ding, Lan; Zou, Yi; Hu, Shui-Qing; Huang, Hai-Guo; Kong, Wei-Bao; Zhang, Ji

    2016-10-01

    Drug-induced liver injury (DILI) is one of the major safety concerns in drug development. Although various toxicological studies assessing DILI risk have been developed, these methods were not sufficient in predicting DILI in humans. Thus, developing new tools and approaches to better predict DILI risk in humans has become an important and urgent task. In this study, we aimed to develop a computational model for assessment of the DILI risk with using a larger scale human dataset and Naïve Bayes classifier. The established Naïve Bayes prediction model was evaluated by 5-fold cross validation and an external test set. For the training set, the overall prediction accuracy of the 5-fold cross validation was 94.0 %. The sensitivity, specificity, positive predictive value and negative predictive value were 97.1, 89.2, 93.5 and 95.1 %, respectively. The test set with the concordance of 72.6 %, sensitivity of 72.5 %, specificity of 72.7 %, positive predictive value of 80.4 %, negative predictive value of 63.2 %. Furthermore, some important molecular descriptors related to DILI risk and some toxic/non-toxic fragments were identified. Thus, we hope the prediction model established here would be employed for the assessment of human DILI risk, and the obtained molecular descriptors and substructures should be taken into consideration in the design of new candidate compounds to help medicinal chemists rationally select the chemicals with the best prospects to be effective and safe.

  11. Drug-induced diseases (DIDs: An experience of a tertiary care teaching hospital from India

    Vishal R Tandon

    2015-01-01

    Full Text Available Background & objectives: Drug-induced diseases (DIDs are well known but least studied. Data on DIDs from India are not available. Hence, this retrospective cross-sectional study was undertaken using suspected adverse drug reaction (ADR data collected form Pharmacovigilance Programme of India (PvPI to evaluate profile of DIDs over two years, in a tertiary care teaching hospital from north India. Methods: The suspected ADRs in the form of DID were evaluated for drug and disease related variables and were classified in terms of causality. Results: DID rate was 38.80 per cent. Mean duration of developing DIDs was 26.05 ± 9.6 days; 25.16 per cent had more than one co-morbid condition. Geriatric population (53.99% accounted for maximum DIDs followed by adult (37.79% and paediatric (8.21%. Maximum events were probable (93.98% followed by possible (6.04%. All DIDs required intervention. Gastritis (7.43%, diarrhoea (5.92%, anaemia (4.79%, hypotension (2.77%, hepatic dysfunction (2.69%, hypertension (1.51%, myalgia (1.05%, and renal dysfunction (1.01% were some of the DIDs. Anti-tubercular treatment (ATT, anti- retroviral treatment (ART, ceftriaxone injection, steroids, non-steroidal anti-inflammatory drugs, antimicrobials and anticancer drugs were found as commonly offending drugs. Interpretation & conclusions: Our findings show that DIDs are a significant health problem in our country, which need more attention.

  12. Rare Occurrence of Drug Induced Subacute Cutaneous Lupus Erythematosus with Leflunomide Therapy.

    Singh, Harpreet; Sukhija, Gagandeep; Tanwar, Vikram; Arora, Sameer; Bhutani, Jaikrit

    2016-10-01

    Leflunomide is an immunomodulatory drug exhibiting anti-inflammatory, anti-proliferative and immunosuppressive effects. It has been widely used for treatment of active rheumatoid arthritis. Despite its good safety profile cutaneous side effects like alopecia, eczema, pruritis and dry skin have been reported with Leflunomide use. Skin ucleration, vasculitis, lichenoid drug rash and Subacute Cutaneous Lupus Erythematosus (SCLE) have been rarely reported with its use. A rare case of Leflunomide induced SCLE is being reported in a female patient with rheumatoid arthritis. The clinical features, histopathological and immunological characteristics were consistent with drug induced SCLE. Withdrawal of Leflunomide along with short course of topical steroids resulted in resolution of symptoms suggesting the drug to be the culprit. As this drug comes into widespread use, it remains to be seen whether more cases of DI-SCLE will occur/be reported. Fortunately, such a condition till times appears rare and is reversible once the drug is discontinued thus avoiding over evaluation and over treatment if the triggering drug is recognized.

  13. Hyperacute drug-induced hepatitis with intravenous amiodarone: case report and review of the literature

    Nasser M

    2013-09-01

    Full Text Available Mohammad Nasser, Timothy R Larsen, Barryton Waanbah, Ibrahim Sidiqi, Peter A McCullough Providence Hospitals and Medical Centers, Department of Medicine, Division of Cardiology, Southfield and Novi, MI, USA Abstract: Amiodarone is a benzofuran class III antiarrhythmic drug used to treat a wide spectrum of ventricular tachyarrhythmias. The parenteral formulation is prepared in polysorbate 80 diluent. We report an unusual case of acute elevation of aminotransaminase concentrations after the initiation of intravenous amiodarone. An 88-year-old Caucasian female developed acute hepatitis and renal failure after initiating intravenous amiodarone for atrial fibrillation with a rapid ventricular response in the setting of acutely decompensated heart failure and hepatic congestion. Liver transaminases returned to baseline within 7 days after discontinuing the drug. Researchers hypothesized that this type of injury is related to liver ischemia with possible superimposed direct drug toxicity. The CIOMS/RUCAM scale identifies our patient’s acute hepatitis as a highly probable adverse drug reaction. Future research is needed to understand the mechanisms by which hyperacute drug toxicity occurs in the setting of impaired hepatic perfusion and venous congestion. Keywords: intravenous amiodarone, acute hepatotoxicity, liver transaminases, drug-induced liver toxicity

  14. Simple and sensitive method for monitoring drug-induced cell injury in cultured cells

    Shirhatti, V.; Krishna, G.

    1985-06-01

    A simple, sensitive method has been developed for evaluating cell injury noninvasively in monolayer cells in culture. The cell ATP pool was radiolabeled by incubating the cells with (/sup 14/C)adenine. The uptake and incorporation of (/sup 14/C)adenine was shown to proportional to the number of cells. As determined by HPLC, about 65-70% of the incorporated /sup 14/C label was in the ATP pool, 15-20% was in the ADP pool, and the rest was in the 5'-AMP pool. When prelabeled cells were exposed to toxic drugs (acetaminophen, calcium ionophore A-23187, or daunomycin) there was a marked decrease in cell ATP with a concomitant increase in leakage of labeled nucleotides, mainly 5'-AMP and 5'IMP. The authors have shown that leakage of /sup 14/C label into the medium from the prelabeled cells may be employed for quantitation of cell injury. This new measure of toxicity was shown to correlate very well with LDH leakage from the cells, which is a well accepted measure of cell injury. The leakage of 5'-(/sup 14/C)AMP also correlated very well with the reduction of cell ATP in cardiac myocytes. This method has been used for monitoring drug-induced toxicity in liver cells, cardiac myocytes, and LB cells.

  15. Drug-Induced Sleep Endoscopy Changes the Treatment Concept in Patients with Obstructive Sleep Apnoea

    Jor, Ondřej; Novák, Vilém; Matoušek, Petr

    2016-01-01

    The present study evaluated whether drug-induced sleep endoscopy (DISE) helps identify the site of obstruction in patients with obstructive sleep apnoea (OSA). A total of 51 consecutive patients with polysomnography-confirmed OSA were enrolled in this prospective study. The presumed site of obstruction was determined according to history, otorhinolaryngologic examination, and polysomnography and a therapeutic plan designed before DISE. In 11 patients with severe OSA and/or previously failed continuous positive airway pressure (CPAP) treatment, DISE with simultaneous CPAP was performed. Multilevel collapse was noted in 49 patients (96.1%). The most frequent multilevel collapse was palatal, oropharyngeal, and tongue base collapse (n = 17, 33.3%), followed by palatal and oropharyngeal collapse (n = 12, 23.5%). Pathology of the larynx (epiglottis) was observed in 16 patients (31.4%). The laryngeal obstruction as a reason for intolerance of CPAP was observed in 3/11 (27.3%) patients. After DISE, the surgical plan was changed in 31 patients (60.8%). The results indicate that DISE helps identify the site of obstruction in the upper airways in patients with OSA more accurately and that the larynx plays an important role in OSA. PMID:28070516

  16. Acute liver failure caused by drug-induced hypersensitivity syndrome associated with hyperferritinemia

    Masayuki Miyazaki; Masatake Tanaka; Akihiro Ueda; Tsuyoshi Yoshimoto; Masaki Kato; Makoto Nakamuta; Kazuhiro Kotoh; Ryoichi Takayanagi

    2011-01-01

    Drug-induced hypersensitivity syndrome (DIHS) is a se-vere reaction usually characterized by fever, rash, and multiorgan failure, occurring 2-6 wk after drug introduction.It is an immune-mediated reaction involving macrophage and T-lymphocyte activation and cytokine release. A 54-year-old woman was diagnosed with rheumatic arthritis and initiated salazosulfapyridine by mouth. About 10 d later, she had a high fever, skin rash and liver dysfunction. She was admitted to hospital and diagnosed with a drug eruption. She was treated with oral prednisolone 30 mg/d; however, she developed high fever again and her blood tests showed acute liver failure and cytopenia associated with hyperferritinemia. She was diagnosed with acute liver failure and hemophagocytosis caused by DIHS. She was transferred to the Department of Medicine and Bioregulatory Science, Kyushu University, where she was treated with arterial steroid injection therapy. Following this treatment, her liver function improved and serum ferritin immediately decreased. We hypothesized that an immune-mediated reaction in DIHS may have generated over-activation of macrophages and T-lymphocytes, followed by a cytokine storm that affected various organs. The measurement of serum ferritin might be a useful marker of the severity of DIHS.

  17. Advances in Engineered Liver Models for Investigating Drug-Induced Liver Injury

    Lin, Christine

    2016-01-01

    Drug-induced liver injury (DILI) is a major cause of drug attrition. Testing drugs on human liver models is essential to mitigate the risk of clinical DILI since animal studies do not always suffice due to species-specific differences in liver pathways. While primary human hepatocytes (PHHs) can be cultured on extracellular matrix proteins, a rapid decline in functions leads to low sensitivity (<50%) in DILI prediction. Semiconductor-driven engineering tools now allow precise control over the hepatocyte microenvironment to enhance and stabilize phenotypic functions. The latest platforms coculture PHHs with stromal cells to achieve hepatic stability and enable crosstalk between the various liver cell types towards capturing complex cellular mechanisms in DILI. The recent introduction of induced pluripotent stem cell-derived human hepatocyte-like cells can potentially allow a better understanding of interindividual differences in idiosyncratic DILI. Liver models are also being coupled to other tissue models via microfluidic perfusion to study the intertissue crosstalk upon drug exposure as in a live organism. Here, we review the major advances being made in the engineering of liver models and readouts as they pertain to DILI investigations. We anticipate that engineered human liver models will reduce drug attrition, animal usage, and cases of DILI in humans. PMID:27725933

  18. The role of eNOS phosphorylation in causing drug-induced vascular injury.

    Tobin, Grainne A McMahon; Zhang, Jun; Goodwin, David; Stewart, Sharron; Xu, Lin; Knapton, Alan; González, Carlos; Bancos, Simona; Zhang, Leshuai; Lawton, Michael P; Enerson, Bradley E; Weaver, James L

    2014-06-01

    Previously we found that regulation of eNOS is an important part of the pathogenic process of Drug-induced vascular injury (DIVI) for PDE4i. The aims of the current study were to examine the phosphorylation of eNOS in mesentery versus aorta at known regulatory sites across DIVI-inducing drug classes and to compare changes across species. We found that phosphorylation at S615 in rats was elevated 35-fold 2 hr after the last dose of CI-1044 in mesentery versus 3-fold in aorta. Immunoprecipitation studies revealed that many of the upstream regulators of eNOS activation were associated with eNOS in 1 or more signalosome complexes. Next rats were treated with drugs from 4 other classes known to cause DIVI. Each drug was given alone and in combination with SIN-1 (NO donor) or L-NAME (eNOS inhibitor), and the level of eNOS phosphorylation in mesentery and aorta tissue was correlated with the extent of vascular injury and measured serum nitrite. Drugs or combinations produced altered serum nitrite levels as well as vascular injury score in the mesentery. The results suggested that phosphorylation of S615 may be associated with DIVI activity. Studies with the species-specific A2A adenosine agonist CI-947 in rats versus primates showed a similar pattern.

  19. Drug induced liver injury: do we still need a routine liver biopsy for diagnosis today?

    Teschke, Rolf; Frenzel, Christian

    For the pathologist, the diagnosis of drug induced liver injury (DILI) is challenging, because histopathological features mimic all primary hepatic and biliary diseases, lacking changes that are specific for DILI. Therefore, in any patient of suspected DILI who underwent liver biopsy, the pathologist will assure the clinician that the observed hepatic changes are compatible with DILI, but this information is less helpful due to lack of specificity. Rather, the pathologist should assess liver biopsies blindly, without knowledge of prior treatment by drugs. This will result in a detailed description of the histological findings, associated with suggestions for potential causes of these hepatic changes. Then, it is up to the physician to reassess carefully the differential diagnoses, if not done before. At present, liver histology is of little impact establishing the diagnosis of DILI with the required degree of certainty, and this shortcoming also applies to herb induced liver injury (HILI). To reach at the correct diagnoses of DILI and HILI, clinical and structured causality assessments are therefore better approaches than liver histology results obtained through liver biopsy, an invasive procedure with a low complication rate.

  20. Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives.

    Fontana, Robert J

    2014-04-01

    Idiosyncratic drug-induced liver injury (DILI) is a rare disease that develops independently of drug dose, route, or duration of administration. Furthermore, idiosyncratic DILI is not a single disease entity but rather a spectrum of rare diseases with varying clinical, histological, and laboratory features. The pathogenesis of DILI is not fully understood. Standardization of the DILI nomenclature and methods to assess causality, along with the information provided by the LiverTox Web site, will harmonize and accelerate research on DILI. Studies of new serum biomarkers such as glutamate dehydrogenase, high mobility group box protein 1, and microRNA-122 could provide information for use in diagnosis and prognosis and provide important insights into the mechanisms of the pathogenesis of DILI. Single nucleotide polymorphisms in the HLA region have been associated with idiosyncratic hepatotoxicity attributed to flucloxacillin, ximelagatran, lapatinib, and amoxicillin-clavulanate. However, genome-wide association studies of pooled cases have not associated any genetic factors with idiosyncratic DILI. Whole genome and whole exome sequencing analyses are under way to study cases of DILI attributed to a single medication. Serum proteomic, transcriptome, and metabolome as well as intestinal microbiome analyses will increase our understanding of the mechanisms of this disorder. Further improvements to in vitro and in vivo test systems should advance our understanding of the causes, risk factors, and mechanisms of idiosyncratic DILI.

  1. Antinuclear antibody-negative, drug-induced lupus caused by lisinopril.

    Carter, J D; Valeriano-Marcet, J; Kanik, K S; Vasey, F B

    2001-11-01

    The clinical symptoms of drug-induced lupus (DIL) are similar to those of idiopathic systemic lupus erythematosus. The literature indicates that in patients with DIL, sera generally contain antinuclear antibodies (ANAs); however, ANA-negative DIL has been reported. The list of medications implicated as etiologic agents in DIL continues to grow. This list includes two different types of angiotensin-converting enzyme inhibitors--captopril and enalapril. We report the first case of DIL caused by lisinopril. Our patient had negative results on ANA testing and had histone antibodies (IgG anti-[H2A-H2B]-DNA) mirroring the disease course. Antibodies to the (H2A-H2B)-DNA complex are seen in more than 90% of patients with active DIL, excluding those with DIL due to hydralazine. Thus, it is important to recognize the clinical significance of IgG anti-(H2A-H2B)-DNA antibodies and that negative ANA test results do not preclude the diagnosis of DIL.

  2. Drug-Induced Nephrotoxicity and Dose Adjustment Recommendations: Agreement Among Four Drug Information Sources.

    Bicalho, Millena Drumond; Soares, Danielly Botelho; Botoni, Fernando Antonio; Reis, Adriano Max Moreira; Martins, Maria Auxiliadora Parreiras

    2015-09-09

    : Hospitalized patients require the use of a variety of drugs, many of which individually or in combination have the potential to cause kidney damage. The use of potentially nephrotoxic drugs is often unavoidable, and the need for dose adjustment should be evaluated. This study is aimed at assessing concordance in information on drug-induced nephrotoxicity and dose adjustment recommendations by comparing four drug information sources (DRUGDEX(®), UpToDate(®), Medscape(®) and the Brazilian Therapeutic Formulary) using the formulary of a Brazilian public hospital. A total of 218 drugs were investigated. The global Fleiss' kappa coefficient was 0.265 for nephrotoxicity (p < 0.001; CI 95%, 0.211-0.319) and 0.346 for recommendations (p < 0.001; CI 95%, 0.292-0.401), indicating fair concordance among the sources. Anti-infectives and anti-hypertensives were the main drugs cited as nephrotoxic by the different sources. There were no clear definitions for qualitative data or quantitative values for dose adjustments among the four information sources. There was no advice for dosing for a large number of the drugs in the international databases. The National Therapeutic Formulary offered imprecise dose adjustment recommendations for many nephrotoxic drugs. Discrepancies among information sources may have a clinical impact on patient care and contribute to drug-related morbidity and mortality.

  3. Drug-Induced Nephrotoxicity and Dose Adjustment Recommendations: Agreement Among Four Drug Information Sources

    Millena Drumond Bicalho

    2015-09-01

    Full Text Available : Hospitalized patients require the use of a variety of drugs, many of which individually or in combination have the potential to cause kidney damage. The use of potentially nephrotoxic drugs is often unavoidable, and the need for dose adjustment should be evaluated. This study is aimed at assessing concordance in information on drug-induced nephrotoxicity and dose adjustment recommendations by comparing four drug information sources (DRUGDEX®, UpToDate®, Medscape® and the Brazilian Therapeutic Formulary using the formulary of a Brazilian public hospital. A total of 218 drugs were investigated. The global Fleiss’ kappa coefficient was 0.265 for nephrotoxicity (p < 0.001; CI 95%, 0.211–0.319 and 0.346 for recommendations (p < 0.001; CI 95%, 0.292–0.401, indicating fair concordance among the sources. Anti-infectives and anti-hypertensives were the main drugs cited as nephrotoxic by the different sources. There were no clear definitions for qualitative data or quantitative values for dose adjustments among the four information sources. There was no advice for dosing for a large number of the drugs in the international databases. The National Therapeutic Formulary offered imprecise dose adjustment recommendations for many nephrotoxic drugs. Discrepancies among information sources may have a clinical impact on patient care and contribute to drug-related morbidity and mortality.

  4. Drug induced interstitial lung disease in oncology phase I trials.

    Yonemori, Kan; Hirakawa, Akihiro; Kawachi, Asuka; Kinoshita, Fumie; Okuma, Hitomi; Nishikawa, Tadaaki; Tamura, Kenji; Fujiwara, Yasuhiro; Takebe, Naoko

    2016-12-01

    Interstitial lung disease is a serious drug-related condition that can cause life threatening organ failure. The incidence and risk factors of drug-induced interstitial lung disease (DILD) are unknown in oncology phase I trials. This study analyzed clinical information from 8906 patients with malignancies who were enrolled in 470 phase I trials sponsored by the Cancer Therapy Evaluation Program, National Cancer Institute, from 1988 to 2014. Logistic and Cox statistical analyses were utilized to determine clinical differences between patients who developed DILD and patients who did not. In this study, the overall incidence rate of patients with pulmonary toxicity was 2.7%. The overall incidence rate for DILD was 0.77%, whereas for grade 3 or 4 DILD it was 0.31%. Median time to occurrence of DILD was 1.4 months. The Cox hazard analysis indicated smaller body surface area and a combination of thoracic radiation with investigational drug regimens were significant risk factors for time to occurrence of interstitial lung disease. Investigators should carefully monitor for DILD in oncology patients enrolled in phase I trials with identified risk factors. A 6-month observation period would be sufficient to detect the onset of most DILD in such patients.

  5. Metabolomics approaches for discovering biomarkers of drug-induced hepatotoxicity and nephrotoxicity.

    Beger, Richard D; Sun, Jinchun; Schnackenberg, Laura K

    2010-03-01

    Hepatotoxicity and nephrotoxicity are two major reasons that drugs are withdrawn post-market, and hence it is of major concern to both the FDA and pharmaceutical companies. The number of cases of serious adverse effects (SAEs) in marketed drugs has climbed faster than the number of total drug prescriptions issued. In some cases, preclinical animal studies fail to identify the potential toxicity of a new chemical entity (NCE) under development. The current clinical chemistry biomarkers of liver and kidney injury are inadequate in terms of sensitivity and/or specificity, prompting the need to discover new translational specific biomarkers of organ injury. Metabolomics along with genomics and proteomics technologies have the capability of providing translational diagnostic and prognostic biomarkers specific for early stages of liver and kidney injury. Metabolomics has several advantages over the other omics platforms such as ease of sample preparation, data acquisition and use of biofluids collected through minimally invasive procedures in preclinical and clinical studies. The metabolomics platform is reviewed with particular emphasis on applications involving drug-induced hepatotoxicity and nephrotoxicity. Analytical platforms for metabolomics, chemometrics for mining metabolomics data and the applications of the metabolomics technologies are covered in detail with emphasis on recent work in the field.

  6. Rare Occurrence of Drug Induced Subacute Cutaneous Lupus Erythematosus with Leflunomide Therapy

    Singh, Harpreet; Tanwar, Vikram; Arora, Sameer; Bhutani, Jaikrit

    2016-01-01

    Leflunomide is an immunomodulatory drug exhibiting anti-inflammatory, anti-proliferative and immunosuppressive effects. It has been widely used for treatment of active rheumatoid arthritis. Despite its good safety profile cutaneous side effects like alopecia, eczema, pruritis and dry skin have been reported with Leflunomide use. Skin ucleration, vasculitis, lichenoid drug rash and Subacute Cutaneous Lupus Erythematosus (SCLE) have been rarely reported with its use. A rare case of Leflunomide induced SCLE is being reported in a female patient with rheumatoid arthritis. The clinical features, histopathological and immunological characteristics were consistent with drug induced SCLE. Withdrawal of Leflunomide along with short course of topical steroids resulted in resolution of symptoms suggesting the drug to be the culprit. As this drug comes into widespread use, it remains to be seen whether more cases of DI-SCLE will occur/be reported. Fortunately, such a condition till times appears rare and is reversible once the drug is discontinued thus avoiding over evaluation and over treatment if the triggering drug is recognized. PMID:27891379

  7. Dynamic Drug-Induced Sleep Computed Tomography in Adults With Obstructive Sleep Apnea

    Li, Hsueh-Yu; Lo, Yu-Lun; Wang, Chao-Jan; Hsin, Li-Jen; Lin, Wan-Ni; Fang, Tuan-Jen; Lee, Li-Ang

    2016-01-01

    Surgical success for obstructive sleep apnea (OSA) depends on identifying sites of obstruction in the upper airway. In this study, we investigated sites of obstruction by evaluating dynamic changes in the upper airway using drug-induced sleep computed tomography (DI-SCT) in patients with OSA. Thirty-five adult patients with OSA were prospectively enrolled. Sleep was induced with propofol under light sedation (bispectral index 70–75), and low-dose 320-detector row CT was performed for 10 seconds over a span of 2–3 respiratory cycles with supporting a continuous positive airway pressure model. Most (89%) of the patients had multi-level obstructions. Total obstruction most commonly occurred in the velum (86%), followed by the tongue (57%), oropharyngeal lateral wall (49%), and epiglottis (26%). There were two types of anterior-posterior obstruction of the soft palate, uvular (94%) and velar (6%), and three types of tongue obstruction, upper (30%), lower (37%), and upper plus lower obstruction (33%). DI-SCT is a fast and safe tool to identify simulated sleep airway obstruction in patients with OSA. It provides data on dynamic airway movement in the sagittal view which can be used to differentiate palate and tongue obstructions, and this can be helpful when planning surgery for patients with OSA. PMID:27762308

  8. Generation of a Drug-inducible Reporter System to Study Cell Reprogramming in Human Cells*

    Ruiz, Sergio; Panopoulos, Athanasia D.; Montserrat, Nuria; Multon, Marie-Christine; Daury, Aurélie; Rocher, Corinne; Spanakis, Emmanuel; Batchelder, Erika M.; Orsini, Cécile; Deleuze, Jean-François; Izpisua Belmonte, Juan Carlos

    2012-01-01

    Reprogramming of somatic cells into induced pluripotent stem cells is achieved by the expression of defined transcription factors. In the last few years, reprogramming strategies on the basis of doxycycline-inducible lentiviruses in mouse cells became highly powerful for screening purposes when the expression of a GFP gene, driven by the reactivation of endogenous stem cell specific promoters, was used as a reprogramming reporter signal. However, similar reporter systems in human cells have not been generated. Here, we describe the derivation of drug-inducible human fibroblast-like cell lines that express different subsets of reprogramming factors containing a GFP gene under the expression of the endogenous OCT4 promoter. These cell lines can be used to screen functional substitutes for reprogramming factors or modifiers of reprogramming efficiency. As a proof of principle of this system, we performed a screening of a library of pluripotent-enriched microRNAs and identified hsa-miR-519a as a novel inducer of reprogramming efficiency. PMID:23019325

  9. Liver injury from Herbals and Dietary Supplements in the US Drug Induced Liver Injury Network

    Navarro, Victor J.; Barnhart, Huiman; Bonkovsky, Herbert L.; Davern, Timothy; Fontana, Robert J.; Grant, Lafaine; Reddy, K. Rajender; Seeff, Leonard B.; Serrano, Jose; Sherker, Averell H.; Stolz, Andrew; Talwalkar, Jayant; Vega, Maricruz; Vuppalanchi, Raj

    2014-01-01

    Background The Drug-Induced Liver Injury Network (DILIN) studies hepatotoxicity due to conventional medications as well as herbals and dietary supplements (HDS). Rationale To characterize hepatotoxicity and its outcomes from HDS versus medications, patients with hepatotoxicity attributed to medications or HDS were enrolled prospectively between 2004 and 2013. The study took place among eight US referral centers that are part of the DILIN. Consecutive patients with liver injury referred to a DILIN center were eligible. The final sample comprised 130 (15.5%) of all subjects enrolled (839) who were judged to have experienced liver injury due to HDS. Hepatotoxicity due to HDS was evaluated by expert opinion. Demographic and clinical characteristics and outcome assessments including death and liver transplantation were ascertained. Cases were stratified and compared according to the type of agent implicated in liver injury; 45 had injury due to bodybuilding HDS, 85 due to non-bodybuilding HDS, and 709 due to medications. Main Results Liver injury due to HDS increased from 7% to 20% (p Bodybuilding HDS caused prolonged jaundice (median 91 days) in young men but did not result in any fatalities or liver transplantation. The remaining HDS cases presented as hepatocellular injury, predominantly in middle-aged women and more frequently led to death or transplantation compared to injury from medications (13% vs. 3%, p bodybuilding HDS is more severe than from bodybuilding HDS or medications, as evidenced by differences in unfavorable outcomes; death and transplantation. PMID:25043597

  10. Quantitative analysis of T-wave morphology increases confidence in drug-induced cardiac repolarization abnormalities: evidence from the investigational IKr inhibitor Lu 35-138

    Graff, Claus; Matz, Jørgen; Christensen, Ellen B;

    2009-01-01

    to determine a combined measure of repolarization morphology (morphology combination score [MCS]), based on asymmetry, flatness, and notching. Replicate measurements were used to determine reliable change and study power for both measures. Lu 35-138 increased the QTc interval with corresponding changes in T...... was 93%. As a covariate to the assessment of QT interval liability, MCS offered important additive information to the effect of Lu 35-138 on cardiac repolarization....

  11. Nitrofurantoin and congenital abnormalities

    Czeizel, A.E.; Rockenbauer, M.; Sørensen, Henrik Toft;

    2001-01-01

    Objective: To study human teratogenic potential of oral nitrofurantoin treatment during pregnancy. Materials and Methods: Pair analysis of cases with congenital abnormalities and matched population controls in the population-based dataset of the Hungarian Case-Control Surveillance of Congenital...... or fetuses with Down’s syndrome (patient controls), 23 (2.8%) pregnant women were treated with nitrofurantoin. The above differences between population controls and cases may be connected with recall bias, because the case-control pair analysis did not indicate a teratogenic potential of nitrofurantoin use...... during the second and the third months of gestation, i.e. in the critical period for major congenital abnormalities. Conclusion: Treatment with nitrofurantoin during pregnancy does not present detectable teratogenic risk to the fetus....

  12. Drug-induced sleep endoscopy: conventional versus target controlled infusion techniques--a randomized controlled study.

    De Vito, Andrea; Agnoletti, Vanni; Berrettini, Stefano; Piraccini, Emanuele; Criscuolo, Armando; Corso, Ruggero; Campanini, Aldo; Gambale, Giorgio; Vicini, Claudio

    2011-03-01

    Understanding the sites of pharyngeal collapse is mandatory for surgical treatment decision-making in obstructive sleep-apnea-hypopnea syndrome patients. Drug-induced sleep endoscopy (DISE) allows for the direct observation of the upper airway during sedative-induced sleep. In order to re-create snoring and apnea patterns related to a spontaneous sleep situation, the authors used a target-controlled infusion (TCI) sleep endoscopy (DISE-TCI), comparing this technique to conventional DISE, in which sedation was reached by a manual bolus injection. The authors conducted a prospective, randomized, unicenter study. The apneic event observation and its correlation with pharyngeal collapse patterns is the primary endpoint; secondary endpoints are defined as stability and safety of sedation plans of DISE-TCI technique. From January 2009 to June 2009, 40 OSAHS patients were included in the study and randomized allocated in two groups: the bolus injection conventional DISE group and the DISE-TCI group. We recorded the complete apnea event at the oropharynx and hypopharynx levels in 4 patients of the conventional DISE group (20%) and in 17 patients of the DISE-TCI group (85%) (P DISE group because of severe desaturation that resulted from the first bolus of propofol (1 mg/kg) (P = 0.4872 ns). We recorded the instability of the sedation plan in 13 patients from the conventional DISE group (65%) and 1 patient from the DISE-TCI group (5%) (P = 0.0001). Our results suggest that the DISE-TCI technique should be the first choice in performing sleep endoscopy because of its increased accuracy, stability and safety.

  13. Drug induced sleep endoscopy in the decision-making process of children with obstructive sleep apnea.

    Galluzzi, Francesca; Pignataro, Lorenzo; Gaini, Renato Maria; Garavello, Werner

    2015-03-01

    Tonsillectomy and adenoidectomy (T&A) is currently recommended in children with Obstructive Sleep Apnea (OSA). However, the condition persists after surgery in about one third of cases. It has been suggested that Drug Induced Sleep Endoscopy (DISE) may be of help for planning a more targeted and effective surgical treatment but evidence is yet weak. The aim of this review is to draw recommendation on the use of DISE in children with OSA. More specifically, we aimed at determine the proportion of cases whose treatment may be influenced by DISE findings. A comprehensive search of articles published from February 1983 to January 2014 listed in the PubMed/MEDLINE databases was performed. The search terms used were: "endoscopy" or "nasoendoscopy" or "DISE" and "obstructive sleep apnea" and "children" or "child" or "pediatric." The main outcome was the rate of naive children with hypertrophic tonsils and/or adenoids. The assumptions are that clinical diagnosis of hypertrophic tonsils and/or adenoids is reliable and does not require DISE, and that exclusive T&A may solve OSA in the vast majority of cases even in the presence of other concomitant sites of obstruction. Five studies were ultimately selected and all were case series. The median (range) number of studied children was 39 (15-82). Mean age varied from 3.2 to 7.8 years. The combined estimate rate of OSA consequent to hypertrophic tonsils and/or adenoids was 71% (95%CI: 64-77%). In children with Down Syndrome, the combined estimated rate of hypertrophic tonsils and/or adenoids was 62% (95%CI: 44-79%). Our findings show that DISE may be of benefit in a minority of children with OSA since up to two thirds of naive cases presents with hypertrophic tonsils and/or adenoids. Its use should be limited to those whose clinical evaluation is unremarkable or when OSA persists after T&A.

  14. Identification and management of in-hospital drug-induced delirium in older patients.

    Catic, Angela G

    2011-09-01

    Delirium, an acute confusional state with changes in attention and cognition, is a common cause of morbidity and mortality among hospitalized elders. Medications are responsible for up to 39% of delirium cases in the elderly. The incidence of drug-induced delirium is particularly high in this population due to the altered pharmacokinetics and pharmacodynamics of aging, high prevalence of polypharmacy and occurrence of co-morbid disease. Although certain medications are more often associated with the development of delirium, including opioids, benzodiazepines, anticholinergics and antidepressants, any medication can cause delirium in the elderly. Evaluation of delirium should include a thorough medication history, which should determine if any new medications have been initiated, if medications have been discontinued, and the details of any recent dosage adjustments. It is important to understand the utility of medications in preventing and treating delirium in the elderly. Acetylcholinesterase inhibitors have not been found to reduce the incidence of delirium or length of hospitalization. Study results regarding the utility of antipsychotic medications in preventing delirium have been mixed. Haloperidol prophylaxis did not reduce the occurrence of delirium, but it did reduce the severity and duration. Olanzapine and risperidone were associated with a reduced incidence of delirium compared with placebo. Pharmacological therapy to treat delirium should be implemented only if patients pose a safety risk to themselves or others. Typical and atypical antipsychotics are effective in treating the symptoms of delirium, but it is important to note that they are not approved by the US FDA for this indication. Short-acting benzodiazepines are second-line therapy and are typically reserved for patients with sedative/alcohol withdrawal, Parkinson's disease or neuroleptic malignant syndrome. Study results regarding the utility of acetylcholinesterase inhibitors have been mixed.

  15. Assessing the risk of drug-induced cholestasis using unbound intrahepatic concentrations.

    Riede, Julia; Poller, Birk; Huwyler, Jorg; Camenisch, Gian

    2017-03-02

    Inhibition of the bile salt export pump (BSEP) has been recognized as a key factor in the development of drug-induced cholestasis (DIC). The risk of DIC in human has previously been assessed using in vitro BSEP inhibition data (IC50) and unbound systemic drug exposure under assumption of the "free drug hypothesis". This concept, however, is unlikely valid as unbound intrahepatic drug concentrations are affected by active transport and metabolism. To investigate this hypothesis we experimentally determined the in vitro liver-to-blood partition coefficients (Kp,uu) for 18 drug compounds using the hepatic Extended Clearance Model (ECM). In vitro-in vivo translatability of Kp,uu values was verified for a subset of compounds in rat. Consequently, unbound intrahepatic concentrations were calculated from clinical exposure (systemic and hepatic inlet) and measured Kp,uu data. Using these values, corresponding safety margins against BSEP IC50 values were determined and compared to the clinical incidence of DIC. Depending on the ECM class of a drug, in vitro Kp,uu values deviated up to 14-fold from unity and unbound intrahepatic concentrations were affected accordingly. The use of in vitro Kp,uu-based safety margins allowed to separate clinical cholestasis frequency into three classes (no cholestasis, cholestasis in ≤ 2%, and in > 2% of subjects) for 17 out of 18 compounds. This assessment was significantly superior compared to using unbound extracellular concentrations as a surrogate for intrahepatic concentrations. Furthermore, the assessment of Kpuu according to ECM provides useful guidance for the quantitative evaluation of genetic and physiological risk factors for the development of cholestasis.

  16. Is periodontal health a predictor of drug-induced gingival overgrowth? A cross-sectional study

    Ruchi Banthia

    2014-01-01

    Full Text Available Background: Gingival overgrowth is a common side-effect of amlodipine regimen on the oral cavity. There is controversy regarding the cause and effect relationship of periodontal health and drug induced gingival overgrowth. Therefore, this study was conducted to investigate and to assess the relationship between the periodontal health and the onset and severity of gingival overgrowth in hypertensive patients receiving amlodipine. Materials and Methods: A total of 99 known hypertensive patients on amlodipine regimen were included in this study. Probing pocket depth (PPD and clinical attachment loss (CAL were noted on four sites of maxillary and mandibular anterior teeth. Gingival enlargement scores were assessed for each patient by employing the hyperplastic index. Oral hygiene status was evaluated using the calculus index (CI. Patients were divided into H, E and L groups based on their periodontal status and responders and non-responders based on their hyperplastic index scores. Differences in means of different periodontal variables in different groups were tested for significance by using ANOVA and unpaired Student t-test. Pearson′s correlation coefficient was calculated to assess the correlation between different variables. For all analyses, P < 0.05 was considered to be significant. Results: All the periodontal parameters were statistically highly significant (P = 0.00 amongst H, E and L groups and between responders and non-responders. Statistically highly significant Pearson correlation coefficients were found between mean PPD and mean hyperplastic score, mean CAL and mean hyperplastic score and mean calculus and mean hyperplastic score. Conclusion: The results of this study indicated a definite association between periodontal health and development and severity of amlodipine-induced gingival overgrowth

  17. Is periodontal health a predictor of drug-induced gingival overgrowth? A cross-sectional study

    Banthia, Ruchi; Gupta, Santosh; Banthia, Priyank; Singh, Pallavi; Raje, Sapna; Kaur, Navkiran

    2014-01-01

    Background: Gingival overgrowth is a common side-effect of amlodipine regimen on the oral cavity. There is controversy regarding the cause and effect relationship of periodontal health and drug induced gingival overgrowth. Therefore, this study was conducted to investigate and to assess the relationship between the periodontal health and the onset and severity of gingival overgrowth in hypertensive patients receiving amlodipine. Materials and Methods: A total of 99 known hypertensive patients on amlodipine regimen were included in this study. Probing pocket depth (PPD) and clinical attachment loss (CAL) were noted on four sites of maxillary and mandibular anterior teeth. Gingival enlargement scores were assessed for each patient by employing the hyperplastic index. Oral hygiene status was evaluated using the calculus index (CI). Patients were divided into H, E and L groups based on their periodontal status and responders and non-responders based on their hyperplastic index scores. Differences in means of different periodontal variables in different groups were tested for significance by using ANOVA and unpaired Student t-test. Pearson's correlation coefficient was calculated to assess the correlation between different variables. For all analyses, P < 0.05 was considered to be significant. Results: All the periodontal parameters were statistically highly significant (P = 0.00) amongst H, E and L groups and between responders and non-responders. Statistically highly significant Pearson correlation coefficients were found between mean PPD and mean hyperplastic score, mean CAL and mean hyperplastic score and mean calculus and mean hyperplastic score. Conclusion: The results of this study indicated a definite association between periodontal health and development and severity of amlodipine-induced gingival overgrowth PMID:25426150

  18. [Case reports of drug-induced liver injury in a reference hospital of Zulia state, Venezuela].

    Mengual-Moreno, Edgardo; Lizarzábal-García, Maribel; Ruiz-Soler, María; Silva-Suarez, Niniveth; Andrade-Bellido, Raúl; Lucena-González, Maribel; Bessone, Fernando; Hernández, Nelia; Sánchez, Adriana; Medina-Cáliz, Inmaculada

    2015-03-01

    Drug-induced liver injury (DILI) is an important cause of morbidity and mortality worldwide, with varied geographical differences. The aim of this prospective, descriptive, cross-sectional study was to identify and characterize cases of DILI in a hospital of Zulia state, Venezuela. Thirteen patients with a presumptive diagnosis of DILI attended by the Department of Gastroenterology, Hospital Universitario, Zulia state, Venezuela, from December-2012 to December-2013 were studied. Ibuprofen (n = 3; 23.1%), acetaminophen (n = 3; 23.1), isoniazid (n = 2; 15.4%) and Herbalife products (n = 2; 15.4%) were the main drugs involved with DILI. Acetaminophen and ibuprofen showed a mixed pattern of liver injury (n = 3; 23.1%) and isoniazid presented a hepatocellular pattern (n = 2; 15.4%). The CIOMS/RUCAMS allowed the identification of possible (n = 7; 53.9%), probable (n = 4; 30.8%) and highly-probable cases (n = 2; 15.4%) of DILI. Amoxicillin/clavulanate, isoniazid, isotretinoin, methotrexate and Herbalife nutritional products were implicated as highly-probable and probable agents. The highest percentage of DILI corresponded to mild cases that recovered after the discontinuation of the agent involved (n = 9; 69.3%). The consumption of Herbalife botanical products is associated with probable causality and fatality (n = 1; 7.7%). In conclusion, the frequency of DILI cases controlled by the Department of Gastroenterology of the Hospital Universitario of Maracaibo was low, being ibuprofen, acetaminophen, isoniazid and products Herbalife the products most commonly involved. It is recommended to continue with the prospective registration of cases, with an extended follow up monitoring period and to facilitate the incorporation of other hospitals in the Zulia State and Venezuela.

  19. Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block

    Vicente, Jose; Johannesen, Lars; Hosseini, Meisam; Mason, Jay W.; Sager, Philip T.; Pueyo, Esther; Strauss, David G.

    2016-01-01

    Background Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Thus, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the “CiPA” initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans. Methods and Results In this study we assess the ability of eight ECG morphology biomarkers to detect late sodium current block in the presence of QTc prolongation by analyzing a clinical trial where a selective hERG potassium channel blocker (dofetilide) was administered alone and then in combination with two late sodium current blockers (lidocaine and mexiletine). We demonstrate that late sodium current block has the greatest effect on the heart-rate corrected J-Tpeak interval (J-Tpeakc), followed by QTc and then T-wave flatness. Furthermore, J-Tpeakc is the only biomarker that improves detection of the presence of late sodium current block compared to using QTc alone (AUC: 0.83 vs. 0.72 respectively, p<0.001). Conclusions Analysis of the J-Tpeakc interval can differentiate drug-induced multichannel block involving the late sodium current from selective hERG potassium channel block. Future methodologies assessing drug effects on cardiac ion channel currents on the ECG should use J-Tpeakc to detect the presence of late sodium current block. Trial Registration NCT02308748 and NCT01873950 PMID:28036334

  20. The utility of a rodent model in detecting pediatric drug-induced nephrotoxicity.

    Espandiari, Parvaneh; Zhang, Jun; Rosenzweig, Barry A; Vaidya, Vishal S; Sun, Jinchun; Schnackenberg, Laura; Herman, Eugene H; Knapton, Alan; Bonventre, Joseph V; Beger, Richard D; Thompson, Karol L; Hanig, Joseph

    2007-10-01

    A multi-age rat model was used to identify potential age-related differences in renal injury following exposure to gentamicin (GM). In this study, 10-, 25-, 40-, and 80-day-old Sprague-Dawley rats were dosed with GM at 0, 50, or 100 mg kg(-1) body weight per day (mkd) sc for 6 or 14 days. Urine samples were collected up to 72 h after initial dosing. The maximum tolerated dose was lower in 10-day-old rats than for other ages (none survived 11 days of treatment). Eighty-day-old rats given the highest dose showed a diminished rate of growth and an increase in serum creatinine, blood urea nitrogen (BUN), urinary kidney injury molecule-1 (Kim-1), and renal pathology. Ten- and 40-day-old rats given 100 mkd of GM for 6- or 14 days also had increased levels of serum BUN and Cr and renal pathology, whereas only mild renal alterations were found in 25-day-old rats. After 6 days of treatment with 100 mkd GM, significant increases in Havcr-1 (Kim-1) gene expression were detected only in 10- and 80-day-old rats. In urine samples, nuclear magnetic resonance and ultra performance liquid chromatography/mass spectrometry analysis detected changes related to GM efficacy (e.g., hippurate) and increases in metabolites related to antioxidant activity, which was greatest in the 80-day-old rats. The magnitude of the genomic, metabonomic, and serum chemistry changes appeared to correlate with the degree of nephropathy. These findings indicate that an experimental animal model that includes several developmental stages can detect age-related differences in drug-induced organ toxicities and may be a useful predictor of pediatric drug safety in preclinical studies.

  1. Drug induced mortality: a multiple cause approach on Italian causes of death Register

    Francesco Grippo

    2015-04-01

    Full Text Available Background: Drug-related mortality is a complex phenomenon that has several health, social and economic effects. In this paper trends of drug-induced mortality in Italy are analysed. Two approaches have been followed: the traditional analysis of the underlying cause of death (UC (data refers to the Istat mortality database from 1980 to 2011, and the multiple cause (MCanalysis, that is the analysis of all conditions reported on the death certificate (data for 2003-2011 period.Methods: Data presented in this paper are based on the Italian mortality register. The selection of Icd codes used for the analysis follows the definition of the European Monitoring Centre for Drugs and Drug Addiction. Using different indicators (crude and standardized rates, ratio multiple to underlying, the results obtained from the two approaches (UC and MC have been compared. Moreover, as a measure of association between drug-related causes and specific conditions on the death certificate, an estimation of the age-standardized relative risk (RR has been used.Results: In the years 2009-2011, the total number of certificates whit mention of drug use was 1,293, 60% higher than the number UC based. The groups of conditions more strongly associated with drug-related causes are the mental and behavioral disorders (especially alcohol consumption, viral hepatitis, cirrhosis and fibrosis of liver, AIDS and endocarditis.Conclusions : The analysis based on multiple cause approach shows, for the first time, a more detailed picture of the drug related death; it allows to better describe the mortality profiles and to re-evaluate  the contribution of a specific cause to death.

  2. Drug-induced immune thrombocytopenia: incidence, clinical features, laboratory testing, and pathogenic mechanisms.

    Curtis, Brian R

    2014-01-01

    Drug-induced immune thrombocytopenia (DIIT) is a relatively uncommon adverse reaction caused by drug-dependent antibodies (DDAbs) that react with platelet membrane glycoproteins only when the implicated drug is present. Although more than 100 drugs have been associated with causing DIIT, recent reviews of available data show that carbamazepine, eptifibatide, ibuprofen, quinidine, quinine, oxaliplatin, rifampin, sulfamethoxazole, trimethoprim, and vancomycin are probably the most frequently implicated. Patients with DIIT typically present with petechiae, bruising, and epistaxis caused by an acute, severe drop in platelet count (often to transfusion refractoriness, and must be differentiated by temporal association of exposure to a candidate drug with an acute, severe drop in platelet count. Treatment consists of immediate withdrawal of the implicated drug. Criteria for strong evidence of DIIT include (1) exposure to candidate drug-preceded thrombocytopenia; (2) sustained normal platelet levels after discontinuing candidate drug; (3) candidate drug was only drug used before onset of thrombocytopenia or other drugs were continued or reintroduced after resolution of thrombocytopenia, and other causes for thrombocytopenia were excluded; and (4) reexposure to the candidate drug resulted in recurrent thrombocytopenia. Flow cytometry testing for DDAbs can be useful in confirmation of a clinical diagnosis, and monoclonal antibody enzyme-linked immunosorbent assay testing can be used to determine the platelet glycoprotein target(s), usually GPIIb/IIIa or GPIb/IX/V, but testing is not widely available. Several pathogenic mechanisms for DIIT have been proposed, including hapten, autoantibody, neoepitope, drug-specific, and quinine-type drug mechanisms. A recent proposal suggests weakly reactive platelet autoantibodies that develop greatly increased affinity for platelet glycoprotein epitopes through bridging interactions facilitated by the drug is a possible mechanism for the

  3. Assessment of time interval between tramadol intake and seizure and second drug-induced attack

    Bahareh Abbasi

    2015-11-01

    Full Text Available Background: Tramadol is a synthetic drug which is prescribed in moderate and severe pain. Tramadol overdose can induce severe complications such as consciousness impairment and convulsions. This study was done to determine the convulsions incidence after tramadol use until one week after hospital discharge. Methods: This prospective study was done in tramadol overdose patients without uncontrolled epilepsy and head injury history. All cases admitted in Loghman and Rasol Akram Hospitals, Tehran, Iran from 1, April 2011 to 1, April 2012 were included and observed for at least 12 hours. Time interval between tramadol intake and first seizure were record. Then, patients with second drug-induced seizure were recognized and log time between the first and second seizure was analyzed. The patients were transferred to the intensive care unit (ICU if clinical worsening status observed. One week after hospital discharge, telephone follow-up was conducted. Results: A total of 150 patients with a history of tramadol induced seizures (141 men, 9 women, age: 23.23±5.94 years were enrolled in this study. Convulsion was seen in 104 patients (69.3%. In 8 out of 104 patients (7.6% two or more convulsion was seen. Time interval between tramadol use and the onset of the first and second seizure were 0.93±0.17 and 2.5±0.75 hours, respectively. Tramadol induced seizures are more likely to occur in males and patients with a history of drug abuse. Finally, one hundred forty nine patients (99.3% were discharged with good condition and the only one patient died from tramadol overdose. Conclusion: The results of the study showed tramadol induced seizure most frequently occurred within the first 4 hours of tramadol intake. The chance of experiencing a second seizure exists in the susceptible population. Thus, 4 hours after drug intake is the best time for patients to be hospital discharged.

  4. [Molecular abnormalities in lymphomas].

    Delsol, G

    2010-11-01

    Numerous molecular abnormalities have been described in lymphomas. They are of diagnostic and prognostic value and are taken into account for the WHO classification of these tumors. They also shed some light on the underlying molecular mechanisms involved in lymphomas. Overall, four types of molecular abnormalities are involved: mutations, translocations, amplifications and deletions of tumor suppressor genes. Several techniques are available to detect these molecular anomalies: conventional cytogenetic analysis, multicolor FISH, CGH array or gene expression profiling using DNA microarrays. In some lymphomas, genetic abnormalities are responsible for the expression of an abnormal protein (e.g. tyrosine-kinase, transcription factor) detectable by immunohistochemistry. In the present review, molecular abnormalities observed in the most frequent B, T or NK cell lymphomas are discussed. In the broad spectrum of diffuse large B-cell lymphomas microarray analysis shows mostly two subgroups of tumors, one with gene expression signature corresponding to germinal center B-cell-like (GCB: CD10+, BCL6 [B-Cell Lymphoma 6]+, centerine+, MUM1-) and a subgroup expressing an activated B-cell-like signature (ABC: CD10-, BCL6-, centerine-, MUM1+). Among other B-cell lymphomas with well characterized molecular abnormalies are follicular lymphoma (BCL2 deregulation), MALT lymphoma (Mucosa Associated Lymphoid Tissue) [API2-MALT1 (mucosa-associated-lymphoid-tissue-lymphoma-translocation-gene1) fusion protein or deregulation BCL10, MALT1, FOXP1. MALT1 transcription factors], mantle cell lymphoma (cycline D1 [CCND1] overexpression) and Burkitt lymphoma (c-Myc expression). Except for ALK (anaplastic lymphoma kinase)-positive anaplastic large cell lymphoma, well characterized molecular anomalies are rare in lymphomas developed from T or NK cells. Peripheral T cell lymphomas not otherwise specified are a heterogeneous group of tumors with frequent but not recurrent molecular abnormalities

  5. DRUG INDUCED HYPOGLYCEMIC COMA IN A NONDIABETIC WITH CHRONIC LIVER DISEASE: A CASE REPORT OF DRUG DISPENSING ERROR

    Krishna M

    2014-08-01

    Full Text Available Hypoglycemia is a common, potentially fatal, yet preventable problem. Drug-induced hypoglycemia remains the commonest cause of hypoglycemia. A 63 year old non-diabetic male, a known case of chronic liver disease, on regular medications, presented with unconsciousness, unresponsiveness since two hours. Immediate random blood sugar was 11 mg/dl. On proper history and clinical examination, diagnosis of oral hypoglycemic agent induced hypoglycemic coma was made and immediately intravenous dextrose resuscitation was started. Patient regained consciousness after four hours and became fully oriented after 24 hours. Throughout his hospital course, strict and frequent glucose monitoring was done and dextrose infused accordingly. Patient remained hemodynamically stable throughout the hospital course. He was discharged from the hospital after 72 hours in an otherwise healthy condition. Drug induced hypoglycemia is now so relatively common that virtually every unconscious patient should be considered hypoglycemic until immediate estimation of the blood sugar level rules the condition in or out.

  6. The role of ultrahigh-frequency audiometry in the early detection of systemic drug-induced hearing loss.

    Singh Chauhan, Rajeev; Saxena, Ravinder Kumar; Varshey, Saurabh

    2011-05-01

    In monitoring patients for drug-induced hearing loss, most audiometric evaluations are limited to the range of frequencies from 0.25 to 8 kHz. However, such testing would fail to detect ototoxicity in patients who have already experienced hearing loss in the ultrahigh frequencies from 10 to 20 kHz. Awareness of ultrahigh-frequency ototoxicity could lead to changes in a drug regimen to prevent further damage. We conducted a prospective study of 105 patients who were receiving a potentially ototoxic drug-either gentamicin, amikacin, or cisplatin-to assess the value of ultrahigh-frequency audiometry in detecting systemic drug-induced hearing loss. We found that expanding audiometry into the ultrahigh-frequency range led to the detection of a substantial number of cases of hearing loss that would have otherwise been missed.

  7. Organotypic functional cultures of human liver cells for long-term maintenance and assessment of drug-induced metabolome effects

    MÜLLER Daniel

    2011-01-01

    The goals of this thesis were (i) to establish and improve organotypic liver cell culture techniques for long-term pharmacological studies and (ii) to develop and apply a metabolomics based approach for the assessment of drug-induced effects. As first model, a 3D bioreactor system was characterized in terms of cell physiology and functionality. Primary human hepatocytes could be kept viable and functional for more than 2 weeks in this system. Optimization of the system allowed determination o...

  8. High-content screening of drug-induced cardiotoxicity using quantitative single cell imaging cytometry on microfluidic device.

    Kim, Min Jung; Lee, Su Chul; Pal, Sukdeb; Han, Eunyoung; Song, Joon Myong

    2011-01-07

    Drug-induced cardiotoxicity or cytotoxicity followed by cell death in cardiac muscle is one of the major concerns in drug development. Herein, we report a high-content quantitative multicolor single cell imaging tool for automatic screening of drug-induced cardiotoxicity in an intact cell. A tunable multicolor imaging system coupled with a miniaturized sample platform was destined to elucidate drug-induced cardiotoxicity via simultaneous quantitative monitoring of intracellular sodium ion concentration, potassium ion channel permeability and apoptosis/necrosis in H9c2(2-1) cell line. Cells were treated with cisapride (a human ether-à-go-go-related gene (hERG) channel blocker), digoxin (Na(+)/K(+)-pump blocker), camptothecin (anticancer agent) and a newly synthesized anti-cancer drug candidate (SH-03). Decrease in potassium channel permeability in cisapride-treated cells indicated that it can also inhibit the trafficking of the hERG channel. Digoxin treatment resulted in an increase of intracellular [Na(+)]. However, it did not affect potassium channel permeability. Camptothecin and SH-03 did not show any cytotoxic effect at normal use (≤300 nM and 10 μM, respectively). This result clearly indicates the potential of SH-03 as a new anticancer drug candidate. The developed method was also used to correlate the cell death pathway with alterations in intracellular [Na(+)]. The developed protocol can directly depict and quantitate targeted cellular responses, subsequently enabling an automated, easy to operate tool that is applicable to drug-induced cytotoxicity monitoring with special reference to next generation drug discovery screening. This multicolor imaging based system has great potential as a complementary system to the conventional patch clamp technique and flow cytometric measurement for the screening of drug cardiotoxicity.

  9. Biomarkers for metabolic drug activation : towards an integrated risk assessment for drug-induced liver injury (DILI)

    Teppner, Marieke

    2014-01-01

    The term drug-induced liver injury (DILI) describes adverse effects upon therapeutic drug treatment. They are relatively rare, affecting only 1 of 10000 - 1000000 patients, and remain mostly unpredictable. Due to development of severe hepatotoxicity or death, drugs causing DILI display a high risk for patients and have been withdrawn from the market or severely restricted in use. For the pharmaceutical industry late stage attrition due to DILI represents a big burden stretching development ti...

  10. Feeling Abnormal: Simulation of Deviancy in Abnormal and Exceptionality Courses.

    Fernald, Charles D.

    1980-01-01

    Describes activity in which student in abnormal psychology and psychology of exceptional children classes personally experience being judged abnormal. The experience allows the students to remember relevant research, become sensitized to the feelings of individuals classified as deviant, and use caution in classifying individuals as abnormal.…

  11. Evaluation of the usefulness of novel biomarkers for drug-induced acute kidney injury in beagle dogs.

    Zhou, Xiaobing; Ma, Ben; Lin, Zhi; Qu, Zhe; Huo, Yan; Wang, Jufeng; Li, Bo

    2014-10-01

    As kidney is a major target organ affected by drug toxicity, early detection of renal injury is critical in preclinical drug development. In past decades, a series of novel biomarkers of drug-induced nephrotoxicity were discovered and verified in rats. However, limited data regarding the performance of novel biomarkers in non-rodent species are publicly available. To increase the applicability of these biomarkers, we evaluated the performance of 4 urinary biomarkers including neutrophil gelatinase-associated lipocalin (NGAL), clusterin, total protein, and N-acetyl-β-D-glucosaminidase (NAG), relative to histopathology and traditional clinical chemistry in beagle dogs with acute kidney injury (AKI) induced by gentamicin. The results showed that urinary NGAL and clusterin levels were significantly elevated in dogs on days 1 and 3 after administration of gentamicin, respectively. Gene expression analysis further provided mechanistic evidence to support that NGAL and clusterin are potential biomarkers for the early assessment of drug-induced renal damage. Furthermore, the high area (both AUCs=1.000) under receiver operator characteristics (ROC) curve also indicated that NGAL and clusterin were the most sensitive biomarkers for detection of gentamicin-induced renal proximal tubular toxicity. Our results also suggested that NAG may be used in routine toxicity testing due to its sensitivity and robustness for detection of tissue injury. The present data will provide insights into the preclinical use of these biomarkers for detection of drug-induced AKI in non-rodent species.

  12. Activation of JNK triggers release of Brd4 from mitotic chromosomes and mediates protection from drug-induced mitotic stress.

    Nishiyama, Akira; Dey, Anup; Tamura, Tomohiko; Ko, Minoru; Ozato, Keiko

    2012-01-01

    Some anti-cancer drugs, including those that alter microtubule dynamics target mitotic cells and induce apoptosis in some cell types. However, such drugs elicit protective responses in other cell types allowing cells to escape from drug-induced mitotic inhibition. Cells with a faulty protective mechanism undergo defective mitosis, leading to genome instability. Brd4 is a double bromodomain protein that remains on chromosomes during mitosis. However, Brd4 is released from mitotic chromosomes when cells are exposed to anti-mitotic drugs including nocodazole. Neither the mechanisms, nor the biological significance of drug-induced Brd4 release has been fully understood. We found that deletion of the internal C-terminal region abolished nocodazole induced Brd4 release from mouse P19 cells. Furthermore, cells expressing truncated Brd4, unable to dissociate from chromosomes were blocked from mitotic progression and failed to complete cell division. We also found that pharmacological and peptide inhibitors of the c-jun-N-terminal kinases (JNK) pathway, but not inhibitors of other MAP kinases, prevented release of Brd4 from chromosomes. The JNK inhibitor that blocked Brd4 release also blocked mitotic progression. Further supporting the role of JNK in Brd4 release, JNK2-/- embryonic fibroblasts were defective in Brd4 release and sustained greater inhibition of cell growth after nocodazole treatment. In sum, activation of JNK pathway triggers release of Brd4 from chromosomes upon nocodazole treatment, which mediates a protective response designed to minimize drug-induced mitotic stress.

  13. The Art and Science of Diagnosing and Managing Drug-induced Liver Injury in 2015 and Beyond.

    Lewis, James H

    2015-11-01

    Drug-induced liver injury (DILI) remains a leading reason why new compounds are dropped from further study or are the subject of product warnings and regulatory actions. Hy's Law of drug-induced hepatocellular jaundice causing a case-fatality rate or need for transplant of 10% or higher has been validated in several large national registries, including the ongoing, prospective U.S. Drug-Induced Liver Injury Network. It serves as the basis for stopping rules in clinical trials and in clinical practice. Because DILI can mimic all known causes of acute and chronic liver disease, establishing causality can be difficult. Histopathologic findings are often nonspecific and rarely, if ever, considered pathognomonic. A daily drug dose >50-100 mg is more likely to be hepatotoxic than does management of DILI have recently been published, although specific therapies remain limited. The LiverTox Web site has been introduced as an interactive online virtual textbook that makes the latest information on more than 650 agents available to clinicians, regulators, and drug developers alike.

  14. Prevention and Treatment of Vaginal Bleeding after Drug-induced Abortion by Yaoliuan Capsule and Its Effects on Menses Recovery

    JIN Zhichun; HUANG Guangying

    2005-01-01

    Summary: In order to explore the effect of Yaoliuan capsule in the prevention and treatment of vaginal bleeding after drug-induced abortion and menses recovery after drug-induced abortion, 323 cases of gestation period ≤ 49 days and without contraindication, were divided randomly into study group (168 cases, taking Yaoliuan capsule) and control group (155 cases, taking placebo capsule). The results showed that in the study group, there were 161 cases (95.8 %) of complete abortion, 7 cases (4.2 %) of incomplete abortion; In the control group, there were 146 cases (94.2 %) of complete abortion, 6 cases (3.9 %) of incomplete abortion, 3 cases (1.9 %) of abortion failure. The vaginal bleeding time was 5-25 days (mean 10.8 days) in study group, while that was 6-62 days (mean 19.1 days) in control group. The menstrual cycle was 30.5±5.2 days and 33.8 d±8.6 days respectively in study and control groups. The menstrual period was 6.1±3.5 days and 9.9±5.1 days respectively in study and control groups. Yaoliuan capsule is an effective drug to prevent and treat vaginal bleeding following drug-induced abortion, promote menstruation recovery and prevent pelvic infection.

  15. Russia: An Abnormal Country

    Steven Rosefielde

    2005-06-01

    Full Text Available Andrei Shleifer and Daniel Treisman recently rendered a summary verdict on the post Soviet Russian transition experience finding that the Federation had become a normal country with the west's assistance, and predicting that it would liberalize and develop further like other successful nations of its type. This essay demonstrates that they are mistaken on the first count, and are likely to be wrong on the second too. It shows factually, and on the norms elaborated by Pareto, Arrow and Bergson that Russia is an abnormal political economy unlikely to democratize, westernize or embrace free enterprise any time soon

  16. Abnormal ionization in sonoluminescence

    Zhang, Wen-Juan; An, Yu

    2015-04-01

    Sonoluminescence is a complex phenomenon, the mechanism of which remains unclear. The present study reveals that an abnormal ionization process is likely to be present in the sonoluminescing bubble. To fit the experimental data of previous studies, we assume that the ionization energies of the molecules and atoms in the bubble decrease as the gas density increases and that the decrease of the ionization energy reaches about 60%-70% as the bubble flashes, which is difficult to explain by using previous models. Project supported by the Research Fund for the Doctoral Program of Higher Education of China (Grant No. 20120002110031) and the National Natural Science Foundation of China (Grant No. 11334005).

  17. Stereoselective Blockage of Quinidine and Quinine in the hERG Channel and the Effect of Their Rescue Potency on Drug-Induced hERG Trafficking Defect

    Meng Yan

    2016-09-01

    Full Text Available Diastereoisomers of quinidine and quinine are used to treat arrhythmia and malaria, respectively. It has been reported that both drugs block the hERG (human ether-a-go-go-related gene potassium channel which is essential for myocardium repolarization. Abnormality of repolarization increases risk of arrhythmia. The aim of our research is to study and compare the impacts of quinidine and quinine on hERG. Results show that both drugs block the hERG channel, with quinine 14-fold less potent than quinidine. In addition, they presented distinct impacts on channel dynamics. The results imply their stereospecific block effect on the hERG channel. However, F656C-hERG reversed this stereoselectivity. The mutation decreases affinity of the two drugs with hERG, and quinine was more potent than quinidine in F656C-hERG blockage. These data suggest that F656 residue contributes to the stereoselective pocket for quinidine and quinine. Further study demonstrates that both drugs do not change hERG protein levels. In rescue experiments, we found that they exert no reverse effect on pentamidine- or desipramine-induced hERG trafficking defect, although quinidine has been reported to rescue trafficking-deficient pore mutation hERG G601S based on the interaction with F656. Our research demonstrated stereoselective effects of quinidine and quinine on the hERG channel, and this is the first study to explore their reversal potency on drug-induced hERG deficiency.

  18. Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines: Marked differences between various antipsychotic drugs

    Vik-Mo Audun O

    2006-10-01

    Full Text Available Abstract Background The etiology of schizophrenia is unknown, but neurodevelopmental disturbances, myelin- and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder. Cholesterol is an essential component of myelin and has proved important for synapse formation. Recently, we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element-binding protein (SREBP transcription factors. We here compare the action of chlorpromazine, haloperidol, clozapine, olanzapine, risperidone and ziprasidone on SREBP activation and SREBP-controlled gene expression (ACAT2, HMGCR, HMGCS1, FDPS, SC5DL, DHCR7, LDLR, FASN and SCD1 in four CNS-relevant human cell lines. Results There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes, with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations. Glial-like cells (GaMg glioma and CCF-STTG1 astrocytoma cell lines displayed more pronounced drug-induced SREBP activation compared to the response in HCN2 human cortical neurons and SH-SY5Y neuroblastoma cells, indicating that antipsychotic-induced activation of lipogenesis is most prominent in glial cells. Conclusion Our present data show a marked variation in the ability of different antipsychotics to induce SREBP-controlled transcriptional activation of lipogenesis in cultured human CNS-relevant cells. We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs.

  19. ABC gene-ranking for prediction of drug-induced cholestasis in rats

    Yauheniya Cherkas

    2016-01-01

    Full Text Available As legacy toxicogenomics databases have become available, improved data mining approaches are now key to extracting and visualizing subtle relationships between toxicants and gene expression. In the present study, a novel “aggregating bundles of clusters” (ABC procedure was applied to separate cholestatic from non-cholestatic drugs and model toxicants in the Johnson & Johnson (Janssen rat liver toxicogenomics database [3]. Drug-induced cholestasis is an important issue, particularly when a new compound enters the market with this liability, with standard preclinical models often mispredicting this toxicity. Three well-characterized cholestasis-responsive genes (Cyp7a1, Mrp3 and Bsep were chosen from a previous in-house Janssen gene expression signature; these three genes show differing, non-redundant responses across the 90+ paradigm compounds in our database. Using the ABC procedure, extraneous contributions were minimized in comparisons of compound gene responses. All genes were assigned weights proportional to their correlations with Cyp7a1, Mrp3 and Bsep, and a resampling technique was used to derive a stable measure of compound similarity. The compounds that were known to be associated with rat cholestasis generally had small values of this measure relative to each other but also had large values of this measure relative to non-cholestatic compounds. Visualization of the data with the ABC-derived signature showed a very tight, essentially identically behaving cluster of robust human cholestatic drugs and experimental cholestatic toxicants (ethinyl estradiol, LPS, ANIT and methylene dianiline, disulfiram, naltrexone, methapyrilene, phenacetin, alpha-methyl dopa, flutamide, the NSAIDs–—indomethacin, flurbiprofen, diclofenac, flufenamic acid, sulindac, and nimesulide, butylated hydroxytoluene, piperonyl butoxide, and bromobenzene, some slightly less active compounds (3′-acetamidofluorene, amsacrine, hydralazine, tannic acid, some

  20. α1-Syntrophin Variant Identified in Drug-Induced Long QT Syndrome Increases Late Sodium Current.

    Choi, Jong-Il; Wang, Chaojian; Thomas, Matthew J; Pitt, Geoffrey S

    2016-01-01

    Drug-induced long-QT syndrome (diLQTS) is often due to drug block of IKr, especially in genetically susceptible patients with subclinical mutations in the IKr-encoding KCHN2. Few variants in the cardiac NaV1.5 Na+ channel complex have been associated with diLQTS. We tested whether a novel SNTA1 (α1-syntrophin) variant (p.E409Q) found in a patient with diLQTS increases late sodium current (INa-L), thereby providing a disease mechanism. Electrophysiological studies were performed in HEK293T cells co-expressing human NaV1.5/nNOS/PMCA4b with either wild type (WT) or SNTA1 variants (A390V-previously reported in congenital LQTS; and E409Q); and in adult rat ventricular cardiomyocytes infected with SNTA1 expressing adenoviruses (WT or one of the two SNTA1 variants). In HEK293T cells and in cardiomyocytes, there was no significant difference in the peak INa densities among the SNTA1 WT and variants. However, both variants increased INa-L (% of peak current) in HEK293T cells (0.58 ± 0.10 in WT vs. 0.90 ± 0.11 in A390V, p = 0.048; vs. 0.88 ± 0.07 in E409Q, p = 0.023). In cardiomyocytes, INa-L was significantly increased by E409Q, but not by A390V compared to WT (0.49 ± 0.14 in WT vs.0.94 ± 0.23 in A390V, p = 0.099; vs. 1.12 ± 0.24 in E409Q, p = 0.019). We demonstrated that a novel SNTA1 variant is likely causative for diLQTS by augmenting INa-L. These data suggest that variants within the NaV1.5-interacting α1-syntrophin are a potential mechanism for diLQTS, thereby expanding the concept that variants within congenital LQTS loci can cause diLQTS.

  1. α1-Syntrophin Variant Identified in Drug-Induced Long QT Syndrome Increases Late Sodium Current.

    Jong-Il Choi

    Full Text Available Drug-induced long-QT syndrome (diLQTS is often due to drug block of IKr, especially in genetically susceptible patients with subclinical mutations in the IKr-encoding KCHN2. Few variants in the cardiac NaV1.5 Na+ channel complex have been associated with diLQTS. We tested whether a novel SNTA1 (α1-syntrophin variant (p.E409Q found in a patient with diLQTS increases late sodium current (INa-L, thereby providing a disease mechanism. Electrophysiological studies were performed in HEK293T cells co-expressing human NaV1.5/nNOS/PMCA4b with either wild type (WT or SNTA1 variants (A390V-previously reported in congenital LQTS; and E409Q; and in adult rat ventricular cardiomyocytes infected with SNTA1 expressing adenoviruses (WT or one of the two SNTA1 variants. In HEK293T cells and in cardiomyocytes, there was no significant difference in the peak INa densities among the SNTA1 WT and variants. However, both variants increased INa-L (% of peak current in HEK293T cells (0.58 ± 0.10 in WT vs. 0.90 ± 0.11 in A390V, p = 0.048; vs. 0.88 ± 0.07 in E409Q, p = 0.023. In cardiomyocytes, INa-L was significantly increased by E409Q, but not by A390V compared to WT (0.49 ± 0.14 in WT vs.0.94 ± 0.23 in A390V, p = 0.099; vs. 1.12 ± 0.24 in E409Q, p = 0.019. We demonstrated that a novel SNTA1 variant is likely causative for diLQTS by augmenting INa-L. These data suggest that variants within the NaV1.5-interacting α1-syntrophin are a potential mechanism for diLQTS, thereby expanding the concept that variants within congenital LQTS loci can cause diLQTS.

  2. Evaluation of prognostic markers in severe drug-induced liver disease

    Bo Li; Zhi Wang; Jian-Jiang Fang; Ci-Yi Xu; Wei-Xing Chen

    2007-01-01

    AIM: To analyze the outcome of patients with severe drug-induced liver disease (DILD) associated with jaundice classified as hepatocellular, cholestatic or mixed liver injury and to evaluate the validity of Hy's rule and the most important predictors for outcome.METHODS: The Adverse Drug Reaction Advisory Committee was set up in 1997 in our hospital to identify all suspicions of DILD following a structured prospective report form. Liver damage was divided into hepatocellular, cholestatic, and mixed types according to laboratory and histologic criteria when available. Further evaluation of causality assessment was performed.RESULTS: From January 1997 to December 2004, 265 patients were diagnosed with DILD, and 140 (52.8%) of them were female. Hepatocellular damage was the most common (72.1%), the incidence of death was 9.9% in patients with hepatocellular damage and 9.5% in patients with cholestatic/mixed damage (P < 0.05). There was no difference in age of dead and recovered patients. The proportion of females and males was similar in recovered and dead patients, no difference was observed in duration of treatment between the two groups. The serum total bilirubin (P < 0.001), direct bilirubin (P < 0.001) and aspartate transaminase (AST) (P = 0.013) values were higher in dead patients than in recovered patients. Chinese herbal medicine was the most frequently prescribed, accounting for 24.2% of the whole series. However, antitubercular drugs (3.4%) were found to be the primary etiological factor for fetal DILD. Factors associated with the development of fulminant hepatic failure were hepatic encephalopathy (OR = 43.66, 95% CI = 8.47-224.95, P < 0.0001), ascite (OR = 28.48, 95% CI = 9.26-87.58, P < 0.0001), jaundice (OR = 11.43, 95% CI = 1.52-85.96, P = 0.003), alcohol abuse (OR = 3.83, 95% CI = 1.26-11.67, P = 0.035) and direct bilirubin (OR = 1.93, 95% CI = 1.25-2.58, P = 0.012).CONCLUSION: Death occurs in 9.8% of patients with DILD. Chinese herbal

  3. A Rare Stapes Abnormality

    Hala Kanona

    2015-01-01

    Full Text Available The aim of this study is to increase awareness of rare presentations, diagnostic difficulties alongside management of conductive hearing loss and ossicular abnormalities. We report the case of a 13-year-old female reporting progressive left-sided hearing loss and high resolution computed tomography was initially reported as normal. Exploratory tympanotomy revealed an absent stapedius tendon and lack of connection between the stapes superstructure and footplate. The footplate was fixed. Stapedotomy and stapes prosthesis insertion resulted in closure of the air-bone gap by 50 dB. A review of world literature was performed using MedLine. Middle ear ossicular discontinuity can result in significant conductive hearing loss. This can be managed effectively with surgery to help restore hearing. However, some patients may not be suitable or decline surgical intervention and can be managed safely conservatively.

  4. Nicotine and Nicotinic Receptor Drugs: Potential for Parkinson's Disease and Drug-Induced Movement Disorders.

    Quik, Maryka; Bordia, Tanuja; Zhang, Danhui; Perez, Xiomara A

    2015-01-01

    Parkinson's disease is a progressive neurodegenerative disorder associated with tremor, rigidity, and bradykinesia, as well as nonmotor symptoms including autonomic impairments, olfactory dysfunction, sleep disturbances, depression, and dementia. Although the major neurological deficit is a loss of nigrostriatal dopaminergic neurons, multiple neurotransmitters systems are compromised in Parkinson's disease. Consistent with this observation, dopamine replacement therapy dramatically improves Parkinson's disease motor symptoms. Additionally, drugs targeting the serotonergic, glutamatergic, adenosine, and other neurotransmitter systems may be beneficial. Recent evidence also indicates that nicotinic cholinergic drugs may be useful for the management of Parkinson's disease. This possibility initially arose from the results of epidemiological studies, which showed that smoking was associated with a decreased incidence of Parkinson's disease, an effect mediated in part by the nicotine in smoke. Further evidence for this idea stemmed from preclinical studies which showed that nicotine administration reduced nigrostriatal damage in parkinsonian rodents and monkeys. In addition to a potential neuroprotective role, emerging work indicates that nicotinic receptor drugs improve the abnormal involuntary movements or dyskinesias that arise as a side effect of l-dopa treatment, the gold standard therapy for Parkinson's disease. Both nicotine and nicotinic receptor drugs reduced l-dopa-induced dyskinesias by over 50% in parkinsonian rodent and monkey models. Notably, nicotine also attenuated the abnormal involuntary movements or tardive dyskinesias that arise with antipsychotic treatment. These observations, coupled with reports that nicotinic receptor drugs have procognitive and antidepressant effects, suggest that central nervous system (CNS) nicotinic receptors may represent useful targets for the treatment of movement disorders.

  5. Selective blockade of drug-induced place preference conditioning by ACPC, a functional NDMA-receptor antagonist.

    Papp, Marius; Gruca, Piotr; Willner, Paul

    2002-11-01

    ACPC (1-aminocyclopropanecarboxylic acid) is a partial agonist at the strychnine-insensitive glycine receptor site on the NMDA receptor complex, and a functional NMDA antagonist. A series of experiments was conducted to assess the effects of ACPC in a biased place conditioning paradigm. As previously reported, ACPC itself did not support either appetitive or aversive place conditioning. However, co-administration of ACPC (200 mg/kg) blocked the acquisition of place preferences conditioned using a variety of psychoactive drugs (amphetamine, cocaine, nomifensine, diazepam, morphine, nicotine). No tolerance was seen to this effect following two weeks of chronic ACPC administration. Overall, ACPC did not affect the expression of place conditioning when administered immediately before the post-conditioning test. However, these effects appeared somewhat variable between drugs, and further analysis showed that ACPC did block the expression of preferences conditioned with some drugs (diazepam, morphine, nicotine), but not others (amphetamine, cocaine, nomifensine). The effects of ACPC could not be accounted for by state dependence, as ACPC blocked morphine and cocaine place preferences when administered during both the acquisition and the expression phase of conditioning. In contrast to the blockade by ACPC of drug-induced place preferences, ACPC had no effect on the acquisition of place preferences conditioned using a variety of natural non-drug reinforcers (food, sucrose, social interaction, novelty). ACPC also had no effect on the acquisition of drug-induced place aversions (naloxone, picrotoxin). Thus, ACPC selectively blocked appetitive conditioning by drug reinforcers, without affecting either appetitive conditioning by natural reinforcers or drug-induced aversions. As place preference conditioning has been demonstrated to have high predictive validity for detecting compounds with an abuse potential in humans, this selective action suggests that ACPC might have some

  6. Stem cell-derived models to improve mechanistic understanding and prediction of human drug-induced liver injury.

    Goldring, Christopher; Antoine, Daniel J; Bonner, Frank; Crozier, Jonathan; Denning, Chris; Fontana, Robert J; Hanley, Neil A; Hay, David C; Ingelman-Sundberg, Magnus; Juhila, Satu; Kitteringham, Neil; Silva-Lima, Beatriz; Norris, Alan; Pridgeon, Chris; Ross, James A; Young, Rowena Sison; Tagle, Danilo; Tornesi, Belen; van de Water, Bob; Weaver, Richard J; Zhang, Fang; Park, B Kevin

    2017-02-01

    Current preclinical drug testing does not predict some forms of adverse drug reactions in humans. Efforts at improving predictability of drug-induced tissue injury in humans include using stem cell technology to generate human cells for screening for adverse effects of drugs in humans. The advent of induced pluripotent stem cells means that it may ultimately be possible to develop personalized toxicology to determine interindividual susceptibility to adverse drug reactions. However, the complexity of idiosyncratic drug-induced liver injury means that no current single-cell model, whether of primary liver tissue origin, from liver cell lines, or derived from stem cells, adequately emulates what is believed to occur during human drug-induced liver injury. Nevertheless, a single-cell model of a human hepatocyte which emulates key features of a hepatocyte is likely to be valuable in assessing potential chemical risk; furthermore, understanding how to generate a relevant hepatocyte will also be critical to efforts to build complex multicellular models of the liver. Currently, hepatocyte-like cells differentiated from stem cells still fall short of recapitulating the full mature hepatocellular phenotype. Therefore, we convened a number of experts from the areas of preclinical and clinical hepatotoxicity and safety assessment, from industry, academia, and regulatory bodies, to specifically explore the application of stem cells in hepatotoxicity safety assessment and to make recommendations for the way forward. In this short review, we particularly discuss the importance of benchmarking stem cell-derived hepatocyte-like cells to their terminally differentiated human counterparts using defined phenotyping, to make sure the cells are relevant and comparable between labs, and outline why this process is essential before the cells are introduced into chemical safety assessment. (Hepatology 2017;65:710-721).

  7. Evaluation of the usefulness of novel biomarkers for drug-induced acute kidney injury in beagle dogs

    Zhou, Xiaobing [National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing 100176 (China); Graduate School of Peking Union Medical College, Dongcheng District, Beijing, 100730 (China); Ma, Ben; Lin, Zhi; Qu, Zhe; Huo, Yan; Wang, Jufeng [National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing 100176 (China); Li, Bo, E-mail: libo@nifdc.org.cn [National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, A8 Hongda Middle Street, Beijing Economic-Technological Development Area, Beijing 100176 (China); Graduate School of Peking Union Medical College, Dongcheng District, Beijing, 100730 (China)

    2014-10-01

    As kidney is a major target organ affected by drug toxicity, early detection of renal injury is critical in preclinical drug development. In past decades, a series of novel biomarkers of drug-induced nephrotoxicity were discovered and verified in rats. However, limited data regarding the performance of novel biomarkers in non-rodent species are publicly available. To increase the applicability of these biomarkers, we evaluated the performance of 4 urinary biomarkers including neutrophil gelatinase-associated lipocalin (NGAL), clusterin, total protein, and N-acetyl-β-D-glucosaminidase (NAG), relative to histopathology and traditional clinical chemistry in beagle dogs with acute kidney injury (AKI) induced by gentamicin. The results showed that urinary NGAL and clusterin levels were significantly elevated in dogs on days 1 and 3 after administration of gentamicin, respectively. Gene expression analysis further provided mechanistic evidence to support that NGAL and clusterin are potential biomarkers for the early assessment of drug-induced renal damage. Furthermore, the high area (both AUCs = 1.000) under receiver operator characteristics (ROC) curve also indicated that NGAL and clusterin were the most sensitive biomarkers for detection of gentamicin-induced renal proximal tubular toxicity. Our results also suggested that NAG may be used in routine toxicity testing due to its sensitivity and robustness for detection of tissue injury. The present data will provide insights into the preclinical use of these biomarkers for detection of drug-induced AKI in non-rodent species. - Highlights: • Urinary NGAL, clusterin and NAG levels were significantly elevated in canine AKI. • NGAL and clusterin gene expression were increased following treatment with gentamicin. • NGAL and clusterin have high specificity and sensitivity for detection of AKI.

  8. Application of a drug-induced apoptosis assay to identify treatment strategies in recurrent or metastatic breast cancer.

    Linda Bosserman

    Full Text Available A drug-induced apoptosis assay has been developed to determine which chemotherapy drugs or regimens can produce higher cell killing in vitro. This study was done to determine if this assay could be performed in patients with recurrent or metastatic breast cancer patients, to characterize the patterns of drug-induced apoptosis, and to evaluate the clinical utility of the assay. A secondary goal was to correlate assay use with clinical outcomes.In a prospective, non-blinded, multi institutional controlled trial, 30 evaluable patients with recurrent or metastatic breast cancer who were treated with chemotherapy had tumor samples submitted for the MiCK drug-induced apoptosis assay. After receiving results within 72 hours after biopsy, physicians could use the test to determine therapy (users, or elect to not use the test (non-users.The assay was able to characterize drug-induced apoptosis in tumor specimens from breast cancer patients and identified which drugs or combinations gave highest levels of apoptosis. Patterns of drug activity were also analyzed in triple negative breast cancer. Different drugs from a single class of agents often produced significantly different amounts of apoptosis. Physician frequently (73% used the assay to help select chemotherapy treatments in patients, Patients whose physicians were users had a higher response (CR+PR rate compared to non-users (38.1% vs 0%, p = 0.04 and a higher disease control (CR+PR+Stable rate (81% vs 25%, p<0.01. Time to relapse was longer in users 7.4 mo compared to non-users 2.2 mo (p<0.01.The MiCK assay can be performed in breast cancer specimens, and results are often used by physicians in breast cancer patients with recurrent or metastatic disease. These results from a good laboratory phase II study can be the basis for a future larger prospective multicenter study to more definitively establish the value of the assay.Clinicaltrials.gov NCT00901264.

  9. The impact of obesity and metabolic syndrome on chronic hepatitis B and drug-induced liver disease.

    Pais, Raluca; Rusu, Elena; Ratziu, Vlad

    2014-02-01

    Steatosis and insulin resistance (IR) are no more frequent in chronic hepatitis B (CHB) than in the general population. Although experimental studies suggest that the HBx protein induces liver fat, human studies have shown that steatosis and IR are related to coexistent metabolic risk factors, thus epidemiologically linked rather than virally induced. Diabetes and obesity are associated with advanced fibrosis and increased risk of hepatocellular carcinoma in CHB. Despite abundant experimental data showing that fatty liver is more susceptible to liver injury, drug-induced liver disease seems no more frequent in NAFLD patients, except, possibly, a higher incidence but not severity of acetaminophen hepatotoxicity.

  10. Application of a Drug-Induced Apoptosis Assay to Identify Treatment Strategies in Recurrent or Metastatic Breast Cancer

    Bosserman, Linda; Rogers, Karl; Willis, Carl; Davidson, Dirk; Whitworth, Pat; Karimi, Misagh; Upadhyaya, Gargi; Rutledge, James; Hallquist, Allan; Perree, Mathieu; Presant, Cary A.

    2015-01-01

    Background A drug-induced apoptosis assay has been developed to determine which chemotherapy drugs or regimens can produce higher cell killing in vitro. This study was done to determine if this assay could be performed in patients with recurrent or metastatic breast cancer patients, to characterize the patterns of drug-induced apoptosis, and to evaluate the clinical utility of the assay. A secondary goal was to correlate assay use with clinical outcomes. Methods In a prospective, non-blinded, multi institutional controlled trial, 30 evaluable patients with recurrent or metastatic breast cancer who were treated with chemotherapy had tumor samples submitted for the MiCK drug-induced apoptosis assay. After receiving results within 72 hours after biopsy, physicians could use the test to determine therapy (users), or elect to not use the test (non-users). Results The assay was able to characterize drug-induced apoptosis in tumor specimens from breast cancer patients and identified which drugs or combinations gave highest levels of apoptosis. Patterns of drug activity were also analyzed in triple negative breast cancer. Different drugs from a single class of agents often produced significantly different amounts of apoptosis. Physician frequently (73%) used the assay to help select chemotherapy treatments in patients, Patients whose physicians were users had a higher response (CR+PR) rate compared to non-users (38.1% vs 0%, p = 0.04) and a higher disease control (CR+PR+Stable) rate (81% vs 25%, p<0.01). Time to relapse was longer in users 7.4 mo compared to non-users 2.2 mo (p<0.01). Conclusions The MiCK assay can be performed in breast cancer specimens, and results are often used by physicians in breast cancer patients with recurrent or metastatic disease. These results from a good laboratory phase II study can be the basis for a future larger prospective multicenter study to more definitively establish the value of the assay. Trial Registration Clinicaltrials.gov NCT

  11. Communication and abnormal behaviour.

    Crown, S

    1979-01-01

    In this paper the similarities between normal and abnormal behaviour are emphasized and selected aspects of communication, normal and aberrant, between persons are explored. Communication in a social system may be verbal or non-verbal: one person's actions cause a response in another person. This response may be cognitive, behavioural or physiological. Communication may be approached through the individual, the social situation or social interaction. Psychoanalysis approaches the individual in terms of the coded communications of psychoneurotic symptoms or psychotic behaviour; the humanist-existential approach is concerned more with emotional expression. Both approaches emphasize the development of individual identity. The interaction between persons and their social background is stressed. Relevant are sociological concepts such as illness behaviour, stigma, labelling, institutionalization and compliance. Two approaches to social interactions are considered: the gamesplaying metaphor, e.g. back pain as a psychosocial manipulation--the 'pain game'; and the 'spiral of reciprocal perspectives' which emphasizes the interactional complexities of social perceptions. Communicatory aspects of psychological treatments are noted: learning a particular metaphor such as 'resolution' of the problem (psychotherapy), learning more 'rewarding' behaviour (learning theory) or learning authenticity or self-actualization (humanist-existential).

  12. Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post-chemotherapy tissues.

    Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

    2015-12-01

    Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens.

  13. Recapitulation of Clinical Individual Susceptibility to Drug-Induced QT Prolongation in Healthy Subjects Using iPSC-Derived Cardiomyocytes

    Tadahiro Shinozawa

    2017-02-01

    Full Text Available To predict drug-induced serious adverse events (SAE in clinical trials, a model using a panel of cells derived from human induced pluripotent stem cells (hiPSCs of individuals with different susceptibilities could facilitate major advancements in translational research in terms of safety and pharmaco-economics. However, it is unclear whether hiPSC-derived cells can recapitulate interindividual differences in drug-induced SAE susceptibility in populations not having genetic disorders such as healthy subjects. Here, we evaluated individual differences in SAE susceptibility based on an in vitro model using hiPSC-derived cardiomyocytes (hiPSC-CMs as a pilot study. hiPSCs were generated from blood samples of ten healthy volunteers with different susceptibilities to moxifloxacin (Mox-induced QT prolongation. Different Mox-induced field potential duration (FPD prolongation values were observed in the hiPSC-CMs from each individual. Interestingly, the QT interval was significantly positively correlated with FPD at clinically relevant concentrations (r > 0.66 in multiple analyses including concentration-QT analysis. Genomic analysis showed no interindividual significant differences in known target-binding sites for Mox and other drugs such as the hERG channel subunit, and baseline QT ranges were normal. The results suggest that hiPSC-CMs from healthy subjects recapitulate susceptibility to Mox-induced QT prolongation and provide proof of concept for in vitro preclinical trials.

  14. Use of a mail-out continuing education article to teach health professionals about drug-induced disease.

    Goldman, S A

    1999-11-01

    A U.S. Food and Drug Administration (FDA)/Georgetown University Medical Center conference was the basis for "Clinical Therapeutics and the Recognition of Drug-Induced Disease," the first MEDWATCH continuing education (CE) mail-out article. Developed as a major component of FDA MEDWATCH post-marketing surveillance outreach, the article used a clinical therapeutic approach to discuss topics including adverse drug events (ADEs) pharmacology and ADE reporting. Distributed nationwide through the MEDWATCH Partners, health professionals applied for CE credit by completing a self-assessment examination. With the overall response rate slightly more than 2%, 15,260 health professionals (55% physicians and 37% pharmacists) received CE credit. Evaluation of the initial approximately two-thirds (N = 10,021) of successfully completed exams found 99% agreement that stated learning objectives were met, and the article relevant to their clinical practice; spontaneous comments/letters were also very positive. The highest percentage responding specialists were internists (28%) and psychiatrists (17%), with notable differences found among specialties for response rate versus relative article distribution (such as relatively low response rates among surgeons and radiology/radiation physics specialists). The number of health professionals receiving CE credit, coupled with examination performance and overall response, indicates that "Clinical Therapeutics and the Recognition of Drug-Induced Disease" was well received and fulfilled learning objectives. The results provide encouragement for this continuing educational approach.

  15. Evaluation of drug-induced neurotoxicity based on metabolomics, proteomics and electrical activity measurements in complementary CNS in vitro models.

    Schultz, Luise; Zurich, Marie-Gabrielle; Culot, Maxime; da Costa, Anaelle; Landry, Christophe; Bellwon, Patricia; Kristl, Theresa; Hörmann, Katrin; Ruzek, Silke; Aiche, Stephan; Reinert, Knut; Bielow, Chris; Gosselet, Fabien; Cecchelli, Romeo; Huber, Christian G; Schroeder, Olaf H-U; Gramowski-Voss, Alexandra; Weiss, Dieter G; Bal-Price, Anna

    2015-12-25

    The present study was performed in an attempt to develop an in vitro integrated testing strategy (ITS) to evaluate drug-induced neurotoxicity. A number of endpoints were analyzed using two complementary brain cell culture models and an in vitro blood-brain barrier (BBB) model after single and repeated exposure treatments with selected drugs that covered the major biological, pharmacological and neuro-toxicological responses. Furthermore, four drugs (diazepam, cyclosporine A, chlorpromazine and amiodarone) were tested more in depth as representatives of different classes of neurotoxicants, inducing toxicity through different pathways of toxicity. The developed in vitro BBB model allowed detection of toxic effects at the level of BBB and evaluation of drug transport through the barrier for predicting free brain concentrations of the studied drugs. The measurement of neuronal electrical activity was found to be a sensitive tool to predict the neuroactivity and neurotoxicity of drugs after acute exposure. The histotypic 3D re-aggregating brain cell cultures, containing all brain cell types, were found to be well suited for OMICs analyses after both acute and long term treatment. The obtained data suggest that an in vitro ITS based on the information obtained from BBB studies and combined with metabolomics, proteomics and neuronal electrical activity measurements performed in stable in vitro neuronal cell culture systems, has high potential to improve current in vitro drug-induced neurotoxicity evaluation.

  16. Systemic abnormalities in liver disease

    Masami Minemura; Kazuto Tajiri; Yukihiro Shimizu

    2009-01-01

    Systemic abnormalities often occur in patients with liver disease. In particular, cardiopulmonary or renal diseases accompanied by advanced liver disease can be serious and may determine the quality of life and prognosis of patients. Therefore, both hepatologists and non-hepatologists should pay attention to such abnormalities in the management of patients with liver diseases.

  17. Abnormal pressure in hydrocarbon environments

    Law, B.E.; Spencer, C.W.

    1998-01-01

    Abnormal pressures, pressures above or below hydrostatic pressures, occur on all continents in a wide range of geological conditions. According to a survey of published literature on abnormal pressures, compaction disequilibrium and hydrocarbon generation are the two most commonly cited causes of abnormally high pressure in petroleum provinces. In young (Tertiary) deltaic sequences, compaction disequilibrium is the dominant cause of abnormal pressure. In older (pre-Tertiary) lithified rocks, hydrocarbon generation, aquathermal expansion, and tectonics are most often cited as the causes of abnormal pressure. The association of abnormal pressures with hydrocarbon accumulations is statistically significant. Within abnormally pressured reservoirs, empirical evidence indicates that the bulk of economically recoverable oil and gas occurs in reservoirs with pressure gradients less than 0.75 psi/ft (17.4 kPa/m) and there is very little production potential from reservoirs that exceed 0.85 psi/ft (19.6 kPa/m). Abnormally pressured rocks are also commonly associated with unconventional gas accumulations where the pressuring phase is gas of either a thermal or microbial origin. In underpressured, thermally mature rocks, the affected reservoirs have most often experienced a significant cooling history and probably evolved from an originally overpressured system.

  18. VITAMINE E IN THE MANAGEMENT OF DRUG INDUCED TARDIVE DYSKINESIA: A DOUBLE BLIND RANDOMIZED CLINICAL TRIAL

    M KAR AHMADI

    2002-12-01

    Full Text Available Introduction. Expresssion of tardive dyskinesia as one of the side effects of antipsychotic drugs causes various problems in psychotic patients. It is the main cause of patient"s drug incompliance.Vitamine E with it"s antioxidants properties might be an effective treatment for tardive dyskinesia. Methods. In a randomized double blind clinical trial, thirty inpatients of the psychiatric hospital in Isfahan were studied. Patients were stratified according to their age, psychiatric disorder and duration, intensity of tardive dyskinesia and antipsychotic dosage. Then they were asssigned randomly into two groups. Vitamine E (600 mg/day was administered to interventional group (15 patients. Another group received placebo (15 patients. Treatment durated for 6 weeks. Abnormal Involuntary Movment Scale (AIMS was used to measure tardive dyskinesia intensity. Results. Average of disorder intensity in those who received vit. E, dropped down from 8.33/10 (befor treatment to 6.13/10 (after treatment. It means 26.3 percent reduction of tardive dyskinesia intensity. This difference was only 7.3 percent in control group. There were no statistical diffrence between two groups after treatment (P>0.05. Discussion. There is no statistical efficacy for vitamine E in the management of tardive dyskinesia. But it is recommended to make another study with more samples.

  19. Drug-Induced Liver Injury Caused by Adalimumab: A Case Report and Review of the Bibliography

    Bernardo Frider

    2013-01-01

    Full Text Available The most serious adverse drug reaction of adalimumab (ADR is tuberculosis reactivation. We describe a case of a 35-year-old man, with rheumatoid arthritis (RA and hepatitis C virus genotype 1a with a liver biopsy in 2001 with a METAVIR score pattern A1 F0; he received interferon alpha 2b for six months, but treatment was suspended because of reactivation of RA. Liver function tests after treatment were similar to previous ones showing a minimal cholestatic pattern. In 2008, methotrexate was prescribed, but the drug was withdrawn at the third month because of the appearance of pruritus and Ggt rise. Viral load at that moment was 9300000 UI/mL, log 6,9. The liver biopsy showed a Metavir Score A2 F1. Adalimumab was started in 2010, and at the third month of treatment, Ggt showed a rise of 23 times normal value (NV, alkaline phosphatase 2,5 times NV with AST and ALT with no change. A new liver biopsy showed portal inflammation with eosinophils and a METAVIR A1 F2. We think that adalimumab appears to be responsible for the liver injury, because of temporal relationship, liver biopsy findings, other clinical conditions being discarded, and the improvement of clinical symptoms and biochemical abnormalities when adalimumab was suspended.

  20. Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries

    Yoshikawa, Yukitaka; Miyashita, Taishi; Higuchi, Satonori [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Tsuneyama, Koichi [Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Sugitani, Toyama 930‐0194 (Japan); Endo, Shinya [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Tsukui, Tohru [Research Center for Genomic Medicine, Saitama Medical University, Yamane, Hidaka 350‐1241 (Japan); Toyoda, Yasuyuki; Fukami, Tatsuki; Nakajima, Miki [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Yokoi, Tsuyoshi, E-mail: tyokoi@p.kanazawa-u.ac.jp [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan)

    2012-10-01

    Although estrogen receptor (ER)α agonists, such as estradiol and ethinylestradiol (EE2), cause cholestasis in mice, they also reduce the degree of liver injury caused by hepatotoxicants as well as ischemia–reperfusion. The functional mechanisms of ERα have yet to be elucidated in drug-induced or chemical-induced liver injury. The present study investigated the effects of an ERα agonist, selective ER modulators (SERMs) and an ER antagonist on drug-induced and chemical-induced liver injuries caused by acetaminophen, bromobenzene, diclofenac, and thioacetamide (TA). We observed hepatoprotective effects of EE2, tamoxifen (TAM) and raloxifene pretreatment in female mice that were exposed to a variety of hepatotoxic compounds. In contrast, the ER antagonist did not show any hepatoprotective effects. DNA microarray analyses suggested that monocyte to macrophage differentiation-associated 2 (Mmd2) protein, which has an unknown function, is commonly increased by TAM and RAL pretreatment, but not by pretreatment with the ER antagonist. In ERα-knockout mice, the hepatoprotective effects of TAM and the increased expression of Mmd2 mRNA were not observed in TA-induced liver injury. To investigate the function of Mmd2, the expression level of Mmd2 mRNA was significantly knocked down to approximately 30% in mice by injection of siRNA for Mmd2 (siMmd2). Mmd2 knockdown resulted in a reduction of the protective effects of TAM on TA-induced liver injury in mice. This is the first report of the involvement of ERα in drug-induced or chemical-induced liver injury. Upregulation of Mmd2 protein in the liver was suggested as the mechanism of the hepatoprotective effects of EE2 and SERMs. -- Highlights: ► Liver injury induced by drugs or chemicals was investigated in mice. ► Liver injury was suppressed by pretreatment with tamoxifen in female mice. ► Mmd2, whose function was unknown, could be a candidate gene for liver protection. ► Tamoxifen up-regulated Mmd2 mRNA expression

  1. Imaging findings of sternal abnormalities

    Franquet, T. [Dept. of Radiology, Hospital de Sant Pau, Universidad Autonoma de Barcelona (Spain); Gimenez, A. [Dept. of Radiology, Hospital de Sant Pau, Universidad Autonoma de Barcelona (Spain); Alegret, X. [Dept. of Radiology, Hospital de Sant Pau, Universidad Autonoma de Barcelona (Spain); Sanchis, E. [Dept. of Radiology, Hospital de Sant Pau, Universidad Autonoma de Barcelona (Spain); Rivas, A. [Dept. of Radiology, Hospital Vall d`Hebron, Universidad Autonoma de Barcelona (Spain)

    1997-05-01

    Radiographic findings in the sternal abnormalities are often nonspecific, showing appearances from a localized benign lesion to an aggressive lesion as seen with infections and malignant neoplasms. A specific diagnosis of sternal abnormalities can be suggested on the basis of CT and MR characteristics. Familiarity with the presentation and variable appearance of sternal abnormalities may aid the radiologist is suggesting a specific diagnosis. We present among others characteristic radiographic findings of hemangioma, chondrosarcoma, hydatid disease, and SAPHO syndrome. In those cases in which findings are not specific, cross-sectional imaging modalities may help the clinician in their management. (orig.)

  2. Assessing common classification methods for the identification of abnormal repolarization using indicators of T-wave morphology and QT interval

    Shakibfar, Saeed; Graff, Claus; Ehlers, Lars Holger;

    2012-01-01

    volunteers and LQT2 carriers were used to train classification algorithms using measures of T-wave morphology and QTc. The ability to correctly classify a third group of test subjects before and after receiving d,l-sotalol was evaluated using classification rules derived from training. As a single......Various parameters based on QTc and T-wave morphology have been shown to be useful discriminators for drug induced I(Kr)-blocking. Using different classification methods this study compares the potential of these two features for identifying abnormal repolarization on the ECG. A group of healthy...

  3. Drug-induced mild therapeutic hypothermia obtained by administration of a transient receptor potential vanilloid type 1 agonist

    Fosgerau, Keld; Weber, Uno J; Gotfredsen, Jacob W

    2010-01-01

    the feasibility of using a transient receptor potential vanilloid type 1 (TRPV1) agonist for obtaining drug-induced sustainable mild hypothermia. Methods First, we screened a heterogeneous group of TRPV1 agonists and secondly we tested the hypothermic properties of a selected candidate by dose-response studies....... Finally we tested the hypothermic properties in a large animal. The screening was in conscious rats, the dose-response experiments in conscious rats and in cynomologus monkeys, and the finally we tested the hypothermic properties in conscious young cattle (calves with a body weight as an adult human......). The investigated TRPV1 agonists were administered by continuous intravenous infusion. Results  Screening: Dihydrocapsaicin (DHC), a component of chili pepper, displayed a desirable hypothermic profile with regards to the duration, depth and control in conscious rats. Dose-response experiments: In both rats...

  4. Investigation of parameters highlighting drug induced small changes of the T-wave's morphology for drug safety studies.

    Baas, Tobias; Gräfe, Ksenija; Khawaja, Antoun; Dössel, Olaf

    2011-01-01

    In guideline E14, the American Food and Drug Administration (FDA) requests for clinical studies to investigate the prolongation of the heart rate corrected QT-interval (QTc) of the ECG. As drug induced QT-prolongation can be caused by changes in the repolarisation of the ventricles, it is so far a thorough ECG biomarker of risk for ventricular tachyarrhythmias and Torsade de Pointes (TdP). Ventricular repolarisation changes not only change QT but also influence the morphology of the T-wave. In a (400 mg single dose) Moxifloxacin positive control study both, QTc and several descriptors describing the T-wave morphology have been measured. Moxifloxacin is changing two shape dependent descriptors significantly (P<0.05) about 3 to 4 hours after a 400 mg oral single dose of Moxifloxacin.

  5. Consensus statement: Management of drug-induced liver injury in HIV-positive patients treated for TB

    E Jong

    2013-09-01

    Full Text Available Drug-induced liver injury (DILI in HIV/tuberculosis (TB co-infected patients is a common problem in the South African setting, and re-introduction of anti-TB drugs can be challenging for the healthcare worker. Although international guidelines on the re-introduction of TB treatment are available, the definition of DILI is not uniform, management of antiretroviral therapy (ART in HIV co-infection is not mentioned, and the guidance on management is not uniform and lacks a practical approach. In this consensus statement, we summarise important aspects of DILI and provide practical guidance for healthcare workers for different patient groups and healthcare settings on the re-introduction of anti-TB drugs and ART in HIV/TB co-infected individuals presenting with DILI.

  6. Skin - abnormally dark or light

    ... ency/article/003242.htm Skin - abnormally dark or light To use the sharing features on this page, ... the hands. The bronze color can range from light to dark (in fair-skinned people) with the ...

  7. Pregnancy Complications: Umbilical Cord Abnormalities

    ... defects. These tests may include a detailed ultrasound, amniocentesis (to check for chromosomal abnormalities) and in some ... the provider may recommend additional tests, such as amniocentesis and a detailed ultrasound, to diagnose or rule ...

  8. Anti-hepatotoxic and antioxidant influence of Ipomoea carnea against anti-tubercular drugs induced acute hepatopathy in experimental rodents

    Ramesh Kumar Gupta; Ashok Kumar Gupta; Sudhansu Ranjan Swain; Vaishali; Gaurav Gupta; Saifuddin Khalid; Didagi Kulkarni Suresh; Rajnish Kumar Singh

    2013-01-01

    Objective: To assess the hepatoprotective effect of Ipomoea carnea (I. carnea) extract against antitubercular drug-induced liver toxicity in experimental animals. Methods: I. carnea extracts (125, 250 and 500 mg/kg, p.o. body weight) were administered daily for 3d5r udg sin experimental animals. Liver toxicity was induced by combination of three antitubercular suspen(siisoonn ifaozr id 7.5 mg/kg, rifampicin 10 mg/kg and pyrazinamide 35 mg/kg) given orally as drugs. 35 d in rats. Treatment groups received I. carnea extracts along with antitubercular aspartaTteh ea mhienpoattroapnrsofeteracstiev,e a alacntiivniet ya mwainso atrsasnessfseerda sues, ianlgk avlainrieo upsh obsipochhaetimsei caanl dp atortaaml ebtielirrsu bliikne. dMiesmanuwtahsiele a, nind- cvaivtaol aasnet iwoxeirdea mnte aascutirveidti eisn aras t lliipviedr pheormoxoigdeantaioten ,a rloendgu cweidth g lutathione, superoxide ATPase and G-6-Pase. The biochemical observations were supplemented by histopathological examination. Results: Obtained results demonstrated that treatment with I. carnea extracts significantly h(Pedrug induced increase in serum levels of peroxidation in theF ulrivtheer rtmisosruee, Ia.n cda rrnesetao reexdt raaccttisv istiigens ifoifc adnetfleyn c(uep atnot iPox

  9. Stem cell-derived models to improve mechanistic understanding and prediction of human drug induced liver injury

    Goldring, Christopher; Antoine, Daniel J.; Bonner, Frank; Crozier, Jonathan; Denning, Chris; Fontana, Robert J.; Hanley, Neil A.; Hay, David C.; Ingelman-Sundberg, Magnus; Juhila, Satu; Kitteringham, Neil; Silva-Lima, Beatriz; Norris, Alan; Pridgeon, Chris; Ross, James A.; Sison Young, Rowena; Tagle, Danilo; Tornesi, Belen; van de Water, Bob; Weaver, Richard J.; Zhang, Fang; Park, B. Kevin

    2016-01-01

    Current preclinical drug testing does not predict some forms of adverse drug reactions in humans. Efforts at improving predictability of drug-induced tissue injury in humans include using stem cell technology to generate human cells for screening for adverse effects of drugs in humans. The advent of induced pluripotent stem cells means that it may ultimately be possible to develop personalised toxicology to determine inter-individual susceptibility to adverse drug reactions. However, the complexity of idiosyncratic drug-induced liver injury (DILI) means that no current single cell model, whether of primary liver tissue origin, from liver cell lines, or derived from stem cells, adequately emulates what is believed to occur during human DILI. Nevertheless, a single cell model of a human hepatocyte which emulates key features of a hepatocyte is likely to be valuable in assessing potential chemical risk; furthermore understanding how to generate a relevant hepatocyte will also be critical to efforts to build complex multicellular models of the liver. Currently, hepatocyte-like cells differentiated from stem cells still fall short of recapitulating the full mature hepatocellular phenotype. Therefore, we convened a number of experts from the areas of preclinical and clinical hepatotoxicity and safety assessment, from industry, academia and regulatory bodies, to specifically explore the application of stem cells in hepatotoxicity safety assessment, and to make recommendations for the way forward. In this short review, we particularly discuss the importance of benchmarking stem cell-derived hepatocyte-like cells to their terminally-differentiated human counterparts using defined phenotyping, to make sure the cells are relevant and comparable between labs, and outline why this process is essential before the cells are introduced into chemical safety assessment. PMID:27775817

  10. Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes.

    Elijah R Behr

    Full Text Available Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants. Cases of drug-induced Torsades de Pointes (diTdP, treatment tolerant controls, and general population controls were ascertained across multiple sites using common definitions, and genotyped on the Illumina 610k or 1M-Duo BeadChips. Principal Components Analysis was used to select 216 Northwestern European diTdP cases and 771 ancestry-matched controls, including treatment-tolerant and general population subjects. With these sample sizes, there is 80% power to detect a variant at genome-wide significance with minor allele frequency of 10% and conferring an odds ratio of ≥2.7. Tests of association were carried out for each single nucleotide polymorphism (SNP by logistic regression adjusting for gender and population structure. No SNP reached genome wide-significance; the variant with the lowest P value was rs2276314, a non-synonymous coding variant in C18orf21 (p  =  3×10(-7, odds ratio = 2, 95% confidence intervals: 1.5-2.6. The haplotype formed by rs2276314 and a second SNP, rs767531, was significantly more frequent in controls than cases (p  =  3×10(-9. Expanding the number of controls and a gene-based analysis did not yield significant associations. This study argues that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs.

  11. Anti-hepatotoxic and antioxidant influence of Ipomoea carnea against anti-tubercular drugs induced acute hepatopathy in experimental rodents

    Ramesh Kumar Gupta

    2013-11-01

    Full Text Available Objective: To assess the hepatoprotective effect of Ipomoea carnea (I. carnea extract against antitubercular drug-induced liver toxicity in experimental animals. Methods: I. carnea extracts (125, 250 and 500 mg/kg, p.o. body weight were administered daily for 35 d in experimental animals. Liver toxicity was induced by combination of three antitubercular drugs (isoniazid 7.5 mg/kg, rifampicin 10 mg/kg and pyrazinamide 35 mg/kg given orally as suspension for 35 d in rats. Treatment groups received I. carnea extracts along with antitubercular drugs. The hepatoprotective activity was assessed using various biochemical parameters like aspartate aminotransferase, alanine aminotransferase, alkaline phosphatise and total bilirubin. Meanwhile, in-vivo antioxidant activities as lipid peroxidation, reduced glutathione, superoxide dismutase and catalase were measured in rat liver homogenate along with ATPase and G-6-Pase. The biochemical observations were supplemented by histopathological examination. Results: Obtained results demonstrated that treatment with I. carnea extracts significantly (P<0.05-P<0.001 and dose-dependently prevented drug induced increase in serum levels of hepatic enzymes. Furthermore, I. carnea extracts significantly (up to P<0.001 reduced the lipid peroxidation in the liver tissue and restored activities of defence antioxidant enzymes, reduced glutathione, superoxide dismutase and catalase towards normal levels. Histopathology of the liver tissue showed that I. carnea extracts attenuated the hepatocellular necrosis, massive fatty changes and led to reduction in inflammatory cells infiltration. Conclusions: The results of this study strongly indicate the protective effect of I. carnea extracts against liver injury, which may be attributed to its hepatoprotective activity, and there by scientifically support its traditional use.

  12. Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro

    Funk, Juergen; Robbins, Justin B.; Crogan-Grundy, Candace; Presnell, Sharon C.; Singer, Thomas; Roth, Adrian B.

    2016-01-01

    Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI). This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM). Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level. PMID:27387377

  13. Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro.

    Deborah G Nguyen

    Full Text Available Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI. This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM. Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level.

  14. Late-Onset Drug-Induced Cholestasis in a Living-Related Liver Transplant Donor With Progressive Familial Intrahepatic Cholestasis.

    Harmancı, Özgür; Ensaroğlu, Fatih; Özçay, Figen; Öcal, Serkan; Korkmaz, Murat; Özdemir, B Handan; Selçuk, Haldun; Moray, Gökhan; Haberal, Mehmet

    2015-11-01

    We present a rare case of progressive familial intrahepatic cholestasis within a family. A 34-yearold female became a living-related liver transplant donor for her son, who had the disease. Nine years after the transplant, the mother developed severe intrahepatic cholestasis, for which she was evaluated after using an oral contraceptive drug. She presented with jaundice, pruritus, and increased bilirubin levels, together with elevated gamma glutamyl transferase and alkaline phosphatase levels. A liver biopsy revealed findings consistent with intrahepatic cholestasis. However, despite follow-up management and cessation of the insulting drug, her total bilirubin count continuously increased to 20 mg/dL and was accompanied by intractable pruritus. A total of 9 plasmapheresis sessions were performed, and she was started on a regimen of ursodeoxycholic acid (13 mg/kg/d) and cholestyramine (4 g, 3 times daily). The clinical and laboratory picture dramatically improved following cessation of the oral contraceptive, plasmapheresis sessions, and drug treatment. The patient's cholestasis normalized within 3 months, and she recovered uneventfully. A genetic analysis of the whole family revealed that both parents were heterozygous for the mutation c.124G>A in ABCB11, and the son was homozygous for this mutation. These findings supported varying degrees of bile salt export pump deficiency in the family members. Defective bile salt excretory system function can result in a wide spectrum of clinical presentations, ranging from progressive familial intrahepatic cholestasis requiring liver transplant to late-onset drug-induced cholestasis. Our findings suggest that, in a heterozygous carrier of a progressive familial intrahepatic cholestasis mutation, drug-induced cholestasis is responsive to treatment, after which the clinical picture can normalize within 3 months.

  15. Rat granulocyte colony-forming unit (CFU-G) assay for the assessment of drug-induced hematotoxicity.

    Matsumura-Takeda, K; Kotosai, K; Ozaki, A; Hara, H; Yamashita, S

    2002-06-01

    To assess the drug-induced hematotoxicity to granulocyte progenitors, we established a modified colony-forming assay using rat bone marrow cells (BMCs). In the presence of various colony-stimulating factors (CSFs), rat BMCs were disseminated on methylcellulose at a concentration of 1.3 x 10(4) cells/cm(2) (5 x 10(4) cells/0.5 ml/well in a 12-well plate). Mouse granulocyte-macrophage colony-stimulating factor (mGM-CSF) stimulated the formation of almost all macrophage colonies. Human granulocyte colony-stimulating factor (hG-CSF) alone or in combination with mouse interleukin-3 (mIL-3) did not significantly effect on the number of rat colony-forming units in culture (CFU-C). When BMCs were seeded at 5.2 x 10(4) cells/cm(2) (5 x 10(5) cells/1 ml/dish in a 35-mm dish), hG-CSF increased the number of the colonies in a dose-dependent manner, and resulted in about 50 colonies at 50 ng/ml. The constituent cells of the colonies were identified as neutrophils. Under these conditions, the effects of 5-fluorouracil (5-FU) on granulocyte colony-forming units (CFU-G) were examined in rats and mice. The inhibitory effect of 5-FU on rat CFU-G was similar to the effect on mouse CFU-G. These results indicate that the rat CFU-G induced by hG-CSF is capable of being used for the evaluation of drug-induced hematotoxicity.

  16. Expression patterns and action analysis of genes associated with drug-induced liver diseases during rat liver regeneration

    Qian-Ji Ning; Shao-Wei Qin; Cun-Shuan Xu

    2006-01-01

    AIM: To study the action of the genes associated with drug-induced liver diseases at the gene transcriptional level during liver regeneration (LR) in rats.METHODS: The genes associated with drug-induced liver diseases were obtained by collecting the data from databases and literature, and the gene expression changes in the regenerating liver were checked by the Rat Genome 230 2.0 array.RESULTS: The initial and total expression numbers of genes occurring in phases of 0.5-4 h after partial hepatectomy (PH), 4-6 h after PH (G0/G1 transition),6-66 h after PH (cell proliferation), 66-168 h after PH (cell differentiation and structure-function reconstruction) were 21, 3, 9, 2 and 21, 9, 19, 18, respectively. It is illustrated that the associated genes were mainly triggered at the initial stage of LR and worked at different phases. According to their expression similarity,these genes were classified into 5 types: only upregulated (12 genes), predominantly up-regulated (4genes), only down-regulated (11 genes), predominantly down-regulated (3 genes), and approximately up-/down-regulated (2 genes). The total times of their upand down-expression were 130 and 79, respectively,demonstrating that expression of most of the genes was increased during LR, while a few decreased. The cell physiological and biochemical activities during LR were staggered according to the time relevance and were diverse and complicated in gene expression patterns.CONCLUSION: Drug metabolic capacity in regenerating liver was enhanced. Thirty-two genes play important roles during liver regeneration in rats.

  17. Drug induced linear IgA disease with unusual features: Koebner phenomenon, local insulin sensitivity and annular blister of the nipples.

    Rashid Dar, Nasser; Raza, Naeem

    2008-01-01

    Linear IgA disease is an autoimmune subepidermal bullous disease in which linear IgA deposits are found at the basement membrane zone. It is classically idiopathic but may be drug induced. We report on a patient with drug induced linear IgA disease who exhibited certain unusual and interesting clinical features including isomorphic Koebner response, annular blister of the nipples and local insulin sensitivity. To the best of our knowledge, these clinical features have not yet been reported in linear IgA disease.

  18. Drug-induced gingival enlargement: biofilm control and surgical therapy with gallium-aluminum-arsenide (GaAlAs) diode laser-A 2-year follow-up.

    de Oliveira Guaré, Renata; Costa, Soraya Carvalho; Baeder, Fernando; de Souza Merli, Luiz Antonio; Dos Santos, Maria Teresa Botti Rodrigues

    2010-01-01

    Drug-induced gingival enlargement has been reported in patients treated with various types of anticonvulsant drugs, and is generally associated with the presence of plaque, gingival inflammation, and a genetic predisposition. Effective treatment includes daily oral hygiene and periodic professional prophylaxis. However, in some patients, surgical removal of the gingival tissue overgrowth becomes necessary. The patient in this case report was mentally impaired and had severe drug-induced gingival enlargement. This report describes the initial protocol, the gingivectomy, and a 2-year follow-up. A diode laser was used as an effective and safe method to remove the patient's overgrown gingival tissue.

  19. [Diagnosticum of abnormalities of plant meiotic division].

    Shamina, N V

    2006-01-01

    Abnormalities of plant meiotic division leading to abnormal meiotic products are summarized schematically in the paper. Causes of formation of monads, abnormal diads, triads, pentads, polyads, etc. have been observed in meiosis with both successive and simultaneous cytokinesis.

  20. Memetics clarification of abnormal behavior

    2007-01-01

    AIM: Biological medicine is hard to fully and scientifically explain the etiological factor and pathogenesis of abnormal behaviors; while, researches on philosophy and psychology (including memetics) are beneficial to better understand and explain etiological factor and pathogenesis of abnormal behaviors. At present, the theory of philosophy and psychology is to investigate the entity of abnormal behavior based on the views of memetics.METHODS: Abnormal behavior was researched in this study based on three aspects, including instinctive behavior disorder, poorly social-adapted behavior disorder and mental or body disease associated behavior disorder. Most main viewpoints of memetics were derived from "The Meme Machine", which was written by Susan Blackmore. When questions about abnormal behaviors induced by mental and psychological diseases and conduct disorder of teenagers were discussed, some researching achievements which were summarized by authors previously were added in this study, such as aggressive behaviors, pathologically aggressive behaviors, etc.RESULTS: The abnormal behaviors mainly referred to a part of people's substandard behaviors which were not according with the realistic social environment, culture background and the pathologic behaviors resulted from people's various psychological diseases. According to the theory of "meme", it demonstrated that the relevant behavioral obstacles of various psychological diseases, for example, the unusual behavior of schizophrenia, were caused, because the old meme was destroyed thoroughly but the new meme was unable to establish; psychoneurosis and personality disorder were resulted in hard establishment of meme; the behavioral obstacles which were ill-adapted to society, for example, various additional and homosexual behaviors, were because of the selfish replications and imitations of "additional meme" and "homosexual meme"; various instinct behavioral and congenital intelligent obstacles were not significance

  1. Thyroid abnormality in perimenopausal women with abnormal uterine bleeding

    Prasanna Byna

    2015-11-01

    Full Text Available Background: AUB is a common but complicated clinical presentation and occurs in 15-20% of women between menarche to menopause and significantly affects the women's health. Women with thyroid dysfunction often have menstrual irregularities, infertility and increased morbidity during pregnancy. The objective of present study is to find the correlation between thyroid disorders and AUB in perimenopausal women attending gynecology OPD. Methods: In the present study, fifty five patients with AUB were included and were evaluated for the cause including thyroid abnormality. Thyroid function tests were done in all patients. Results: Among 55 patients, 12 patients were diagnosed as hypothyroidism and 7 as hyperthyroidism, women with AUB 36 (65.4% were euthyroid. Among 19 women with thyroid abnormality, heavy menstrual bleeding was seen in 8 (42% women, 6 (31.57% had polymenorrhagia, 5 (26.31% had oligomenorrhoea. The frequent menstrual abnormality in women with hypothyroidism (12 women was heavy menstrual bleeding in 5 (41.6% women, 3 (25% had oligomennorhoea, 4 (33.3% had polymenorrhagia. Out of 7 women with hyperthyroidism, 2 (28.57% had oligomenorrhoea, 3 (42.8% had heavy menstrual bleeding, 2 (28.57% had polymenorrhagia. In a total of 55 patients with AUB, 11 (20% had structural abnormalities in uterus and ovaries. 5 (9% had adenomyosis, 3 (5.4% had ovarian cysts, 3 (5.4% had fibroids. Conclusions: It is important to screen all women for thyroid abnormality who are presenting with AUB especially with non-structural causes of AUB. Correction of thyroid abnormalities also relieves AUB. This will avoid unnecessary hormonal treatment and surgery. [Int J Res Med Sci 2015; 3(11.000: 3250-3253

  2. 药物诱导自身免疫性肝炎的研究进展%Progress in research of drug-induced autoimmune hepatitis

    张彦亮; 史会连; 陶臻

    2011-01-01

    药物诱导自身免疫性肝炎(drug induced autoimmune hepatitis,DIAIH) 近年来国内外已有不少相关个案报道,其兼有药物性肝损(drug induced liver injury,DILI) 以及自身免疫性肝炎(autoimmune hepatitis,IH) 两者之特征,深入了解DIAIH 的流行病学现状、病因机制、临床表现和病理特点,将有助于我们加深对其的认知,并为DIAIH 的防治提供依据.%Drug-induced autoimmune hepatitis (DIAIH) has been reported to be caused by many drugs, which possesses the characteristics of both drug induced liver injury (DILI) and autoimmune hepatitis (AIH). A better understanding of the epidemiology, pathogenesis, pathology and clinical symptoms of DIAIH can help us better diagnose and treat this disease.

  3. A Large Candidate Gene Survey Identifies the KCNE1 D85N Polymorphism as a Possible Modulator of Drug-Induced Torsades de Pointes

    Kaeaeb, Stefan; Crawford, Dana C.; Sinner, Moritz F.; Behr, Elijah R.; Kannankeril, Prince J.; Wilde, Arthur A. M.; Bezzina, Connie R.; Schulze-Bahr, Eric; Guicheney, Pascale; Bishopric, Nanette H.; Myerburg, Robert J.; Schott, Jean-Jacques; Pfeufer, Arne; Beckmann, Britt-Maria; Martens, Eimo; Zhang, Taifang; Stallmeyer, Birgit; Zumhagen, Sven; Denjoy, Isabelle; Bardai, Abdennasser; Van Gelder, Isabelle C.; Jamshidi, Yalda; Dalageorgou, Chrysoula; Marshall, Vanessa; Jeffery, Steve; Shakir, Saad; Camm, A. John; Steinbeck, Gerhard; Perz, Siegfried; Lichtner, Peter; Meitinger, Thomas; Peters, Annette; Wichmann, H. -Erich; Ingram, Christiana; Bradford, Yuki; Carter, Shannon; Norris, Kris; Ritchie, Marylyn D.; George, Alfred L.; Roden, Dan M.

    2012-01-01

    Background-Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS. Methods and Results-In a ca

  4. Proteomic profiling in incubation medium of mouse, rat and human precision-cut liver slices for biomarker detection regarding acute drug-induced liver injury

    van Swelm, Rachel P. L.; Hadi, Mackenzie; Laarakkers, Coby M. M.; Masereeuw, Rosalinde; Groothuis, Geny M. M.; Russel, Frans G. M.

    2014-01-01

    Drug-induced liver injury is one of the leading causes of drug withdrawal from the market. In this study, we investigated the applicability of protein profiling of the incubation medium of human, mouse and rat precision-cut liver slices (PCLS) exposed to liver injury-inducing drugs for biomarker ide

  5. A Case of Sublingual Ranula That Responded Successfully to Localized Injection Treatment with OK-432 after Healing from Drug Induced Hypersensitivity Syndrome

    Kunio Yoshizawa

    2016-01-01

    Full Text Available A ranula is a mucus retention cyst or pseudocyst caused by leakage of mucus from the sublingual gland and generally occurs in the oral floor. In addition, drug induced hypersensitivity syndrome (DIHS is a rare but well-recognized serious adverse effect characterized by fever, skin rashes, generalized lymphadenopathy, hepatitis, and hepatosplenomegaly and oral stomatitis. This paper presents the first case of successfully treated sublingual ranula with localized injection of OK-432 after healing from drug induced hypersensitivity syndrome, which has previously been unreported in the literature. We present the case of a 38-year-old Japanese woman with sublingual ranula that responded successfully to localized injection treatment with OK-432 after healing from drug induced hypersensitivity syndrome. She was affected with cutaneous myositis and interstitial lung disease when she was 26 years old. At the age 34 years, she received additional oral treatment of diaminodiphenyl-sulfone due to deterioration of the cutaneous myositis, which resulted in drug induced hypersensitivity syndrome (DIHS with severe oral stomatitis. Local injection of OK-432 to the ranula may be a very safe and useful treatment method even if the patient has a history of drug allergy and has connective tissue disease such as cutaneous myositis.

  6. A Case of Sublingual Ranula That Responded Successfully to Localized Injection Treatment with OK-432 after Healing from Drug Induced Hypersensitivity Syndrome

    Yoshizawa, Kunio; Moroi, Akinori; Kawashiri, Shuichi; Ueki, Koichiro

    2016-01-01

    A ranula is a mucus retention cyst or pseudocyst caused by leakage of mucus from the sublingual gland and generally occurs in the oral floor. In addition, drug induced hypersensitivity syndrome (DIHS) is a rare but well-recognized serious adverse effect characterized by fever, skin rashes, generalized lymphadenopathy, hepatitis, and hepatosplenomegaly and oral stomatitis. This paper presents the first case of successfully treated sublingual ranula with localized injection of OK-432 after healing from drug induced hypersensitivity syndrome, which has previously been unreported in the literature. We present the case of a 38-year-old Japanese woman with sublingual ranula that responded successfully to localized injection treatment with OK-432 after healing from drug induced hypersensitivity syndrome. She was affected with cutaneous myositis and interstitial lung disease when she was 26 years old. At the age 34 years, she received additional oral treatment of diaminodiphenyl-sulfone due to deterioration of the cutaneous myositis, which resulted in drug induced hypersensitivity syndrome (DIHS) with severe oral stomatitis. Local injection of OK-432 to the ranula may be a very safe and useful treatment method even if the patient has a history of drug allergy and has connective tissue disease such as cutaneous myositis. PMID:27144039

  7. Abnormal insulin levels and vertigo.

    Proctor, C A

    1981-10-01

    Fifty patients with unexplained vertigo (36) or lightheadedness (14) are evaluated, all of whom had abnormal ENGs and normal audiograms. Five hour insulin glucose tolerance tests were performance on all patients, with insulin levels being obtained fasting and at one-half, one, two, and three hours. The results of this investigation were remarkable. Borderline or abnormal insulin levels were discovered in 82% of patients; 90% were found to have either an abnormal glucose tolerance test or at least borderline insulin levels. The response to treatment in these dizzy patients was also startling, with appropriate low carbohydrate diets improving the patient's symptoms in 90% of cases. It is, therefore, apparent that the earliest identification of carbohydrate imbalance with an insulin glucose tolerance test is extremely important in the work-up of the dizzy patients.

  8. A Common Genetic Variant Risk Score is Associated with Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study.

    Strauss, David G; Vicente, Jose; Johannesen, Lars; Blinova, Ksenia; Mason, Jay W; Weeke, Peter; Behr, Elijah R; Roden, Dan M; Woosley, Raymond; Kosova, Gulum; Rosenberg, Michael A; Newton-Cheh, Christopher

    2017-02-17

    Background -Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known. Methods -We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs. Genetic analysis of 22 subjects was performed in a secondary analysis of a randomized, double-blind, placebo-controlled, cross-over trial of 3 QT-prolonging drugs with 15 time-matched QT and plasma drug concentration measurements. Subjects received single doses of dofetilide, quinidine, ranolazine and placebo. The outcome was the correlation between a genetic QT score comprising 61 common genetic variants and the slope of an individual subject's drug-induced increase in heart rate corrected QT (QTc) vs. drug concentration. Results -The genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide (r = 0.55 [95% CI, 0.09-0.81], P = 0.02), 23% in response to quinidine (r = 0.48 [95% CI, -0.03 to 0.79], P = 0.06) and 27% in response to ranolazine (r = 0.52 [95% CI, 0.05 to 0.80], P = 0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared to 771 controls (r(2) = 12%, P = 1x10(-7)). Conclusions -We demonstrate that a genetic QT score comprising 61 common genetic variants explains a significant proportion of the variability in drug-induced QT prolongation and is a significant predictor of drug-induced torsade de pointes. These findings highlight an opportunity for recent genetic discoveries to improve

  9. Drug-induced acute myocardial infarction: identifying 'prime suspects' from electronic healthcare records-based surveillance system.

    Preciosa M Coloma

    Full Text Available BACKGROUND: Drug-related adverse events remain an important cause of morbidity and mortality and impose huge burden on healthcare costs. Routinely collected electronic healthcare data give a good snapshot of how drugs are being used in 'real-world' settings. OBJECTIVE: To describe a strategy that identifies potentially drug-induced acute myocardial infarction (AMI from a large international healthcare data network. METHODS: Post-marketing safety surveillance was conducted in seven population-based healthcare databases in three countries (Denmark, Italy, and the Netherlands using anonymised demographic, clinical, and prescription/dispensing data representing 21,171,291 individuals with 154,474,063 person-years of follow-up in the period 1996-2010. Primary care physicians' medical records and administrative claims containing reimbursements for filled prescriptions, laboratory tests, and hospitalisations were evaluated using a three-tier triage system of detection, filtering, and substantiation that generated a list of drugs potentially associated with AMI. Outcome of interest was statistically significant increased risk of AMI during drug exposure that has not been previously described in current literature and is biologically plausible. RESULTS: Overall, 163 drugs were identified to be associated with increased risk of AMI during preliminary screening. Of these, 124 drugs were eliminated after adjustment for possible bias and confounding. With subsequent application of criteria for novelty and biological plausibility, association with AMI remained for nine drugs ('prime suspects': azithromycin; erythromycin; roxithromycin; metoclopramide; cisapride; domperidone; betamethasone; fluconazole; and megestrol acetate. LIMITATIONS: Although global health status, co-morbidities, and time-invariant factors were adjusted for, residual confounding cannot be ruled out. CONCLUSION: A strategy to identify potentially drug-induced AMI from electronic healthcare

  10. Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats

    Yamazaki, Makoto; Miyake, Manami; Sato, Hiroko; Masutomi, Naoya; Tsutsui, Naohisa [Mitsubishi Tanabe Pharma Corporation, Kisarazu, Chiba 292-0818 (Japan); Adam, Klaus-Peter; Alexander, Danny C.; Lawton, Kay A.; Milburn, Michael V.; Ryals, John A.; Wulff, Jacob E. [Metabolon Inc., 617 Davis Drive, Suite 400, Durham, NC 27713 (United States); Guo, Lining, E-mail: lguo@metabolon.com [Metabolon Inc., 617 Davis Drive, Suite 400, Durham, NC 27713 (United States)

    2013-04-01

    Drug-induced liver injury (DILI) is a significant consideration for drug development. Current preclinical DILI assessment relying on histopathology and clinical chemistry has limitations in sensitivity and discordance with human. To gain insights on DILI pathogenesis and identify potential biomarkers for improved DILI detection, we performed untargeted metabolomic analyses on rats treated with thirteen known hepatotoxins causing various types of DILI: necrosis (acetaminophen, bendazac, cyclosporine A, carbon tetrachloride, ethionine), cholestasis (methapyrilene and naphthylisothiocyanate), steatosis (tetracycline and ticlopidine), and idiosyncratic (carbamazepine, chlorzoxasone, flutamide, and nimesulide) at two doses and two time points. Statistical analysis and pathway mapping of the nearly 1900 metabolites profiled in the plasma, urine, and liver revealed diverse time and dose dependent metabolic cascades leading to DILI by the hepatotoxins. The most consistent change induced by the hepatotoxins, detectable even at the early time point/low dose, was the significant elevations of a panel of bile acids in the plasma and urine, suggesting that DILI impaired hepatic bile acid uptake from the circulation. Furthermore, bile acid amidation in the hepatocytes was altered depending on the severity of the hepatotoxin-induced oxidative stress. The alteration of the bile acids was most evident by the necrosis and cholestasis hepatotoxins, with more subtle effects by the steatosis and idiosyncratic hepatotoxins. Taking together, our data suggest that the perturbation of bile acid homeostasis is an early event of DILI. Upon further validation, selected bile acids in the circulation could be potentially used as sensitive and early DILI preclinical biomarkers. - Highlights: ► We used metabolomics to gain insights on drug induced liver injury (DILI) in rats. ► We profiled rats treated with thirteen hepatotoxins at two doses and two time points. ► The toxins decreased the

  11. Mitochondrial bioenergetics and drug-induced toxicity in a panel of mouse embryonic fibroblasts with mitochondrial DNA single nucleotide polymorphisms

    Pereira, Claudia V.; Oliveira, Paulo J. [CNC—Center for Neuroscience and Cell Biology, University of Coimbra (Portugal); Will, Yvonne [Compound Safety Prediction, Pfizer Global Research and Development, Groton, CT (United States); Nadanaciva, Sashi, E-mail: sashi.nadanaciva@pfizer.com [Compound Safety Prediction, Pfizer Global Research and Development, Groton, CT (United States)

    2012-10-15

    Mitochondrial DNA (mtDNA) variations including single nucleotide polymorphisms (SNPs) have been proposed to be involved in idiosyncratic drug reactions. However, current in vitro and in vivo models lack the genetic diversity seen in the human population. Our hypothesis is that different cell strains with distinct mtDNA SNPs may have different mitochondrial bioenergetic profiles and may therefore vary in their response to drug-induced toxicity. Therefore, we used an in vitro system composed of four strains of mouse embryonic fibroblasts (MEFs) with mtDNA polymorphisms. We sequenced mtDNA from embryonic fibroblasts isolated from four mouse strains, C57BL/6J, MOLF/EiJ, CZECHII/EiJ and PERA/EiJ, with the latter two being sequenced for the first time. The bioenergetic profile of the four strains of MEFs was investigated at both passages 3 and 10. Our results showed that there were clear differences among the four strains of MEFs at both passages, with CZECHII/EiJ having a lower mitochondrial robustness when compared to C57BL/6J, followed by MOLF/EiJ and PERA/EiJ. Seven drugs known to impair mitochondrial function were tested for their effect on the ATP content of the four strains of MEFs in both glucose- and galactose-containing media. Our results showed that there were strain-dependent differences in the response to some of the drugs. We propose that this model is a useful starting point to study compounds that may cause mitochondrial off-target toxicity in early stages of drug development, thus decreasing the number of experimental animals used. -- Highlights: ► mtDNA SNPs may be linked to individual predisposition to drug-induced toxicity. ► CZECHII/EiJ and PERA/EiJ mtDNA was sequenced for the first time in this study. ► Strain-dependent mitochondrial capacity differences were measured. ► Strain-dependent differences in response to mitochondrial toxicants were observed.

  12. Cardiac abnormalities after subarachnoid hemorrhage

    Bilt, I.A.C. van der

    2016-01-01

    Aneurysmal subarachnoid hemorrhage(aSAH) is a devastating neurological disease. During the course of the aSAH several neurological and medical complications may occur. Cardiac abnormalities after aSAH are observed often and resemble stress cardiomyopathy or Tako-tsubo cardiomyopathy(Broken Heart Syn

  13. Congenital abnormalities in methylmercury poisoning

    Gilani, S.H.

    1975-04-01

    This study was undertaken to determine the teratogenic potential of methylmercury on chick embryogenesis. Methylmercuric chloride was dissolved in sodium bicarbonate (0.2%) and administered to the chick embryos at doses ranging from 0.0009 to 0.010 mg per egg. The injections were made at days 2 and 3 on incubation (Groups A and B). All the embryos including controls were examined on the 7th day of incubation. Methylmercury poisoning was observed to be both embryolethal and teratogenic. Within the two groups, embryolethality was higher in Group A. The following congenital abnormalities were observed: exencephaly, shortened and twisted limbs, microphthalmia, shortened and twisted neck, beak abnormalities, everted viscera, reduced body size and hemorrhage all over the body. Exencephaly and limb abnormalities were very common. No differences in the incidence and types of gross abnormalities within both the groups (A and B) were noted. The incidence of malformations among the controls was low. The results of present investigation show that methylmercury poisoning is both embryolethal and teratogenic to early chick embryogenesis. (auth)

  14. Effect of subclinical, clinical and supraclinical doses of calcium channel blockers on models of drug-induced hepatotoxicity in rats.

    Okwa, Iniviefien B; Akindele, Abidemi J; Agbaje, Esther O; Oshinuga, Oladoyin T; Anunobi, Chidozie C; Adeyemi, Olufunmilayo O

    2013-01-01

    Drug-related hepatotoxicity is the leading cause of acute liver failure, and hepatic problems are responsible for a significant number of liver transplantations and deaths worldwide. Calcium has been associated with various metabolic processes that lead to cell death and apoptosis, and increased cytosolic Ca(2+) has been implicated in hepatotoxicity. This study was designed to investigate the effects of calcium channel blockers (CCBs) on isoniazid-rifampicin, zidovudine and erythromycin-induced hepatotoxicity in rats. Treatment groups comprised control, hepatotoxicant, hepatotoxicant along with each of silymarin, nifedipine, verapamil and diltiazem at subclinical, clinical and supraclinical doses. A day to the end of treatment for each model, rats were subjected to the hexobarbitone-induced hypnosis test. On the last days of treatment, blood samples were collected and serum was analyzed for relevant biochemical parameters. Animals were sacrificed after blood collection and livers were harvested, and samples obtained for in vivo antioxidant indices assay and histopathology. The hepatotoxicants significantly increased serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), as well as duration of sleep in the hypnosis test. These drugs significantly reduced the hepatic levels of reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and increased the level of malondialdehyde (MDA). The CCBs at the various doses significantly reversed the effects of isoniazid-rifampicin, zidovudine and erythromycin. The results obtained in this study suggest that the CCBs possess hepatoprotective activity in drug-induced hepatotoxicity and may be beneficial at the subclinical and clinical doses.

  15. TGF-beta isoforms and TGF-beta receptors in drug-induced and hereditary gingival overgrowth.

    Wright, H J; Chapple, I L; Matthews, J B

    2001-05-01

    Drug therapy and hereditary factors are two of the main causes of gingival overgrowth (GO). Both of these forms of GO are associated with increased extracellular matrix production by fibroblasts. Transforming growth factor beta (TGF-beta) is an important mediator of wound healing and tissue regeneration, which stimulates fibroblasts to produce extracellular matrix materials. The aim of this immunohistochemical study was to determine whether there is any altered expression of TGF-beta isoforms or its receptors in tissue from patients with drug-induced GO (DIGO; n=10) and hereditary gingival fibromatosis (n=10) when compared to non-overgrowth tissue (n=10). Compared to control tissues, significantly more fibroblasts expressed TGF-beta1 in both DIGO and hereditary gingival fibromatosis tissues (Pfibroblast densities between groups, there was a proportional increase in TGF-beta3 as well as TGF-beta1 expressing cells within both overgrowth populations (Preceptor-positive cells in the total cell population analysed in overgrowth tissues (Pisoform and receptor expression by fibroblasts in gingival overgrowth that may contribute to disease pathogenesis.

  16. Late sodium current block for drug-induced long QT syndrome: Results from a prospective clinical trial.

    Johannesen, L; Vicente, J; Mason, J W; Erato, C; Sanabria, C; Waite-Labott, K; Hong, M; Lin, J; Guo, P; Mutlib, A; Wang, J; Crumb, W J; Blinova, K; Chan, D; Stohlman, J; Florian, J; Ugander, M; Stockbridge, N; Strauss, D G

    2016-02-01

    Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market. At the same time, the current regulatory paradigm for screening new drugs causing long QT syndrome is preventing drugs from reaching the market, sometimes inappropriately. In this study, we report the results of a first-of-a-kind clinical trial studying late sodium (mexiletine and lidocaine) and calcium (diltiazem) current blocking drugs to counteract the effects of hERG potassium channel blocking drugs (dofetilide and moxifloxacin). We demonstrate that both mexiletine and lidocaine substantially reduce heart-rate corrected QT (QTc) prolongation from dofetilide by 20 ms. Furthermore, all QTc shortening occurs in the heart-rate corrected J-Tpeak (J-Tpeak c) interval, the biomarker we identified as a sign of late sodium current block. This clinical trial demonstrates that late sodium blocking drugs can substantially reduce QTc prolongation from hERG potassium channel block and assessment of J-Tpeak c may add value beyond only assessing QTc.

  17. Reprogramming of sheep fibroblasts into pluripotency under a drug-inducible expression of mouse-derived defined factors.

    Yang Li

    Full Text Available Animal embryonic stem cells (ESCs provide powerful tool for studies of early embryonic development, gene targeting, cloning, and regenerative medicine. However, the majority of attempts to establish ESC lines from large animals, especially ungulate mammals have failed. Recently, another type of pluripotent stem cells, known as induced pluripotent stem cells (iPSCs, have been successfully generated from mouse, human, monkey, rat and pig. In this study we show sheep fibroblasts can be reprogrammed to pluripotency by defined factors using a drug-inducible system. Sheep iPSCs derived in this fashion have a normal karyotype, exhibit morphological features similar to those of human ESCs and express AP, Oct4, Sox2, Nanog and the cell surface marker SSEA-4. Pluripotency of these cells was further confirmed by embryoid body (EB and teratoma formation assays which generated derivatives of all three germ layers. Our results also show that the substitution of knockout serum replacement (KSR with fetal bovine serum in culture improves the reprogramming efficiency of sheep iPSCs. Generation of sheep iPSCs places sheep on the front lines of large animal preclinical trials and experiments involving modification of animal genomes.

  18. 药物诱发的免疫性溶血性贫血%Drug-induced immune hemolytic anemia

    刘代红

    2012-01-01

    药物诱发的免疫性溶血性贫血( DIIHA)少见.临床表现为中重度溶血性贫血常见机制是产生药物依赖性抗体,常见药物为抗生素(如头孢替坦、头孢曲松钠和哌拉西林).少见机制是产生非药物依赖的自身抗体,致特发性温抗体型自身免疫性溶血性贫血,最常见药物是氟达拉滨.治疗首要是停药,并积极处理合并症.%Drug-induced immune hemolytic anemia (DHHA) is seldom seen,whose clinical manifestation is mild-to-severe hemolytic anemia. The common mechanism is the presence of drug-dependent antibodies,and the common drugs are antibiotics, such as cefotetan,ceftriaxone and piperacillin. On other hand,the uncommon mechanism is the presence of non-drug-dependent antibodies that can lead to idiopathic autoimmune hemolytic anemia. In such case,the most common drug is flu-darabine. Importantly,drug use should be stopped and the complications be actively treated.

  19. 茵栀黄颗粒致药物性肝炎2例%Two cases of drug-induced hepatitis caused by Yinzhihuang granules

    蒋杰; 劳国琴; 张谊芳

    2014-01-01

    Case 1:one 46-year-old male patient developed vomiting, lack of power, yellow urine with chill and fever after receiving Yinzhihuang granules for the treatment of abnormal liver function. The highest body temperature was 39.0℃. All the above symptoms alleviated after discontinuation of the drug. Two months later, Yinzhihuang granules were taken again and the symptoms of chill, fever, lack of power and yellow urine reappeared. Laboratory examinations were as follows:TBIL 65.7 µmol·L-1, DBIL 34.8 µmol·L-1, ALT 939.2 IU·L-1, AST 489.9 IU·L-1,γ-GT 785.0 IU·L-1. Drug-induced hepatitis was diagnosed and Yinzhihuang granules were stopped. Treatments of protecting liver function, depressing transaminase and abating jaundice were given to the patient. After 45 days, the patient discharged with normal liver function. Case 2:one 51-year-old female patient was admitted to hospital because of acute hepatitis E. The liver function of the patient recovered after 2-month treatment, and then the patient discharged with Yinzhihuang granules. Ten days later, the patient developed fever, vomiting, abdominal distention and anorexia. Laboratory ifndings were:TBIL 22.8 µmol·L-1, DBIL 16.0 µmol·L-1, ALT 308.0 IU·L-1, AST 309.0 IU·L-1,γ-GT 237.0 IU·L-1, AKP 258.0 IU·L-1. The patient was hospitalized again and the clinical diagnosis was drug-induced hepatitis. Yinzhihuang granules were stopped, and the symptomatic treatments of protecting liver function, depressing transaminase and abating jaundice were given immediately. About 35 days later, hepatic function of the patient recovered to normal.%病例1:患者,男性,46岁,因肝功能异常服用茵栀黄颗粒降酶退黄治疗,后出现呕吐、乏力,小便颜色进行性加深,并伴有畏寒、发热,体温最高达39.0℃。自行停药后体温降至正常,症状缓解。2个月后再次服用茵栀黄颗粒,畏寒、发热、乏力、尿黄症状再次出现。于外院查肝功能示:TBIL 65

  20. Nail abnormalities in rheumatoid arthritis.

    Michel, C; Cribier, B; Sibilia, J; Kuntz, J L; Grosshans, E

    1997-12-01

    Many nail abnormalities have traditionally been described in association with rheumatoid arthritis (RA), but their specificity has never been assessed in a controlled study. Our purpose was to evaluate the frequency and the specificity of nail changes associated with RA in a case-controlled study including 50 patients suffering from RA and 50 controls. For each patient, a general skin examination was performed and the 20 nails were examined. The nail features were noted and classified. A chi 2 test or a Fisher test was used to compare the two groups. The only nail abnormalities significantly associated with RA were longitudinal ridging on nine or 10 finger nails (29 patients in the RA group vs. three in the controls, chi 2: P nail (24 patients vs. 10, chi 2: P nail changes were noticed but were not frequent enough to be significant. The presence of longitudinal ridging on the finger nails was significantly associated with RA.

  1. Neuroendocrine abnormalities in Parkinson's disease.

    De Pablo-Fernández, Eduardo; Breen, David P; Bouloux, Pierre M; Barker, Roger A; Foltynie, Thomas; Warner, Thomas T

    2017-02-01

    Neuroendocrine abnormalities are common in Parkinson's disease (PD) and include disruption of melatonin secretion, disturbances of glucose, insulin resistance and bone metabolism, and body weight changes. They have been associated with multiple non-motor symptoms in PD and have important clinical consequences, including therapeutics. Some of the underlying mechanisms have been implicated in the pathogenesis of PD and represent promising targets for the development of disease biomarkers and neuroprotective therapies. In this systems-based review, we describe clinically relevant neuroendocrine abnormalities in Parkinson's disease to highlight their role in overall phenotype. We discuss pathophysiological mechanisms, clinical implications, and pharmacological and non-pharmacological interventions based on the current evidence. We also review recent advances in the field, focusing on the potential targets for development of neuroprotective drugs in Parkinson's disease and suggest future areas for research.

  2. Radiological appearances of sinonasal abnormalities

    El-Beltagi, A.H.; Sobeih, A.A.; Valvoda, M.; Dahniya, M.H.; Badr, S.S

    2002-08-01

    The aim of this pictorial review is to present a variety of abnormalities of the sinonasal cavities to emphasize the diversity of lesions occurring in this region. These include congenital, neoplastic and granulomatous disorders and some allergic and inflammatory lesions with uncommon radiological appearances, as well as expanding lesions of the facial bones or of dental origin with secondary involvement of the related sinus(es). El-Beltagi, A.H. et al. (2002). Clinical Radiology 57, 702-718.

  3. Computed tomography of thymic abnormalities

    Schnyder, P.; Candardjis, G.

    1987-05-01

    Computed tomographic examinations of 38 patients with surgically and histologically proven diagnosis were reviewed. Twenty subjects (52%) had an invasive thymoma and 16% an hyperplastic thymus. Myasthenia gravis was present in 6 cases (16%) of thymic abnormalities, four (10,5%) with invasive thymoma and two (5%) with thymic hyperplasia. Graves' disease was also present in one case of thymic hyperplasia. We emphasize the contribution of CT to the diagnosis and the prognosis.

  4. Drug-induced diarrhea

    ... cancer Drugs used to treat heartburn and stomach ulcers, such as omeprazole (Prilosec), esomeprazole (Nexium), lansoprazole (Prevacid), rabeprazole (AcipHex), pantoprazole (Protonix), cimetidine (Tagamet), ranitidine ( ...

  5. Drug-induced tremor

    ... medicine without first talking to your provider. Possible Complications Severe tremor can interfere with daily activities, especially fine motor skills such as writing, and other activities such ...

  6. Meiotic abnormalities in infertile males.

    Egozcue, J; Sarrate, Z; Codina-Pascual, M; Egozcue, S; Oliver-Bonet, M; Blanco, J; Navarro, J; Benet, J; Vidal, F

    2005-01-01

    Meiotic anomalies, as reviewed here, are synaptic chromosome abnormalities, limited to germ cells that cannot be detected through the study of the karyotype. Although the importance of synaptic errors has been underestimated for many years, their presence is related to many cases of human male infertility. Synaptic anomalies can be studied by immunostaining of synaptonemal complexes (SCs), but in this case their frequency is probably underestimated due to the phenomenon of synaptic adjustment. They can also be studied in classic meiotic preparations, which, from a clinical point of view, is still the best approach, especially if multiplex fluorescence in situ hybridization is at hand to solve difficult cases. Sperm chromosome FISH studies also provide indirect evidence of their presence. Synaptic anomalies can affect the rate of recombination of all bivalents, produce achiasmate small univalents, partially achiasmate medium-sized or large bivalents, or affect all bivalents in the cell. The frequency is variable, interindividually and intraindividually. The baseline incidence of synaptic anomalies is 6-8%, which may be increased to 17.6% in males with a severe oligozoospermia, and to 27% in normozoospermic males with one or more previous IVF failures. The clinical consequences are the production of abnormal spermatozoa that will produce a higher number of chromosomally abnormal embryos. The indications for a meiotic study in testicular biopsy are provided.

  7. Amelioration of anti-tuberculosis drug induced oxidative stress in kidneys by Spirulina fusiformis in a rat model.

    Martin, Sherry Joseph; Sabina, Evan Prince

    2016-08-01

    Nephrotoxicity is a rare complication caused by anti-tuberculosis therapy-induced oxidative stress. The Cyanobacterium Spirulina fusiformis Voronikhin belonging to Oscillatoriaceae family is used traditionally as a source of antioxidants against oxidative stress. We aimed to investigate the efficacy of S. fusiformis in modifying isoniazid (INH) and rifampicin (RIF)-induced changes in Wistar rat kidneys. Animals were divided into six groups: normal control rats; toxic control (INH & RIF-50 mg/kg b.w./d each; p.o.); INH & RIF + S. fusiformis (400 mg/kg b.w./d); INH & RIF + S. fusiformis (800 mg/kg b.w./d); S. fusiformis (800 mg/kg b.w./d) alone-treated rats; INH & RIF + silymarin (25 mg/kg b.w./d). Study duration was 28 d after which blood and kidneys were analyzed. We also studied the binding and interactions of the transcription factors Liver X Receptor (LXR) and Farnesoid X Receptor (FXR) with INH, RIF, and representative active compounds of S. fusiformis by in silico methods. INH & RIF treatment caused significant (p< 0.05) decrease in antioxidant levels and significant (p< 0.05) increase in the levels of creatinine, urea, and uric acid showing impaired kidney function. Spirulina fusiformis ameliorated these effects in a dose dependent manner. Histological examination of kidneys supported these findings. Results of the in silico analyses showed that selected active components of S. fusiformis interact with LXR and FXR and could be a possible mechanism of action. S. fusiformis rendered protection against anti-tuberculosis drugs-induced oxidative stress in kidney tissues of rats.

  8. A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: application to acetaminophen

    Michaut, Anaïs; Le Guillou, Dounia; Moreau, Caroline; Bucher, Simon; McGill, Mitchell R.; Martinais, Sophie; Gicquel, Thomas; Morel, Isabelle; Robin, Marie-Anne; Jaeschke, Hartmut; Fromenty, Bernard

    2016-01-01

    Obesity and nonalcoholic fatty liver disease (NAFLD) can increase susceptibility to hepatotoxicity induced by some xenobiotics including drugs, but the involved mechanisms are poorly understood. For acetaminophen (APAP), a role of hepatic cytochrome P450 2E1 (CYP2E1) is suspected since the activity of this enzyme is consistently enhanced during NAFLD. The first aim of our study was to set up a cellular model of NAFLD characterized not only by triglyceride accumulation but also by higher CYP2E1 activity. To this end, human HepaRG cells were incubated for one week with stearic acid or oleic acid, in the presence of different concentrations of insulin. Although cellular triglycerides and the expression of lipid-responsive genes were similar with both fatty acids, CYP2E1 activity was significantly increased only by stearic acid. CYP2E1 activity was reduced by insulin and this effect was reproduced in cultured primary human hepatocytes. Next, APAP cytotoxicity was assessed in HepaRG cells with or without lipid accretion and CYP2E1 induction. Experiments with a large range of APAP concentrations showed that the loss of ATP and glutathione was almost always greater in the presence of stearic acid. In cells pretreated with the CYP2E1 inhibitor chlormethiazole, recovery of ATP was significantly higher in the presence of stearate with low (2.5 mM) or high (20 mM) concentrations of APAP. Levels of APAP-glucuronide were significantly enhanced by insulin. Hence, HepaRG cells can be used as a valuable model of NAFLD to unveil important metabolic and hormonal factors which can increase susceptibility to drug-induced hepatotoxicity. PMID:26739624

  9. An integrated perspective on diabetic, alcoholic, and drug-induced neuropathy, etiology, and treatment in the US

    Zeng, Lily; Alongkronrusmee, Doungkamol; van Rijn, Richard M

    2017-01-01

    Neuropathic pain (NeuP) is a syndrome that results from damaged nerves and/or aberrant regeneration. Common etiologies of neuropathy include chronic illnesses and medication use. Chronic disorders, such as diabetes and alcoholism, can cause neuronal injury and consequently NeuP. Certain medications with antineoplastic effects also carry an exquisitely high risk for neuropathy. These culprits are a few of many that are fueling the NeuP epidemic, which currently affects 7%–10% of the population. It has been estimated that approximately 10% and 7% of US adults carry a diagnosis of diabetes and alcohol disorder, respectively. Despite its pervasiveness, many physicians are unfamiliar with adequate treatment of NeuP, partly due to the few reviews that are available that have integrated basic science and clinical practice. In light of the recent Centers for Disease Control and Prevention guidelines that advise against the routine use of μ-opioid receptor-selective opioids for chronic pain management, such a review is timely. Here, we provide a succinct overview of the etiology and treatment options of diabetic and alcohol- and drug-induced neuropathy, three different and prevalent neuropathies fusing the combined clinical and preclinical pharmacological expertise in NeuP of the authors. We discuss the anatomy of pain and pain transmission, with special attention to key ion channels, receptors, and neurotransmitters. An understanding of pain neurophysiology will lead to a better understanding of the rationale for the effectiveness of current treatment options, and may lead to better diagnostic tools to help distinguish types of neuropathy. We close with a discussion of ongoing research efforts to develop additional treatments for NeuP. PMID:28176937

  10. Drug-Induced Sleep Endoscopy (DISE) with Target Controlled Infusion (TCI) and Bispectral Analysis in Obstructive Sleep Apnea.

    Traxdorf, Maximilian; Tschaikowsky, Klaus; Scherl, Claudia; Bauer, Judith; Iro, Heinrich; Angerer, Florian

    2016-12-06

    The aim of this study was to establish a standardized protocol for drug-induced sleep endoscopy (DISE) to differentiate obstruction patterns in obstructive sleep apnea (OSA). Target-controlled infusion (TCI) of the sedative propofol was combined with real-time monitoring of the depth of sedation using bispectral analysis. In an observational study 57 patients (mean age 44.8 years, ± SD 10.5; mean apnea hypopnea Index (AHI) 30.8/hr, ± SD 21.6, mean BMI 28.2 kg/m(2), ± SD 5.3) underwent cardiorespiratory polysomnography followed by DISE with TCI and bispectral analysis. Sleep was induced solely by the intravenous infusion of propofol with a TCI-pump, with an initial target plasma level of 2.0 µg/ml. Under continuous monitoring of the patient's respiration, state of consciousness and value of the bispectral analysis, the target plasma propofol level was raised in steps of 0.2 µg/ml/2 min until the desired depth of sedation was reached. The mean value of the bispectral analysis at the target depth of sedation was determined and the obstruction patterns during DISE-TCI-bispectral analysis then classified according to the VOTE-system. Subsequently the results were analyzed according to polysomnographic and anthropometric data. The occurrence of multilevel obstruction sites across all degrees of severity of OSA clarifies the need for sleep endoscopy prior to upper airway surgery. The advantage of this technique is the reproducibility of the protocol even for heterogeneous groups of patients. In addition, the gradual controlled and standardized increase of the plasma level of propofol with real-time control of the bispectral index leads to a precisely controllable depth of sedation. The DISE-TCI-bispectral analysis procedure is a step towards a required reproducible protocol of sleep endoscopy - capable of standardization. However it is not yet known whether these observed obstruction patterns also correspond to findings in natural sleep.

  11. Development of a prediction system for anti-tuberculosis drug-induced liver injury in Japanese patients

    Mushiroda, Taisei; Yanai, Hideki; Yoshiyama, Takashi; Sasaki, Yuka; Okumura, Masao; Ogata, Hideo; Tokunaga, Katsushi

    2016-01-01

    Drug-induced liver injury (DILI) is a common adverse drug reaction in patients receiving antituberculosis (anti-TB) treatment. Among the anti-TB agents, isoniazid (INH) is the primary drug that causes hepatotoxicity in TB patients with DILI. Previous reports in several populations have consistently demonstrated an association between polymorphisms in the N-acetyltransferase 2 (NAT2) gene, which is responsible for INH hepatic metabolism, and a risk of DILI in TB patients. In this study, the genetic and baseline clinical data from 366 Japanese patients with TB (73 patients with DILI and 293 without DILI) were used to develop a system to predict DILI risk due to anti-TB agents. The distribution of the NAT2 acetylator status among the TB patients with DILI was 31 (42.5%), 29 (39.7%), and 13 (17.8%) for rapid, intermediate, and slow acetylators, respectively. A significant association was observed between NAT2 slow acetylators and DILI risk (odds ratio 4.32, 95% confidence interval 1.93–9.66, P value=5.56×10−4). A logistic regression model based on age and NAT2 genotype revealed that the area under the curve for the receiver-operating characteristic curve was 0.717. The findings demonstrated that slow NAT2 acetylator status is a significant predictor of the risk of DILI by anti-TB agents, and a personalized anti-TB treatment approach may aid in making treatment decisions and reducing the incidence of DILI. PMID:27340556

  12. Prediction of Drug-Induced Liver Injury in HepG2 Cells Cultured with Human Liver Microsomes.

    Choi, Jong Min; Oh, Soo Jin; Lee, Ji-Yoon; Jeon, Jang Su; Ryu, Chang Seon; Kim, Young-Mi; Lee, Kiho; Kim, Sang Kyum

    2015-05-18

    Drug-induced liver injury (DILI) via metabolic activation by drug-metabolizing enzymes, especially cytochrome P450 (CYP), is a major cause of drug failure and drug withdrawal. In this study, an in vitro model using HepG2 cells in combination with human liver microsomes was developed for the prediction of DILI. The cytotoxicity of cyclophosphamide, a model drug for bioactivation, was augmented in HepG2 cells cultured with microsomes in a manner dependent on exposure time, microsomal protein concentration, and NADPH. Experiments using pan- or isoform-selective CYP inhibitors showed that CYP2B6 and CYP3A4 are responsible for the bioactivation of cyclophosphamide. In a metabolite identification study employing LC-ESI-QTrap and LC-ESI-QTOF, cyclophosphamide metabolites including phosphoramide mustard, a toxic metabolite, were detected in HepG2 cells cultured with microsomes, but not without microsomes. The cytotoxic effects of acetaminophen and diclofenac were also potentiated by microsomes. The potentiation of acetaminophen cytotoxicity was dependent on CYP-dependent metabolism, and the augmentation of diclofenac cytotoxicity was not mediated by either CYP- or UDP-glucuronosyltransferase-dependent metabolism. The cytotoxic effects of leflunomide, nefazodone, and bakuchiol were attenuated by microsomes. The detoxication of leflunomide by microsomes was attributed to mainly CYP3A4-dependent metabolism. The protective effect of microsomes against nefazodone cytotoxicity was dependent on both CYP-mediated metabolism and nonspecific protein binding. Nonspecific protein binding but not CYP-dependent metabolism played a critical role in the attenuation of bakuchiol cytotoxicity. The present study suggests that HepG2 cells cultured with human liver microsomes can be a reliable model in which to predict DILI via bioactivation by drug metabolizing enzymes.

  13. Hepatoprotective activity of aqueous alcoholic (70% extract of Rhodomyrtus tomentosa (Aiton Hassk against antitubercular drugs induced hepatic damage

    Kannoth Mukundan Geetha

    2012-01-01

    Full Text Available Background: Rhodomyrtus tomentosa of family Myrtaceae has been used traditionally in Chinese medicine for the treatment of liver disorders. However, there is no scientific evidence on the hepatoprotective potential of the plant. Aim: The present study was aimed at evaluating the hepatoprotective and antioxidant potential of the aqueous alcoholic (70% extract of Rhodomyrtus tomentosa leaves (RTLE based on its traditional claim in liver diseases. Materials and Methods: Hepatotoxicity was induced in albino rats by administering a combination of three antitubercular drugs, Isoniazid (7.5 mg/kg, Pyrazinamide (35 mg/kg and Rifampicin (10 mg/kg orally for 45 days. Alkaline phosphatase (ALP, Aspartate amino transferase (AST, Alanine aminotransferase (ALT, total protein and total bilirubin (TB levels were estimated in serum samples using diagnostic kits. Antioxidant parameters were estimated in liver homogenates using standard methods. Statistical Analysis: The experimental mean values were compared statistically with that of toxicant group by using One-way ANOVA followed by Newman-Keul′s multiple tests. Results: Hepatoprotective activity of the extract was evident from the significant decrease in the elevated levels of ALT, AST, ALP and total bilirubin and an increase in the levels of total protein in comparison to toxicant control. Increased activity of antioxidant enzymes supports the in vivo antioxidant activity of the extract. Histopathological changes of the liver in the treated and control group of rats were in agreement with the hepatoprotective finding. Conclusion: RTLE exhibited hepatoprotective activity against antitubercular drug induced hepatotoxicity through a free radical scavenging effect and reduces oxidative damage caused by antitubercular drugs.

  14. Upper airway collapse during drug induced sleep endoscopy: head rotation in supine position compared with lateral head and trunk position.

    Safiruddin, Faiza; Koutsourelakis, Ioannis; de Vries, Nico

    2015-02-01

    Drug induced sedated sleep endoscopy (DISE) is often employed to determine the site, severity and pattern of obstruction in patients with sleep apnea. DISE is usually performed in supine position. We recently showed that the obstruction pattern is different when DISE is performed in lateral position. In this study, we compared the outcomes of DISE performed in supine position with head rotated, with the outcomes of DISE performed with head and trunk in lateral position. The Prospective study design was used in the present study. Sixty patients with OSA (44 male; mean apnea hypopnea index (AHI) 20.8 ± 17.5 events/h) underwent DISE under propofol sedation. Patients were placed in lateral position, and the upper airway collapse was evaluated. The patients were then placed in supine position with the head rotated to the right side. DISE outcomes were scored using the VOTE classification system. In lateral position, nine patients (15.0%) had a complete antero-posterior (A-P) collapse at the level of the velum, nine had a partial A-P collapse. During head rotation and trunk in supine position, at the level of the velum, four patients (6.7%) had a complete A-P collapse, while two patients (3.3%) had a partial A-P collapse. For all other sites, the patterns of collapse were not significantly different between head rotation and lateral position. During DISE, rotation of the head in supine position, and lateral head and trunk position present similar sites, severity and patterns of upper airway collapse, with the exception of collapse at the level of the velum. Here the severity of A-P collapse is less severe during head rotation than in lateral head and trunk position.

  15. The anti-cancer drug-induced pica in rats is related to their clinical emetogenic potential.

    Yamamoto, Kouichi; Nakai, Miho; Nohara, Kyoko; Yamatodani, Atsushi

    2007-01-05

    Cancer chemotherapy is frequently accompanied by severe emesis. The anti-cancer drugs are classified according to their clinical emetogenic potential. We have already found that kaolin ingestion behavior "pica" is analogous to emesis in rats. The aim of this study was to examine the effects of the clinical emetogenic potential of anti-cancer drugs on the induction of the pica in rats. Rats were housed in individual cages with free access to food and kaolin pellets and the daily food and kaolin intakes were measured for 3 days after the intraperitoneal administration of anti-cancer drugs (cisplatin, cyclophosphamide, actinomycin D, 5-fluorouracil and vincristine). The drugs with high potential for inducing emesis, such as cisplatin and cyclophosphamide, induced pica in all animals on the day of administration and the behavior lasted during the observation period. The drugs with moderate emetogenic potential, i.e. actinomycin D and 5-fluorouracil, also induced pica on the first and second day after the drug administration but the kaolin intake was less than that of the drugs with high potential. Vincristine, a drug with low emetogenic potential, slightly increased the kaolin intake in rats on the only first day of the administration. Cyclophosphamide, actinomycin D and vincristine induced anorexia and decreased their body weight during the observation period. These results suggested that the both amounts of kaolin intake and duration of behavior in the anti-cancer drug-induced pica are related to the clinical emetogenic potential of the drugs and the incidence of the anorexia is not related to their emetogenic potential.

  16. Chemosensitivity of human small cell carcinoma of the lung detected by flow cytometric DNA analysis of drug-induced cell cycle perturbations in vitro

    Engelholm, S A; Spang-Thomsen, M; Vindeløv, L L

    1986-01-01

    A method based on detection of drug-induced cell cycle perturbation by flow cytometric DNA analysis has previously been described in Ehrlich ascites tumors as a way to estimate chemosensitivity. The method is extended to test human small-cell carcinoma of the lung. Three tumors with different...... sensitivities to melphalan in nude mice were used. Tumors were disaggregated by a combined mechanical and enzymatic method and thereafter have incubated with different doses of melphalan. After incubation the cells were plated in vitro on agar, and drug induced cell cycle changes were monitored by flow...... cytometric DNA analysis. Melphalan produced a dose-related S phase accumulation in the two sensitive tumors, whereas no changes in the cell cycle distribution were found in the resistant tumor. The size of S phase accumulation correlated to the chemosensitivity in vivo. For low concentrations of melphalan...

  17. Identification and Treatment of Psychotropic Drug-induced Alopecia%精神药物致脱发的识别与处理

    孙振晓; 于相芬

    2014-01-01

    多种精神药物可引起脱发,本文对脱发的概念、精神药物所致脱发的诊断、鉴别诊断、发病机制及处理等作一综述,以提高临床对精神药物所致脱发的认识。%A variety of psychotropic drugs can cause alopecia . In order to make a better understanding of psy-chotropic drug-induced alopecia , this article made a review on the definition of alopecia , diagnosis , differential diag-nosis , pathomechanism and the treatment of psychotropic drug-induced alopecia .

  18. Clinical Analysis of 1 056 Cases of Drug-induced Hematuria in Children%儿童药物性血尿1056例临床分析

    王玉刚; 张亚明

    2011-01-01

    目的:探讨儿童药物性血尿的原因和机制,提出预防措施,促进临床合理用药.方法:对2005-2010年国内公开发表的医药期刊报道的1 056例儿童(≤16岁)药物性血尿进行统计、分析.结果:本研究中药物性血尿共涉及5类药物41个品种,以抗微生物药、解热镇痛抗炎药和抗感冒药为主,且与年龄、给药剂量、给药途径等有关.结论:充分认识药物性血尿产生的原因,安全、合理地使用药品,积极采取预防措施,对避免或减少儿童药物性血尿的发生有重要的临床意义.%OBJECTIVE: To investigate the characteristics and regularity of drug-induced hematuria in children, and to put forwards prevention measures in order to promote rational use of drugs in the clinic. METHODS: We summarized and analyzed 1056 cases of drug-induced hematuria in children (≤16 years old) published on public medical journals from 2005 to 2010. RESULTS: 5 categories and 41 kinds of drugs were involved, which included anti-microbial drugs, antipyretics-analgesic and anti-inflammatory drugs, anti-cold drugs. Besides, some cases happened due to patients' age, drug dosage, route of administration, etc. CONCLUSIONS: We come to recognize the causes of drug-induced hematuria, use drugs safely and properly, take preventive measures actively to avoid or reduce drug-induced hematuria in children.

  19. Literature Analysis of 66 Cases of Drug-induced Hyperkalemia%66例药源性高钾血症文献分析

    任晓蕾; 詹轶秋; 张春燕; 张海英; 冯婉玉

    2015-01-01

    目的:探讨药源性高钾血症的特点及相关因素,为临床合理用药提供依据。方法:检索1979-2014年国内医药期刊公开报道的药源性高钾血症的个案和群案文献46篇,共计病例66例,并进行统计分析。结果:66例药源性高钾血症病例中主要涉及心血管药物和免疫抑制剂。大部分停药及对症治疗后好转,其中2例患者死亡。结论:药物诱发高钾血症具有潜在的危险性,需提高警惕,重视防治。%OBJECTIVE:To investigate the characteristics and related factors of drug-induced hyperkalemia,present preven-tive measures and provide reference for the rational drug use. METHODS:46 literatures of individual cases and group cases of drug-induced hyperkalemia publicly reported in domestic medical journals from 1979 to 2014 were collected and analyzed statistical-ly,including 66 cases. RESULTS:66 cases with drug-induced hyperkalemia were mainly involved in cardiovascular drugs and im-munosuppressants. Most of them were improved after drug withdrawal and symptomatic treatment,and 2 cases died. CONCLU-SIONS:Drug-induced hyperkalemia are potentially dangerous. It is necessary to be vigilant,prevent and control timely and reduce the incidence of severe adverse reactions.

  20. Research Advances in Drug-induced Autoimmune Disordersw%药物诱导性自身免疫性疾病的研究进展

    钟佩茹

    2011-01-01

    药物诱导性自身免疫性疾病是长期用药引发的一种不良反应,其作用机制因药物种类不同而不同.但最终会因机体丧失对自身抗原的免疫耐受而产生自身抗体.认识原发性和药物诱导性自身免疫反应,将有助于提高对这些疾病机制的理解.并且通过分析药物诱导性自身免疫性疾病的发病机制,为药物不良反应的预防以及临床治疗提供帮助.%Drug-induced autoimmune disease is an adverse effect caused by the long-term use of drug. The mechanisma of actions depend the properties of drugs. The auto-antibodies are produced due to the loss of immune tolerance to the auto-antigens. The understanding of primary and drug-induced autoimmune response helps to improve the study of the pathogenesis of drug-induced autoimmune disease. The analysis.f pathogenesis of drug-in-duced autoimmune disease helps to improve the prevention and treatment of adverse drug reactions.

  1. 181例药源性肺水肿文献分析%Literature Analysis of 181 Cases of Drug-induced Pulmonary Edemas

    张艳丛

    2011-01-01

    OBJECTIVE To discuss the characteristics and general pattern of drug-induced pulmonary edemas. METHODS A total of 181 drug-induced pulmonary edema cases reported in internal medical journals published from January 1990 to April 2010 were collected by retrieving China Hospital Digital Library and analyzed statistically. RESULTS Leading the routes of administration inducing pulmonary edemas were oral administration, intramuscular injection, intravenous administration, and so on. The pulmonary edemas were predominantly caused by anti-psychotic drug and dehydration drugs. CONCLUSION Clinic should attach great importance to drugs-induced pulmonary edemas.%目的 探讨药物引起肺水肿的特点及一般规律.方法 检索,对1990年1月-2010年4月国内医药学术期刊报道的药物引起肺水肿181例进行统计、分析.结果 药物引起肺水肿的给药途径为口服给药、肌肉注射、静脉给药等;引起肺水肿的药物种类以抗精神病药、利尿脱水药较多.结论 临床应重视药物引起的肺水肿.

  2. The Hepatoprotection Provided by Taurine and Glycine against Antineoplastic Drugs Induced Liver Injury in an Ex Vivo Model of Normothermic Recirculating Isolated Perfused Rat Liver

    Reza Heidari

    2016-03-01

    Full Text Available Taurine (2-aminoethane sulfonic acid is a non-protein amino acid found in high concentration in different tissues. Glycine (Amino acetic acid is the simplest amino acid incorporated in the structure of proteins. Several investigations indicate the hepatoprotective properties of these amino acids. On the other hand, antineoplastic agents-induced serum transaminase elevation and liver injury is a clinical complication. The current investigation was designed to screen the possible hepatoprotective properties of taurine and glycine against antineoplastic drugs-induced hepatic injury in an ex vivo model of isolated perfused rat liver. Rat liver was perfused with different concentration (10 μM, 100 μM and 1000 μM of antineoplastic drugs (Mitoxantrone, Cyclophosphamide, Cisplatin, 5 Fluorouracil, Doxorubicin and Dacarbazine via portal vein. Taurine and glycine were administered to drug-treated livers and liver perfusate samples were collected for biochemical measurements (ALT, LDH, AST, and K+. Markers of oxidative stress (reactive oxygen species formation, lipid peroxidation, total antioxidant capacity and glutathione were also assessed in liver tissue. Antineoplastic drugs caused significant pathological changes in perfusate biochemistry. Furthermore, markers of oxidative stress were significantly elevated in drug treated livers. It was found that taurine (5 and 10 mM and glycine (5 and 10 mM administration significantly mitigated the biomarkers of liver injury and attenuated drug induced oxidative stress. Our data indicate that taurine and glycine supplementation might help as potential therapeutic options to encounter anticancer drugs-induced liver injury.

  3. Low-set ears and pinna abnormalities

    Low-set ears; Microtia; "Lop" ear; Pinna abnormalities; Genetic defect-pinna; Congenital defect-pinna ... conditions: Abnormal folds or location of the pinna Low-set ears No opening to the ear canal ...

  4. [Phenomenology of abnormal body perceptions].

    Schäfer, M L

    1983-01-01

    The present paper deals with the problematic nature of the phenomenological grasping of the consciousness of the body and its pathological modifications. The reasoning is oriented by the doctrine of Husserl of the so-called sentiments as the fundamentals of the experience of the own body. This basic approach does not only seem to be basically for a psychology of the consciousness of the body, but also to give the theoretical-conceptual structure for a great number of psychopathological modifications. Subsequent to a criticism of the conventional use of the term 'hallucination of the body' we attempt to chart elements of a scheme of the abnormal consciousness of the body.

  5. On Regularity of Abnormal Subriemannian Geodesics

    Tan, Kanghai

    2012-01-01

    We prove the smoothness of abnormal minimizers of subriemannian manifolds of step 3 with a nilpotent basis. We prove that rank 2 Carnot groups of step 4 admit no strictly abnormal minimizers. For any subriemannian manifolds of step less than 7, we show all abnormal minimizers have no corner type singularities, which partly generalize the main result of Leonardi-Monti.

  6. Chromosomal phenotypes and submicroscopic abnormalities

    Devriendt Koen

    2004-01-01

    Full Text Available Abstract The finding, during the last decade, that several common, clinically delineated syndromes are caused by submicroscopic deletions or, more rarely, by duplications, has provided a powerful tool in the annotation of the human genome. Since most microdeletion/microduplication syndromes are defined by a common deleted/duplicated region, abnormal dosage of genes located within these regions can explain the phenotypic similarities among individuals with a specific syndrome. As such, they provide a unique resource towards the genetic dissection of complex phenotypes such as congenital heart defects, mental and growth retardation and abnormal behaviour. In addition, the study of phenotypic differences in individuals with the same microdeletion syndrome may also become a treasury for the identification of modifying factors for complex phenotypes. The molecular analysis of these chromosomal anomalies has led to a growing understanding of their mechanisms of origin. Novel tools to uncover additional submicroscopic chromosomal anomalies at a higher resolution and higher speed, as well as the novel tools at hand for deciphering the modifying factors and epistatic interactors, are 'on the doorstep' and will, besides their obvious diagnostic role, play a pivotal role in the genetic dissection of complex phenotypes.

  7. Abnormal visuomotor processing in schizophrenia

    Siân E. Robson

    2016-01-01

    Full Text Available Subtle disturbances of visual and motor function are known features of schizophrenia and can greatly impact quality of life; however, few studies investigate these abnormalities using simple visuomotor stimuli. In healthy people, electrophysiological data show that beta band oscillations in sensorimotor cortex decrease during movement execution (event-related beta desynchronisation (ERBD, then increase above baseline for a short time after the movement (post-movement beta rebound (PMBR; whilst in visual cortex, gamma oscillations are increased throughout stimulus presentation. In this study, we used a self-paced visuomotor paradigm and magnetoencephalography (MEG to contrast these responses in patients with schizophrenia and control volunteers. We found significant reductions in the peak-to-peak change in amplitude from ERBD to PMBR in schizophrenia compared with controls. This effect was strongest in patients who made fewer movements, whereas beta was not modulated by movement in controls. There was no significant difference in the amplitude of visual gamma between patients and controls. These data demonstrate that clear abnormalities in basic sensorimotor processing in schizophrenia can be observed using a very simple MEG paradigm.

  8. Abnormal Returns and Contrarian Strategies

    Ivana Dall'Agnol

    2003-12-01

    Full Text Available We test the hypothesis that strategies which are long on portfolios of looser stocks and short on portfolios of winner stocks generate abnormal returns in Brazil. This type of evidence for the US stock market was interpreted by The Bondt and Thaler (1985 as reflecting systematic evaluation mistakes caused by investors overreaction to news related to the firm performance. We found evidence of contrarian strategies profitability for horizons from 3 months to 3 years in a sample of stock returns from BOVESPA and SOMA from 1986 to 2000. The strategies are more profitable for shorter horizons. Therefore, there was no trace of the momentum effect found by Jagadeesh and Titman (1993 for the same horizons with US data. There are remaing unexplained positive returns for contrarian strategies after accounting for risk, size, and liquidity. We also found that the strategy profitability is reduced after the Real Plan, which suggests that the Brazilian stock market became more efficient after inflation stabilization.

  9. Protective effect of geranylgeranylacetone, an inducer of heat shock protein 70, against drug-induced lung injury/fibrosis in an animal model

    Hasegawa Yoshinori

    2009-09-01

    Full Text Available Abstract Background To determine whether oral administration of geranylgeranylacetone (GGA, a nontoxic anti-ulcer drug that is an inducer of heat shock protein (HSP 70, protects against drug-induced lung injury/fibrosis in vivo. Methods We used a bleomycin (BLM-induced lung fibrosis model in which mice were treated with oral 600 mg/kg of GGA before and after BLM administration. Inflammation and fibrosis were evaluated by histological scoring, hydroxyproline content in the lung and inflammatory cell count, and quantification by ELISA of macrophage inflammatory protein-2 (MIP-2 in bronchoalveolar lavage fluid. Apoptosis was evaluated by the TUNEL method. The induction of HSP70 in the lung was examined with western blot analysis and its localization was determined by immunohistochemistry. Results We confirmed the presence of inflammation and fibrosis in the BLM-induced lung injury model and induction of HSP70 by oral administration of GGA. GGA prevented apoptosis of cellular constituents of lung tissue, such as epithelial cells, most likely related to the de novo induction of HSP70 in the lungs. GGA-treated mice also showed less fibrosis of the lungs, associated with the findings of suppression of both production of MIP-2 and inflammatory cell accumulation in the injured lung, compared with vehicle-treated mice. Conclusion GGA had a protective effect on drug-induced lung injury/fibrosis. Disease-modifying antirheumatic drugs such as methotrexate, which are indispensable for the treatment of rheumatoid arthritis, often cause interstitial lung diseases, an adverse event that currently cannot be prevented. Clinical use of GGA for drug-induced pulmonary fibrosis might be considered in the future.

  10. Drug-induced chimerism and prevention of graft-versus-host disease in lethally irradiated mice transplanted with rat bone marrow. [Gamma radiation

    Pierpaoli, W.; Maestroni, G.J.M.

    1978-12-01

    L-5-hydroxytryptophan, haloperidol, and phentolamine were administered subcutaneously to groups of mice. Some groups were inoculated i.p. or i.v. with bone marrow cells. The mice were given a dose of 900 rad of whole-body gamma radiation. Observations were made on survival rate, reconstitution with rat hematopoietic tissue, and capacity to reject or accept skin grafts. Results indicate that the combination of drug-induced tolerance and a newly established preconditioning regimen that eliminated postradiation damage and mortality results in reduction in incidence or delay in onset of GVHD, successful bone marrow grafting, and induction of persistent rat chimerism. (HLW)

  11. Clinical observation of 60 cases of drug induced liver disease%药物性肝病60例临床观察

    马志敏

    2016-01-01

    目的:观察分析药物性肝病患者的疾病类型、预后情况以及影响因素。方法:收治药物性肝病患者60例,对其进行回顾性分析。结果:60例患者临床症状、体征表现与临床分型各有不同;HBsAg呈阴性影响相关性大,阳性相关性小;患者长期饮酒习惯相关性大;不同类型药物长期服用相关性大;采用有效治疗措施可对药物性肝病患者起到良好的治疗效果。结论:药物性肝病的发病因素与患者饮酒习惯、用药史、病症史等具有较大的相关性,在停药采取积极治疗后,可取得较好的治疗效果。%Objective:To observe and analyze the disease type,prognosis and influencing factors of drug induced liver disease. Methods:60 cases of drug induced liver disease were selected.We analyzed the data of them retrospectively.Results:The clinical manifestation,signs expression and clinical types of 60 patients were different;HBsAg showed negative correlation was big,and the positive correlation was small;long term drinking habits of patients with large correlation;long-term use of different types of drugs related to large;the effective treatment can had good therapeutic effect when used to treat patients with drug-induced liver disease. Conclusion:The factors of drug induced liver disease are related to drinking habits,history of drug use,history of disease and so on. Stopping the medicine to take the active treatment can obtain the good treatment effect.

  12. 心肺复苏发展史及2010指南简介%Statistic analysis of the 9355 patients with drug induced liver injury

    程立顺; 李从圣

    2011-01-01

    Aim To investigate the causes,clinical classification and prognosis of drug induced liver injury. Methods Drug induced liver injury used as Key words, case analysis literatures on drug induced liver injury from 2001 to 2011 Chinese periodical full-text database were searched ,downloaded and gender,age, drugs,characters,clinical classifications and prognosis data were recorded. Results Among the recorded information,there were 4 737( 50.6% )male and 4 548( 49.0% ) female,age ranging from 5 months to 92 years old with the average(42.3 ± 13.1 )years. Drugs of Chinese herbs, antituberculotics, antibiotics, and anti hyperthyroidism drugs and antineoplastics were 1 979( 21.15% ), 1 898( 20.29% ), 1 135( 12.13% ),740( 7.91% ), 662( 7.07% ), and 382( 4.08% )patients respectively. 5 005( 62.73% )cases were classified to hepatocellular type,2 039( 23.84% )cases cholestasis type and 1 508( 17.63% )cases mixed type. As for the prognosis,8 144( 95.23% )cases cured or improved well,604( 6.90% )cases no change or worse to dead. Conclusion It is reported in China that drug induced liver injury occurred egually in males and females. Chinese herbs antituberculotics, non-steroid anti-inflammatory drugs antibiotics, anti-hyperthyroidism drugs, and the common hepatic injury was hepatocyte injury. Most patients were hepatocellular and generally the prognosis is good.%@@ 心肺复苏(Cardiopulmonary Resuscitation,简称CPR)的历史和人类的历史几乎一样悠久[1];早在1700多年前的东汉时期,名医张仲景在中就已经提到复苏方法:"救自缢死…上下安被卧之,一人以手按据胸上,数动之…"."安被卧之"是指平卧位,"以手按据胸上,数动之"是指连续胸外按压,这应该是世界上最早有关心肺复苏的详细描述.晋代葛洪所著的中写到:"塞两鼻孔,以芦管内其口中至咽,令人嘘之."

  13. New microRNA Biomarkers for Drug-Induced Steatosis and Their Potential to Predict the Contribution of Drugs to Non-alcoholic Fatty Liver Disease

    López-Riera, Mireia; Conde, Isabel; Tolosa, Laia; Zaragoza, Ángela; Castell, José V.; Gómez-Lechón, María J.; Jover, Ramiro

    2017-01-01

    Background and Aims: Drug-induced steatosis is a major reason for drug failure in clinical trials and post-marketing withdrawal; and therefore, predictive biomarkers are essential. These could be particularly relevant in non-alcoholic fatty liver disease (NAFLD), where most patients show features of the metabolic syndrome and are prescribed with combined chronic therapies, which can contribute to fatty liver. However, specific biomarkers to assess the contribution of drugs to NAFLD are lacking. We aimed to find microRNAs (miRNAs) responsive to steatotic drugs and to investigate if they could become circulating biomarkers for drug-induced steatosis. Methods: Human HepG2 cells were treated with drugs and changes in miRNA levels were measured by microarray and qRT-PCR. Drug-induced fat accumulation in HepG2 was analyzed by high-content screening and enzymatic methods. miRNA biomarkers were also analyzed in the sera of 44 biopsy-proven NAFLD patients and in 10 controls. Results: We found a set of 10 miRNAs [miR-22-5p, -3929, -24-2-5p, -663a, -29a-3p, -21 (5p and 3p), -27a-5p, -1260 and -202-3p] that were induced in human HepG2 cells and secreted to the culture medium upon incubation with model steatotic drugs (valproate, doxycycline, cyclosporin A and tamoxifen). Moreover, cell exposure to 17 common drugs for NAFLD patients showed that some of them (e.g., irbesartan, fenofibrate, and omeprazole) also induced these miRNAs and increased intracellular triglycerides, particularly in combinations. Finally, we found that most of these miRNAs (60%) were detected in human serum, and that NAFLD patients under fibrates showed both induction of these miRNAs and a more severe steatosis grade. Conclusion: Steatotic drugs induce a common set of hepatic miRNAs that could be used in drug screening during preclinical development. Moreover, most of these miRNAs are serum circulating biomarkers that could become useful in the diagnosis of iatrogenic steatosis. PMID:28179883

  14. A long-term three dimensional liver co-culture system for improved prediction of clinically relevant drug-induced hepatotoxicity

    Kostadinova, Radina; Boess, Franziska [Non-Clinical Safety, Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Building 73 / Room 117b, 4070 Basel (Switzerland); Applegate, Dawn [RegeneMed, 9855 Towne Centre Drive Suite 200, San Diego, CA 92121 (United States); Suter, Laura; Weiser, Thomas; Singer, Thomas [Non-Clinical Safety, Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Building 73 / Room 117b, 4070 Basel (Switzerland); Naughton, Brian [RegeneMed, 9855 Towne Centre Drive Suite 200, San Diego, CA 92121 (United States); Roth, Adrian, E-mail: adrian_b.roth@roche.com [Non-Clinical Safety, Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Building 73 / Room 117b, 4070 Basel (Switzerland)

    2013-04-01

    Drug-induced liver injury (DILI) is the major cause for liver failure and post-marketing drug withdrawals. Due to species-specific differences in hepatocellular function, animal experiments to assess potential liabilities of drug candidates can predict hepatotoxicity in humans only to a certain extent. In addition to animal experimentation, primary hepatocytes from rat or human are widely used for pre-clinical safety assessment. However, as many toxic responses in vivo are mediated by a complex interplay among different cell types and often require chronic drug exposures, the predictive performance of hepatocytes is very limited. Here, we established and characterized human and rat in vitro three-dimensional (3D) liver co-culture systems containing primary parenchymal and non-parenchymal hepatic cells. Our data demonstrate that cells cultured on a 3D scaffold have a preserved composition of hepatocytes, stellate, Kupffer and endothelial cells and maintain liver function for up to 3 months, as measured by the production of albumin, fibrinogen, transferrin and urea. Additionally, 3D liver co-cultures maintain cytochrome P450 inducibility, form bile canaliculi-like structures and respond to inflammatory stimuli. Upon incubation with selected hepatotoxicants including drugs which have been shown to induce idiosyncratic toxicity, we demonstrated that this model better detected in vivo drug-induced toxicity, including species-specific drug effects, when compared to monolayer hepatocyte cultures. In conclusion, our results underline the importance of more complex and long lasting in vitro cell culture models that contain all liver cell types and allow repeated drug-treatments for detection of in vivo-relevant adverse drug effects. - Highlights: ► 3D liver co-cultures maintain liver specific functions for up to three months. ► Activities of Cytochrome P450s remain drug- inducible accross three months. ► 3D liver co-cultures recapitulate drug-induced liver toxicity

  15. 精神药物所致口吃的识别与处理%Identification and treatment of psychotropic drug-induced mental stuttering

    付云婕

    2015-01-01

    Stuttering was a rare adverse reactions of psychotropic substances,in order to raise awareness of clinicians,the definition and classification of stuttering,diagnosis of drug-induced stuttering,pathogenesis and treatment were reviewed by this paper.%口吃是精神药物罕见的不良反应,为了提高临床医师的认识,本文对口吃的定义及分类、精神药物所致口吃的诊断、发病机制及处理等作一综述。

  16. ABNORMAL CARDIOVASCULAR REFLEXES IN PATIENTS WITH ACHALASIA

    戈峰; 李泽坚; 柯美云

    1994-01-01

    Using 3 non-invasive tests,abnormalities of cardiovascular reflex function were found in 7 of 15 patients with achalasia.Abnormalities of heart rate responses to the Valsalva maneuver,deep breathing ,and standing were moted in patients with autonomic neuropathy defect.The findings are consistent with the hypothesis that an abnormality of vagal function may contribute to the pathogenesis of achalasia.

  17. Semen abnormalities with SSRI antidepressants.

    2015-01-01

    Despite decades of widespread use, the adverse effect profile of "selective" serotonin reuptake inhibitor (SSRI) antidepressants has still not been fully elucidated. Studies in male animals have shown delayed sexual development and reduced fertility. Three prospective cohort studies conducted in over one hundred patients exposed to an SSRI for periods ranging from 5 weeks to 24 months found altered semen param-eters after as little as 3 months of exposure: reduced sperm concentration, reduced sperm motility, a higher percentage of abnormal spermatozoa, and increased levels of sperm DNA fragmentation. One clinical trial showed growth retardation in children considered depressed who were exposed to SSRls. SSRls may have endocrine disrupting properties. Dapoxetine is a short-acting serotonin reuptake inhibitor that is chemically related to fluoxetine and marketed in the European Union for men complaining of premature ejaculation. But the corresponding European summary of product characteristics does not mention any effects on fertility. In practice, based on the data available as of mid-2014, the effects of SSRI exposure on male fertility are unclear. However, it is a risk that should be taken into account and pointed out to male patients who would like to father a child or who are experiencing fertility problems.

  18. [Renal abnormalities in ankylosing spondylitis].

    Samia, Barbouch; Hazgui, Faiçal; Abdelghani, Khaoula Ben; Hamida, Fethi Ben; Goucha, Rym; Hedri, Hafedh; Taarit, Chokri Ben; Maiz, Hedi Ben; Kheder, Adel

    2012-07-01

    We will study the epidemiologic, clinical, biological, therapeutic, prognostic characteristics and predictive factors of development of nephropathy in ankylosing spondylitis patients. We retrospectively reviewed the medical record of 32 cases with renal involvement among 212 cases of ankylosing spondylitis followed in our service during the period spread out between 1978 and 2006. The renal involvement occurred in all patients a mean of 12 years after the clinical onset of the rheumatic disease. Thirty-two patients presented one or more signs of renal involvement: microscopic hematuria in 22 patients, proteinuria in 23 patients, nephrotic syndrome in 11 patients and decreased renal function in 24 patients (75%). Secondary renal amyloidosis (13 patients), which corresponds to a prevalence of 6,1% and tubulointerstitial nephropathy (7 patients) were the most common cause of renal involvement in ankylosing spondylitis followed by IgA nephropathy (4 patients). Seventeen patients evolved to the end stage renal disease after an average time of 29.8 ± 46 months. The average follow-up of the patients was 4,4 years. By comparing the 32 patients presenting a SPA and renal disease to 88 with SPA and without nephropathy, we detected the predictive factors of occurred of nephropathy: tobacco, intense inflammatory syndrome, sacroileite stage 3 or 4 and presence of column bamboo. The finding of 75% of the patients presented a renal failure at the time of the diagnosis of renal involvement suggests that evidence of renal abnormality involvement should be actively sought in this disease.

  19. Biochemical abnormalities in Pearson syndrome.

    Crippa, Beatrice Letizia; Leon, Eyby; Calhoun, Amy; Lowichik, Amy; Pasquali, Marzia; Longo, Nicola

    2015-03-01

    Pearson marrow-pancreas syndrome is a multisystem mitochondrial disorder characterized by bone marrow failure and pancreatic insufficiency. Children who survive the severe bone marrow dysfunction in childhood develop Kearns-Sayre syndrome later in life. Here we report on four new cases with this condition and define their biochemical abnormalities. Three out of four patients presented with failure to thrive, with most of them having normal development and head size. All patients had evidence of bone marrow involvement that spontaneously improved in three out of four patients. Unique findings in our patients were acute pancreatitis (one out of four), renal Fanconi syndrome (present in all patients, but symptomatic only in one), and an unusual organic aciduria with 3-hydroxyisobutyric aciduria in one patient. Biochemical analysis indicated low levels of plasma citrulline and arginine, despite low-normal ammonia levels. Regression analysis indicated a significant correlation between each intermediate of the urea cycle and the next, except between ornithine and citrulline. This suggested that the reaction catalyzed by ornithine transcarbamylase (that converts ornithine to citrulline) might not be very efficient in patients with Pearson syndrome. In view of low-normal ammonia levels, we hypothesize that ammonia and carbamylphosphate could be diverted from the urea cycle to the synthesis of nucleotides in patients with Pearson syndrome and possibly other mitochondrial disorders.

  20. Hemostatic abnormalities in liver cirrhosis

    Kendal YALÇIN

    2009-06-01

    Full Text Available In this study, 44 patients with liver cirrhosis were investigated for hemostatic parameters. Patients with spontaneous bacterial peritonitis, hepatocellular carcinoma, hepatorenal syndrome and cholestatic liver diseases were excluded. Patients were classified by Child-Pugh criterion and according to this 4 patients were in Class A, 20 in Class B and 20 in C. Regarding to these results, it was aimed to investigate the haematological disturbances in liver cirrhotic patients.In the result there was a correlation between activated partial thromboplastin time, serum iron, ferritin, transferrin, haptoglobin and Child-Pugh classification. Besides there was no correlation between prothrombin time, factor 8 and 9, protein C and S, anti-thrombin 3, fibrinogen, fibrin degradation products, serum iron binding capacity, hemoglobin, leukocyte, mean corpuscular volume and Child-Pugh classification.There were significant difference, in terms of AST, ferritin, haptoglobulin, sex and presence of ascites between groups (p0.05. In the summary, we have found correlation between hemostatic abnormalities and disease activity and clinical prognosis in patients with liver cirrhosis which is important in the management of these patients. This is also important for identification of liver transplant candidiates earlier.

  1. Drug-induced hypotension SEP test and acetazolamide test using sup 133 Xe SPECT in patients with occlusive carotid disease; Selection of candidates for extracranial-intracranial bypass

    Kuroda, Satoshi; Kamiyama, Hiroyasu; Abe, Hiroshi; Takigawa, Shugo (Hokkaido Univ., Sapporo (Japan). School of Medicine); Mitsumori, Kenji; Nomura, Mikio; Saitoh, Hisatoshi

    1991-01-01

    The correlation between the drug-induced hypotension somatosensory evoked potential (SEP) test and regional cerebral blood flow changes after acetazolamide administration was studied. Fourteen patients presenting with transient ischemic attack, reversible ischemic neurological deficits, or minor completed stroke were evaluated. All patients had no or only localized low-density areas on computed tomographic scans, and unilateral occlusion or severe stenosis of the internal carotid or middle cerebral artery on cerebral angiograms. The Diamox asymmetry enhancement (DAE) was studied to detect reduced cerebral perfusion reserve in the affected hemispheres. The DAE was 7.9+-5.8% in seven patients positive in the SEP test, significantly higher than -1.5+-2.9% in patients negative in the SEP test. Postoperative SEP tests were negative in all five patients who underwent extracranial-intracranial (EC-IC) bypass surgery, suggesting that the EC-IC bypass improved the cerebral perfusion reserve in the affected hemispheres. The DAE decreased significantly in four of these patients. This study disclosed a significant correlation between the drug-induced hypotension SEP test and DAE. These parameters are considered important for evaluating patients with hemodynamic compromise and/or suitable candidates for EC-IC bypass. (author).

  2. DMH1 (4-[6-(4-isopropoxyphenylpyrazolo[1,5-a]pyrimidin-3-yl]quinoline inhibits chemotherapeutic drug-induced autophagy

    Yue Sheng

    2015-07-01

    Full Text Available Our previous work found that DMH1 (4-[6-(4-isopropoxyphenylpyrazolo [1,5-a]pyrimidin-3-yl]quinoline was a novel autophagy inhibitor. Here, we aimed to investigate the effects of DMH1 on chemotherapeutic drug-induced autophagy as well as the efficacy of chemotherapeutic drugs in different cancer cells. We found that DMH1 inhibited tamoxifen- and cispcis-diaminedichloroplatinum (II (CDDP-induced autophagy responses in MCF-7 and HeLa cells, and potentiated the anti-tumor activity of tamoxifen and CDDP for both cells. DMH1 inhibited 5-fluorouracil (5-FU-induced autophagy responses in MCF-7 and HeLa cells, but did not affect the anti-tumor activity of 5-FU for these two cell lines. DMH1 itself did not induce cell death in MCF-7 and HeLa cells, but inhibited the proliferation of these cells. In conclusion, DMH1 inhibits chemotherapeutic drug-induced autophagy response and the enhancement of efficacy of chemotherapeutic drugs by DMH1 is dependent on the cell sensitivity to drugs.

  3. 精神药物所致咳嗽的识别与处理%Identification and Treatment of Psychotropic Drug-induced Cough

    于相芬; 孙振晓

    2014-01-01

    Many psychotropic drugs could cause cough which may have no typical symptoms and is difficult to distinguish at an early stage. In order to make a better understanding of psychotropic drug-induced cough, this article made a review on the definition and causes of cough, and the diagnosis, differential diagnosis, pathomechanism and management of psychotropic drug-induced cough. Clinicians should strengthen the ability of discrimination and treatment of cough induced by psychotropic drugs.%多种精神药物可引起咳嗽,且表现无典型特征,早期难以发现。本文对咳嗽的定义及原因、精神药物所致咳嗽的诊断、鉴别诊断、发病机制及处理等作一综述。临床应加强对精神药物引起的咳嗽进行识别和处理。

  4. Data mining reveals a network of early-response genes as a consensus signature of drug-induced in vitro and in vivo toxicity.

    Zhang, J D; Berntenis, N; Roth, A; Ebeling, M

    2014-06-01

    Gene signatures of drug-induced toxicity are of broad interest, but they are often identified from small-scale, single-time point experiments, and are therefore of limited applicability. To address this issue, we performed multivariate analysis of gene expression, cell-based assays, and histopathological data in the TG-GATEs (Toxicogenomics Project-Genomics Assisted Toxicity Evaluation system) database. Data mining highlights four genes-EGR1, ATF3, GDF15 and FGF21-that are induced 2 h after drug administration in human and rat primary hepatocytes poised to eventually undergo cytotoxicity-induced cell death. Modelling and simulation reveals that these early stress-response genes form a functional network with evolutionarily conserved structure and intrinsic dynamics. This is underlined by the fact that early induction of this network in vivo predicts drug-induced liver and kidney pathology with high accuracy. Our findings demonstrate the value of early gene-expression signatures in predicting and understanding compound-induced toxicity. The identified network can empower first-line tests that reduce animal use and costs of safety evaluation.

  5. Platelet enzyme abnormalities in leukemias

    S Sharma

    2011-01-01

    Full Text Available Aim of the Study: The aim of this study was to evaluate platelet enzyme activity in cases of leukemia. Materials and Methods: Platelet enzymes glucose-6-phosphate dehydrogenase (G6PD, pyruvate kinase (PK and hexokinase (HK were studied in 47 patients of acute and chronic leukemia patients, 16 patients with acute myeloid leukemia (AML(13 relapse, three in remission, 12 patients with acute lymphocytic leukemia (ALL (five in relapse, seven in remission, 19 patients with chronic myeloid leukemia (CML. Results: The platelet G6PD activity was significantly low in cases of AML, ALL and also in CML. G6PD activity was normalized during AML remission. G6PD activity, although persistently low during ALL remission, increased significantly to near-normal during remission (P < 0.05 as compared with relapse (P < 0.01. Platelet PK activity was high during AML relapse (P < 0.05, which was normalized during remission. Platelet HK however was found to be decreased during all remission (P < 0.05. There was a significant positive correlation between G6PD and PK in cases of AML (P < 0.001 but not in ALL and CML. G6PD activity did not correlate with HK activity in any of the leukemic groups. A significant positive correlation was however seen between PK and HK activity in cases of ALL remission (P < 0.01 and CML (P < 0.05. Conclusions: Both red cell and platelet enzymes were studied in 36 leukemic patients and there was no statistically significant correlation between red cell and platelet enzymes. Platelet enzyme defect in leukemias suggests the inherent abnormality in megakaryopoiesis and would explain the functional platelet defects in leukemias.

  6. Nail abnormalities in patients with vitiligo*

    Topal, Ilteris Oguz; Gungor, Sule; Kocaturk, Ozgur Emek; Duman, Hatice; Durmuscan, Mustafa

    2016-01-01

    Background Vitiligo is an acquired pigmentary skin disorder affecting 0.1-4% of the general population. The nails may be affected in patients with an autoimmune disease such as psoriasis, and in those with alopecia areata. It has been suggested that nail abnormalities should be apparent in vitiligo patients. Objective We sought to document the frequency and clinical presentation of nail abnormalities in vitiligo patients compared to healthy volunteers. We also examined the correlations between nail abnormalities and various clinical parameters. Methods This study included 100 vitiligo patients and 100 healthy subjects. Full medical histories were collected from the subjects, who underwent thorough general and nail examinations. All nail changes were noted. In the event of clinical suspicion of a fungal infection, additional mycological investigations were performed. Results Nail abnormalities were more prevalent in the patients (78%) than in the controls (55%) (p=0.001). Longitudinal ridging was the most common finding (42%), followed by (in descending order): leukonychia, an absent lunula, onycholysis, nail bed pallor, onychomycosis, splinter hemorrhage and nail plate thinning. The frequency of longitudinal ridging was significantly higher in patients than in controls (p<0.001). Conclusions Nail abnormalities were more prevalent in vitiligo patients than in controls. Systematic examination of the nails in such patients is useful because nail abnormalities are frequent. However, the causes of such abnormalities require further study. Longitudinal ridging and leukonychia were the most common abnormalities observed in this study. PMID:27579738

  7. An Abnormal Psychology Community Based Interview Assignment

    White, Geoffry D.

    1977-01-01

    A course option in abnormal psychology involves students in interviewing and observing the activities of individuals in the off-campus community who are concerned with some aspect of abnormal psychology. The technique generates student interest in the field when they interview people about topics such as drug abuse, transsexualism, and abuse of…

  8. Abnormal Event Detection Using Local Sparse Representation

    Ren, Huamin; Moeslund, Thomas B.

    2014-01-01

    measurement based on the difference between the normal space and local space. Specifically, we provide a reasonable normal bases through repeated K spectral clustering. Then for each testing feature we first use temporal neighbors to form a local space. An abnormal event is found if any abnormal feature...

  9. An Abnormal Vibrational Mode of Torsion Pendulum

    赵亮; 涂英; 顾邦明; 胡忠坤; 罗俊

    2003-01-01

    In the experiment for the determination of the gravitational constant G, we found an abnormal vibrational mode of the torsion pendulum. The abnormal mode disappeared as a magnetic damper was introduced to the torsion pendulum system. Our experimental results also show that the magnetic damper can be used to suppress the high frequency vibrational noises to torsion pendulums effectively.

  10. Abnormal Raman spectral phenomenon of silicon nanowires

    2000-01-01

    The Raman spectra of two one-dimensional silicon nanowire samples with different excitation wavelengths were measured and an abnormal phenomenon was discovered that the Raman spectral features change with the wavelengths of excitation. Closer analysis of the crystalline structure of samples and the changes in Raman spectral features showed that the abnormal behavior is the result of resonance Raman scattering selection effect.

  11. Drug-induced hemolytic anemia and thrombocytopenia associated with alterations of cell membrane lipids and acanthocyte formation.

    Poulet, Frederique M; Penraat, Kelley; Collins, Nathaniel; Evans, Ellen; Thackaberry, Evan; Manfra, Denise; Engstrom, Laura; Geissler, Richard; Geraci-Erck, Maria; Frugone, Carlos; Abutarif, Malaz; Fine, Jay S; Peterson, Brianna L; Cummings, Brian S; Johnson, Robert C

    2010-10-01

    CXCR3 is a chemokine receptor, upregulated upon activation of T cells and expressed on nearly 100% of T cells in sites of inflammation. SCH 900875 is a selective CXCR3 receptor antagonist. Thrombocytopenia and severe hemolytic anemia with acanthocytosis occurred in rats at doses of 75, 100, and 150 mg/kg/day. Massively enlarged spleens corresponded histologically to extramedullary hematopoiesis, macrophages, and hemosiderin pigment and sinus congestion. Phagocytosed erythrocytes and platelets were within splenic macrophages. IgG and/or IgM were not detected on erythrocyte and platelet membranes. Ex vivo increased osmotic fragility of RBCs was observed. Lipid analysis of the RBC membrane revealed modifications in phosphatidylcholine, overall cholesterol, and/or sphingomyelin. Platelets exhibited slender filiform processes on their plasma membranes, analogous to those of acanthocytes. The presence of similar morphological abnormalities in acanthocytes and platelets suggests that possibly similar alterations in the lipid composition of the plasma membrane have taken place in both cell types. This phenotype correlated with alterations in plasma lipids (hypercholesterolemia and low triglycerides) that occurred after SCH 900875 administration, although other factors cannot be excluded. The increased cell destruction was considered triggered by alterations in the lipid profile of the plasma membranes of erythrocytes and platelets, as reflected morphologically.

  12. A Review of Anti-Inflammatory Drug-Induced Gastrointestinal Injury: Focus on Prevention of Small Intestinal Injury

    Shunji Fujimori

    2010-04-01

    Full Text Available Capsule endoscopy and balloon endoscopy, advanced modalities that allow full investigation of the entire small intestine, have revealed that nonsteroidal anti-inflammatory drugs (NSAIDs can cause a variety of abnormalities in the small intestine. Recently, several reports show that traditional NSAIDs (tNSAIDs and acetylsalicylic acid (ASA can induce small intestinal injuries. These reports have shown that the preventive effect of proton pump inhibitors (PPIs does not extend to the small intestine, suggesting that concomitant therapy may be required to prevent small intestinal side effects associated with tNSAID/ASA use. Recently, several randomized controlled trials used capsule endoscopy to evaluate the preventive effect of mucoprotective drugs against tNSAID/ASA-induced small intestinal injury. These studies show that misoprostol and rebamipide reduce the number and types of tNSAID-induced small intestinal mucosal injuries. However, those studies were limited to a small number of subjects and tested short-term tNSAID/ ASA treatment. Therefore, further extensive studies are clearly required to ascertain the beneficial effect of these drugs.

  13. Chromosomal abnormalities in patients with sperm disorders

    L. Y. Pylyp

    2013-02-01

    Full Text Available Chromosomal abnormalities are among the most common genetic causes of spermatogenic disruptions. Carriers of chromosomal abnormalities are at increased risk of infertility, miscarriage or birth of a child with unbalanced karyotype due to the production of unbalanced gametes. The natural selection against chromosomally abnormal sperm usually prevents fertilization with sperm barring in cases of serious chromosomal abnormalities. However, assisted reproductive technologies in general and intracytoplasmic sperm injection in particular, enable the transmission of chromosomal abnormalities to the progeny. Therefore, cytogenetic studies are important in patients with male factor infertility before assisted reproduction treatment. The purpose of the current study was to investigate the types and frequencies of chromosomal abnormalities in 724 patients with infertility and to estimate the risk of chromosomal abnormalities detection in subgroups of patients depending on the severity of spermatogenic disruption, aiming at identifying groups of patients in need of cytogenetic studies. Karyotype analysis was performed in 724 blood samples of men attending infertility clinic. Chromosomal preparation was performed by standard techniques. At least 20 GTG-banded metaphase plates with the resolution from 450 to 750 bands per haploid set were analysed in each case. When chromosomal mosaicism was suspected, this number was increased to 50. Abnormal karyotypes were observed in 48 (6.6% patients, including 67% of autosomal abnormalities and 33% of gonosomal abnormalities. Autosomal abnormalities were represented by structural rearrangements. Reciprocal translocations were the most common type of structural chromosomal abnormalities in the studied group, detected with the frequency of 2.6% (n = 19, followed by Robertsonian translocation, observed with the frequency of 1.2% (n = 9. The frequency of inversions was 0.6% (n = 4. Gonosomal abnormalities included 14 cases

  14. Drug-induced trafficking of p-glycoprotein in human brain capillary endothelial cells as demonstrated by exposure to mitomycin C.

    Noack, Andreas; Noack, Sandra; Hoffmann, Andrea; Maalouf, Katia; Buettner, Manuela; Couraud, Pierre-Olivier; Romero, Ignacio A; Weksler, Babette; Alms, Dana; Römermann, Kerstin; Naim, Hassan Y; Löscher, Wolfgang

    2014-01-01

    P-glycoprotein (Pgp; ABCB1/MDR1) is a major efflux transporter at the blood-brain barrier (BBB), restricting the penetration of various compounds. In other tissues, trafficking of Pgp from subcellular stores to the cell surface has been demonstrated and may constitute a rapid way of the cell to respond to toxic compounds by functional membrane insertion of the transporter. It is not known whether drug-induced Pgp trafficking also occurs in brain capillary endothelial cells that form the BBB. In this study, trafficking of Pgp was investigated in human brain capillary endothelial cells (hCMEC/D3) that were stably transfected with a doxycycline-inducible MDR1-EGFP fusion plasmid. In the presence of doxycycline, these cells exhibited a 15-fold increase in Pgp-EGFP fusion protein expression, which was associated with an increased efflux of the Pgp substrate rhodamine 123 (Rho123). The chemotherapeutic agent mitomycin C (MMC) was used to study drug-induced trafficking of Pgp. Confocal fluorescence microscopy of single hCMEC/D3-MDR1-EGFP cells revealed that Pgp redistribution from intracellular pools to the cell surface occurred within 2 h of MMC exposure. Pgp-EGFP exhibited a punctuate pattern at the cell surface compatible with concentrated regions of the fusion protein in membrane microdomains, i.e., lipid rafts, which was confirmed by Western blot analysis of biotinylated cell surface proteins in Lubrol-resistant membranes. MMC exposure also increased the functionality of Pgp as assessed in three functional assays with Pgp substrates (Rho123, eFluxx-ID Gold, calcein-AM). However, this increase occurred with some delay after the increased Pgp expression and coincided with the release of Pgp from the Lubrol-resistant membrane complexes. Disrupting rafts by depleting the membrane of cholesterol increased the functionality of Pgp. Our data present the first direct evidence of drug-induced Pgp trafficking at the human BBB and indicate that Pgp has to be released from lipid

  15. The importance of drug-induced sedation endoscopy (D.I.S.E.) techniques in surgical decision making: conventional versus target controlled infusion techniques-a prospective randomized controlled study and a retrospective surgical outcomes analysis.

    De Vito, Andrea; Agnoletti, Vanni; Zani, Gianluca; Corso, Ruggero Massimo; D'Agostino, Giovanni; Firinu, Elisabetta; Marchi, Chiara; Hsu, Ying-Shuo; Maitan, Stefano; Vicini, Claudio

    2017-02-17

    Drug-Induced Sedation Endoscopy (DISE) consists of the direct observation of the upper airways during sedative-induced sleep, allowing the identification of the sites of pharyngeal collapse, which is the main pathological event in Obstructive Sleep Apnea (OSA). The Authors have compared Target Controlled Infusion (TCI) sedation endoscopy (TCI-DISE) technique to conventional DISE (CDISE), performed by a manual bolus injection of sedative agent, to recreate accurately and safely snoring and apnea patterns comparable to natural sleep. The authors conducted a prospective, randomized, long-term study and a retrospective analysis of surgical outcomes. The apnea-event observation and its correlation with pharyngeal collapse patterns is the primary endpoint; secondary endpoints are defined as stability and safety of sedation plan of DISE-TCI technique. From January 2009 to January 2011, OSA patients were included in the study and randomly allocated into two groups: the bolus injection conventional DISE group and the TCI-DISE group. Third endpoint is to compare the surgical outcomes enrolling OSA patients from January 2009 to June 2015. We recorded the complete apnea-event at oropharynx and hypopharynx levels in 15/50 pts in conventional DISE group (30%) and in 99/123 pts in TCI-DISE group (81%) (p DISE group because a severe desaturation occurred during the first bolus of propofol (1 mg/kg) (p = 0.4872 ns). We recorded instability of the sedation plan in 13 patients of conventional DISE group (65%) and 1 patient of the TCI-DISE group (5%) (p = 0.0001). In 37 TCI-DISE group surgical patients we reported a significant reduction of postoperative AHI (from 42.7 ± 20.2 to 11.4 ± 10.3) in comparison with postoperative AHI in 15 C-DISE group surgical patients (from 41.3 ± 23.4 to 20.4 ± 15.5) (p = 0.05). Our results suggest the DISE-TCI technique as first choice in performing sleep-endoscopy because of its increased accuracy, stability and

  16. Numerically abnormal chromosome constitutions in humans

    NONE

    1993-12-31

    Chapter 24, discusses numerically abnormal chromosome constitutions in humans. This involves abnormalities of human chromosome number, including polyploidy (when the number of sets of chromosomes increases) and aneuploidy (when the number of individual normal chromosomes changes). Chapter sections discuss the following chromosomal abnormalities: human triploids, imprinting and uniparental disomy, human tetraploids, hydatidiform moles, anomalies caused by chromosomal imbalance, 13 trisomy (D{sub 1} trisomy, Patau syndrome), 21 trisomy (Down syndrome), 18 trisomy syndrome (Edwards syndrome), other autosomal aneuploidy syndromes, and spontaneous abortions. The chapter concludes with remarks on the nonrandom participation of chromosomes in trisomy. 69 refs., 3 figs., 4 tabs.

  17. A Framework of Knowledge Integration and Discovery for Supporting Pharmacogenomics Target Predication of Adverse Drug Events: A Case Study of Drug-Induced Long QT Syndrome.

    Jiang, Guoqian; Wang, Chen; Zhu, Qian; Chute, Christopher G

    2013-01-01

    Knowledge-driven text mining is becoming an important research area for identifying pharmacogenomics target genes. However, few of such studies have been focused on the pharmacogenomics targets of adverse drug events (ADEs). The objective of the present study is to build a framework of knowledge integration and discovery that aims to support pharmacogenomics target predication of ADEs. We integrate a semantically annotated literature corpus Semantic MEDLINE with a semantically coded ADE knowledgebase known as ADEpedia using a semantic web based framework. We developed a knowledge discovery approach combining a network analysis of a protein-protein interaction (PPI) network and a gene functional classification approach. We performed a case study of drug-induced long QT syndrome for demonstrating the usefulness of the framework in predicting potential pharmacogenomics targets of ADEs.

  18. CYP1A2 and CYP2D6 Gene Polymorphisms in Schizophrenic Patients with Neuroleptic Drug-Induced Side Effects.

    Ivanova, S A; Filipenko, M L; Vyalova, N M; Voronina, E N; Pozhidaev, I V; Osmanova, D Z; Ivanov, M V; Fedorenko, O Yu; Semke, A V; Bokhan, N A

    2016-03-01

    Polymorphic variants of CYP1A2 and CYP2D6 genes of the cytochrome P450 system were studied in patients with schizophrenia with drug-induced motor disorders and hyperprolactinemia against the background of long-term neuroleptic therapy. We revealed an association of polymorphic variant C-163A CYP1A2*1F of CYP1A2 gene with tardive dyskinesia and association of polymorphic variant 1846G>A CY2D6*4 and genotype A/A of CYP2D6 gene (responsible for debrisoquin-4-hydroxylase synthesis) with limbotruncal tardive dyskinesia in patients with schizophrenia receiving neuroleptics for a long time.

  19. Drug-Induced QT Prolongation as a Result of an Escitalopram Overdose in a Patient with Previously Undiagnosed Congenital Long QT Syndrome

    Paul Singh

    2014-01-01

    Full Text Available We present a case of drug-induced QT prolongation caused by an escitalopram overdose in a patient with previously undiagnosed congenital LQTS. A 15-year-old Caucasian female presented following a suicide attempt via an escitalopram overdose. The patient was found to have a prolonged QT interval with episodes of torsades de pointes. The patient was admitted to the telemetry unit and treated. Despite the resolution of the torsades de pointes, she continued to demonstrate a persistently prolonged QT interval. She was seen by the cardiology service and diagnosed with congenital long QT syndrome. This case illustrates the potential for an escitalopram overdose to cause an acute QT prolongation in a patient with congenital LQTS and suggests the importance of a screening electrocardiogram prior to the initiation of SSRIs, especially in patients at high risk for QT prolongation.

  20. Compartmentalized accumulation of cAMP near complexes of multidrug resistance protein 4 (MRP4) and cystic fibrosis transmembrane conductance regulator (CFTR) contributes to drug-induced diarrhea.

    Moon, Changsuk; Zhang, Weiqiang; Ren, Aixia; Arora, Kavisha; Sinha, Chandrima; Yarlagadda, Sunitha; Woodrooffe, Koryse; Schuetz, John D; Valasani, Koteswara Rao; de Jonge, Hugo R; Shanmukhappa, Shiva Kumar; Shata, Mohamed Tarek M; Buddington, Randal K; Parthasarathi, Kaushik; Naren, Anjaparavanda P

    2015-05-01

    Diarrhea is one of the most common adverse side effects observed in ∼7% of individuals consuming Food and Drug Administration (FDA)-approved drugs. The mechanism of how these drugs alter fluid secretion in the gut and induce diarrhea is not clearly understood. Several drugs are either substrates or inhibitors of multidrug resistance protein 4 (MRP4), such as the anti-colon cancer drug irinotecan and an anti-retroviral used to treat HIV infection, 3'-azido-3'-deoxythymidine (AZT). These drugs activate cystic fibrosis transmembrane conductance regulator (CFTR)-mediated fluid secretion by inhibiting MRP4-mediated cAMP efflux. Binding of drugs to MRP4 augments the formation of MRP4-CFTR-containing macromolecular complexes that is mediated via scaffolding protein PDZK1. Importantly, HIV patients on AZT treatment demonstrate augmented MRP4-CFTR complex formation in the colon, which defines a novel paradigm of drug-induced diarrhea.

  1. Is the drug-induced hypersensitivity syndrome (DIHS due to human herpesvirus 6 infection or to allergy-mediated viral reactivation? Report of a case and literature review

    Borgia Guglielmo

    2010-03-01

    Full Text Available Abstract Background Drug-Induced Hypersensitivity Syndrome (DIHS is a severe and rare systemic reaction triggered by a drug (usually an antiepileptic drug. We present a case of DISH and we review studies on the clinical features and treatment of DIHS, and on its pathogenesis in which two elements (Herpesvirus infection and the drug interact with the immune system to trigger such a syndrome that can lead to death in about 20% of cases. Case presentation We report the case of a 26-year old woman with fever, systemic maculopapular rash, lymphadenopathy, hepatitis and eosinophilic leukocytosis. She had been treated with antibiotics that gave no benefit. She was taking escitalopram and lamotrigine for a bipolar disease 30 days before fever onset. Because the patient's general condition deteriorated, betamethasone and acyclovir were started. This treatment resulted in a mild improvement of symptoms. Steroids were rapidly tapered and this was followed with a relapse of fever and a worsening of laboratory parameters. Human herpesvirus 6 (HHV-6 DNA was positive as shown by PCR. Drug-Induced Hypersensitivity Syndrome (DIHS was diagnosed. Symptoms regressed on prednisone (at a dose of 50 mg/die that was tapered very slowly. The patient recovered completely. Conclusions The search for rare causes of fever led to complete resolution of a very difficult case. As DIHS is a rare disease the most relevant issue is to suspect and include it in differential diagnosis of fevers of unknown origin. Once diagnosed, the therapy is easy (steroidal administration and often successful. However our case strongly confirms that attention should be paid on the steroidal tapering that should be very slow to avoid a relapse.

  2. The glycometabolism abnormality among schizophrenia patients

    吴小立

    2013-01-01

    Objective To explore the potential glycometabolism abnormality and the related factors of schizophrenia patients in China. Methods This cross-sectional study included 44 healthy controls(group 1) and 178 inpatient

  3. Amphibian abnormalities on National Wildlife Refuges

    US Fish and Wildlife Service, Department of the Interior — This fact sheet outlines a study done to 1) find the percentage of abnormal frogs and toads on the nation’s National Wildlife Refuges and 2) determine how the...

  4. Heterotaxy syndromes and abnormal bowel rotation

    Newman, Beverley [Stanford University, Lucile Packard Children' s Hospital, Department of Radiology, Stanford, CA (United States); Koppolu, Raji; Sylvester, Karl [Lucile Packard Children' s Hospital at Stanford, Department of Surgery, Stanford, CA (United States); Murphy, Daniel [Lucile Packard Children' s Hospital at Stanford, Department of Cardiology, Stanford, CA (United States)

    2014-05-15

    Bowel rotation abnormalities in heterotaxy are common. As more children survive cardiac surgery, the management of gastrointestinal abnormalities has become controversial. To evaluate imaging of malrotation in heterotaxy with surgical correlation and provide an algorithm for management. Imaging reports of heterotaxic children with upper gastrointestinal (UGI) and/or small bowel follow-through (SBFT) were reviewed. Subsequently, fluoroscopic images were re-reviewed in conjunction with CT/MR studies. The original reports and re-reviewed images were compared and correlated with surgical findings. Nineteen of 34 children with heterotaxy underwent UGI, 13/19 also had SBFT. In 15/19 reports, bowel rotation was called abnormal: 11 malrotation, 4 non-rotation, no cases of volvulus. Re-review, including CT (10/19) and MR (2/19), designated 17/19 (90%) as abnormal, 10 malrotation (abnormal bowel arrangement, narrow or uncertain length of mesentery) and 7 non-rotation (small bowel and colon on opposite sides plus low cecum with probable broad mesentery). The most useful CT/MR findings were absence of retroperitoneal duodenum in most abnormal cases and location of bowel, especially cecum. Abnormal orientation of mesenteric vessels suggested malrotation but was not universal. Nine children had elective bowel surgery; non-rotation was found in 4/9 and malrotation was found in 5/9, with discrepancies (non-rotation at surgery, malrotation on imaging) with 4 original interpretations and 1 re-review. We recommend routine, early UGI and SBFT studies once other, urgent clinical concerns have been stabilized, with elective laparoscopic surgery in abnormal or equivocal cases. Cross-sectional imaging, usually obtained for other reasons, can contribute diagnostically. Attempting to assess mesenteric width is important in differentiating non-rotation from malrotation and more accurately identifies appropriate surgical candidates. (orig.)

  5. Abnormal Chromosome Segregation May Trigger Tumors

    2005-01-01

    @@ Cancer is a primary threat to human health as it kills millions of people each year.Scientists have shown that 75% of human cancers have an abnormal number of chromosomes in cells,and the proportion of the cells with an abnormal chromosome number is tightly and positively related to malignance progression and metastasis of cancers. But the pathological mechanism behind the anomaly still remains unknown.

  6. Nail abnormalities in patients with vitiligo

    Topal, Ilteris Oguz; Gungor, Sule; Kocaturk, Ozgur Emek; Duman, Hatice; Durmuscan, Mustafa

    2016-01-01

    Abstract: Background: Vitiligo is an acquired pigmentary skin disorder affecting 0.1-4% of the general population. The nails may be affected in patients with an autoimmune disease such as psoriasis, and in those with alopecia areata. It has been suggested that nail abnormalities should be apparent in vitiligo patients. Objective: We sought to document the frequency and clinical presentation of nail abnormalities in vitiligo patients compared to healthy volunteers. We also examined the corre...

  7. Prevalence of asymptomatic urinary abnormalities among adolescents

    Mohamed Fouad

    2016-01-01

    Full Text Available To determine the prevalence of asymptomatic urinary abnormalities in adolescents, first morning clean mid-stream urine specimens were obtained from 2500 individuals and examined by dipstick and light microscopy. Adolescents with abnormal screening results were reexamined after two weeks and those who had abnormal results twice were subjected to systemic clinical examination and further clinical and laboratory investigations. Eight hundred and three (32.1% individuals had urinary abnormalities at the first screening, which significantly decreased to 345 (13.8% at the second screening, (P <0.001. Hematuria was the most common urinary abnormalities detected in 245 (9.8% adolescents who had persistent urine abnormalities; 228 (9.1% individuals had non glomerular hematuria. The hematuria was isolated in 150 (6% individuals, combined with leukocyturia in 83 (3.3% individuals, and combined with proteinuria in 12 (0.5% individuals. Leukocyturia was detected in 150 (6% of all studied adolescents; it was isolated in 39 (1.6% individuals and combined with proteinuria in 28 (1.1% of them. Asymp- tomatic bacteriuria was detected in 23 (0.9% of all studied adolescents; all the cases were females. Proteinuria was detected in 65 (2.6% of all the studied adolescents; 45 (1.8% indivi- duals had <0.5 g/day and twenty (0.8% individuals had 0.5-3 g/day. Asymptomatic urinary abnormalities were more common in males than females and adolescents from rural than urban areas (P <0.01 and (P <0.001, respectively. The present study found a high prevalence of asymptomatic urinary abnormalities among adolescents in our population.

  8. Basilar artery migraine and reversible imaging abnormalities.

    Maytal, J; Libman, R B; Lustrin, E S

    1998-01-01

    We report a case of a basilar artery migraine in a 17-year-old boy with transient CT and MR abnormalities after each of two migraine episodes. A repeat MR study 6 months after the last event showed complete resolution of the lesion. Transient abnormalities on brain images similar to those shown in our case have been reported in patients with migraine and other neurologic conditions and are most likely related to cerebral vasogenic edema.

  9. Abnormal Asymmetry of Brain Connectivity in Schizophrenia

    Ribolsi, Michele; Zafiris J Daskalakis; Siracusano, Alberto; Koch, Giacomo

    2014-01-01

    Recently, a growing body of data has revealed that beyond a dysfunction of connectivity among different brain areas in schizophrenia patients (SCZ), there is also an abnormal asymmetry of functional connectivity compared with healthy subjects. The loss of the cerebral torque and the abnormalities of gyrification, with an increased or more complex cortical folding in the right hemisphere may provide an anatomical basis for such aberrant connectivity in SCZ. Furthermore, diffusion tensor imagin...

  10. Characterisation of liver chemistry abnormalities associated with pazopanib monotherapy: a systematic review and meta-analysis of clinical trials in advanced cancer patients.

    Powles, Thomas; Bracarda, Sergio; Chen, Mei; Norry, Elliot; Compton, Natalie; Heise, Mark; Hutson, Thomas; Harter, Philipp; Carpenter, Christopher; Pandite, Lini; Kaplowitz, Neil

    2015-07-01

    Drug-induced liver chemistry abnormalities, primarily transaminase elevations, are commonly observed in pazopanib-treated patients. This meta-analysis characterises liver chemistry abnormalities associated with pazopanib. Data of pazopanib-treated patients from nine prospective trials were integrated (N=2080). Laboratory datasets were used to characterise the incidence, timing, recovery and patterns of liver events, and subsequent rechallenge with pazopanib. Severe cases of liver chemistry abnormalities were clinically reviewed. Multivariate analyses identified predisposing factors. Twenty percent of patients developed elevated alanine aminotransferase (ALT) >3×ULN. Incidence of peak ALT >3-5×ULN, >5-8×ULN, >8-20×ULN and >20×ULN was 8%, 5%, 5% and 1%, respectively. Median time to onset for all events was 42days; 91% of events were observed within 18weeks. Recovery rates based on peak ALT >3-5×ULN, >5-8×ULN, >8-20×ULN and >20×ULN were 91%, 90%, 90% and 64%, respectively. Median time from onset to recovery was 30days, but longer in patients without dose interruption. Based on clinical review, no deaths were associated with drug-induced liver injury. Overall, 38% of rechallenged patients had ALT elevation recurrence, with 9-day median time to recurrence. Multivariate analysis showed that older age was associated with development of ALT >8×ULN. There was no correlation between hypertension and transaminitis. Our data support the current guidelines on regular liver chemistry tests after initiation of pazopanib, especially during the first 9 or 10weeks, and also demonstrate the safety of rechallenge with pazopanib.

  11. Electrocardiographic abnormalities and serum magnesium in patients with subarachnoid hemorrhage

    van den Bergh, Walter M; Algra, Ale; Rinkel, Gabriël J E

    2004-01-01

    BACKGROUND AND PURPOSE: ECG abnormalities and hypomagnesemia frequently occur after aneurysmal subarachnoid hemorrhage (SAH). Because hypomagnesemia is associated with several ECG abnormalities, we studied whether hypomagnesemia mediates ECG abnormalities after SAH. METHODS: We prospectively studied

  12. Fetal calcifications are associated with chromosomal abnormalities.

    Ellika Sahlin

    Full Text Available The biological importance of calcifications occasionally noted in fetal tissues (mainly liver at autopsy or ultrasound is largely unexplored. Previous reports hint at an association to infection, circulatory compromise, malformations or chromosomal abnormalities. To identify factors associated with calcifications, we have performed a case-control study on the largest cohort of fetuses with calcifications described thus far.One-hundred and fifty-one fetuses with calcifications and 302 matched controls were selected from the archives of the Department of Pathology, Karolinska University Hospital. Chromosome analysis by karyotyping or quantitative fluorescence-polymerase chain reaction was performed. Autopsy and placenta reports were scrutinized for presence of malformations and signs of infection.Calcifications were mainly located in the liver, but also in heart, bowel, and other tissues. Fetuses with calcifications showed a significantly higher proportion of chromosomal abnormalities than controls; 50% vs. 20% (p<0.001. The most frequent aberrations among cases included trisomy 21 (33%, trisomy 18 (22%, and monosomy X (18%. A similar distribution was seen among controls. When comparing cases and controls with chromosomal abnormalities, the cases had a significantly higher prevalence of malformations (95% vs. 77%, p=0.004. Analyzed the other way around, cases with malformations had a significantly higher proportion of chromosomal abnormalities compared with controls, (66% vs. 31%, p<0.001.The presence of fetal calcifications is associated with high risk of chromosomal abnormality in combination with malformations. Identification of a calcification together with a malformation at autopsy more than doubles the probability of detecting a chromosomal abnormality, compared with identification of a malformation only. We propose that identification of a fetal tissue calcification at autopsy, and potentially also at ultrasound examination, should infer

  13. Dopaminergic system abnormalities Etiopathogenesis of dystonia

    Shuhui Wu; Huifang Shang; Xiaoyi Zou

    2008-01-01

    BACKGROUND: Much research has focused on the close relationship between etiopathogenesis of dystonia and abnormalities of the dopaminergic system. Nevertheless, details of the mechanism are still not clear.OBJECTIVE: To review studies from the past few years about pathogenesis and molecular interactions involved in the relationship between dystonia and abnormalities of the dopaminergic system.RETRIEVAL STRATEGY: Using the key words "dystonia" and "dopamine", PubMed database and SCI databases were searched from January 1990 to December 2005 for relevant English publications. A total of 73 articles were searched and, initially, all articles were selected. Inclusive criteria: studies based on pathogenesis and molecular interactions involved in the relationship between dystonia and abnormalities of the dopaminergic system. Exclusive criteria: duplicated studies. A total of 19 articles were extracted after preliminary screening.LITERATURE EVALUATION: The data sources were the PubMed and SCI databases. The types of articles chosen were reviews and original articles.DATA SYNTHESIS: Metabolism and function of dopamine in the central nervous system: the chemical constitution of dopamine is a single benzene ring. The encephalic regions of dopamine synthesis and their fiber projections comprise four nervous system pathways. One of these pathways is the substantia nigra-striatum dopamine pathway, which is a side-loop of the basal ganglia circuitry that participates in movement control and plays a main role in the adjustment of extracorticospinal tract movement. Dopamine can lead to the facilitation of movement. Dystonia and abnormalities of the dopaminergic system: different modes of dopamine abnormality exist in various forms of dystonia. Abnormalities of the dopaminergic system in several primary dystonias: at present, fifteen gene loci of primary dystonia have been reported (DYT1-DYT15). The relationship between abnormalities of the dopaminergic system and the

  14. MRI of fetal GI tract abnormalities.

    Veyrac, C; Couture, A; Saguintaah, M; Baud, C

    2004-01-01

    We describe the magnetic resonance (MR) patterns of a variety of fetal gastrointestinal (GI) abnormalities. Thirty-two fetuses between 23 and 38 weeks' gestation with abnormal appearance of the GI tract by ultrasound underwent MR imaging with T1- and T2-weighted sequences. The MR aspect of intestinal atresia (duodenal atresia, one case; small bowel atresia, nine cases) included dilatation of the bowel loops, accurate assessment of the normal bowel distal to the atresia (except in the patient with multiple atresia and apple-peel syndrome), and micro-rectum with decreased T1 signal (except in the patient with duodenal atresia). Megacystis-microcolon-intestinal hypoperistalsis syndrome (one case) was indicated by an abnormal signal of the entire bowel and an abnormal pattern for the urinary tract. Meconium pseudocysts (two cases) were easily differentiated from enteric cysts (two cases). High anorectal malformations with (two cases) or without (one case) urinary fistula and cloacal malformation (one case) are described and MR findings are discussed. The capability of MR imaging to demonstrate the normal bowel with intraperitoneal anomalies (e.g., congenital diaphragmatic hernia, and sacrococcygeal teratoma) is emphasized. MR imaging is informative in the diagnosis of GI tract abnormalities, especially the severe malformations, with much more accuracy than sonography.

  15. Prevalence of asymptomatic urinary abnormalities among adolescents.

    Fouad, Mohamed; Boraie, Maher

    2016-05-01

    To determine the prevalence of asymptomatic urinary abnormalities in adolescents, first morning clean mid-stream urine specimens were obtained from 2500 individuals and examined by dipstick and light microscopy. Adolescents with abnormal screening results were reexamined after two weeks and those who had abnormal results twice were subjected to systemic clinical examination and further clinical and laboratory investigations. Eight hundred and three (32.1%) individuals had urinary abnormalities at the first screening, which significantly decreased to 345 (13.8%) at the second screening, (P adolescents who had persistent urine abnormalities; 228 (9.1%) individuals had non glomerular hematuria. The hematuria was isolated in 150 (6%) individuals, combined with leukocyturia in 83 (3.3%) individuals, and combined with proteinuria in 12 (0.5%) individuals. Leukocyturia was detected in 150 (6%) of all studied adolescents; it was isolated in 39 (1.6%) individuals and combined with proteinuria in 28 (1.1%) of them. Asymptomatic bacteriuria was detected in 23 (0.9%) of all studied adolescents; all the cases were females. Proteinuria was detected in 65 (2.6%) of all the studied adolescents; 45 (1.8%) individuals had adolescents from rural than urban areas (P adolescents in our population.

  16. Abnormal cervical cytology and health care use

    Frederiksen, Maria Eiholm; Baillet, Miguel Vázquez-Prada; Dugué, Pierre-Antoine

    2015-01-01

    OBJECTIVE: This study aimed to assess the long-term use of health care services in women with abnormal cytology results compared to women with normal cytology results. METHODS: We did a nationwide population-based study, using women aged 23 to 59years participating in the national organized cervi...... they have the abnormal cytology. This difference is further enhanced after the abnormal cytology result.......OBJECTIVE: This study aimed to assess the long-term use of health care services in women with abnormal cytology results compared to women with normal cytology results. METHODS: We did a nationwide population-based study, using women aged 23 to 59years participating in the national organized...... cervical cancer screening program. We included a study population of 40,153 women with abnormal cytology (exposed) and 752,627 women with normal cytology (non-exposed). We retrieved data from the Danish Civil Registration System, the Danish Pathology Data Bank, the National Health Service, the National...

  17. OPHTHALMOLOGIC ABNORMALITIES IN CHILDREN WITH IMPAIRED HEARING

    Inderjit

    2014-02-01

    Full Text Available AIM: To determine the nature of ophthalmologic abnormalities in severe and profound grades of hearing impaired children and to treat visual impairment if any at the earliest . MATERIAL AND METHODS: Study was conducted on100 children in the age group of 5 - 14 years with severe and profound hearing loss visiting outpatient department of Ram Lal Eye and ENT hospital Govt. Medical College Amritsar and subjected to detailed ophthalmological examination. RESULTS: 100 children in the age group 5 - 14 years with hearing impairment were enrolled for t he study , 68 had profound and 32 had severe hearing loss . Visual disorders were found to be as high as 71%. Highest percentage was seen in children aged 7 years. Majority of them (50% had refractive error. Out of these 50 children , 28(56% had myopia , 10 (20% hypermetropia and 12(24% had astigmatism . The other ophthalmic abnormalities in our study were conjunctivitis 14(19.71% , fundus abnormalities and squint 11(15.49% , blepharitis 5 (7.04% , vitamin A deficiency 6 (8.04% , amblyopia 8 (11.26% , pupil disorder 3 (4.22% , cataract 3 (4.22% and heterochromia iridis 7 (9.85%. CONCLUSION : The high prevalence of ophthalmic abnormalities in deaf children mandate screening them for possible ophthalmic abnormalities. Early diagnosis and correction of visual d isturbances would go a long way in social and professional performance of these children.

  18. 药物诱发自身免疫性肝炎的研究进展%Progress of drug-induced autoimmune hepatitis

    陈慧; 郑聘聘; 王炳元

    2011-01-01

    More and more cases of drug-induced liver injury have been reported. Drug-induced autoimmune hepatitis (DI-AIH) may occur because some drugs or its metabolites may bind to a hepatocyte surface protein, forming a neoantigen and activating autoimmune reaction, and/or due to such factors as genetic susceptibility, female and advanced age, etc. The symptoms of DIAIH are often concealed, but a few DIAIH patients can develop liver failure rapidly. Significant increase in biliary enzyme levels and disorder of bilirubin metabolism are general manifestations, while AST and ALT may elevate moderately. Unlike AIH, the autoantibodies in DIAIH patinets can change to be negative with disease improvement. In radiological findings, DIAIH usually presents with lobe liver atrophy, delayed-phase images, and few can develop cirrhosis. Diagnosis depends on the roussel uclaf causality assessment method (RUCAM) and clinical diagnostic scale (modified RUCAM). Good response to corticosteroids (CS) treatment is also an important prognostic factor. Complete remission in 1 -3 months and no relapse after withdrawal of CS mean fine prognosis. DIAIH is an a-cute auto-limit disease, and has a good outcome if diagnosis and treatment are given correctly and promptly.%随着药物(或中草药、保健品)的滥用和“被用”,药物性肝损害不断增加.某些药物本身或代谢产物可与蛋白结合形成半抗原,刺激机体发生免疫反应,和(或)由于宿主的遗传易感性、女性、高龄等因素,导致药物诱发自身免疫性肝炎( drug-induced autoimmune hepatitis,DIAIH)的发生.DIAIH的临床症状多数隐匿,但也可迅速发展致肝衰竭.一般表现为胆道酶增加和胆红素排泄障碍,AST和ALT通常为中等度升高.自身抗体的出现与AIH相似,但随着疾病的好转迅速转阴.影像学上DIAIH可见明显的肝叶萎缩、门脉期强化和造影剂排泄延迟,多数不发展至肝硬化.诊断包括因果关系评估方法(roussel uclaf

  19. Advances in understanding paternally transmitted Chromosomal Abnormalities

    Marchetti, F; Sloter, E; Wyrobek, A J

    2001-03-01

    Multicolor FISH has been adapted for detecting the major types of chromosomal abnormalities in human sperm including aneuploidies for clinically-relevant chromosomes, chromosomal aberrations including breaks and rearrangements, and other numerical abnormalities. The various sperm FISH assays have been used to evaluate healthy men, men of advanced age, and men who have received mutagenic cancer therapy. The mouse has also been used as a model to investigate the mechanism of paternally transmitted genetic damage. Sperm FISH for the mouse has been used to detect chromosomally abnormal mouse sperm, while the PAINT/DAPI analysis of mouse zygotes has been used to evaluate the types of chromosomal defects that can be paternally transmitted to the embryo and their effects on embryonic development.

  20. Persistent Pain and Sensory Abnormalities after Abdominoplasty

    Presman, Benjamin; Finnerup, Kenneth; Andresen, Sven Robert

    2015-01-01

    University Hospital, Denmark. The questionnaire included questions about pain and sensory abnormalities located to the abdominal skin, and physical and psychological function; patient satisfaction with surgery was rated on a 4-point scale. RESULTS: One hundred seventy patients answered the questionnaire......%) patients. The majority of patients reported improvement on all physical and psychological factors. Patients with pain were more often disappointed with the surgery and unwilling to recommend the surgery. CONCLUSIONS: Overall, patients were satisfied with the procedure, although abnormal abdominal skin....... Fourteen patients (8.2%) reported pain within the past 7 days related to the abdominoplasty. Abnormal abdominal skin sensation was common and reported by 138 patients (81%). Sensory hypersensitivity was associated with the presence of persistent pain. Satisfaction with the procedure was reported by 149 (88...

  1. Neurological abnormalities associated with CDMA exposure.

    Hocking, B; Westerman, R

    2001-09-01

    Dysaesthesiae of the scalp and neurological abnormality after mobile phone use have been reported previously, but the roles of the phone per se or the radiations in causing these findings have been questioned. We report finding a neurological abnormality in a patient after accidental exposure of the left side of the face to mobile phone radiation [code division multiple access (CDMA)] from a down-powered mobile phone base station antenna. He had headaches, unilateral left blurred vision and pupil constriction, unilateral altered sensation on the forehead, and abnormalities of current perception thresholds on testing the left trigeminal ophthalmic nerve. His nerve function recovered during 6 months follow-up. His exposure was 0.015-0.06 mW/cm(2) over 1-2 h. The implications regarding health effects of radiofrequency radiation are discussed.

  2. XYY chromosome abnormality in sexual homicide perpetrators.

    Briken, Peer; Habermann, Niels; Berner, Wolfgang; Hill, Andreas

    2006-03-05

    In a retrospective investigation of the court reports about sexual homicide perpetrators chromosome analysis had been carried out in 13 of 166 (7.8%) men. Three men (1.8%) with XYY chromosome abnormality were found. This rate is much higher than that found in unselected samples of prisoners (0.7-0.9%) or in the general population (0.01%). The three men had shown prepubescent abnormalities, school problems, and had suffered from physical abuse. The chromosome analysis in all cases had been carried out in connection with the forensic psychiatric court report due to the sexual homicide. However, two men had earlier psychiatric referrals. All were diagnosed as sexual sadistic, showed a psychopathic syndrome or psychopathy according to the Psychopathy Checklist-Revised [Hare RD, 1991, The Hare Psychopathy Checklist-Revised, Toronto, Ontario, Canada: Multi-Health Systems]. Two were multiple murderers. Especially forensic psychiatrists should be vigilant of the possibility of XYY chromosome abnormalities in sexual offenders.

  3. Parsing abnormal grain growth in specialty aluminas

    Lawrence, Abigail Kremer

    Grain growth in alumina is strongly affected by the impurities present in the material. Certain impurity elements are known to have characteristic effects on abnormal grain growth in alumina. Specialty alumina powders contain multiple impurity species including MgO, CaO, SiO2, and Na 2O. In this work, sintered samples made from alumina powders containing various amounts of the impurities in question were characterized by their grain size and aspect ratio distributions. Multiple quantitative methods were used to characterize and classify samples with varying microstructures. The grain size distributions were used to partition the grain size population into subpopulations depending on the observed deviation from normal behavior. Using both grain size and aspect ratio a new visual representation for a microstructure was introduced called a morphology frequency map that gives a fingerprint for the material. The number of subpopulations within a sample and the shape of the distribution on the morphology map provided the basis for a classification scheme for different types of microstructures. Also using the two parameters a series of five metrics were calculated that describe the character of the abnormal grains in the sample, these were called abnormal character values. The abnormal character values describe the fraction of grains that are considered abnormal, the average magnitude of abnormality (including both grain size and aspect ratio), the average size, and variance in size. The final metric is the correlation between grain size and aspect ratio for the entire population of grains. The abnormal character values give a sense of how different from "normal" the sample is, given the assumption that a normal sample has a lognormal distribution of grain size and a Gaussian distribution of aspect ratios. In the second part of the work the quantified measures of abnormality were correlated with processing parameters such as composition and heat treatment conditions. A

  4. Abnormal Head Position in Infantile Nystagmus Syndrome

    Noval, Susana; González-Manrique, Mar; Rodríguez-Del Valle, José María; Rodríguez-Sánchez, José María

    2011-01-01

    Infantile nystagmus is an involuntary, bilateral, conjugate, and rhythmic oscillation of the eyes which is present at birth or develops within the first 6 months of life. It may be pendular or jerk-like and, its intensity usually increases in lateral gaze, decreasing with convergence. Up to 64% of all patients with nystagmus also present strabismus, and even more patients have an abnormal head position. The abnormal head positions are more often horizontal, but they may also be vertical or take the form of a tilt, even though the nystagmus itself is horizontal. The aim of this article is to review available information about the origin and treatment of the abnormal head position associated to nystagmus, and to describe our treatment strategies. PMID:24533187

  5. Enhanced monitoring of abnormal emergency department demands

    Harrou, Fouzi

    2016-06-13

    This paper presents a statistical technique for detecting signs of abnormal situation generated by the influx of patients at emergency department (ED). The monitoring strategy developed was able to provide early alert mechanisms in the event of abnormal situations caused by abnormal patient arrivals to the ED. More specifically, This work proposed the application of autoregressive moving average (ARMA) models combined with the generalized likelihood ratio (GLR) test for anomaly-detection. ARMA was used as the modelling framework of the ARMA-based GLR anomaly-detection methodology. The GLR test was applied to the uncorrelated residuals obtained from the ARMA model to detect anomalies when the data did not fit the reference ARMA model. The ARMA-based GLR hypothesis testing scheme was successfully applied to the practical data collected from the database of the pediatric emergency department (PED) at Lille regional hospital center, France. © 2015 IEEE.

  6. 药物性血尿52例临床分析%Clinical analysis of 52 cases of drug-induced hematuria

    叶惠尧; 温小春

    2009-01-01

    Objective:To explore the cause of drug-induced hematuria. Methods:To analyse for clinical information of 52 cases of drug-induced hematuria in the data and reason. Results:The drugs causing hematuria were sulfa drugs, diclofenac, indocin, centamyein, cefradine, cefletin, ciprofloxacin, oflxaein and amethopterin.These patients had historical to use related drugs. Clinical maniteslations: hematufia, cryslats by microscopic examination of uria, skin rash in a small mumber of patients. Old people were more (51.92%) in these patients. All patients were fully recovered by stoping drugs and symptomatic treatment. All patients recovered not recured by following and visiting them at six months. Conclusion:In order to avoid occurrence of the disease, clinical doctors should master strictly medication indications and prevent to abuse drugs and try to use fewer or no drugs of nephrotoxicity particularly in elderly patients and educate patients to use drugs under the guidance of doctor as much as possible and no blind.%目的:探讨药物所致血尿的病因.方法:对52例药物性血尿的临床资料进行数理分析.结果:表明引起血尿的药物有磺胺类、双氯酚酸、消炎痛、庆大霉素、头孢拉啶、头孢氨苄、环丙沙星、氧氟沙星、甲氨蝶呤.患者有使用相关药物史,临床表现为血尿,镜检尿液有结晶体,少数患者有皮疹,老年患者较多(51.9%).停用药物及对症处理后痊愈.随访6个月无复发.结论:为避免该症的发生,临床医生应严格掌握用药指征,防止滥用药物,尽量少用或不用肾毒性药物,特别是老年患者,并教育患者应尽可能在医生指导下用药、不要盲目用药.

  7. 药物致Q-T间期延长的文献分析%Literature Analysis of Drug-induced Q-T Interval Prolongation

    穆维静; 任晓蕾; 张海英

    2013-01-01

    近年来,临床实践有许多药物都会导致Q-T间期延长甚至尖端扭转型室性心律失常(TdP)。本文通过对1979年-2013年国内医药期刊公开报道的药物致Q-T间期延长的个案进行统计和分析,总结了56个病例的一般情况、引起Q-T间期延长的药物、发生时间及转归等,致Q-T间期延长药物中排在前三位的分别为抗心律失常药、抗微生物药、抗组胺药。大部分患者在用药后一个月内出现,停药及对症治疗后好转。临床医师应正确地认识药物致Q-T间期延长发生机制和易感因素,才能保证临床安全有效地使用药物。%Many medications can cause QT prolongation and torsades de pointes ventricular tachycardia (TdP), which were gradually discovered in recent years. Based on year 1979-2013 domestic medical journals and public report about drug-induced QT prolongation were collected and analyzed. Total of 56 cases were collected and summarized in respect of general condition of patients, drugs involved, occurrence times of ADR, outcomes and so on. The top three classes of drugs causing Q-T interval prolongation are antiarrhythmic drugs, antimicrobials and antihistamines. Most ADRs occurred within one month after treatment. ADRs relieved after drug withdrawal and symptomatic treatment. Physicians should pay more attention to the medications’ mechanisms and risk factors of drug-induced Q-T interval prolongation to ensure medication administration safety.

  8. Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment

    Liu, Nanjun; Tengstrand, Elizabeth A.; Chourb, Lisa; Hsieh, Frank Y., E-mail: frank.hsieh@nextcea.com

    2014-09-15

    The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann–Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that lead to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7-specificity and 100-sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p ≤ 0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated laboratory animals (rats, mice, dogs, and monkeys) and human subjects to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings. - Highlights: • A reliable biomarker of drug-induced phospholipidosis (DIPL) is needed for humans. • Di-22:6-BMP is specific/sensitive for DIPL in animals as published in literatures. • The di-22:6-BMP biomarker can be validated for humans via NPC patients. • DIPL

  9. Expression of Integrins in Drug-induced Gingival Overgrowth%整合素在药物性牙龈增生中的表达研究

    周洁

    2012-01-01

    Objective: To investigate the possible correlation between integrin al , a2 and (31 expression and excessive collagen synthesis in fibroblasts from drug-induced gingival overgrowth (DIGO) patients. Methods: Gingival fibroblasts from five DIGO patients and five healthy subjects were included. The expression of al, a2 and (31 integrin subunits was examined by immunohistochemistry and quantitative PCR. Results: Our results demonstrate that the expression of al was significantly lower in HGF fibroblasts compared with control fibroblasts (P<0. 01). No significant differences in the expression of a2 and (31 were detected. Conclusion: The decreased expression of integrin al in DIGO fibroblasts may be related to the excessive collagen deposition in DIGO patients.%目的:检测整合素α1、α2和β1在来源于药物性牙龈增生(drug-induced gingival overgrowth,DIGO)患者的牙龈成纤维细胞中的表达水平变化,探讨其与DIGO胶原聚集的相关性.方法:采用免疫组织化学法和实时定量PCR分别检测整合素α1、α2和β1在来源于DIGO和正常人群牙龈组织和成纤维细胞中的表达水平.结果:整合素α1在DIGO牙龈成纤维细胞中的表达水平显著性低于其在正常牙龈成纤维细胞中的表达水平(P<0.01).而整合索α2和β1在2组牙龈成纤维细胞中的表达水平无显著性差异.结论:整合素α1在DIGO牙龈成纤维细胞中的低表达可能与胶原聚集相关.

  10. Is drug-induced toxicity a good predictor of response to neo-adjuvant chemotherapy in patients with breast cancer? -A prospective clinical study

    Singh JP

    2004-08-01

    Full Text Available Abstract Background Neo-adjuvant chemotherapy is an integral part of multi-modality approach in the management of locally advanced breast cancer and it is vital to predict the response in order to tailor the regime for a patient. The common final pathway in the tumor cell death is believed to be apoptosis or programmed cell death and chemotherapeutic drugs like other DNA-damaging agents act on rapidly multiplying cells including both the tumor and the normal cells by following the same common final pathway. This could account for both the toxic effects and the response. Absence or decreased apoptosis has been found to be associated with chemo resistance. The change in expression of apoptotic markers (Bcl-2 and Bax proteins brought about by various chemotherapeutic regimens is being used to identify drug resistance in the tumor cells. A prospective clinical study was conducted to assess whether chemotherapy induced toxic effects could serve as reliable predictors of apoptosis or response to neo-adjuvant chemotherapy in patients with locally advanced breast cancer. Methods 50 cases of locally advanced breast cancer after complete routine and metastatic work up were subjected to trucut biopsy and the tissue evaluated immunohistochemically for apoptotic markers (bcl-2/bax ratio. Three cycles of Neoadjuvant Chemotherapy using FAC regime (5-fluorouracil, adriamycin, cyclophosphamide were given at three weekly intervals and patients assessed for clinical response as well as toxicity after each cycle. Modified radical mastectomy was performed in all patients three weeks after the last cycle and the specimen were re-evaluated for any change in the bcl-2/bax ratio. The clinical response, immunohistochemical response and the drug-induced toxicity were correlated and compared. Descriptive studies were performed with SPSS version 10 and the significance of response was assessed using paired t-test. Significance of correlation between various variables was

  11. Hemorheological abnormalities in human arterial hypertension

    Lo Presti, Rosalia; Hopps, Eugenia; Caimi, Gregorio

    2014-05-01

    Blood rheology is impaired in hypertensive patients. The alteration involves blood and plasma viscosity, and the erythrocyte behaviour is often abnormal. The hemorheological pattern appears to be related to some pathophysiological mechanisms of hypertension and to organ damage, in particular left ventricular hypertrophy and myocardial ischemia. Abnormalities have been observed in erythrocyte membrane fluidity, explored by fluorescence spectroscopy and electron spin resonance. This may be relevant for red cell flow in microvessels and oxygen delivery to tissues. Although blood viscosity is not a direct target of antihypertensive therapy, the rheological properties of blood play a role in the pathophysiology of arterial hypertension and its vascular complications.

  12. Nonpathologizing trauma interventions in abnormal psychology courses.

    Hoover, Stephanie M; Luchner, Andrew F; Pickett, Rachel F

    2016-01-01

    Because abnormal psychology courses presuppose a focus on pathological human functioning, nonpathologizing interventions within these classes are particularly powerful and can reach survivors, bystanders, and perpetrators. Interventions are needed to improve the social response to trauma on college campuses. By applying psychodynamic and feminist multicultural theory, instructors can deliver nonpathologizing interventions about trauma and trauma response within these classes. We recommend class-based interventions with the following aims: (a) intentionally using nonpathologizing language, (b) normalizing trauma responses, (c) subjectively defining trauma, (d) challenging secondary victimization, and (e) questioning the delineation of abnormal and normal. The recommendations promote implications for instructor self-reflection, therapy interventions, and future research.

  13. Occult intraspinal abnormalities and congenital scoliosis

    Mohammad Ali Erfani

    2007-06-01

    Full Text Available

    BACKGROUND: Congenital scoliosis occurs because of either the failure of formation or the failure of segmentation or both. Evaluation of the incidence and the types of occult intraspinal abnormalities in congenital scoliosis is the subject of this study.

    METHODS: During a period of 29 years, 103 patients with congenital scoliosis were studied. MRI was used in 46 patients, myelography or CT myelography was used in 64 patients and both MRI and myelography or CT myelography were used in 7 patients for intraspinal abnormalities.

    RESULTS: In the MRI group, among the 46 patients, 19 patients (41.3% had intraspinal abnormalities consisting syringomyelia in 9 (19.5% diastematomyelia in 8 (17.4%, tethered cord syndrome in 6 (13%, low conus in 5 (10.8% and diplomyelia in 3 (6.5% of the patients. In the myelography group, among the 64 patients, 17 (26.5% had intraspinal abnormalities and diastematomyelia was the most common one found in 14 (21.8% patients.

    CONCLUSIONS: Intraspinal abnormalities are frequent in congenital scoliosis. Syringomyelia may be associated with congenital scoliosis. In congenital scoliosis, rib fusion may be an indicator of intraspinal abnormalities in MRI. A significant difference between clinical findings and intraspinal anomalies (P<0.05 was noted. Moreover, we believe that total spinal MRI with coronal, sagittal and axial views is a valuable tool in determining the intraspinal abnormalities in congenital scoliosis. This method is highly

  14. Anaesthesia in operations of congenital craniofacial abnormalities

    Jahangirie B

    1996-07-01

    Full Text Available Some syndromes that are characterized by abnormalities of the skull, facial bones, and mandibule, most of these patients are from the pediatric population. For the anaesthetic management of patients with various craniofacial dysostosis are as follows: 1 The necessary for careful evaluation of the airway by simply observing the patient. 2 Evaluation of the patient for abnormalities of the heart and lungs. 3 Patients may also have increased intracranial pressure. 4 Anaesthetic drugs and techniques: no particular drugs is recommended. Techniques controlled ventilation. 5 All patients should be cared in the intensive care unit after operation between 24-48 hours

  15. Temporal abnormalities in children with developmental dyscalculia.

    Vicario, Carmelo Mario; Rappo, Gaetano; Pepi, Annamaria; Pavan, Andrea; Martino, Davide

    2012-01-01

    Recent imaging studies have associated Developmental dyscalculia (DD) to structural and functional alterations corresponding Parietal and the Prefrontal cortex (PFC). Since these areas were shown also to be involved in timing abilities, we hypothesized that time processing is abnormal in DD. We compared time processing abilities between 10 children with pure DD (8 years old) and 11 age-matched healthy children. Results show that the DD group underestimated duration of a sub-second scale when asked to perform a time comparison task. The timing abnormality observed in our DD participants is consistent with evidence of a shared fronto-parietal neural network for representing time and quantity.

  16. Craniofacial abnormalities among patients with Edwards Syndrome

    Rafael Fabiano M. Rosa

    2013-09-01

    Full Text Available OBJECTIVE To determine the frequency and types of craniofacial abnormalities observed in patients with trisomy 18 or Edwards syndrome (ES. METHODS This descriptive and retrospective study of a case series included all patients diagnosed with ES in a Clinical Genetics Service of a reference hospital in Southern Brazil from 1975 to 2008. The results of the karyotypic analysis, along with clinical data, were collected from medical records. RESULTS: The sample consisted of 50 patients, of which 66% were female. The median age at first evaluation was 14 days. Regarding the karyotypes, full trisomy of chromosome 18 was the main alteration (90%. Mosaicism was observed in 10%. The main craniofacial abnormalities were: microretrognathia (76%, abnormalities of the ear helix/dysplastic ears (70%, prominent occiput (52%, posteriorly rotated (46% and low set ears (44%, and short palpebral fissures/blepharophimosis (46%. Other uncommon - but relevant - abnormalities included: microtia (18%, orofacial clefts (12%, preauricular tags (10%, facial palsy (4%, encephalocele (4%, absence of external auditory canal (2% and asymmetric face (2%. One patient had an initial suspicion of oculo-auriculo-vertebral spectrum (OAVS or Goldenhar syndrome. CONCLUSIONS: Despite the literature description of a characteristic clinical presentation for ES, craniofacial alterations may be variable among these patients. The OAVS findings in this sample are noteworthy. The association of ES with OAVS has been reported once in the literature.

  17. Engineering molecular crystals with abnormally weak cohesion.

    Maly, Kenneth E; Gagnon, Eric; Wuest, James D

    2011-05-14

    Adding astutely placed methyl groups to hexaphenylbenzene increases molecular weight but simultaneously weakens key C-H···π interactions, thereby leading to decreased enthalpies of sublimation and showing that materials with abnormally weak cohesion can be made by identifying and then obstructing interactions that help control association.

  18. Schizophrenogenic Parenting in Abnormal Psychology Textbooks.

    Wahl, Otto F.

    1989-01-01

    Considers the treatment of family causation of schizophrenia in undergraduate abnormal psychology textbooks. Reviews texts published only after 1986. Points out a number of implications for psychologists which arise from the inclusion in these texts of the idea that parents cause schizophrenia, not the least of which is the potential for…

  19. Teaching Abnormal Psychology in a Multimedia Classroom.

    Brewster, JoAnne

    1996-01-01

    Examines the techniques used in teaching an abnormal psychology class in a multimedia environment with two computers and a variety of audiovisual equipment. Students respond anonymously to various questions via keypads mounted on their desks, then immediately view and discuss summaries of their responses. (MJP)

  20. Psychology Faculty Perceptions of Abnormal Psychology Textbooks

    Rapport, Zachary

    2011-01-01

    The problem. The purpose of the current study was to investigate the perceptions and opinions of psychology professors regarding the accuracy and inclusiveness of abnormal psychology textbooks. It sought answers from psychology professors to the following questions: (1) What are the expectations of the psychology faculty at a private university of…

  1. [Y chromosome structural abnormalities and Turner's syndrome].

    Ravel, C; Siffroi, J-P

    2009-06-01

    Although specifically male, the human Y chromosome may be observed in female karyotypes, mostly in women with Turner syndrome stigmata. In women with isolated gonadal dysgenesis but otherwise normal stature, the testis determining factor or SRY gene may have been removed from the Y chromosome or may be mutated. In other women with Turner syndrome, the karyotype is usually abnormal and shows a frequent 45,X/46,XY mosaicism. In these cases, the phenotype depends on the ratio between Y positive and 45,X cell lines in the body. When in mosaicism, Y chromosomes are likely to carry structural abnormalities which explain mitotic instability, such as the existence of two centromeres. Dicentric Y isochromosomes for the short arm (idic[Yp]) or ring Y chromosomes (r[Y]) are the most frequent abnormal Y chromosomes found in infertile patients and in Turner syndrome in mosaic with 45,X cells. Although monocentric, deleted Y chromosomes for the long arm and those carrying microdeletions in the AZF region are also instable and are frequently associated with a 45,X cell line. Management of infertile patients carrying such abnormal Y chromosomes must take into account the risk and the consequences of a mosaicism in the offspring.

  2. Neurobehavioural Correlates of Abnormal Repetitive Behaviour

    R. A. Ford

    1991-01-01

    Full Text Available Conditions in which echolalia and echopraxia occur are reviewed, followed by an attempt to elicit possible mechanisms of these phenomena. A brief description of stereotypical and perseverative behaviour and obsessional phenomena is given. It is suggested that abnormal repetitive behaviour may occur partly as a result of central dopaminergic dysfunction.

  3. Metabolic Abnormalities in Children with Asthma

    2010-01-01

    Rationale: Childhood asthma and obesity have reached epidemic proportions worldwide, and the latter is also contributing to increasing rates of related metabolic disorders, such as diabetes. Yet, the relationship between asthma, obesity, and abnormal lipid and glucose metabolism is not well understood, nor has it been adequately explored in children.

  4. Morphological Abnormalities of Thalamic Subnuclei in Migraine

    Magon, Stefano; May, Arne; Stankewitz, Anne

    2015-01-01

    . SIGNIFICANCE STATEMENT: This multicenter imaging study shows morphological thalamic abnormalities in a large cohort of patients with episodic migraine compared with healthy subjects using state-of-the-art MRI and advanced, fully automated multiatlas segmentation techniques. The results stress that migraine...

  5. Abnormal Events for Emergency Trip in HANARO

    Ahn, Guk Hun; Choi, M. J.; Park, S. I.; Kim, H. W.; Kim, S. J.; Park, J. H.; Kwon, I. C

    2006-12-15

    This report gathers abnormal events related to emergency trip of HANARO that happened during its operation over 10 years since the first criticality on February 1995. The collected examples will be utilized to the HANARO's operators as a useful guide.

  6. Esophageal motility abnormalities in gastroesophageal reflux disease

    Irene; Martinucci; Nicola; de; Bortoli; Maria; Giacchino; Giorgia; Bodini; Elisa; Marabotto; Santino; Marchi; Vincenzo; Savarino; Edoardo; Savarino

    2014-01-01

    Esophageal motility abnormalities are among the main factors implicated in the pathogenesis of gastroesophageal reflux disease. The recent introduction in clinical and research practice of novel esophageal testing has markedly improved our understanding of the mechanisms contributing to the development of gastroesophageal reflux disease, allowing a better management of patients with this disorder. In this context, the present article intends to provide an overview of the current literature about esophageal motility dysfunctions in patients with gastroesophageal reflux disease. Esophageal manometry, by recording intraluminal pressure, represents the gold standard to diagnose esophagealmotility abnormalities. In particular, using novel techniques, such as high resolution manometry with or without concurrent intraluminal impedance monitoring, transient lower esophageal sphincter (LES) relaxations, hypotensive LES, ineffective esophageal peristalsis and bolus transit abnormalities have been better defined and strongly implicated in gastroesophageal reflux disease development. Overall, recent findings suggest that esophageal motility abnormalities are increasingly prevalent with increasing severity of reflux disease, from nonerosive reflux disease to erosive reflux disease and Barrett’s esophagus. Characterizing esophageal dysmotility among different subgroups of patients with reflux disease may represent a fundamental approach to properly diagnose these patients and, thus, to set up the best therapeutic management. Currently, surgery represents the only reliable way to restore the esophagogastric junction integrity and to reduce transient LES relaxations that are considered to be the predominant mechanism by which gastric contents can enter the esophagus. On that ground, more in depth future studies assessing the pathogenetic role of dysmotility in patients with reflux disease are warranted.

  7. Esophageal motility abnormalities in gastroesophageal reflux disease.

    Martinucci, Irene; de Bortoli, Nicola; Giacchino, Maria; Bodini, Giorgia; Marabotto, Elisa; Marchi, Santino; Savarino, Vincenzo; Savarino, Edoardo

    2014-05-06

    Esophageal motility abnormalities are among the main factors implicated in the pathogenesis of gastroesophageal reflux disease. The recent introduction in clinical and research practice of novel esophageal testing has markedly improved our understanding of the mechanisms contributing to the development of gastroesophageal reflux disease, allowing a better management of patients with this disorder. In this context, the present article intends to provide an overview of the current literature about esophageal motility dysfunctions in patients with gastroesophageal reflux disease. Esophageal manometry, by recording intraluminal pressure, represents the gold standard to diagnose esophageal motility abnormalities. In particular, using novel techniques, such as high resolution manometry with or without concurrent intraluminal impedance monitoring, transient lower esophageal sphincter (LES) relaxations, hypotensive LES, ineffective esophageal peristalsis and bolus transit abnormalities have been better defined and strongly implicated in gastroesophageal reflux disease development. Overall, recent findings suggest that esophageal motility abnormalities are increasingly prevalent with increasing severity of reflux disease, from non-erosive reflux disease to erosive reflux disease and Barrett's esophagus. Characterizing esophageal dysmotility among different subgroups of patients with reflux disease may represent a fundamental approach to properly diagnose these patients and, thus, to set up the best therapeutic management. Currently, surgery represents the only reliable way to restore the esophagogastric junction integrity and to reduce transient LES relaxations that are considered to be the predominant mechanism by which gastric contents can enter the esophagus. On that ground, more in depth future studies assessing the pathogenetic role of dysmotility in patients with reflux disease are warranted.

  8. Meiotic chromosome abnormalities in human spermatogenesis.

    Martin, Renée H

    2006-08-01

    The last few years have witnessed an explosion in the information about chromosome abnormalities in human sperm and the meiotic events that predispose to these abnormalities. We have determined that all chromosomes are susceptible to nondisjunction, but chromosomes 21 and 22 and, especially, the sex chromosomes have an increased frequency of aneuploidy. Studies are just beginning on the effects of potential mutagens on the chromosomal constitution of human sperm. The effects of pesticides and cancer therapeutic agents have been reviewed. In the last decade, there has been a great impetus to study chromosome abnormalities in sperm from infertile men because the advent of intracytoplasmic sperm injection (ICSI) made it possible for these men to father pregnancies. A large number of studies have demonstrated that infertile men have an increased frequency of chromosomally abnormal sperm and children, even when they have a normal somatic karyotype. Meiotic studies on the pachytene stage of spermatogenesis have demonstrated that infertile men have impaired chromosome synapsis, a significantly decreased frequency of recombination, and an increased frequency of chromosomes completely lacking a recombination site. Such errors make these cells susceptible to meiotic arrest and the production of aneuploid gametes.

  9. Experimental evaluation of prophylactic and curative effect of a herbal drug Hemidesmus indicus R.Br. in drug induced ulcers in wistar albino rats

    Shishira Bharadwaj

    2013-06-01

    Full Text Available Peptic Ulcers are the most common condition experienced by most of the people due to urbanized lifestyle. Hemidesmus indicus R.Br. is a herbal drug mentioned for its treatment in the ancient Indian traditional medicine. To compare the Prophylactic and Curative effects of aqueous and Alcoholic extracts of Hemidesmus indicus in Drug induced ulcers. Aqueous and Alcoholic extracts of the drug were studied for their ulcer healing activity in Wistar Albino rats. Ninety Wistar albino rats were divided into nine groups with one control, four prophylactic and four curative groups. Ulcers were induced with Indomethacin in a dose of 20 mg/kg body weight twice in a gap of 15 hours. Aqueous extract was given in a dose of 500 mg/kg body weight and alcohol in a dose of 100 mg/kg body weight. It was found that both have potential ulcer healing activity with alcoholic extract marginally better than aqueous extract. It can thus be concluded that Hemidesmus indicus R. Br is a effective drug in peptic ulcers. [Int J Res Med Sci 2013; 1(3.000: 243-247

  10. Comparison of Liver Biopsy Findings with the Digestive Disease Week Japan 2004 Scale for Diagnosis of Drug-Induced Liver Injury.

    Tsutsui, Akemi; Nakanuma, Yasuni; Takaguchi, Kouichi; Nakamura, Satoko; Shibata, Hiroshi; Baba, Nobuyuki; Senoh, Tomonori; Nagano, Takuya; Ikeda, Hiroko

    2015-01-01

    The liver biopsy remains a valuable tool in the diagnosis of drug-induced liver injury (DILI). The Digestive Disease Week Japan 2004 (DDW-J) scale proposed as an objective tool for the diagnosis of DILI has been widely used in Japan. So far, the histological features have not been compared with DDW-J scale in detail. Herein, we examined the correlation between liver biopsy findings and clinical features, particularly DDW-J scales. A total of 80 patients with liver injuries of unknown cause were enrolled. Based on the histological findings, these cases were categorized into 3 groups: A (DILI was strongly suspected), B (DILI was suspected), and C (DILI should be considered in the differential diagnosis). Histological groups and DDW-J scale were moderately correlated (κ = 0.60). The mean total DDW-J scale scores were as follows: 4.89 for A, 3.26 for B, and 0.75 for C (p biopsy findings and DDW-J scale were well correlated, and the hepatocellular type of liver injuries was well coincided by both evaluations, though there were several discrepant cases, particularly in cholestatic type.

  11. Research advances in drug-induced autoimmune hepatitis%药物诱导的自身免疫性肝炎研究进展

    李春敏; 张静怡; 唐颖悦; 茅益民

    2016-01-01

    Drug induced autoimmune hepatitis (DIAIH) refers to the liver injury mediated by druginduced autoimmune reaction.Since it has similar clinical features as idiopathic autoimmune hepatitis,it is often difficult to make differential diagnosis in clinical practice.A deep understanding of the development,pathogenesis,related drugs,risk factors,and clinical and histological features of DIAIH helps with the correct diagnosis and treatment of DIAIH.%药物诱导的自身免疫性肝炎是由药物诱发的自身免疫反应所介导的肝损伤,由于与特发性自身免疫性肝炎的临床特征相似,临床上鉴别诊断往往非常困难.深入了解药物诱导的自身免疫性肝炎的发生情况、发病机制、所涉及的相关药物、风险因素、临床和组织学特点等,有助于更好地正确诊断和治疗本病.

  12. NAT2 variants are associated with drug-induced liver injury caused by anti-tuberculosis drugs in Indonesian patients with tuberculosis.

    Yuliwulandari, Rika; Susilowati, Retno Wilujeng; Wicaksono, Britanto Dani; Viyati, Kencono; Prayuni, Kinasih; Razari, Intan; Kristin, Erna; Syafrizal; Subagyo; Sri Diana, Eva; Setiawati, Suci; Ariyani, Aziza; Mahasirimongkol, Surakameth; Yanai, Hideki; Mushiroda, Taisei; Tokunaga, Katsushi

    2016-06-01

    Drug-induced liver injury (DILI) is the most common adverse drug reaction in the treatment of tuberculosis (TB). Several studies showed that patients with TB and the slow-acetylator phenotype caused by NAT2 variants are highly susceptible to DILI caused by anti-TB drugs, hereafter designated AT-DILI. However, the role of NAT2 variants in AT-DILI has never been assessed for an Indonesian population. We recruited 50 patients with TB and AT-DILI and 191 patients with TB but without AT-DILI; we then used direct DNA sequencing to assess single-nucleotide polymorphisms in the coding region of NAT2. NAT2*6A was significantly associated with susceptibility to AT-DILI (P=7.7 × 10(-4), odds ratio (OR)=4.75 (1.8-12.55)). Moreover, patients with TB and the NAT2-associated slow-acetylator phenotype showed higher risk of AT-DILI than patients with the rapid- or intermediate-acetylator phenotypes (P=1.7 × 10(-4), OR=3.45 (1.79-6.67)). In conclusion, this study confirms the significance of the association between slow-acetylator NAT2 variants and susceptibility to AT-DILI in an Indonesian population.

  13. Abnormal Selective Attention Normalizes P3 Amplitudes in PDD

    Hoeksma, Marco R.; Kemner, Chantal; Kenemans, J. Leon; van Engeland, Herman

    2006-01-01

    This paper studied whether abnormal P3 amplitudes in PDD are a corollary of abnormalities in ERP components related to selective attention in visual and auditory tasks. Furthermore, this study sought to clarify possible age differences in such abnormalities. Children with PDD showed smaller P3 amplitudes than controls, but no abnormalities in…

  14. Aphrodisiac drug-induced hemolysis.

    Stalnikowicz, Ruth; Amitai, Yona; Bentur, Yedidia

    2004-01-01

    Volatile alkyl nitrites have been used during the past decades for "recreational purposes," and for intensifying sexual experience. Their use has been associated with methemoglobinemia and hemolysis. We report three patients who presented over the past year with acute hemolysis after inhalation of butyl nitrite, two of them had glucose-6-phosphate dehydrogenase (G6PD) deficiency.

  15. Drug-induced lupus erythematosus

    ... A chest x-ray may show signs of pleuritis or pericarditis (inflammation around the lining of the ... anti-inflammatory drugs (NSAIDs) to treat arthritis and pleurisy Corticosteroid creams to treat skin rashes Antimalarial drugs ( ...

  16. Drug-induced acute pancreatitis

    I.A. Eland (Ingo)

    2003-01-01

    textabstractAcute pancreatitis is an inflammatory disease of the pancreas with sudden onset. The severity of acute pancreatitis may vary from mild to life threatening. There are many risk factors for acute pancreatitis, among which gallstones and alcohol abuse are most widely known. Drugs are consid

  17. Chromosomal abnormalities in a psychiatric population

    Lewis, K.E.; Lubetsky, M.J.; Wenger, S.L.; Steele, M.W. [Univ. of Pittsburgh Medical Center, PA (United States)

    1995-02-27

    Over a 3.5 year period of time, 345 patients hospitalized for psychiatric problems were evaluated cytogenetically. The patient population included 76% males and 94% children with a mean age of 12 years. The criteria for testing was an undiagnosed etiology for mental retardation and/or autism. Cytogenetic studies identified 11, or 3%, with abnormal karyotypes, including 4 fragile X positive individuals (2 males, 2 females), and 8 with chromosomal aneuploidy, rearrangements, or deletions. While individuals with chromosomal abnormalities do not demonstrate specific behavioral, psychiatric, or developmental problems relative to other psychiatric patients, our results demonstrate the need for an increased awareness to order chromosomal analysis and fragile X testing in those individuals who have combinations of behavioral/psychiatric, learning, communication, or cognitive disturbance. 5 refs., 1 fig., 2 tabs.

  18. Migraine and structural abnormalities in the brain

    Hougaard, Anders; Amin, Faisal Mohammad; Ashina, Messoud

    2014-01-01

    PURPOSE OF REVIEW: The aim is to provide an overview of recent studies of structural brain abnormalities in migraine and to discuss the potential clinical significance of their findings. RECENT FINDINGS: Brain structure continues to be a topic of extensive research in migraine. Despite advances...... in neuroimaging techniques, it is not yet clear if migraine is associated with grey matter changes. Recent large population-based studies sustain the notion of increased prevalence of white matter abnormalities in migraine, and possibly of silent infarct-like lesions. The clinical relevance of this association...... is not clear. Structural changes are not related to cognitive decline, but a link to an increased risk of stroke, especially in patients with aura, cannot be ruled out. SUMMARY: Migraine may be a risk factor for structural changes in the brain. It is not yet clear how factors such as migraine sub-type, attack...

  19. Developmental pragmatics in normal and abnormal children.

    Bara, B G; Bosco, F M; Bucciarelli, M

    1999-07-01

    We propose a critical review of current theories of developmental pragmatics. The underlying assumption is that such a theory ought to account for both normal and abnormal development. From a clinical point of view, we are concerned with the effects of brain damage on the emergence of pragmatic competence. In particular, the paper deals with direct speech acts, indirect speech acts, irony, and deceit in children with head injury, closed head injury, hydrocephalus, focal brain damage, and autism. Since no single theory covers systematically the emergence of pragmatic capacity in normal children, it is not surprising that we have not found a systematic account of deficits in the communicative performance of brain injured children. In our view, the challenge for a pragmatic theory is the determination of the normal developmental pattern within which different pragmatic phenomena may find a precise role. Such a framework of normal behavior would then permit the systematic study of abnormal pragmatic development.

  20. [Abnormal hemoglobins in Negroid Ecuadorian populations].

    Jara, N O; Guevara Espinoza, A; Guderian, R H

    1989-02-01

    The prevalence of hemoglobinopathies was determined in the black race located in two distinct geographical areas in Ecuador; in the coastal province of Esmeraldas, particularly the Santiago basin (Rio Cayapas and Rio Onzoles) and in the province of Imbabura, particularly in the intermoutain valley, Valle de Chota. A total of 2038 blood samples were analyzed, 1734 in Esmeraldas and 304 in Inbabura, of which 23.2% (473 individuals) were found to be carriers of abnormal hemoglobins, 25.4% (441) in Esmeraldas and 10.5% (32) in Imbabura. The abnormal hemoglobins found in Esmeraldas were Hb AS (19.2%), Hb AC (5.0%), Hb SS (0.6%) and Hb SC (0.5%) while in Imbabura only Hb AS (9.5%) and Hb AC (0.9%) were found. The factors that could influence the difference in prevalence found in the two geographical areas are discussed.

  1. Spinal cord injury without radiographic abnormality

    Singh Anil

    2006-01-01

    Full Text Available Spinal cord injury without radiological abnormality is rare in adults. Below we present a case report of 20 yrs old male with isolated cervical cord injury, without accompanying vertebral dislocation or fracture involving the spinal canal rim. He fell down on plain and smooth ground while carrying 40 kg weight overhead and developed quadriparesis with difficulty in respiration. Plain radiographs of the neck revealed no fractures or dislocations. MRI showed bulky spinal cord and an abnormal hyper intense signal on the T2W image from C2 vertebral body level to C3/4 intervertebral disc level predominantly in the anterior aspect of the cord The patient was managed conservatively with head halter traction and invasive ventilatory support for the initial 7 days period in the ICU. In our patient recovery was good and most of the neurological deficit improved over 4 weeks with conservative management.

  2. Mitochondrial abnormalities in the myofibrillar myopathies.

    Jackson, S; Schaefer, J; Meinhardt, M; Reichmann, H

    2015-11-01

    Myofibrillar myopathies are a genetically diverse group of skeletal muscle disorders, with distinctive muscle histopathology. Causative mutations have been identified in the genes MYOT, LDB3, DES, CRYAB, FLNC, BAG3, DNAJB6, FHL1, PLEC and TTN, which encode proteins which either reside in the Z-disc or associate with the Z-disc. Mitochondrial abnormalities have been described in muscle from patients with a myofibrillar myopathy. We reviewed the literature to determine the extent of mitochondrial dysfunction in each of the myofibrillar myopathy subtypes. Abnormal mitochondrial distribution is a frequent finding in each of the subtypes, but a high frequency of COX-negative or ragged red fibres, a characteristic finding in some of the conventional mitochondrial myopathies, is a rare finding. Few in vitro studies of mitochondrial function have been performed in affected patients.

  3. Binocular combination in abnormal binocular vision.

    Ding, Jian; Klein, Stanley A; Levi, Dennis M

    2013-02-08

    We investigated suprathreshold binocular combination in humans with abnormal binocular visual experience early in life. In the first experiment we presented the two eyes with equal but opposite phase shifted sine waves and measured the perceived phase of the cyclopean sine wave. Normal observers have balanced vision between the two eyes when the two eyes' images have equal contrast (i.e., both eyes contribute equally to the perceived image and perceived phase = 0°). However, in observers with strabismus and/or amblyopia, balanced vision requires a higher contrast image in the nondominant eye (NDE) than the dominant eye (DE). This asymmetry between the two eyes is larger than predicted from the contrast sensitivities or monocular perceived contrast of the two eyes and is dependent on contrast and spatial frequency: more asymmetric with higher contrast and/or spatial frequency. Our results also revealed a surprising NDE-to-DE enhancement in some of our abnormal observers. This enhancement is not evident in normal vision because it is normally masked by interocular suppression. However, in these abnormal observers the NDE-to-DE suppression was weak or absent. In the second experiment, we used the identical stimuli to measure the perceived contrast of a cyclopean grating by matching the binocular combined contrast to a standard contrast presented to the DE. These measures provide strong constraints for model fitting. We found asymmetric interocular interactions in binocular contrast perception, which was dependent on both contrast and spatial frequency in the same way as in phase perception. By introducing asymmetric parameters to the modified Ding-Sperling model including interocular contrast gain enhancement, we succeeded in accounting for both binocular combined phase and contrast simultaneously. Adding binocular contrast gain control to the modified Ding-Sperling model enabled us to predict the results of dichoptic and binocular contrast discrimination experiments

  4. Abnormal calcium homeostasis in peripheral neuropathies

    2009-01-01

    Abnormal neuronal calcium (Ca2+) homeostasis has been implicated in numerous diseases of the nervous system. The pathogenesis of two increasingly common disorders of the peripheral nervous system, namely neuropathic pain and diabetic polyneuropathy, has been associated with aberrant Ca2+ channel expression and function. Here we review the current state of knowledge regarding the role of Ca2+ dyshomeostasis and associated mitochondrial dysfunction in painful and diabetic neuropathies. The cent...

  5. OPHTHALMOLOGIC ABNORMALITIES IN CHILDREN WITH IMPAIRED HEARING

    Inderjit; Jagdeepak; Prempal; Anup Narayanrao

    2014-01-01

    AIM: To determine the nature of ophthalmologic abnormalities in severe and profound grades of hearing impaired children and to treat visual impairment if any at the earliest . MATERIAL AND METHODS: Study was conducted on100 children in the age group of 5 - 14 years with severe and profound hearing loss visiting outpatient department of Ram Lal Eye and ENT hospital Govt. Medical College Amritsar and subjected to detailed ophthalmological examination. R...

  6. ABNORMALITIES OF ERG IN CONGENITAL ANIRIDIA

    1991-01-01

    Congenital aniridia is generally associated with nystagmus, corneal pannus, cataract, ectopia lentis, glaucoma, macular hypoplasia, optic nerve hypoplasia and compromised visual function. Many theories have been proposed, including a failure in the development of the neural ectoderm and/or an aberrant development of mesoderm. We observed the ERG from 19 patients with congenital aniridia. Fourteen patients had abnormal ERG, including the reduced a wave trough under dark adapted red stimuli with dark adap...

  7. Dysglycemia induces abnormal circadian blood pressure variability

    Kumarasamy Sivarajan

    2011-11-01

    Full Text Available Abstract Background Prediabetes (PreDM in asymptomatic adults is associated with abnormal circadian blood pressure variability (abnormal CBPV. Hypothesis Systemic inflammation and glycemia influence circadian blood pressure variability. Methods Dahl salt-sensitive (S rats (n = 19 after weaning were fed either an American (AD or a standard (SD diet. The AD (high-glycemic-index, high-fat simulated customary human diet, provided daily overabundant calories which over time lead to body weight gain. The SD (low-glycemic-index, low-fat mirrored desirable balanced human diet for maintaining body weight. Body weight and serum concentrations for fasting glucose (FG, adipokines (leptin and adiponectin, and proinflammatory cytokines [monocyte chemoattractant protein-1 (MCP-1 and tumor necrosis factor-α (TNF-α] were measured. Rats were surgically implanted with C40 transmitters and blood pressure (BP-both systolic; SBP and diastolic; DBP and heart rate (HR were recorded by telemetry every 5 minutes during both sleep (day and active (night periods. Pulse pressure (PP was calculated (PP = SBP-DBP. Results [mean(SEM]: The AD fed group displayed significant increase in body weight (after 90 days; p Conclusion These data validate our stated hypothesis that systemic inflammation and glycemia influence circadian blood pressure variability. This study, for the first time, demonstrates a cause and effect relationship between caloric excess, enhanced systemic inflammation, dysglycemia, loss of blood pressure control and abnormal CBPV. Our results provide the fundamental basis for examining the relationship between dysglycemia and perturbation of the underlying mechanisms (adipose tissue dysfunction induced local and systemic inflammation, insulin resistance and alteration of adipose tissue precursors for the renin-aldosterone-angiotensin system which generate abnormal CBPV.

  8. Trading networks, abnormal motifs and stock manipulation

    2012-01-01

    We study trade-based manipulation of stock prices from the perspective of complex trading networks constructed by using detailed information of trades. A stock trading network consists of nodes and directed links, where every trader is a node and a link is formed from one trader to the other if the former sells shares to the latter. Specifically, three abnormal network motifs are investigated, which are found to be formed by a few traders, implying potential intention of price manipulation. W...

  9. Computed tomography in abnormalities of the hip

    Visser, J.D.; Jonkers, A.; Klasen, H.J. (Rijksuniversiteit Groningen (Netherlands). Academisch Ziekenhuis); Hillen, B. (Rijksuniversiteit Groningen (Netherlands). Lab. voor Anatomie en Embryologie)

    1982-06-26

    The value of computed tomography in the assessment of abnormalities of the hip is demonstrated with the aid of an anatomical preparation and in patients with, respectively, congenital dislocation of a hip, dislocation of the hip in spina bifida, an acetabular fracture and a Ewing tumour. The anteversion of the acetabulum and femur and the instability index of the hip joint can be measured by means of computed tomography.

  10. Abnormal calcium homeostasis in peripheral neuropathies.

    Fernyhough, Paul; Calcutt, Nigel A

    2010-02-01

    Abnormal neuronal calcium (Ca2+) homeostasis has been implicated in numerous diseases of the nervous system. The pathogenesis of two increasingly common disorders of the peripheral nervous system, namely neuropathic pain and diabetic polyneuropathy, has been associated with aberrant Ca2+ channel expression and function. Here we review the current state of knowledge regarding the role of Ca2+ dyshomeostasis and associated mitochondrial dysfunction in painful and diabetic neuropathies. The central impact of both alterations of Ca2+ signalling at the plasma membrane and also intracellular Ca2+ handling on sensory neurone function is discussed and related to abnormal endoplasmic reticulum performance. We also present new data highlighting sub-optimal axonal Ca2+ signalling in diabetic neuropathy and discuss the putative role for this abnormality in the induction of axonal degeneration in peripheral neuropathies. The accumulating evidence implicating Ca2+ dysregulation in both painful and degenerative neuropathies, along with recent advances in understanding of regional variations in Ca2+ channel and pump structures, makes modulation of neuronal Ca2+ handling an increasingly viable approach for therapeutic interventions against the painful and degenerative aspects of many peripheral neuropathies.

  11. Schizophrenia, abnormal connection, and brain evolution.

    Randall, P L

    1983-03-01

    Abnormalities of functional connection between specialized areas in the human brain may underlie the symptoms which constitute the schizophrenia syndrome. Callosal and intrahemispheric fibres may be equally involved. The clinical emergence of symptoms in the later stages of brain maturation may be dependent on myelination of these fibre groups, both of which have extended myelination cycles. Ontogenetically earlier variants of the same mechanism could theoretically result in dyslexia and the syndromes of Kanner and Gilles de la Tourette. As new and unique extensions of specialized function emerge within the evolving brain, biological trial and error of connection both within and between them may produce individuals possessing phylogenetically advanced abilities, or equally, others possessing a wide range of abnormalities including those which comprise the schizophrenia syndrome. A dormant phenotypic potential for schizophrenia may exist in individuals who never develop symptoms during the course of a lifetime though some of these may become clinically apparent under the influence of various precipitating factors. It is concluded that abnormal functional connection and its normal and "supernormal" counterparts may be natural, essential, and inevitable consequences of brain evolution, and that this may have been so throughout the history of vertebrate brain evolution.

  12. Abnormal parietal encephalomalacia associated with schizophrenia

    Pan, Fen; Wang, Jun-Yuan; Xu, Yi; Huang, Man-Li

    2017-01-01

    Abstract Rationale: It is widely believed that structural abnormalities of the brain contribute to the pathophysiology of schizophrenia. The parietal lobe is a central hub of multisensory integration, and abnormities in this region might account for the clinical features of schizophrenia. However, few cases of parietal encephalomalacia associated with schizophrenia have been described. Patient concerns and Diagnoses: In this paper, we present a case of a 25-year-old schizophrenia patient with abnormal parietal encephalomalacia. The patient had poor nutrition and frequently had upper respiratory infections during childhood and adolescence. She showed severe schizophrenic symptoms such as visual hallucinations for 2 years. After examining all her possible medical conditions, we found that the patient had a lesion consistent with the diagnosis of encephalomalacia in her right parietal lobe and slight brain atrophy. Interventions: The patient was prescribed olanzapine (10 mg per day). Outcomes: Her symptoms significantly improved after antipsychotic treatment and were still well controlled 1 year later. Lessons: This case suggested that parietal encephalomalacia, which might be caused by inflammatory and infectious conditions in early life and be aggravated by undernutrition, might be implicated in the etiology of schizophrenia. PMID:28272261

  13. Abnormal Activity Detection Using Pyroelectric Infrared Sensors

    Xiaomu Luo

    2016-06-01

    Full Text Available Healthy aging is one of the most important social issues. In this paper, we propose a method for abnormal activity detection without any manual labeling of the training samples. By leveraging the Field of View (FOV modulation, the spatio-temporal characteristic of human activity is encoded into low-dimension data stream generated by the ceiling-mounted Pyroelectric Infrared (PIR sensors. The similarity between normal training samples are measured based on Kullback-Leibler (KL divergence of each pair of them. The natural clustering of normal activities is discovered through a self-tuning spectral clustering algorithm with unsupervised model selection on the eigenvectors of a modified similarity matrix. Hidden Markov Models (HMMs are employed to model each cluster of normal activities and form feature vectors. One-Class Support Vector Machines (OSVMs are used to profile the normal activities and detect abnormal activities. To validate the efficacy of our method, we conducted experiments in real indoor environments. The encouraging results show that our method is able to detect abnormal activities given only the normal training samples, which aims to avoid the laborious and inconsistent data labeling process.

  14. Abnormal Activity Detection Using Pyroelectric Infrared Sensors.

    Luo, Xiaomu; Tan, Huoyuan; Guan, Qiuju; Liu, Tong; Zhuo, Hankz Hankui; Shen, Baihua

    2016-06-03

    Healthy aging is one of the most important social issues. In this paper, we propose a method for abnormal activity detection without any manual labeling of the training samples. By leveraging the Field of View (FOV) modulation, the spatio-temporal characteristic of human activity is encoded into low-dimension data stream generated by the ceiling-mounted Pyroelectric Infrared (PIR) sensors. The similarity between normal training samples are measured based on Kullback-Leibler (KL) divergence of each pair of them. The natural clustering of normal activities is discovered through a self-tuning spectral clustering algorithm with unsupervised model selection on the eigenvectors of a modified similarity matrix. Hidden Markov Models (HMMs) are employed to model each cluster of normal activities and form feature vectors. One-Class Support Vector Machines (OSVMs) are used to profile the normal activities and detect abnormal activities. To validate the efficacy of our method, we conducted experiments in real indoor environments. The encouraging results show that our method is able to detect abnormal activities given only the normal training samples, which aims to avoid the laborious and inconsistent data labeling process.

  15. Abnormal asymmetry of brain connectivity in schizophrenia.

    Ribolsi, Michele; Daskalakis, Zafiris J; Siracusano, Alberto; Koch, Giacomo

    2014-01-01

    Recently, a growing body of data has revealed that beyond a dysfunction of connectivity among different brain areas in schizophrenia patients (SCZ), there is also an abnormal asymmetry of functional connectivity compared with healthy subjects. The loss of the cerebral torque and the abnormalities of gyrification, with an increased or more complex cortical folding in the right hemisphere may provide an anatomical basis for such aberrant connectivity in SCZ. Furthermore, diffusion tensor imaging studies have shown a significant reduction of leftward asymmetry in some key white-matter tracts in SCZ. In this paper, we review the studies that investigated both structural brain asymmetry and asymmetry of functional connectivity in healthy subjects and SCZ. From an analysis of the existing literature on this topic, we can hypothesize an overall generally attenuated asymmetry of functional connectivity in SCZ compared to healthy controls. Such attenuated asymmetry increases with the duration of the disease and correlates with psychotic symptoms. Finally, we hypothesize that structural deficits across the corpus callosum may contribute to the abnormal asymmetry of intra-hemispheric connectivity in schizophrenia.

  16. Drug-induced sleep endoscopy as a selection tool for mandibular advancement therapy by oral device in patients with mild to moderate obstructive sleep apnoea.

    De Corso, E; Bastanza, G; Della Marca, G; Grippaudo, C; Rizzotto, G; Marchese, M R; Fiorita, A; Sergi, B; Meucci, D; Di Nardo, W; Paludetti, G; Scarano, E

    2015-12-01

    Nowadays oral appliance therapy is recognised as an effective therapy for many patients with primary snoring and mild to moderate obstructive sleep apnoea (OSA), as well as those with more severe OSA who cannot tolerate positive airway pressure (PAP) therapies. For this reason, it is important to focus on objective criteria to indicate which subjects may benefit from treatment with a mandibular advancement device (MAD). Various anthropometric and polysomnographic predictors have been described in the literature, whereas there are still controversies about the role of drug-induced sleep endoscopy (DISE) and advancement bimanual manoeuvre as predictor factors of treatment outcome by oral device. Herein, we report our experience in treatment of mild moderate OSA by oral appliance selected by DISE. We performed a single institution, longitudinal prospective evaluation of a consecutive group of mild moderate patients with obstructive sleep apnoea syndrome who underwent DISE. During sleep endoscopy, gentle manoeuvre of mandibular advancement less than 5 mm was performed. In 30 of 65 patients (46.2%) we obtained an unsuccessful improvement of airway patency whereas in 35 of 65 patients (53.8%) the improvement was successful and patients were considered suitable for oral device application. Because 7 of 35 patients were excluded due to conditions interfering with oral appliance therapy, we finally treated 28 patients. After 3 months of treatment, we observed a significant improvement in the Epworth medium index [(7.35 ± 2.8 versus 4.1 ± 2.2 (p DISE for MAD therapy. In the current study, mandibular advancement splint therapy was successfully prescribed on the basis not only of severity of disease, as determined by the subject's initial AHI, but also by DISE findings combined with results of gentle mandibular advancement manoeuvre allowing direct view of the effects of mandibular protrusion on breathing spaces in obstruction sites, and showing good optimisation of

  17. Drug-induced sleep endoscopy and simulated snoring in patients with sleep-disordered breathing: agreement of anatomic changes in the upper airway.

    Herzog, Michael; Kellner, Patrick; Plößl, Sebastian; Glien, Alexander; Rohrmeier, Christian; Kühnel, Thomas; Plontke, Stefan; Herzog, Beatrice

    2015-09-01

    Drug-induced sleep endoscopy (DISE) and simulated snoring (SimS) are performed as part of the diagnostic procedure in patients with suspected sleep-disordered breathing (SDB). Despite both techniques frequently performed, they have rarely been evaluated yet in terms of agreement of the obtained results. Both diagnostic procedures were performed consecutively in 40 patients with SDB and documented identically. The obtained data were analysed with respect to the agreement of both procedure at different levels of the oropharynx as well as different patterns of obstruction and vibration. The anterior-posterior collapsibility of the soft palate/uvula revealed a moderate agreement between SimS and DISE (κ = 0.42; 95 % CI 0.22-0.63). The dorsal shift of the tongue base agreed moderate for patients with an AHI below 10 (κ = 0.47) and above 25 (κ = 0.44) between SimS ad DISE. The lateral and circular pharyngeal collapsibility at velum and tongue base level did not agree between SimS and DISE, was higher for DISE and could be partially reversed by mandibular protrusion. Collapse patterns of the soft palate and uvula can be induced by SimS and resemble the patterns induced by DISE. The dorsalization of the tongue base can be simulated to a lower extent by SimS. Lateral and circular patterns of collapse at the upper and lower oropharynx induced by DISE do not seem to be simulated by SimS. SimS seems to be an additional method to screen the collapsibility of the soft palate and uvula prior to DISE.

  18. Mitochondrial toxicity of diclofenac and its metabolites via inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria: Possible role in drug induced liver injury (DILI).

    Syed, Muzeeb; Skonberg, Christian; Hansen, Steen Honoré

    2016-03-01

    Diclofenac is a widely prescribed NSAID, which by itself and its reactive metabolites (Phase-I and Phase-II) may be involved in serious idiosyncratic hepatotoxicity. Mitochondrial injury is one of the mechanisms of drug induced liver injury (DILI). In the present work, an investigation of the inhibitory effects of diclofenac (Dic) and its phase I [4-hydroxy diclofenac (4'-OH-Dic) and 5-hydroxy diclofenac (5-OH-dic)] and Phase-II [diclofenac acyl glucuronide (DicGluA) and diclofenac glutathione thioester (DicSG)] metabolites, on ATP synthesis in rat liver mitochondria was carried out. A mechanism based inhibition of ATP synthesis is exerted by diclofenac and its metabolites. Phase-I metabolite (4'-OH-Dic) and Phase-II metabolites (DicGluA and DicSG) showed potent inhibition (2-5 fold) of ATP synthesis, where as 5-OH-Dic, one of the Phase-I metabolite, was a less potent inhibitor as compared to Dic. The calculated kinetic constants of mechanism based inhibition of ATP synthesis by Dic showed maximal rate of inactivation (Kinact) of 2.64 ± 0.15 min(-1) and half maximal rate of inactivation (KI) of 7.69 ± 2.48 μM with Kinact/KI ratio of 0.343 min(-1) μM(-1). Co-incubation of mitochondria with Dic and reduced GSH exhibited a protective effect on Dic mediated inhibition of ATP synthesis. Our data from this study strongly indicate that Dic as well as its metabolites could be involved in the hepato-toxic action through inhibition of ATP synthesis.

  19. Integrated comparison of drug-related and drug-induced ultra performance liquid chromatography/mass spectrometry metabonomic profiles using human hepatocyte cultures.

    Croixmarie, Vincent; Umbdenstock, Thierry; Cloarec, Olivier; Moreau, Amélie; Pascussi, Jean-Marc; Boursier-Neyret, Claire; Walther, Bernard

    2009-08-01

    approach coupled to a statistical pretreatment of the data, enabling the separate capture of both drug related and drug induced biomarkers, represents a powerful technique for future mechanistic studies using cellular tools.

  20. Evidence-based selection of training compounds for use in the mechanism-based integrated prediction of drug-induced liver injury in man.

    Dragovic, Sanja; Vermeulen, Nico P E; Gerets, Helga H; Hewitt, Philip G; Ingelman-Sundberg, Magnus; Park, B Kevin; Juhila, Satu; Snoeys, Jan; Weaver, Richard J

    2016-12-01

    The current test systems employed by pharmaceutical industry are poorly predictive for drug-induced liver injury (DILI). The 'MIP-DILI' project addresses this situation by the development of innovative preclinical test systems which are both mechanism-based and of physiological, pharmacological and pathological relevance to DILI in humans. An iterative, tiered approach with respect to test compounds, test systems, bioanalysis and systems analysis is adopted to evaluate existing models and develop new models that can provide validated test systems with respect to the prediction of specific forms of DILI and further elucidation of mechanisms. An essential component of this effort is the choice of compound training set that will be used to inform refinement and/or development of new model systems that allow prediction based on knowledge of mechanisms, in a tiered fashion. In this review, we focus on the selection of MIP-DILI training compounds for mechanism-based evaluation of non-clinical prediction of DILI. The selected compounds address both hepatocellular and cholestatic DILI patterns in man, covering a broad range of pharmacologies and chemistries, and taking into account available data on potential DILI mechanisms (e.g. mitochondrial injury, reactive metabolites, biliary transport inhibition, and immune responses). Known mechanisms by which these compounds are believed to cause liver injury have been described, where many if not all drugs in this review appear to exhibit multiple toxicological mechanisms. Thus, the training compounds selection offered a valuable tool to profile DILI mechanisms and to interrogate existing and novel in vitro systems for the prediction of human DILI.

  1. Drug-Induced Liver Injury Associated With Antidepressive Psychopharmacotherapy: An Explorative Assessment Based on Quantitative Signal Detection Using Different MedDRA Terms.

    Gahr, Maximilian; Zeiss, René; Lang, Dirk; Connemann, Bernhard J; Hiemke, Christoph; Schönfeldt-Lecuona, Carlos

    2016-06-01

    Drug-induced liver injury is a major problem of pharmacotherapy and is also frequent with antidepressive psychopharmacotherapy. However, there are only few studies using a consistent methodologic approach to study hepatotoxicity of a larger group of antidepress ants. We performed a quantitative signal detection analysis using data from the Uppsala Monitoring Centre from the WHO that records adverse drug reaction (ADR) data from worldwide sources; we retrieved substance- and country-specific (Australia, France, Germany, Italy, Spain, the United Kingdom, and the United States) ADR data and calculated reporting odds ratios as measures for disproportionality within a case/noncase approach. To allow for identification of agents that cause severe forms of hepatotoxic ADRs, we used 2 terms of the MedDRA ("drug-related hepatic disorders-comprehensive search" [DRHD-CS] and "… -severe events only" [DRHD-SEO]). Distribution of signals was heterogeneous throughout the different data sets, and consistent findings were present for only a few substances: agomelatine (AGM) and tianeptine as well as both positive control agents (amineptine, nefazodone) generated signals related to DRHD-CS and DRHD-SEO in all analyzed data sets. Tri- and tetracyclic antidepressants (here amitriptyline, clomipramine, mianserin, mirtazapine, trimipramine) were associated with hepatotoxicity in several data sets. Using 2 MedDRA terms did not allow for detection of agents that cause severe hepatotoxic ADR. Our results support the findings of previous, primarily literature-based, systematic analyses of hepatotoxicity related to antidepressive psychopharmacotherapy. No new safety information could be generated. Application of 2 MedDRA terms did not increase the substance-specific safety information.

  2. Cyclooxygenase-2 inhibitor celecoxib augments chemotherapeutic drug-induced apoptosis by enhancing activation of caspase-3 and -9 in prostate cancer cells.

    Dandekar, Devendra S; Lopez, Monica; Carey, Robert I; Lokeshwar, Bal L

    2005-06-20

    Many tumors constitutively express high levels of the inducible form of proinflammatory enzyme, cyclooxygenase-2 (COX-2). Increased COX-2 expression is associated with tumor cell resistance to many cytotoxic chemotherapy drugs. Furthermore, increased resistance to cytotoxic antitumor drugs is also known to be dependent on associated stromal cells in many tumors. We investigated whether prostate tumor-associated stromal cells, marrow-derived osteoblasts, affect cytotoxicity of 2 antitumor drugs, COL-3 and docetaxel (TXTR), and whether it is dependent on COX-2 activity. We further examined whether inhibiting the activity of COX-2 negate the stroma-induced decrease in drug sensitivity in tumor cells. COX-2-specific inhibitor celecoxib (CXB) was used to inhibit COX-2 activity and associated alteration in cell death signaling was investigated. Coculturing PC-3ML cells with osteoblasts decreased the cytotoxicity of the tested antitumor drugs and was associated with increased COX-2 activity in PC-3ML cells. A significant decrease in drug-induced PGE(2) increase and an increase in cytotoxicity were observed when cells were treated with COL-3 or TXTR combined with CXB. Cytotoxicity of single or combination treatment increased apoptosis, which was associated with caspase-3 and -9 activation, PARP cleavage, increased BAD protein, but decreased protein levels of XIAP and BCL-(xL). Oral administration of CXB (40 mg/kg) to mice with PC-3ML tumors for 42 days increased tumor latency, decreased tumor growth and enhanced tumor control with COL-3 or TXTR. Overall, a synergistic enhancement of antitumor activity in combination treatment was observed in vitro and an additive effect in vivo. These observations suggest a potential clinical use of combined dosing of COX-2 inhibitors and cytotoxic drugs at lower, nontoxic dose than currently used to treat advanced prostate cancer.

  3. Usefulness of in vitro combination assays of mitochondrial dysfunction and apoptosis for the estimation of potential risk of idiosyncratic drug induced liver injury.

    Goda, Keisuke; Takahashi, Tadakazu; Kobayashi, Akio; Shoda, Toshiyuki; Kuno, Hideyuki; Sugai, Shoichiro

    2016-01-01

    Drug-induced liver injury (DILI) is one of the serious and frequent drug-related adverse events. This adverse event is a main reason for regulatory action pertaining to drugs, including restrictions in clinical indications and withdrawal from clinical trials or the marketplace. Idiosyncratic DILI especially has become a major clinical concern because of its unpredictable nature, frequent hospitalization, need for liver transplantation and high mortality. The estimation of the potential for compounds to induce idiosyncratic DILI is very difficult in non-clinical studies because the precise mechanism of idiosyncratic DILI is still unknown. Recently, many in vitro assays which indicate a possibility of the prediction of the idiosyncratic DILI have been reported. Among these, some in vitro assays focus on the effects of compounds on mitochondrial function and the apoptotic effects of compounds on human hepatocytes. In this study, we measured oxygen consumption rate (OCR) and caspase-3/7 activity as an endpoint of mitochondrial dysfunction and apoptosis, respectively, with human hepatocytes after treatment with compounds causing idiosyncratic DILI (troglitazone, leflunomide, ranitidine and diclofenac). Troglitazone and leflunomide decreased the OCR but did not affect caspase-3/7 activity. Ranitidine increased caspase-3/7 activity but did not affect the OCR. Diclofenac decreased the OCR and increased caspase-3/7 activity. Acetaminophen and ethanol, which are also hepatotoxicants but do not induce idiosyncratic DILI, did not affect the OCR or caspase-3/7 activity. These results indicate that a combination assay of mitochondrial dysfunction and apoptosis is useful for the estimation of potential risk of compounds to induce idiosyncratic DILI.

  4. 柳氮磺吡啶致药物超敏反应综合征%Drug-induced hypersensitivity syndrome induced by sulfasalazine:a case report

    李兴天; 刘莉萍; 李遇梅

    2014-01-01

    A case of sulfasalazine-induced hypersensitivity syndrome was reported. A 34-year-old male, presented macu-lopapular rash with fever, alterations of white cell populations and dysfunction of the liver after one-month treatment with sul-fasalazine for ulcerative colitis. Dermatological examination showed scarlet and partly confluent maculopapules over the entire body. The rash blanches on pressure. According to the history of treatment with sulfasalazine, clinical manifestation and labo-ratory examination, drug-induced hypersensitivity syndrome was diagnosed. The treatment produced a marked improvement af-ter the initiation of systemic corticosteroids, immunoglobulin and supportive therapy.%报告1例柳氮磺吡啶致药物超敏反应综合征。患者男,34岁。因溃疡性结肠炎使用柳氮磺吡啶1个月后出现皮疹,伴发热、白细胞及肝功能异常。皮肤科检查:全身可见泛发鲜红色斑丘疹,部分融合成片,触压皮肤可褪色。结合用药史、临床表现及实验室检查诊断为药物超敏反应综合征,给予系统应用糖皮质激素、静脉注射用人免疫球蛋白、保肝及护胃等治疗后病情好转。

  5. Selected ABCB1, ABCB4 and ABCC2 Polymorphisms Do Not Enhance the Risk of Drug-Induced Hepatotoxicity in a Spanish Cohort

    Ulzurrun, Eugenia; Stephens, Camilla; Ruiz-Cabello, Francisco; Robles-Diaz, Mercedes; Saenz-López, Pablo; Hallal, Hacibe; Soriano, German; Roman, Eva; Fernandez, M. Carmen; Lucena, M. Isabel; Andrade, Raúl J.

    2014-01-01

    Background and Aims Flawed ABC transporter functions may contribute to increased risk of drug-induced liver injury (DILI). We aimed to analyse the influence of genetic variations in ABC transporters on the risk of DILI development and clinical presentations in a large Spanish DILI cohort. Methods A total of ten polymorphisms in ABCB1 (1236T>C, 2677G>T,A, 3435T>C), ABCB4 (1954A>G) and ABCC2 (−1774G>del, −1549A>G, −24C>T, 1249G>A, 3972C>T and 4544G>A) were genotyped using Taqman 5′ allelic discrimination assays or sequencing in 141 Spanish DILI patients and 161 controls. The influence of specific genotypes, alleles and haplotypes on the risk of DILI development and clinical presentations was analysed. Results None of the individual polymorphisms or haplotypes was found to be associated with DILI development. Carriers homozygous for the ABCC2 −1774del allele were however only found in DILI patients. Hence, this genotype could potentially be associated with increased risk, though its low frequency in our Spanish cohort prevented a final conclusion. Furthermore, carriers homozygous for the ABCC2 −1774G/−1549A/−24T/1249G/3972T/4544G haplotype were found to have a higher propensity for total bilirubin elevations when developing DILI. Conclusions Our findings do not support a role for the analysed polymorphisms in the ABCB1, ABCB4 and ABCC2 transporter genes in DILI development in Spanish patients. The ABCC2 −1774deldel genotype was however restricted to DILI cases and could potentially contribute to enhanced DILI susceptibility. PMID:24732756

  6. Persistence of autoreactive T cell drive is required to elicit anti-chromatin antibodies in a murine model of drug-induced lupus.

    Kretz-Rommel, A; Rubin, R L

    1999-01-15

    Long-term treatment with procainamide and numerous other medications is occasionally associated with the development of drug-induced lupus. We recently established a murine model for this syndrome by disrupting central T cell tolerance. Two intrathymic injections of procainamide-hydroxylamine (PAHA), a reactive metabolite of procainamide, into (C57BL/6 x DBA/2)F1 mice resulted in the appearance of chromatin-reactive T cells and anti-chromatin autoantibodies. The current study explores in this model the role of autoreactive T cells in autoantibody production and examines why autoantibodies after a single intrathymic drug injection were much more limited in isotype and specificity. Injection of as few as 5000 chromatin-reactive T cells into naive, syngeneic mice induced a rapid IgM anti-denatured DNA response, while injection of at least 100-fold greater number of activated T cells was required for induction of IgG anti-chromatin Abs, suggesting that small numbers of autoreactive T cells can be homeostatically controlled. Mice subjected to a single intrathymic PAHA injection after receiving splenic B cells from an intrathymic PAHA-injected syngeneic donor also developed anti-chromatin Abs, but adoptive transfer of similarly primed T cells or of B cells without intrathymic PAHA injection of the recipient failed to produce an anti-chromatin response. However, anti-chromatin Abs developed after a single intrathymic PAHA injection in Fas-deficient C57BL/6-lpr/lpr mice, suggesting that activation-induced cell death limited autoimmunity in normal mice. Taken together, these results imply that chromatin-reactive T cells produced by intrathymic PAHA created a B cell population primed to somatically mutate and Ig class switch when subjected to a heavy load or second wave of autoreactive T cells.

  7. Abnormalities Occurring during Female Gametophyte Development Result in the Diversity of Abnormal Embryo Sacs and Leads to Abnormal Fertilization in indicaljaponica Hybrids in Rice

    Yu-Xiang Zeng; Chao-Yue Hu; Yong-Gen Lu; Jin-Quan Li; Xiang-Dong Liu

    2009-01-01

    Embryo sac abortion is one of the major masons for sterility in indicaljaponica hybrids In rice. To clarify the causal mechanism of embryo sac abortion, we studied the female gametophyte development in two indicaljaponica hybrids via an eosin B staining procedure for embryo sac scanning using confocal laser scanning microscope. Different types of abnormalities occurred during megasporogenesis and megagamatogenesis were demonstrated. The earliest abnormality was observed in the megasporocyte. A lot of the chalazal-most megaspores were degenerated before the mono-nucleate embryo sac stage. Disordered positioning of nucleus and abnormal nucallus tissue were characteristics of the abnormal female gametes from the mono-nucleate to four-nucleate embryo sac stages. The abnormalities that occurred from the early stage of the eight-nucleate embryo sac development to the mature embryo sac stage were characterized by smaller sizes and wrinkled antipodals. Asynchronous nuclear migration, abnormal positioning of nucleus, and degeneration of egg apparatus were also found at the eight-nucleate embryo sac stage. The abnormalities that occurred during female gametophyte development resulted in five major types of abnormal embryo sacs. These abnormal embryo sacs led to abnormal fertilization. Hand pollination using normal pollens on the spikelets during anthesis showed that normal pollens could not exclude the effect of abnormal embryo sac on seed setting.

  8. 血小板活化因子在药源性严重过敏反应中的研究现状%Advance of platelet activating factor in drug-induced anaphylaxis

    马翔; 李潇潇; 刘维; 翟所迪

    2015-01-01

    药源性严重过敏反应有难以预测、发作突然和致命性等特点,从而成为困扰临床药物使用的重要安全性因素。由于目前尚无严格的随机对照试验支持抢救药物的推荐,医生常根据临床经验用肾上腺素、抗组胺药和/或糖皮质激素应对突发的药源性严重过敏反应。血小板活化因子( PAF)信号通路可为研究药源性严重过敏反应提供崭新的视角。本文将就药源性严重过敏反应的临床和流行病学特点、PAF通路、抗PAF通路的药物等进行概述。%The acute unpredictably life -threatening characteristic of drug-induced anaphylaxis hinders the safe use of clinical medication.In the absence of rigid randomized controlled trials supporting the recommen-dations for the treatment of immediate onset, doctors often treat drug-induced anaphylaxis with epinephrine, antihistamines and/or glucocorticoids.The researches in platelet activating factor signaling path-way could provide a novel perspective for drug-induced anaphylaxis.This review will briefly introduce the clinical and epidemiological characteristics of drug-induced anaphylaxis, platelet activating factor pathway and drugs targeting at this pathway.

  9. 药源性高血压的发病机制、致病药物及其防治%Drug-induced hypertension: mechanism, causative durgs, prevention, and management

    刘琛; 王育琴

    2012-01-01

    Drug-induced hypertension is one of the common adverse drug reactions. The mechanism of drug-induced hypertension may involve stimulation of sympathetic nervous system activity, sodium and water retention, renin-angiotensin-aldosterone system activation, and changes in function and structure of arterial elasticity. Clinical presentations are increased blood pressure, rebound phenomenon, and even hypertensive crisis. The risk factors for drug-induced hypertension are advanced age, sex, genetic causes, previous history of hypertension, overweight, susceptibity to sodium, and underlying diseases. The drugs known to cause hypertension should be avoided in high-risk patients; if drug treatment is necessary, the treatment should start with a minimum dosage and blood pressure should be monitored during treatment. Once drug-induced hypertension occurs, the drug should be discontinued immediately or the dosage should be reduced, and symptomatic treatment should be given.%药源性高血压为常见药物不良反应之一,其发病机制包括交感神经活动亢进,肾性水钠潴留,肾素-血管紧张素-醛固酮系统激活,以及动脉弹性功能和结构改变.临床表现为血压升高、反跳现象,甚至出现高血压危象.高危因素包括高龄、性别、遗传原因、既往高血压病史、超重、钠敏感、基础疾病.高危人群应避免使用可致血压升高的药物;必须使用时,应从最小剂量开始并应监测血压水平.一旦出现高血压应立即停药或减少剂量,并予对症治疗.

  10. 苯丙胺类药物所致精神病性障碍患者脑白质微结构改变的弥散张量成像研究%The brain white-matter microstructural changes of the inpatients with amphetamine type drugs-induced psychiatric disorders: a diffusion tensor imaging study

    赵晓丹; 徐芳芳; 苏中华; 郝伟

    2013-01-01

    Objective To detect the microstructural changes of the brain white-matter in multiple regions of the inpatients with amphetamine type drugs-induced psychiatric disorders, and to explore the relationship between the brain whiter-matter microstructural changes and psychiatric symptoms. Methods Forty inpatients with amphetamine type drugs-induced psychiatric disorders and forty healthy comparison subjects were recruited to detect white-matter by diffusion tensor imaging (DTI) in 14 ROI and to assess clinical symptoms using The Brief Psychiatric Rating Scale (BPRS).The student's J-test and the Pearson correlation were employed for statistical analysis. Results Compared with healthy comparison subjects, the inpatients with amphetamine type drugs-induced psychiatric disorders group exhibited lower fraction alanisotropy (FA) value in left prefrontal white-matter [(0.42±0.12) vs. (0.46±0.08), P<0.05], higher apparent diffusion coefficient (ADC) value in genu of corpus callosum[ (0.79±0.06) vs. (0.76±0.05), P<0.01],bilateral parietal lobe [ (0.76±0.09)vs. (0.71 ±0.04), P<0.01; (0.74±0.08) vs. (0.71 ±0.05), P<0.05] and right hippocampus [ (0.86+0.11) vs.(0.80±0.05), P<0.01) ]. ADC value of left parietal lobe white-matter (r=0.44,P<0.01; r=0.47, P<0.01; r= 0.37, P<0.05) and right hippocampus (r=0.36, P<0.05; r=0.46, P<0.01; r=0.39, P<0.05) was positive correlated with BPRS score, lack of vitality, disorders of thought factor scores within the patients group. Besides, left parietal lobe showed a positive correlation of ADC value with hostile suspicion factor score (r=0.33, P<0.05). Conclusions The findings support the idea that the inpatients with amphetamine type drugs-induced psychiatric disorders produces white-matter microstructural abnormalities of integrity and connectivity in prefrontal white-matter, parietal lobe, and hippocampus. The parietal lobe and hippocampal microstructural abnormalities are linked to psychiatric symptoms.%目的 探讨苯丙胺类药

  11. Placental loctogen levels associated with gross fetal abnormality.

    Gau, G S; Cadle, G

    1977-02-01

    Four cases of severe congenital abnormality associated with persistently low maternal serum human placental lactogen levels are described. It is thought that this pattern might act as a warning of severe fetal abnormality.

  12. Phenotype abnormality: 36 [Arabidopsis Phenome Database[Archive

    Full Text Available 36 http://metadb.riken.jp/db/SciNetS_ria224i/cria224u1ria224u542i abnormal for trait of behavioral quality...tyledon ... abnormal ... anatomical structure arrangement ... behavioral quality

  13. Phenotype abnormality: 41 [Arabidopsis Phenome Database[Archive

    Full Text Available 41 http://metadb.riken.jp/db/SciNetS_ria224i/cria224u1ria224u547i abnormal for trait of behavioral quality...ganelle ... abnormal ... anatomical structure arrangement ... behavioral quality

  14. Phenotype abnormality: 38 [Arabidopsis Phenome Database[Archive

    Full Text Available 38 http://metadb.riken.jp/db/SciNetS_ria224i/cria224u1ria224u544i abnormal for trait of behavioral quality...idermis ... abnormal ... anatomical structure arrangement ... behavioral quality

  15. Electrocardiographic and Echocardiographic Abnormalities in Chronic Alcoholics

    H.D. Attar

    2017-01-01

    Full Text Available Objective: Alcohol is most commonly abused drug worldwide. It has been shown to produce toxic effects in almost every organ system in the body. Many of these medical conditions can be attributed to direct effects of alcohol whereas others are indirect sequelae that may result from nutritional deficiencies or predisposition to trauma. Alcohol consumption has been associated with a variety of cardio vascular disorders this study was thus undertaken to know the Electrocardiographic and Echocardiographic abnormalities in asymptomatic chronic alcoholic patients. Materials and Methods: 50 Patients attending the out-patient clinic & who were admitted in Al Ameen Medical College Hospital and District hospital, Bijapur were selected for the study. It was a prospective study design subjects in age group 20-40, having history of chronic alcoholism as defined, for more than 5 years were evaluated by electrocardiography and echocardiography. Patients with known diabetics, hypertensive and cardiovascular disorders were excluded from the study group. Results: The prevalence of cardiovascular abnormalities in patients of chronic alcoholism is 37% in our study. Most common ECG changes are sinus tachycardia (18%, and Non specific ST-T changes (9%. Most common 2D ECHO changes was increased posterior wall thickness (11% and followed by increased interventricular septum thickness and decreased ejection fraction (<40%. The prevalence of cardio vascular abnormalities are more with increased duration of alcohol consumption and also high in advanced age group. Conclusions: This study confirms that many electrocardiographic as well as echocardiographic changes occur prior to symptomatic cardiac disorders established to be caused by chronic alcohol intake such as alcoholic cardiomyopathy .which probably are early indictors of ongoing effects of alcohol and are reversible during the early stages detected by non invasive investigations like Electrocardiography and

  16. Hereditary sideroblastic anemia with associated platelet abnormalities.

    Soslau, G; Brodsky, I

    1989-12-01

    A 62 year old male (R.H.) presented with a mild anemia (Hb 11-12 gm%) and a history of multiple hemorrhagic episodes. The marrow had 40-50% sideroblasts. Marrow chromosomes were normal. His wife was hematologically normal, while one daughter, age 30 years, had a sideroblastic anemia (Hb 11-12 gm%) with 40-50% sideroblasts in the marrow. Her anemia was first noted at age 15 years. Administration of vitamin B6 did not correct the anemia in either the father or daughter. Platelet abnormalities inherited jointly with this disorder are described for the first time. Both R.H. and his daughter had prolonged bleeding times, with normal PTT, PT times, fVIII:C, fVIII:Ag levels, and vWF multimers, which may rule out a von Willebrand's disease. They have normal platelet numbers but abnormally low platelet adhesiveness and greatly depressed ADP, collagen, and epinephrine responsiveness. Response to ristocetin was in the low normal range, and aggregation with thrombin was normal. While desmopressin completely normalized R.H.'s bleeding time, none of these platelet parameters were improved. No differences in the SDS PAGE protein patterns of RH platelets could be detected in comparison to normal samples. His platelets took up and released serotonin (5HT) normally, and electron micrographs defined no morphological abnormalities. However, no ATP was released from platelets activated with collagen, and when followed by thrombin about fourfold greater ATP was released by control platelets as compared to RH platelets. The dense granule fraction derived from RH platelets contained about 20% the level of ATP, 40% the level of ADP, and 50% the level of 5HT detected in a normal sample. The results indicate that the bleeding disorder is related to a non-classical heritable storage pool defect. The connection between the inherited sideroblastic anemia and platelet defects is obscure.

  17. Sexsomnia: abnormal sexual behavior during sleep.

    Andersen, Monica L; Poyares, Dalva; Alves, Rosana S C; Skomro, Robert; Tufik, Sergio

    2007-12-01

    This review attempts to assemble the characteristics of a distinct variant of sleepwalking called sexsomnia/sleepsex from the seemingly scarce literature into a coherent theoretical framework. Common features of sexsomnia include sexual arousal with autonomic activation (e.g. nocturnal erection, vaginal lubrication, nocturnal emission, dream orgasms). Somnambulistic sexual behavior and its clinical implications, the role of precipitating factors, diagnostic, treatment, and medico-legal issues are also reviewed. The characteristics of several individuals described in literature including their family/personal history of parasomnia as well as the abnormal behaviors occurring during sleep are reported.

  18. Radiological and orthopedic abnormalities in Satoyoshi syndrome

    Haymon, M.L. [Children`s Hospital, New Orleans, LA (United States). Dept. of Radiology; Willis, R.B. [Children`s Hospital, New Orleans, LA (United States). Dept. of Orthopedics; Ehlayel, M.S. [Div. of Genetics, Dept. of Pediatrics, Louisiana State Univ. Medical Center, Orleans, LA (United States)]|[Louisiana State Medical Center, New Orleans, LA (United States). Center for Molecular and Human Genetics; Lacassie, Y. [Div. of Genetics, Dept. of Pediatrics, Louisiana State Univ. Medical Center, Orleans, LA (United States)]|[Louisiana State Medical Center, New Orleans, LA (United States). Center for Molecular and Human Genetics]|[Children`s Hospital, New Orleans, LA (United States). Dept. of Pediatrics

    1997-05-01

    Satoyoshi syndrome is a are disorder on unknown etiology characterized by progressive, painful intermittent muscle spasms, serve skeletal abnormalities mimicking a skeletal dyplasia, malabsorption, alopecia, and amenorrhea. We further report on a 20{sup 1}/{sub 2}-year-old Caucasian woman whith characteristic manifestation of the syndrome. Since the establishment of the diagnostic 1 year ago, she has been treated with prednisone with good response. However, treatment of the multiple deformities and fractures has been difficult and challenging. The early recognition and treatment of this disorder is of utmost importance, as the skeletal deformities and fractures seem to be secondary to the muscular spasms, as suggested by Satoyoshi.

  19. Cranial computed tomographic abnormalities in leptomeningeal metastasis

    Lee, Y.Y.; Glass, J.P.; Geoffray, A.; Wallace, S.

    1984-11-01

    Sixty-four (57.6%) of 111 cancer patients with cerebrospinal fluid cytology positive for malignant cells had cranial computed tomographic (CT) scans within 2 weeks before or after a lumbar puncture. Twenty-two (34.3%) of the 64 had abnormal CT findings indicative of leptomeningeal metastasis. Thirteen (59.6%) of these 22 patients had associated parenchymal metastases. Recognition of leptomeningeal disease may alter the management of patients with parenchymal metastases. Communicating hydrocephalus in cancer patients should be considered to be related to leptomeningeal metastasis until proven otherwise.

  20. Skeletal abnormalities of acrogeria, a progeroid syndrome

    Ho, A.; White, S.J.; Rasmussen, J.E.

    1987-08-01

    We report the skeletal abnormalities in a 4 1/2-year-old boy with acrogeria, a progeroid syndrome of premature aging of the skin without the involvement of internal organs seen in Hutchinson-Gilford progeria syndrome. Acro-osteolysis of the distal phalanges, delayed cranial suture closure with wormian bones, linear lucent defects of the metaphyses, and antegonial notching of the mandible are the predominant skeletal features of the disorder. The skeletal features described in 21 other reported cases of acrogeria are summarized.

  1. Abnormal immune parameters in HIV-seronegative haemophilic patients

    Allersma, DP; Smid, WM; Briet, E

    1996-01-01

    In HIV-seronegative haemophiliac patients abnormal immune parameters have been demonstrated. In this review data on these abnormalities, their aetiology and clinical consequences are summarized and discussed. The data reviewed show abnormalities at different levels of the adaptive immune system. Mos

  2. Abnormal Behavior in Relation to Cage Size in Rhesus Monkeys

    Paulk, H. H.; And Others

    1977-01-01

    Examines the effects of cage size on stereotyped and normal locomotion and on other abnormal behaviors in singly caged animals, whether observed abnormal behaviors tend to co-occur, and if the development of an abnormal behavior repertoire leads to reduction in the number of normal behavior categories. (Author/RK)

  3. The Spacing Principle for Unlearning Abnormal Neuronal Synchrony

    Popovych, Oleksandr V.; Markos N Xenakis; Tass, Peter A.

    2015-01-01

    Desynchronizing stimulation techniques were developed to specifically counteract abnormal neuronal synchronization relevant to several neurological and psychiatric disorders. The goal of our approach is to achieve an anti-kindling, where the affected neural networks unlearn abnormal synaptic connectivity and, hence, abnormal neuronal synchrony, by means of desynchronizing stimulation, in particular, Coordinated Reset (CR) stimulation. As known from neuroscience, psychology and education, lear...

  4. Seizure increases electroencephalographic abnormalities in children with tuberculous meningitis

    Prastiya Indra Gunawan

    2016-04-01

    The EEG pattern in children with TBM varies, and EEG abnormalities were more frequently localized in the frontotemporal region. Seizures were associated with EEG abnormalities in children with TBM. EEG abnormalities occurring simultaneously with seizures may predict the occurrence of seizures.

  5. 药物性肝损伤200例临床分析%Retrospective analysis of 200 patients with drug induced liver injury

    张长平; 崔向丽; 王咏梅

    2014-01-01

    目的:探讨药物性肝损伤患者的临床特点及发病因素。方法回顾性分析药物性肝损伤患者服药史、临床表现、基础疾病、治疗及转归等。结果200例患者中女139例,男61例,涉及药品169种,其中前3位是中药(48.5%)、抗感染药(11.2%)、抗肿瘤药(8.2%)。患者基础疾病主要为心血管病(14.5%)、感染性疾病(10.3%)、皮肤病(8.8%)、骨关节病(8.4%)、肿瘤(7.9%)等。200例患者治愈146例,好转53例,死亡1例。结论引起肝损伤的药物以中药为主,临床表现形式多样,但转归较好。%Objective To investigate the characteristics and risk etiological factors of drug-induced liver injury(DILI) cases,and provide information for clinical prevention and treatment.Methods The clinical data of 200 patients (including 139 female and 71 male ) with DILI was retrospectively analyzed according to their history of medicine, clinical manifestations,underlying diseases,treatment and prognosis.Results These 200 cases involved 169 etiological drugs,of which the top 3 were traditional Chinese medicine,anti-infective drugs and anti-tumor drugs.The primary underlying diseases of these patients were cardiovascular disease,infectious diseases,skin diseases,osteoarthrosis,tumors and so on. Of those 200 patients,146 were cured,53 improved and 1 died.Conclusion DILI is dominated by traditional Chinese medicine,with various clinical manifestations and favorable prognosis.

  6. Incidence, clinical features and impact on anti-tuberculosis treatment of anti-tuberculosis drug induced liver injury (ATLI in China.

    Penghui Shang

    Full Text Available BACKGROUND: Anti-tuberculosis drug induced liver injury (ATLI is emerging as a significant threat to tuberculosis control in China, though limited data is available about the burden of ATLI at population level. This study aimed to estimate the incidence of ATLI, to better understand its clinical features, and to evaluate its impact on anti-tuberculosis (TB treatment in China. METHODOLOGY/PRINCIPAL FINDINGS: In a population-based prospective study, we monitored 4,304 TB patients receiving directly observed treatment strategy (DOTS treatment, and found that 106 patients developed ATLI with a cumulative incidence of 2.55% (95% Confidence Interval [CI], 2.04%-3.06%. Nausea, vomiting and anorexia were the top three most frequently observed symptoms. There were 35 (33.02% ATLI patients with no symptoms, including 8 with severe hepatotoxicity. Regarding the prognosis of ATLI, 84 cases (79.25% recovered, 18 (16.98% improved, 2 (1.89% failed to respond to the treatment with continued elevation of serum alanine aminotransferase, and 2 (1.89% died as result of ATLI. Of all the ATLI cases, 74 (69.81% cases changed their anti-TB treatment, including 4 (3.77% cases with medication administration change, 21 (19.81% cases with drugs replacement, 54 (50.94% cases with therapy interruption, and 12 (11.32% cases who discontinued therapy. In terms of treatment outcomes, 53 (51.46% cases had TB cured in time, 48 (46.60% cases had therapy prolonged, and 2 (1.94% cases died. Compared with non-ATLI patients, ATLI patients had a 9.25-fold (95%CI, 5.69-15.05 risk of unsuccessful anti-TB treatment outcomes and a 2.11-fold (95%CI, 1.23-3.60 risk of prolonged intensive treatment phase. CONCLUSIONS/SIGNIFICANCE: ATLI could considerably impact the outcomes of anti-TB treatment. Given the incidence of ATLI and the size of TB population in China, the negative impact is substantial. Therefore, more research and efforts are warranted in order to enhance the diagnosis and the

  7. 药物性肝病248例临床分析%Clinical analysis of 248 cases of drug induced liver diseases

    杨立新

    2012-01-01

    Objective To explore the etiology, clinical features and prognosis of drug-induced liver disease (DILD). Methods A retrospective analysis was taken of DILD in hospitalized for medication history, clinical manifestations. Results The causes of DILD were mainly antibiotics (12. 1% ), medicine (23.0% ), anti-TB drugs (8.0% ), anti-cancer drugs (7. 2%), immunosuppressive agents (14..5%). The clinical manifestations were mainly anorexia (62.5%), fatigue (55. 1%), nausea (51.3%), jaundice (37.2%), abdominal pain (18.3%), pruritus (12.9% ), rash (4.6% ). Conclusion Clinicians should pay attention to and strengthen the DILD prevention, diagnosis and treatment.%目的 分析药物性肝病( DILD)的病因、临床特点及预后,提高临床医生对DILD的诊疗水平.方法 采用回顾性分析的方法对248例DILD住院患者的用药史、临床表现以及预后等进行研究.结果 引起DILD的药物以抗生素类药物(12.1%)、中药(23.0%)、抗结核药物(8.0%)、抗肿瘤药物(7.2%)、免疫抑制剂(14.5%)为常见.临床表现以纳差(62.5%)、乏力(55.1%)、恶心(51.3%)、黄疸(37.2%)、腹痛(18.3%)、瘙痒(12.9%)、皮疹(4.6%)等多见;肝性脑病、腹水、凝血酶原时间、黄疸等因素与患者死亡相关.结论 临床医生应重视和加强DILD的预防、诊断和治疗.

  8. Sex bias in experimental immune-mediated, drug-induced liver injury in BALB/c mice: suggested roles for Tregs, estrogen, and IL-6.

    Joonhee Cho

    Full Text Available BACKGROUND AND AIMS: Immune-mediated, drug-induced liver injury (DILI triggered by drug haptens is more prevalent in women than in men. However, mechanisms responsible for this sex bias are not clear. Immune regulation by CD4+CD25+FoxP3+ regulatory T-cells (Tregs and 17β-estradiol is crucial in the pathogenesis of sex bias in cancer and autoimmunity. Therefore, we investigated their role in a mouse model of immune-mediated DILI. METHODS: To model DILI, we immunized BALB/c, BALB/cBy, IL-6-deficient, and castrated BALB/c mice with trifluoroacetyl chloride-haptenated liver proteins. We then measured degree of hepatitis, cytokines, antibodies, and Treg and splenocyte function. RESULTS: BALB/c females developed more severe hepatitis (p<0.01 and produced more pro-inflammatory hepatic cytokines and antibodies (p<0.05 than did males. Castrated males developed more severe hepatitis than did intact males (p<0.001 and females (p<0.05. Splenocytes cultured from female mice exhibited fewer Tregs (p<0.01 and higher IL-1β (p<0.01 and IL-6 (p<0.05 than did those from males. However, Treg function did not differ by sex, as evidenced by absence of sex bias in programmed death receptor-1 and responses to IL-6, anti-IL-10, anti-CD3, and anti-CD28. Diminished hepatitis in IL-6-deficient, anti-IL-6 receptor α-treated, ovariectomized, or male mice; undetectable IL-6 levels in splenocyte supernatants from ovariectomized and male mice; elevated splenic IL-6 and serum estrogen levels in castrated male mice, and IL-6 induction by 17β-estradiol in splenocytes from naïve female mice (p<0.05 suggested that 17β-estradiol may enhance sex bias through IL-6 induction, which subsequently discourages Treg survival. Treg transfer from naïve female mice to those with DILI reduced hepatitis severity and hepatic IL-6. CONCLUSIONS: 17β-estradiol and IL-6 may act synergistically to promote sex bias in experimental DILI by reducing Tregs. Modulating Treg numbers may provide a

  9. The role of drug-induced sleep endoscopy in the diagnosis and management of obstructive sleep apnoea syndrome: our personal experience.

    DE Corso, E; Fiorita, A; Rizzotto, G; Mennuni, G F; Meucci, D; Giuliani, M; Marchese, M R; Levantesi, L; Della Marca, G; Paludetti, G; Scarano, E

    2013-12-01

    Nowadays, drug-induced sleep endoscopy (DISE) is performed widely and its validity and reliability has been demonstrated by several studies; in fact, it provides clinical information not available by routine clinical inspection alone. Its safety and utility are promising, but still needs to be improved to reach the level of excellence expected of gold standard tests used in clinical practice. Our study compares the results of clinical and diagnostic evaluation with those of sleep endoscopy, evaluating the correlation between clinical indexes of routine clinical diagnosis and sites of obstruction in terms of number of sites involved, entity of obstruction and pattern of closure. This study consists in a longitudinal prospective evaluation of 138 patients who successfully underwent sleep endoscopy at our institution. Patients were induced to sleep with a low dose of midazolam followed by titration with propofol. Sedation level was monitored using bispectral index monitoring. Our results suggest that the multilevel complete collapse was statistically significantly associated with higher apnoea hypopnea index values. By including partial sites of obstruction greater than 50%, our results also suggest that multilevel collapse remains statistically and significantly associated with higher apnoea hypopnoea index values. Analyzing BMI distribution based on number of sites with complete and partial obstruction there was no significant difference. Finally, analyzing Epworth Sleepiness Score distribution based on number of sites with complete obstruction, there was a statistically significant difference between patients with 3-4 sites of obstruction compared to those with two sites or uni-level obstruction. In conclusion, our data suggest that DISE is safe, easy to perform, valid and reliable, as previously reported. Furthermore, we found a good correlation between DISE findings and clinical characteristics such as AHI and EPS. Consequently, adequate assessment by DISE of all

  10. Functional neuroimaging abnormalities in idiopathic generalized epilepsy

    Megan L. McGill

    2014-01-01

    Full Text Available Magnetic resonance imaging (MRI techniques have been used to quantitatively assess focal and network abnormalities. Idiopathic generalized epilepsy (IGE is characterized by bilateral synchronous spike–wave discharges on electroencephalography (EEG but normal clinical MRI. Dysfunctions involving the neocortex, particularly the prefrontal cortex, and thalamus likely contribute to seizure activity. To identify possible morphometric and functional differences in the brains of IGE patients and normal controls, we employed measures of thalamic volumes, cortical thickness, gray–white blurring, fractional anisotropy (FA measures from diffusion tensor imaging (DTI and fractional amplitude of low frequency fluctuations (fALFF in thalamic subregions from resting state functional MRI. Data from 27 patients with IGE and 27 age- and sex-matched controls showed similar thalamic volumes, cortical thickness and gray–white contrast. There were no differences in FA values on DTI in tracts connecting the thalamus and prefrontal cortex. Functional analysis revealed decreased fALFF in the prefrontal cortex (PFC subregion of the thalamus in patients with IGE. We provide minimum detectable effect sizes for each measure used in the study. Our analysis indicates that fMRI-based methods are more sensitive than quantitative structural techniques for characterizing brain abnormalities in IGE.

  11. First trimester ultrasound screening of chromosomal abnormalities

    Trninić-Pjević Aleksandra

    2007-01-01

    Full Text Available Introduction: A retrocervical subcutaneous collection of fluid at 11-14 weeks of gestation, can be visualized by ultrasound as nuchal translucency (NT. Objective. To examine the distribution of fetal nuchal translucency in low risk population, to determine the detection rate of chromosomal abnormalities in the population of interest based on maternal age and NT measurement. Method. Screening for chromosomal defects, advocated by The Fetal Medicine Foundation (FMF, was performed in 1,341 pregnancies in the period January 2000 - April 2004. Initial risk for chromosomal defects (based on maternal and gestational age and corrected risk, after the NT measurement, were calculated. Complete data were collected from 1,048 patients. Results. Out of 1,048 pregnancies followed, 8 cases of Down’s syndrome were observed, 7 were detected antenatally and 6 out of 7 were detected due to screening that combines maternal age and NT measurement. According to our results, sensitivity of the screening for aneuploidies based on maternal age alone was 12.5% and false positive rate 13.1%, showing that screening based on NT measurement is of great importance. Screening by a combination of maternal age and NT, and selecting a screening-positive group for invasive testing enabled detection of 75% of fetuses with trisomy 21. Conclusion. In screening for chromosomal abnormalities, an approach which combines maternal age and NT is effective and increases the detection rate compared to the use of any single test. .

  12. Klinefelter syndrome: cardiovascular abnormalities and metabolic disorders.

    Calogero, A E; Giagulli, V A; Mongioì, L M; Triggiani, V; Radicioni, A F; Jannini, E A; Pasquali, D

    2017-03-03

    Klinefelter syndrome (KS) is one of the most common genetic causes of male infertility. This condition is associated with much comorbidity and with a lower life expectancy. The aim of this review is to explore more in depth cardiovascular and metabolic disorders associated to KS. KS patients have an increased risk of cerebrovascular disease (standardized mortality ratio, SMR, 2.2; 95% confidence interval, CI, 1.6-3.0), but it is not clear whether the cause of the death is of thrombotic or hemorrhagic nature. Cardiovascular congenital anomalies (SMR, 7.3; 95% CI, 2.4-17.1) and the development of thrombosis or leg ulcers (SMR, 7.9; 95% CI, 2.9-17.2) are also more frequent in these subjects. Moreover, cardiovascular abnormalities may be at least partially reversed by testosterone replacement therapy (TRT). KS patients have also an increased probability of endocrine and/or metabolic disease, especially obesity, metabolic syndrome and type 2 diabetes mellitus. The effects of TRT on these abnormalities are not entirely clear.

  13. DNA methylation abnormalities in congenital heart disease.

    Serra-Juhé, Clara; Cuscó, Ivon; Homs, Aïda; Flores, Raquel; Torán, Núria; Pérez-Jurado, Luis A

    2015-01-01

    Congenital heart defects represent the most common malformation at birth, occurring also in ∼50% of individuals with Down syndrome. Congenital heart defects are thought to have multifactorial etiology, but the main causes are largely unknown. We have explored the global methylation profile of fetal heart DNA in comparison to blood DNA from control subjects: an absolute correlation with the type of tissue was detected. Pathway analysis revealed a significant enrichment of differential methylation at genes related to muscle contraction and cardiomyopathies in the developing heart DNA. We have also searched for abnormal methylation profiles on developing heart-tissue DNA of syndromic and non-syndromic congenital heart defects. On average, 3 regions with aberrant methylation were detected per sample and 18 regions were found differentially methylated between groups. Several epimutations were detected in candidate genes involved in growth regulation, apoptosis and folate pathway. A likely pathogenic hypermethylation of several intragenic sites at the MSX1 gene, involved in outflow tract morphogenesis, was found in a fetus with isolated heart malformation. In addition, hypermethylation of the GATA4 gene was present in fetuses with Down syndrome with or without congenital heart defects, as well as in fetuses with isolated heart malformations. Expression deregulation of the abnormally methylated genes was detected. Our data indicate that epigenetic alterations of relevant genes are present in developing heart DNA in fetuses with both isolated and syndromic heart malformations. These epimutations likely contribute to the pathogenesis of the malformation by cis-acting effects on gene expression.

  14. Brain Abnormalities in Neuromyelitis Optica Spectrum Disorder

    Woojun Kim

    2012-01-01

    Full Text Available Neuromyelitis optica (NMO is an idiopathic inflammatory syndrome of the central nervous system that is characterized by severe attacks of optic neuritis (ON and myelitis. Until recently, NMO was considered a disease without brain involvement. However, since the discovery of NMO-IgG/antiaqaporin-4 antibody, the concept of NMO was broadened to NMO spectrum disorder (NMOSD, and brain lesions are commonly recognized. Furthermore, some patients present with brain symptoms as their first manifestation and develop recurrent brain symptoms without ON or myelitis. Brain lesions with characteristic locations and configurations can be helpful in the diagnosis of NMOSD. Due to the growing recognition of brain abnormalities in NMOSD, these have been included in the NMO and NMOSD diagnostic criteria or guidelines. Recent technical developments such as diffusion tensor imaging, MR spectroscopy, and voxel-based morphometry reveal new findings related to brain abnormalities in NMOSD that were not identified using conventional MRI. This paper focuses on the incidence and characteristics of the brain lesions found in NMOSD and the symptoms that they cause. Recent studies using advanced imaging techniques are also introduced.

  15. Real-time Multiple Abnormality Detection in Video Data

    Have, Simon Hartmann; Ren, Huamin; Moeslund, Thomas B.

    2013-01-01

    Automatic abnormality detection in video sequences has recently gained an increasing attention within the research community. Although progress has been seen, there are still some limitations in current research. While most systems are designed at detecting specific abnormality, others which...... are capable of detecting more than two types of abnormalities rely on heavy computation. Therefore, we provide a framework for detecting abnormalities in video surveillance by using multiple features and cascade classifiers, yet achieve above real-time processing speed. Experimental results on two datasets...... show that the proposed framework can reliably detect abnormalities in the video sequence, outperforming the current state-of-the-art methods....

  16. Meiotic abnormalities and spermatogenic parameters in severe oligoasthenozoospermia.

    Vendrell, J M; García, F; Veiga, A; Calderón, G; Egozcue, S; Egozcue, J; Barri, P N

    1999-02-01

    The incidence of meiotic abnormalities and their relationship with different spermatogenic parameters was assessed in 103 male patients with presumably idiopathic severe oligoasthenozoospermia (motile sperm concentration Meiotic patterns included normal meiosis and two meiotic abnormalities, i.e. severe arrest and synaptic anomalies. A normal pattern was found in 64 (62.1%), severe arrest in 21 (20.4%) and synaptic anomalies in 18 (17.5%). The overall rate of meiotic abnormalities was 37.9%. Most (66.7%) meiotic abnormalities occurred in patients with a sperm concentration meiotic abnormalities were found in 57.8% of the patients; of these, 26.7% had synaptic anomalies. When the sperm concentration was meiotic abnormalities occurred in 54.8% (synaptic anomalies in 22.6%). There were statistically significant differences among the three meiotic patterns in relation to sperm concentration (P 10 IU/l were the only predictors of meiotic abnormalities.

  17. Abnormal epidermal changes after argon laser treatment

    Neumann, R.A.; Knobler, R.M.; Aberer, E.; Klein, W.; Kocsis, F.; Ott, E. (Univ. of Vienna (Austria))

    1991-02-01

    A 26-year-old woman with a congenital port-wine stain on the forehead was treated three times at 2-month intervals with an argon laser. Six months after the last treatment, moderate blanching and mild scaling confined to the treated area was observed. A biopsy specimen of the treated area revealed a significant decrease in ectatic vessels. However, epidermal changes similar to those of actinic keratosis with disorganized cell layers and marked cytologic abnormalities were seen. Analysis of peripheral blood lymphocytes for a defect in DNA repair was negative. Multiple, argon laser-induced photothermal effects may be responsible for the changes observed in our case and may lead to premalignant epidermal transformation.

  18. Residual gait abnormalities in surgically treated spondylolisthesis.

    Shelokov, A; Haideri, N; Roach, J

    1993-11-01

    The authors retrospectively studied seven patients who had in situ fusion as adolescents for high-grade (IV, V) spondylolisthesis unresponsive to more conservative means. All patients achieved solid bony union; their pain was relieved; and hamstring spasm had resolved. The authors sought to determine whether crouch gait or any other abnormalities could be demonstrated in patients exhibiting clinical parameters of success. Each patient underwent gait analysis, radiographic analysis, and a physical examination. Four of seven patients demonstrated slight degrees of forward trunk lean during varying phases of gait accompanied by increased hip flexion. One patient demonstrated increased trunk extension accompanied by limited hip flexion. Two patients were essentially normal. The authors were unable to quantify residual crouch in these patients with solidly fused high-grade spondylolisthesis.

  19. Kidney abnormalities in sickle cell disease.

    López Revuelta, K; Ricard Andrés, M P

    2011-01-01

    Patients with sickle cell disease exhibits numerous kidney structural and functional abnormalities, changes that are seen along the entire length of the nephron. Changes are most marked in patients with homozygous sickle cell anemia, but are also seen in those with compound heterozygous states and the sickle cell trait. The renal features of sickle cell disease include some of the most common reasons for referral to nephrologists, such as hematuria, proteinuria, tubular disturbances and chronic kidney disease. Therapy of these conditions requires specialized knowledge of their distinct pathogenic mechanisms. Spanish Haemathology and Hemotherapy Association has recently publicated their Clinical Practice Guidelines of SCD management. Renal chapter is reproduced in this article for Nefrología difussion.

  20. Abnormal uterine bleeding: a clinicohistopathological analysis

    Anupamasuresh Y

    2014-06-01

    Methods: In our prospective study of 359 Patients of the age between 46 and 73 years, clinical characteristics and the pattern of endometrial histopathology and their association in women, who present with abnormal uterine bleeding, are categorised into six groups. Results: In our study, a significant correlation of histopathology and BMI was observed with endometrial hyperplasia and malignancy in obese patient i.e. 37 out 96 and 13 out of 23 respectively. The incidence of malignancy has been increasing with the age being 1.6% in 46-50 years to 60% in 70-75 years. In our study 116 (32.3% had hypertension, 33 patients (9.2% had diabetes mellitus, 40 patients (11.1% had hypothyroidism. Conclusions: We found a maximum incidence of AUB in multiparous women. Clinicohistopathological analysis of AUB revealed endometrial hyperplasia in majority of patients. [Int J Reprod Contracept Obstet Gynecol 2014; 3(3.000: 656-661

  1. Computed tomography of the abnormal thymus

    Baron, R.L.; Lee, J.K.T.; Sagel, S.S.; Levitt, R.G.

    1982-01-01

    Computed tomography (CT) should be the imaging method of choice following plain chest radiographs when a suspected thymic abnormality requires further evaluation. Based upon a six-year experience, including the evaluation of 25 patients with thymic pathology, CT was found useful in suggesting or excluding a diagnosis of thymoma and in distinguishing thymic hyperplasis from thymoma in patients with myasthenia gravis. The thickness of the thymic lobes determined by CT was found to be a more accurate indicator of infiltrative disease (thymic hyperplasia and lymphoma) than the width. CT was helpful in differentiating benign thymic cysts from solid tumors, and in defining the extent of a thymic neoplasms. On occasion, CT may suggest the specific histologic nature of a thymic lesion.

  2. Abnormal Presentation of Choriocarcinoma and Literature Review

    Yousefi, Zohreh; Mottaghi, Mansorhe; Rezaei, Alireza; Ghasemian, Sedighe

    2016-01-01

    Introduction Gestational trophoblastic neoplasms have highly been malignant potential, which usually occurred in child-bearing age women. Unusual feature of this malignancy would be rare, it was important to take in mind the possibility of GTN in different manifestation. Based on the above mentioned, the aim of this presentation would be the management and outcome of a case series of choriocarcinoma patients with abnormal manifestation. Case Presentation We have presented four patients, first who initially manifestation with signs of septic shock, the second case with severe gastrointestinal hemorrhage, the third case with postpartum infection and the forth case was a postmenopausal bleeding patient. Conclusions In case of metastatic choriocarcinoma with precise history, accurate diagnosis and appropriate treatment have led us to curable results. PMID:27482332

  3. [Ultrasonic diagnosis of congenital uterine abnormalities].

    Funk, A; Fendel, H

    1988-01-01

    1-2% of women has abnormal uterine development due to nonunification of the Müllerian ducts in the embryonal period. At the RWTH Aachen, in the department of gynaecology and obstetrics, between January and June 1987, we had searched systematically for maldevelopment of the uterus in 2299 echosonografies. In 13 cases we found maldevelopment of internal genital; 5 of these cases were diagnosed by an echosonografic routine-examination. The echografic criteria of the different grades of uterine malformations have been determined, systematized and discussed in relation to the symptoms. The most frequent malformations as uterus subseptus, uterus septus, uterus bicornis and uterus duplex are subject of a detailed discussion. This work demonstrates that echosonografic is a very efficient instrument to diagnose uterine malformations and gives us a very exact anatomic interpretation of malformations.

  4. Skeletal muscle abnormalities in patients with fibromyalgia.

    Olsen, N J; Park, J H

    1998-06-01

    Widespread muscle pain and tender points are the most common complaints of fibromyalgia patients, and the underlying mechanisms responsible for these symptoms have been studied intensively during the past decade. It has been suggested that fatigue and pain may lead to decreased levels of physical activity in many patients. The resulting deconditioned state may itself contribute to muscle abnormalities. Associated symptoms such as disturbed sleep, anxiety, depression, or irritable bowel also may have a negative impact on muscle function and level of daily activities. The important interactions between the central nervous and musculoskeletal systems may involve another element, the neuroendocrine stress-response system. This review will consider both the current state of knowledge and also future studies which might be designed to answer more effectively the outstanding questions regarding the underlying pathogenesis of fibromyalgia.

  5. Eye-head coordination abnormalities in schizophrenia.

    Simon Schwab

    Full Text Available BACKGROUND: Eye-movement abnormalities in schizophrenia are a well-established phenomenon that has been observed in many studies. In such studies, visual targets are usually presented in the center of the visual field, and the subject's head remains fixed. However, in every-day life, targets may also appear in the periphery. This study is among the first to investigate eye and head movements in schizophrenia by presenting targets in the periphery of the visual field. METHODOLOGY/PRINCIPAL FINDINGS: Two different visual recognition tasks, color recognition and Landolt orientation tasks, were presented at the periphery (at a visual angle of 55° from the center of the field of view. Each subject viewed 96 trials, and all eye and head movements were simultaneously recorded using video-based oculography and magnetic motion tracking of the head. Data from 14 patients with schizophrenia and 14 controls were considered. The patients had similar saccadic latencies in both tasks, whereas controls had shorter saccadic latencies in the Landolt task. Patients performed more head movements, and had increased eye-head offsets during combined eye-head shifts than controls. CONCLUSIONS/SIGNIFICANCE: Patients with schizophrenia may not be able to adapt to the two different tasks to the same extent as controls, as seen by the former's task-specific saccadic latency pattern. This can be interpreted as a specific oculomotoric attentional dysfunction and may support the hypothesis that schizophrenia patients have difficulties determining the relevance of stimuli. Patients may also show an uneconomic over-performance of head-movements, which is possibly caused by alterations in frontal executive function that impair the inhibition of head shifts. In addition, a model was created explaining 93% of the variance of the response times as a function of eye and head amplitude, which was only observed in the controls, indicating abnormal eye-head coordination in patients

  6. 53例药源性间质性肺炎的文献分析%Literature Analysis of 53 Reports of Drug-induced Interstitial Pneumonia

    胡美绘; 孙安修

    2014-01-01

    目的:探讨引起间质性肺炎的药品种类及其临床表现特点。方法检索中国医院数字图书馆、中国知网、万方数据库中1994~2013年,关键词为“间质性肺炎”的相关文献,进行归纳总结。结果共检索出相关文献74篇,报道53例药源性间质性肺炎,涉及15种药物,包括吉非替尼(15例)、利妥西单抗(9例)、来氟米特(8例)、胺碘酮(8例)、厄洛替尼(5例)、干扰素(2例)、5-氟尿嘧啶(1例)、粒细胞集落刺激因子(1例)、吉西他滨(1例)、卡莫司汀(1例)、麻疹疫苗(1例)、百草枯(1例)等。53例患者中,2例治疗结果不详;治愈17例(33.33%),好转19例(37.26%),死亡15例(29.41%)。结论各药品引起间质性肺炎发病机制尚不明确,临床表现相似。发病率较高的药物有吉非替尼、利妥西单抗、来氟米特、胺碘酮、厄洛替尼。%Objective To study the drugs leading to interstitial pneumonia and analyze their clinical characteristics. Methods We searched the literatures from 1994 to 2013 by key words of "interstitial pneumonia" in China Digital Library, China National Knowledge Infrastructure, Wanfang Database, and summarized them. Results A total of 74 relevant articles were identified, which reported 53 cases of drug-induced interstitial neumonia, involving 15 kinds of drugs. The drugs included gefitinib(15), rituximab(9), leflunomide(8), amiodarone(8), erlotinib(5), interferon(2), 5-fluorouracil(1), granulocyte colony-stimulating factor(1), gemcitabine(1), carmustine (1), measles vaccine (1), paraquat(1), et al.The result showed that 53 cases contained 17 cases(33.33%) cured, 19 cases(37.26%) improved , 15 cases(29.41%) died and 2 cases unclear. Conclusion The clinical manifestations of interstitial pneumonia induced by drugs were similar, but the pathogenesis was unknown. The drugs leading to higher incidence were gefitinib, rituximab

  7. Targeting Mcl-1 for multiple myeloma (MM) therapy: drug-induced generation of Mcl-1 fragment Mcl-1(128-350) triggers MM cell death via c-Jun upregulation.

    Fan, Fengjuan; Tonon, Giovanni; Bashari, Muhammad Hasan; Vallet, Sonia; Antonini, Elena; Goldschmidt, Hartmut; Schulze-Bergkamen, Henning; Opferman, Joseph T; Sattler, Martin; Anderson, Kenneth C; Jäger, Dirk; Podar, Klaus

    2014-02-28

    Myeloid cell leukemia-1 (Mcl-1, HGNC: 6943), a pro-survival member of the Bcl-2 family, plays a crucial role in Multiple Myeloma (MM) pathogenesis and drug resistance, thus representing a promising therapeutic target in MM. A novel strategy to inhibit Mcl-1 activity is the induction of ubiquitin-independent Mcl-1 degradation. Our own and other previous studies have demonstrated caspase-dependent generation of a 28kDa Mcl-1 fragment, Mcl-1(128-350), which inhibits MM cell proliferation and survival. Here, we show that similar to bortezomib, the novel proteasome inhibitors carfilzomib and ixazomib, as well as staurosporine and adaphostin, induce the generation of Mcl-1(128-350) in MM cells. Next, the molecular sequelae downstream of Mcl-1(128-350), which mediate its pro-apoptotic activity, were delineated. Surprisingly, we observed nuclear accumulation of drug-induced or exogenously overexpressed Mcl-1(128-350), followed by elevated mRNA and protein levels of c-Jun, as well as enhanced AP-1 reporter activity. Moreover, drug-induced AP-1 activity was blocked after introducing a point mutation into the highly conserved Mcl-1 caspase-cleavage site Asp127, but not Asp157. Consequently, drug-triggered cell death was significantly decreased in MM cells transfected with Mcl-1 D127A, but not with Mcl-1 D157A. Consistent with these data, treatment with bortezomib triggered c-Jun upregulation followed by apoptosis in Mcl-1(wt/wt), but not Mcl-1(Δ/null) murine embryonic fibroblasts (MEFs). Transfection of a plasmid carrying Mcl-1(wt) into Mcl-1(Δ/null) MEFs restored bortezomib-induced Mcl-1 fragmentation, c-Jun upregulation and AP-1 reporter activity. Finally, our data indicate that drug-induced generation of a pro-apoptotic Mcl-1 fragment followed by c-Jun upregulation may also be a novel therapeutic approach in other tumor entities.

  8. Comparative observation of primiparae undergone drug-induced abortion or artificial abortion on subsequent pregnancy%初产妇药物流产与人工流产术后对再妊娠影响的对比观察

    丘东海; 叶娉婷

    2013-01-01

    目的:比较初产妇药物流产后和人工流产术后对再妊娠的影响,为选择合适、安全的流产方式提供临床参考.方法:采用回顾性调查方法对135例有人工流产术史、126例有药物流产史及130例无流产史的初产妇进行比较,观察其妊娠期和分娩期并发症的发生情况以及妊娠结局.结果:妊娠期人流组先兆流产发生率明显高于药流组和无流产组,差异有统计学意义(χ2=14.993,P0.05).分娩期人流组产后出血、胎盘粘连和胎盘残留的发生率明显高于药流组和无流产组,χ2分别为22.146、12.211、9.387,P值均0.05).结论:初产妇药物流产后对再次妊娠影响小于人工流产术后,可考虑作为临床终止早孕的首先选择.%Objective :To observe the efforts of drug-induced aboition or aitifirial aboition for primiparous women on their subsequent pregnancies for cliniral evidence to determine a safe and adequate means for termination of pregnancy. Methods: Retrospective comparative study was performed in 135 primiparae undergone artificial aboition, 126 with drug-induced aboition history and 130 primiparity without aboition to examine outcomes of subsequent pregnancy and complications associated with gestation and delivery. Results : Higher incidence of threatened aboition during the gestation period was found in women undergone artificial aboition as compared with those with drug-induced aboition or without aboition history. The difference was significant ( x2 = 14. 993 , P 0. 05 ). Similarly, Mothers with a history of artificial aboition had significantly higher incidence of postpaitum hemorrhage, placenta! adherence and residual placenta in labor than those experienced drug-induced aboition or no aboition ( x2 - 22. 146, x2 -12.211, x2 - 9. 387 , respectively ,P 0. 05 ). Conclusion-. Ding-induced aboition for prhnigravidas seem to produce less effects on their subsequent pregnancies than artificial intervention, and may be recommended as

  9. Abnormal grain growth in undoped strontium and barium titanate

    Baeurer, M., E-mail: m.baeurer@ikm.uka.de [Institut fuer Keramik im Maschinenbau, Universitaet Karlsruhe, Karlsruhe (Germany); Shih, S.-J.; Bishop, C. [Department of Materials, University of Oxford, Oxford (United Kingdom); Harmer, M.P. [Center for Advanced Materials and Nanotechnology, Lehigh University, Bethlehem, PA (United States); Cockayne, D. [Department of Materials, University of Oxford, Oxford (United Kingdom); Hoffmann, M.J. [Institut fuer Keramik im Maschinenbau, Universitaet Karlsruhe, Karlsruhe (Germany)

    2010-01-15

    Abnormal grain growth is a commonly observed phenomenon in perovskite materials. In order to study this phenomenon, grain growth experiments were conducted over a temperature range from 1425 to 1600 deg. C for the model system SrTiO{sub 3} to analyse the nucleation of abnormal grains and to identify the growth mechanism involved for normal and abnormal grains. Grain boundaries of normal and abnormal grains were investigated in quenched samples by high-resolution transmission electron microscopy and by energy-dispersive spectroscopy in a scanning transmission electron microscope. No amorphous film was observed at the grain boundaries for either normal or abnormal grains. Non-stoichiometry at the grain boundaries was identified as a possible reason for the differences in growth speed. The results are compared to the nucleation and growth of abnormal grains in BaTiO{sub 3}.

  10. The time of onset of abnormal calcification in spondylometaepiphyseal dysplasia, short limb-abnormal calcification type

    Tueysuez, Beyhan [Istanbul University, Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul (Turkey); Gazioglu, Nurperi [Istanbul University, Department of Neurosurgery, Cerrahpasa Medical School, Istanbul (Turkey); Uenguer, Savas [Istanbul University, Department of Pediatric Radiology, Cerrahpasa Medical School, Istanbul (Turkey); Aji, Dolly Yafet [Istanbul University, Department of Pediatrics, Cerrahpasa Medical School, Istanbul (Turkey); Tuerkmen, Seval [Istanbul University, Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul (Turkey); Universitatsklinikum Berlin, Charite Virchow-Klinik, Berlin (Germany)

    2009-01-15

    A 1-month-old boy with shortness of extremities on prenatal US was referred to our department with a provisional diagnosis of achondroplasia. His height was normal but he had short extremities and platyspondyly, premature carpal epiphyses on both hands, and short tubular bones with irregular metaphyses on radiographs. Re-evaluation of the patient at the age of 1 year revealed very short height and premature calcification of the costal cartilages and epiphyses. Spondylometaepiphyseal dysplasia (SMED), short limb-abnormal calcification type was diagnosed. This condition is a very rare autosomal recessively inherited disorder, and most of the patients die in early childhood due to neurological involvement. At the age of 2 years and 5 months, a CT scan showed narrowing of the cervical spinal canal. One month later he died suddenly because of spinal cord injury. In conclusion early diagnosis is very important because the recurrence risk is high and patients may die due to early neurological complications. The time of onset of abnormal calcifications, a diagnostic finding of the disease, is at the age of around 1 year in most patients. When abnormal calcifications are not yet present, but radiological changes associated with SMED are present, this rare disease must be considered. (orig.)

  11. The time of onset of abnormal calcification in spondylometaepiphyseal dysplasia, short limb-abnormal calcification type.

    Tüysüz, Beyhan; Gazioğlu, Nurperi; Ungür, Savaş; Aji, Dolly Yafet; Türkmen, Seval

    2009-01-01

    A 1-month-old boy with shortness of extremities on prenatal US was referred to our department with a provisional diagnosis of achondroplasia. His height was normal but he had short extremities and platyspondyly, premature carpal epiphyses on both hands, and short tubular bones with irregular metaphyses on radiographs. Re-evaluation of the patient at the age of 1 year revealed very short height and premature calcification of the costal cartilages and epiphyses. Spondylometaepiphyseal dysplasia (SMED), short limb-abnormal calcification type was diagnosed. This condition is a very rare autosomal recessively inherited disorder, and most of the patients die in early childhood due to neurological involvement. At the age of 2 years and 5 months, a CT scan showed narrowing of the cervical spinal canal. One month later he died suddenly because of spinal cord injury. In conclusion early diagnosis is very important because the recurrence risk is high and patients may die due to early neurological complications. The time of onset of abnormal calcifications, a diagnostic finding of the disease, is at the age of around 1 year in most patients. When abnormal calcifications are not yet present, but radiological changes associated with SMED are present, this rare disease must be considered.

  12. Effects of Yishenyangxuehuoxue decoction on colporrhagia and menstruation after drug induced abortion%益肾养血活血汤对药物流产后阴道出血及月经的影响

    李海霞

    2015-01-01

    Objective To investigate the effects of Yishenyangxuehuoxue decoction( YSYXHX decoction) on colporrhagia and menstruation after drug induced abortion.Methods One hundred and forty-eight women with early pregnancy were selected, and divided into simple medical abortion group(n=47), medical abortion+traditional Chi-nese medicine group(n=50), operation abortion group(n=51).The simple medical abortion group was given oral mifepristone tablets.The medical abortion+traditional Chinese medicine group was given YSYXHX decoction based on the same treatment as the simple medical abortion group.The operation abortion group used vacuum aspiration a-bortion.The changes of reproductive hormone, vaginal bleeding duration, vaginal bleeding amount and occurrence of menstrual disorder were compared among the three groups during the follow-up period.Results HCG, LH, P at the seventh days after discharge of gestational sac in the operation abortion group and in the medical abortion+traditional Chinese medicine group were significantly lower than those in the simple medical abortion group(P<0.05), and than those in the operation abortion group(P<0.05).The FSH, E2 at the seventh days after discharge of gestational sac in the operation abortion group and in the medical abortion+traditional Chinese medicine group were significantly higher than those in the simple medical abortion group.And than those in the operation abortion group(P<0.05). The rates of vaginal bleeding duration at 8~15 days and more than 15 days in the operation abortion group and the medical abortion+traditional Chinese medicine group were lower than those in the simple medical abortion group( P<0.05 ) .The rates of abnormal vaginal bleeding in the operation abortion group and in the medical abortion+tradition-al Chinese medicine group were lower than that in the simple abortion group(P<0.05).The incidences of menstrual disorders in the operation abortion group and in the medical abortion+traditional Chinese medicine

  13. Abnormal Bleeding During Menopause Hormone Therapy: Insights for Clinical Management

    2013-01-01

    Objective Our objective was to review the involved mechanisms and propose actions for controlling/treating abnormal uterine bleeding during climacteric hormone therapy. Methods A systemic search of the databases SciELO, MEDLINE, and Pubmed was performed for identifying relevant publications on normal endometrial bleeding, abnormal uterine bleeding, and hormone therapy bleeding. Results Before starting hormone therapy, it is essential to exclude any abnormal organic condition, identify women a...

  14. Coagulation abnormalities in the cirrhotic patient.

    Muciño-Bermejo, Jimena; Carrillo-Esper, Raúl; Uribe, Misael; Méndez-Sánchez, Nahum

    2013-01-01

    The clotting process is a dynamic array of multiple processes which can be described in four phases: platelet plug initiation and formation, clotting process propagation by the coagulation cascade, clotting termination by antithrombotic mechanisms and clot removal by fibrinolysis. The liver plays a central role in each of these phases of clotting process, as it synthesizes the majority of coagulation factors and proteins involved in fibrinolysis as well as thrombopoeitin, which is responsible for platelet production from megakaryocytes. Many pathological processes associated with cirrhosis, such as portal hypertension and endothelial dysfunction, as well as co-morbid conditions, may also alter the coagulation process. Consequently, patients with liver disease have a disturbed balance of procoagulant and anti-coagulant factors which deviates from the normal coagulation cascade. This situation poses an additional problem in the diagnostic and therapeutic approach to this group of patients, since traditional coagulation test may not be reliable for assessing bleeding or thrombotic risk and traditional transfusional strategies may not be applicable in cirrhotic patients. In this article, we review the pathophysiological bases of coagulation abnormalities, in cirrhotic patients, the diagnostic therapeutic strategies to be followed and its impact on the clinical outcome in the cirrhotic patient.

  15. Abnormal tyrosine metabolism in chronic cluster headache.

    D'Andrea, Giovanni; Leone, Massimo; Bussone, Gennaro; Fiore, Paola Di; Bolner, Andrea; Aguggia, Marco; Saracco, Maria Gabriella; Perini, Francesco; Giordano, Giuseppe; Gucciardi, Antonina; Leon, Alberta

    2017-02-01

    Objective Episodic cluster headache is characterized by abnormalities in tyrosine metabolism (i.e. elevated levels of dopamine, tyramine, octopamine and synephrine and low levels of noradrenalin in plasma and platelets.) It is unknown, however, if such biochemical anomalies are present and/or constitute a predisposing factor in chronic cluster headache. To test this hypothesis, we measured the levels of dopamine and noradrenaline together with those of elusive amines, such as tyramine, octopamine and synephrine, in plasma of chronic cluster patients and control individuals. Methods Plasma levels of dopamine, noradrenaline and trace amines, including tyramine, octopamine and synephrine, were measured in a group of 23 chronic cluster headache patients (10 chronic cluster ab initio and 13 transformed from episodic cluster), and 16 control participants. Results The plasma levels of dopamine, noradrenaline and tyramine were several times higher in chronic cluster headache patients compared with controls. The levels of octopamine and synephrine were significantly lower in plasma of these patients with respect to control individuals. Conclusions These results suggest that anomalies in tyrosine metabolism play a role in the pathogenesis of chronic cluster headache and constitute a predisposing factor for the transformation of the episodic into a chronic form of this primary headache.

  16. Abnormal hopping conduction in semiconducting polycrystalline graphene

    Park, Jeongho; Mitchel, William C.; Elhamri, Said; Grazulis, Larry; Altfeder, Igor

    2013-07-01

    We report the observation of an abnormal carrier transport phenomenon in polycrystalline semiconducting graphene grown by solid carbon source molecular beam epitaxy. At the lowest temperatures in samples with small grain size, the conduction does not obey the two-dimensional Mott-type variable-range hopping (VRH) conduction often reported in semiconducting graphene. The hopping exponent p is found to deviate from the 1/3 value expected for Mott VRH with several samples exhibiting a p=2/5 dependence. We also show that the maximum energy difference between hopping sites is larger than the activation energy for nearest-neighbor hopping, violating the assumptions of the Mott model. The 2/5 dependence more closely agrees with the quasi-one-dimensional VRH model proposed by Fogler, Teber, and Shklovskii (FTS). In the FTS model, conduction occurs by tunneling between neighboring metallic wires. We suggest that metallic edge states and conductive grain boundaries play the role of the metallic wires in the FTS model.

  17. Imaging findings in fetal diaphragmatic abnormalities

    Alamo, Leonor; Gudinchet, Francois [University Hospital Center of Lausanne, Unit of Radiopediatrics, Department of Radiology, Lausanne (Switzerland); Meuli, Reto [University Hospital Center of Lausanne, Department of Radiology, Lausanne (Switzerland)

    2015-12-15

    Imaging plays a key role in the detection of a diaphragmatic pathology in utero. US is the screening method, but MRI is increasingly performed. Congenital diaphragmatic hernia is by far the most often diagnosed diaphragmatic pathology, but unilateral or bilateral eventration or paralysis can also be identified. Extralobar pulmonary sequestration can be located in the diaphragm and, exceptionally, diaphragmatic tumors or secondary infiltration of the diaphragm from tumors originating from an adjacent organ have been observed in utero. Congenital abnormalities of the diaphragm impair normal lung development. Prenatal imaging provides a detailed anatomical evaluation of the fetus and allows volumetric lung measurements. The comparison of these data with those from normal fetuses at the same gestational age provides information about the severity of pulmonary hypoplasia and improves predictions about the fetus's outcome. This information can help doctors and families to make decisions about management during pregnancy and after birth. We describe a wide spectrum of congenital pathologies of the diaphragm and analyze their embryological basis. Moreover, we describe their prenatal imaging findings with emphasis on MR studies, discuss their differential diagnosis and evaluate the limits of imaging methods in predicting postnatal outcome. (orig.)

  18. Salivary abnormalities in Prader-Willi Syndrome

    Hart, S.; Poshva, C. [Bowman Gray School of Medicine, Winston-Salem, NC (United States)

    1994-09-01

    Although abnormal saliva is a well documented finding in PWS, little is known about the saliva in these individuals. We have recently undertaken a study to characterize the salivary composition from PW patients and to see if there is any correlation with their underlying molecular diagnosis (deletion vs. disomy). We have collected whole saliva on 3 patients; 2 had normal high-resolution karyotype analysis (Cases 1 & 3) and 1 had a deletion of 15q11q13 (Case 3). For all parameters, Case 3`s values were notably different from those of his unaffected sibling. The salivary flow rates and concentrations for all 3 PW patients are similar and are significantly different from normal controls (mean {plus_minus} SE) (p<0.05). Although this data is from only 3 PW patients, it provides valuable information. First, decreased flow appears to be due to an effect of PWS and not medications since Cases 2 & 3 are not on any medications. Second, decreased flow appears to be present in younger as well as older individuals. Third, deviations from normal in the salivary composition are evident. It is possible that these alterations are concentration effects relative to a decrease in flow rate. We are currently obtaining saliva from more PW individuals to see if these alterations are present in all PW patients and whether they can be applied as a screening test.

  19. Brain MRI abnormalities in neuromyelitis optica

    Wang Fei, E-mail: feiwang1973@gmail.com [Department of Radiology, Xuanwu Hospital, Capital University of Medical Sciences, 45 Chang-Chun St, Xuanwu District, Beijing 100053 (China); Liu Yaou, E-mail: asiaeurope80@gmail.com [Department of Radiology, Xuanwu Hospital, Capital University of Medical Sciences, 45 Chang-Chun St, Xuanwu District, Beijing 100053 (China); Duan Yunyun, E-mail: duanyun2003@sohu.com [Department of Radiology, Xuanwu Hospital, Capital University of Medical Sciences, 45 Chang-Chun St, Xuanwu District, Beijing 100053 (China); Li Kuncheng, E-mail: kunchengli@yahoo.com.cn [Department of Radiology, Xuanwu Hospital, Capital University of Medical Sciences, 45 Chang-Chun St, Xuanwu District, Beijing 100053 (China); Education Ministry Key Laboratory for Neurodegenerative Disease, Xuanwu Hospital, Capital University of Medical Sciences, 45 Chang-Chun St, Xuanwu District, Beijing 100053 (China)

    2011-11-15

    Objective: The purpose of this study was to explore brain MRI findings in neuromyelitis optica (NMO) and to investigate specific brain lesions with respect to the localization of aquaporin-4 (AQP-4). Materials and methods: Forty admitted patients (36 women) who satisfied the 2006 criteria of Wingerchuk et al. for NMO were included in this study. All patients received a neurological examination and MRI scanning including brain and spinal cord. MRIs were classified as normal, nonspecific, multiple sclerosis-like, typical abnormalities. MS-like lesions were too few to satisfy the Barkhof et al. criteria for MS. Confluent lesions involving high AQP-4 regions were considered typical. Non-enhancing deep white matter lesions other than MS-like lesions or typical lesions were classified as nonspecific. Results: Brain MRI lesions were delineated in 12 patients (25%). Four patients (10%) had hypothalamus, brainstem or periventricle lesions. Six (15%) patients were nonspecific, and 2 (5%) patients had multiple sclerosis-like lesions. Conclusion: Brain MRIs are negative in most NMO, and brain lesions do not exclude the diagnosis of NMO. Hypothalamus, brainstem or periventricle lesions, corresponding to high sites of AQP-4 in the brain, are indicative of lesions of NMO.

  20. Abnormal parietal function in conversion paresis.

    Marije van Beilen

    Full Text Available The etiology of medically unexplained symptoms such as conversion disorder is poorly understood. This is partly because the interpretation of neuroimaging results in conversion paresis has been complicated by the use of different control groups, tasks and statistical comparisons. The present study includes these different aspects in a single data set. In our study we included both normal controls and feigners to control for conversion paresis. We studied both movement execution and imagery, and we contrasted both within-group and between-group activation. Moreover, to reveal hemisphere-specific effects that have not been reported before, we performed these analyses using both flipped and unflipped data. This approach resulted in the identification of abnormal parietal activation which was specific for conversion paresis patients. Patients also showed reduced activity in the prefrontal cortex, supramarginal gyrus and precuneus, including hemisphere-specific activation that is lateralized in the same hemisphere, regardless of right- or left-sided paresis. We propose that these regions are candidates for an interface between psychological mechanisms and disturbed higher-order motor control. Our study presents an integrative neurophysiological view of the mechanisms that contribute to the etiology of this puzzling psychological disorder, which can be further investigated with other types of conversion symptoms.

  1. Control of Abnormal Synchronization in Neurological Disorders

    Oleksandr V. Popovych

    2014-12-01

    Full Text Available In the nervous system synchronization processes play an important role, e.g., in the context of information processing and motor control. However, pathological, excessive synchronization may strongly impair brain function and is a hallmark of several neurological disorders. This focused review addresses the question of how an abnormal neuronal synchronization can specifically be counteracted by invasive and non-invasive brain stimulation as, for instance, by deep brain stimulation for the treatment of Parkinson's disease, or by acoustic stimulation for the treatment of tinnitus. On the example of coordinated reset (CR neuromodulation we illustrate how insights into the dynamics of complex systems contribute to successful model-based approaches, which use methods from synergetics, nonlinear dynamics, and statistical physics, for the development of novel therapies for normalization of brain function and synaptic connectivity. Based on the intrinsic multistability of the neuronal populations induced by spike timing-dependent plasticity (STDP,CR neuromodulation utilizes the mutual interdependence between synaptic connectivity and dynamics of the neuronal networks in order to restore more physiological patterns of connectivity via desynchronization of neuronal activity. The very goal is to shift the neuronal population by stimulation from anabnormally coupled and synchronized state to a desynchronized regime with normalized synaptic connectivity, which significantly outlasts the stimulation cessation, so that long-lasting therapeutic effects can be achieved.

  2. Electroencephalographic abnormalities in antisocial personality disorder.

    Calzada-Reyes, Ana; Alvarez-Amador, Alfredo; Galán-García, Lídice; Valdés-Sosa, Mitchell

    2012-01-01

    The presence of brain dysfunction in violent offenders has been frequently examined with inconsistent results. The aim of the study was to assess the EEG of 84 violent offenders by visual inspection and frequency-domain quantitative analysis in 84 violent prisoners. Low-resolution electromagnetic tomography (LORETA) was also employed for theta band of the EEG spectra. Antisocial personality disorder (ASPD) was present in 50 of the offenders and it was absent in the remaining 34. The prevalence of EEG abnormalities, by visual inspection, was similar for both the ASPD group (82%) and non-ASPD group (79%). The brain topography of these anomalies also did not differ between groups, in contrast to results of the EEG quantitative analysis (QEEG) and LORETA that showed remarkable regional differences between both groups. QEEG analysis showed a pattern of excess of theta-delta activities and decrease of alpha band on the right fronto-temporal and left temporo-parietal regions in the ASPD group. LORETA signified an increase of theta activity (5.08 Hz) in ASPD group relative to non-ASPD group within left temporal and parietal regions. Findings indicate that QEEG analysis and techniques of source localization may reveal differences in brain electrical activity among offenders with ASPD, which was not obvious to visual inspection.

  3. Gait abnormalities following slipped capital femoral epiphysis.

    Song, Kit M; Halliday, Suzanne; Reilly, Chris; Keezel, William

    2004-01-01

    The authors evaluated 30 subjects with treated unilateral slipped capital femoral epiphysis and a range of severity from mild to severe to characterize gait and strength abnormalities using instrumented three-dimensional gait analysis and isokinetic muscle testing. For slip angles less than 30 degrees, kinematic, kinetic, and strength variables were not significantly different from age- and weight-matched controls. For moderate to severe slips, as slip angle increased, passive hip flexion, hip abduction, and internal rotation in the flexed and extended positions decreased significantly. Persistent pelvic obliquity, medial lateral trunk sway, and trunk obliquity in stance increased, as did extension, adduction, and external rotation during gait. Gait velocity and step length decreased with increased amount of time spent in double limb stance. Hip abductor moment, hip extension moment, knee flexion moment, and ankle dorsiflexion moment were all decreased on the involved side. Hip and knee strength also decreased with increasing slip severity. All of these changes were present on the affected and to a lesser degree the unaffected side. Body center of mass translation or pelvic obliquity in mid-stance greater than one standard deviation above normal correlated well with the impression of compensated or uncompensated Trendelenburg gait.

  4. Hematological abnormalities in severe anorexia nervosa.

    Sabel, Allison L; Gaudiani, Jennifer L; Statland, Barbara; Mehler, Philip S

    2013-05-01

    Little is known about the prevalence of hematologic abnormalities in adults with severe anorexia nervosa. We report the first major analysis of hematologic dysfunction in such patients. We retrospectively analyzed the charts of 53 men and women with severe anorexia nervosa, admitted between October 2008 and December 2010 for medical stabilization to our center, which has a national referral base. Patients were predominantly female (89 %), with a median age of 28 years (range 17-65), and were hospitalized for a median duration of 15 days (I.Q.R. 9-29). Nadir body mass index during hospitalization was markedly low at 12.4 kg/m(2) (range 8.4-15.7), and the mean discharge BMI was 13.8 kg/m(2) (range 10.2-16.8). 83 % of patients were anemic (hematocrit  400 k/μL) during their hospitalization. Eighty-nine percent of patients had resolved their neutropenia by discharge. Marked hematologic deficiencies are often present in patients with severe anorexia nervosa, generally attributed to starvation-mediated gelatinous marrow transformation which resolves with proper nutritional rehabilitation. Improved provider awareness of this association may reduce unnecessary testing and costly treatment interventions.

  5. Abnormal high density lipoproteins in cerebrotendinous xanthomatosis

    Shore, V. (Lawrence Livermore Lab., CA); Salen, G.; Cheng, F.W.; Forte, T.; Shefer, S.; Tint, G.S.

    1981-11-01

    The plasma lipoprotein profiles and high density lipoproteins (HDL) were characterized in patients with the genetic disease cerebrotendinous xanthomatosis (CTX). The mean HDL-cholesterol concentration in the CTX plasmas was 14.5 +/- 3.2 mg/dl, about one-third the normal value. The low HDL-cholesterol reflects a low concentration and an abnormal lipid composition of the plasma HDL. Relative to normal HDL, the cholesteryl esters are low, free cholesterol and phospholipids essentially normal, and triglycerides increased. The ratio of apoprotein (apo) to total cholesterol in the HDL of CTX was two to three times greater than normal. In the CTX HDL, the ratio of apoAI to apoAII was high, the proportion of apoC low, and a normally minor form of apoAI increased relative to other forms. The HDL in electron micrographs appeared normal morphologically and in particle size. The adnormalities in lipoprotein distribution profiles and composition of the plasma HDL result from metabolic defects that are not understood but may be linked to the genetic defect in bile acid synthesis in CTX. As a consequence, it is probable that the normal functions of the HDL, possibly including modulation of LDL-cholesterol uptake and the removal of excess cholesterol from peripheral tissues, are perturbed significantly in this disease.

  6. Abnormal traffic flow data detection based on wavelet analysis

    Xiao Qian

    2016-01-01

    Full Text Available In view of the traffic flow data of non-stationary, the abnormal data detection is difficult.proposed basing on the wavelet analysis and least squares method of abnormal traffic flow data detection in this paper.First using wavelet analysis to make the traffic flow data of high frequency and low frequency component and separation, and then, combined with least square method to find abnormal points in the reconstructed signal data.Wavelet analysis and least square method, the simulation results show that using wavelet analysis of abnormal traffic flow data detection, effectively reduce the detection results of misjudgment rate and false negative rate.

  7. Abnormal behavior in caged birds kept as pets.

    van Hoek, C S; ten Cate, C

    1998-01-01

    There are a limited number of studies dealing with abnormal behavior in caged birds kept as pets. However, these studies demonstrate the presence of abnormal behavior in both songbirds and parrots. Ethological studies on these birds, as well as studies on domestic and zoo birds, indicate that inappropriate rearing and housing conditions may lead to behavioral abnormalities. Together these data indicate that behavioral abnormalities occur among both wild-caught and domesticated pet birds. The severity and magnitude of these abnormalities is probably underestimated, and there is a need for systematic studies on the nature, origin, variability, species-specificity, and reversibility of behavioral problems in pet birds. Abnormal behavior in caged birds may to some extent be prevented and reduced by environmental enrichment. However, most enrichment studies are anecdotal and not based on a thorough analysis of the behavioral abnormalities, which may lead to measures resulting in a reduction of symptoms rather than the underlying causes. Although it is likely that several of these problems could be reduced by modifying rearing and housing conditions, the current insights into the causal mechanisms underlying abnormal behavior of domesticated and wild-caught pet birds are limited, as are the insights into the possibilities of preventing or curing abnormal behavior.

  8. Chromosomal abnormalities associated with mental retardation in female subjects

    Dutta Samikshan

    2009-01-01

    Full Text Available Chromosomal abnormalities are thought to be the most common cause of mental retardation (MR. However, apart from a few selected types with typical aneuploidy, like Downs syndrome, Klinefelter syndrome, Turner syndrome, etc., the frequency of detectable chromosomal abnormalities in association with idiopathic MR is very low. In this study, we have investigated chromosomal abnormalities in female MR subjects (n = 150 by high-resolution GTG banding. Of them, 30 cases were diagnosed as Downs syndrome. Among the remaining (n = 120, chromosomal abnormalities/marked polymorphisms were detectable in only three MR cases (0.025.

  9. Chromosomal abnormalities associated with mental retardation in female subjects.

    Dutta, Samikshan; Shaw, Jyothi; Sinha, Swagata; Mukhopadhyay, Kanchan

    2009-01-01

    Chromosomal abnormalities are thought to be the most common cause of mental retardation (MR). However, apart from a few selected types with typical aneuploidy, like Downs syndrome, Klinefelter syndrome, Turner syndrome, etc., the frequency of detectable chromosomal abnormalities in association with idiopathic MR is very low. In this study, we have investigated chromosomal abnormalities in female MR subjects (n = 150) by high-resolution GTG banding. Of them, 30 cases were diagnosed as Downs syndrome. Among the remaining (n = 120), chromosomal abnormalities/marked polymorphisms were detectable in only three MR cases (0.025).

  10. Cytogenetic Analysis for Suspected Chromosomal Abnormalities; A Five Years Experience

    Karra, Vijay Kumar; Jindal, Ankur; Puppala, Madhavi; Singh, Pratiksha; Rawat, Kanchan; Kapoor, Seema

    2016-01-01

    Introduction Chromosomal abnormalities are the results of alterations in the number or structure of chromosomes causing significant human morbidity and mortality. They are responsible for a large proportion of miscarriages, developmental delay, disorders of sexual development, congenital malformations and mental retardation. Aim The aim of this study was to describe the prevalence of different chromosomal abnormalities in North Indian patients referred for cytogenetic analysis. Materials and Methods Total of 859 patients ranging from newborn to 37 years of age were referred to the division of genetics, Department of Paediatrics between 2010 and 2015, with a variety of clinical disorders; Down syndrome (DS), Turner’s syndrome (TS) and Klinefelter syndrome; amenorrhea; ambiguous sex and multiple congenital malformations. Chromosomal analysis was performed on lymphocyte culture according to standard methods. Results Of the 859 cases studied, 371 (43.1%) had chromosomal abnormalities. The most common autosomal abnormalities were DS 302 (81.4%) and sex chromosomal abnormalities were TS 51 (13.7%). Numerical abnormalities were accounted for 353 (41.0%) and structural abnormalities 18 (2.0%), respectively. Various other chromosomal anomalies were also reported. Conclusion We have reviewed the incidence and distribution of chromosomal abnormalities and found higher rate of chromosomal abnormalities 43.1% in the referred cases. Our data suggest that chromosomal analysis is important tool in the evaluation of genetic disorders and helps clinicians to provide accurate diagnosis and proper genetic counselling. PMID:27790464

  11. miR-140-5p attenuates chemotherapeutic drug-induced cell death by regulating autophagy through inositol 1,4,5-trisphosphate kinase 2 (IP3k2) in human osteosarcoma cells

    Wei, Renxiong; Cao, Gang; Deng, Zhouming; Su, Jiajia; Cai, Lin

    2016-01-01

    Acquisition of drug-resistant phenotypes is often associated with chemotherapy in osteosarcoma. A number of studies have demonstrated a critical role for autophagy in osteosarcoma development, therapy and drug resistance. However, the molecular mechanisms underlying the autophagy-mediated chemotherapy resistance of osteosarcoma cells remain largely unknown. In the present study, we determined the autophagy and microRNA-140 (miR-140-5p, miRBase ID: MIMAT0000431) expression induced by chemotherapeutic drugs in osteosarcoma cells. Then we determined the promotory role of miR-140-5p to the chemotherapy-induced autophagy. Our results demonstrated that miR-140-5p expression was highly induced during chemotherapy of osteosarcoma cells, and this was accompanied by up-regulated autophagy. The increased miR-140-5p expression levels up-regulated anticancer drug-induced autophagy in osteosarcoma cells and ameliorated the anticancer drug-induced cell proliferation and viability decrease. Importantly, miR-140-5p regulates this context-specific autophagy through its target, inositol 1,4,5-trisphosphate kinase 2 (IP3k2). Therefore, the results of the present study demonstrated that miR-140-5p mediated drug-resistance in osteosarcoma cells by inducing autophagy. The present study provides evidence of miRNA regulation of autophagy through modulation of IP3 signalling. The present study recognized a novel mechanism of chemoresistance in osteosarcoma cancers. PMID:27582507

  12. Obstructive Sleep Apnea and Lipid Abnormalities

    Karkinski, Dimitar; Georgievski, Oliver; Dzekova-Vidimliski, Pavlina; Milenkovic, Tatjana; Dokic, Dejan

    2017-01-01

    BACKGROUND: There has been a great interest in the interaction between obstructive sleep apnea (OSA) and metabolic dysfunction, but there is no consistent data suggesting that OSA is a risk factor for dyslipidemia. AIM: The aim of this cross-sectional study was to evaluate the prevalence of lipid abnormalities in patients suspected of OSA, referred to our sleep laboratory for polysomnography. MATERIAL AND METHODS: Two hundred patients referred to our hospital with suspected OSA, and all of them underwent for standard polysomnography. All patients with respiratory disturbance index (RDI) above 15 were diagnosed with OSA. In the morning after 12 hours fasting, the blood sample was collected from all patients. Blood levels of triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL) and low-density lipoprotein cholesterol (LDL), were determined in all study patients. In the study, both OSA positive and OSA negative patients were divided according to the body mass index (BMI) in two groups. The first group with BMI ≤ 30 kg/m^2 and the second group with BMI > 30 kg/m^2. RESULTS: OSA positive patients with BMI ≤ 30 kg/m^2 had statistically significant higher levels of triglycerides and total cholesterol, and statistically significant lower level of HDL compared to OSA negative patients with BMI ≤ 30. There were no statistically significant differences in age and LDL levels between these groups. OSA positive patients with BMI > 30 kg/m^2 had higher levels of triglycerides, total cholesterol and LDL and lower levels of HDL versus OSA negative patients with BMI > 30 kg/m^2, but without statistically significant differences. CONCLUSION: OSA and obesity are potent risk factors for dyslipidemias. OSA could play a significant role in worsening of lipid metabolism in non-obese patients. But in obese patients, the extra weight makes the metabolic changes of lipid metabolism, and the role of OSA is not that very important like in non-obese patients. PMID

  13. ADEPT - Abnormal Doppler Enteral Prescription Trial

    McCormick Kenny

    2009-10-01

    Full Text Available Abstract Background Pregnancies complicated by abnormal umbilical artery Doppler blood flow patterns often result in the baby being born both preterm and growth-restricted. These babies are at high risk of milk intolerance and necrotising enterocolitis, as well as post-natal growth failure, and there is no clinical consensus about how best to feed them. Policies of both early milk feeding and late milk feeding are widely used. This randomised controlled trial aims to determine whether a policy of early initiation of milk feeds is beneficial compared with late initiation. Optimising neonatal feeding for this group of babies may have long-term health implications and if either of these policies is shown to be beneficial it can be immediately adopted into clinical practice. Methods and Design Babies with gestational age below 35 weeks, and with birth weight below 10th centile for gestational age, will be randomly allocated to an "early" or "late" enteral feeding regimen, commencing milk feeds on day 2 and day 6 after birth, respectively. Feeds will be gradually increased over 9-13 days (depending on gestational age using a schedule derived from those used in hospitals in the Eastern and South Western Regions of England, based on surveys of feeding practice. Primary outcome measures are time to establish full enteral feeding and necrotising enterocolitis; secondary outcomes include sepsis and growth. The target sample size is 400 babies. This sample size is large enough to detect a clinically meaningful difference of 3 days in time to establish full enteral feeds between the two feeding policies, with 90% power and a 5% 2-sided significance level. Initial recruitment period was 24 months, subsequently extended to 38 months. Discussion There is limited evidence from randomised controlled trials on which to base decisions regarding feeding policy in high risk preterm infants. This multicentre trial will help to guide clinical practice and may also

  14. Executive function abnormalities in pathological gamblers

    Mungai Francesco

    2008-03-01

    Full Text Available Abstract Background Pathological gambling (PG is an impulse control disorder characterized by persistent and maladaptive gambling behaviors with disruptive consequences for familial, occupational and social functions. The pathophysiology of PG is still unclear, but it is hypothesized that it might include environmental factors coupled with a genetic vulnerability and dysfunctions of different neurotransmitters and selected brain areas. Our study aimed to evaluate a group of patients suffering from PG by means of some neuropsychological tests in order to explore the brain areas related to the disorder. Methods Twenty outpatients (15 men, 5 women, with a diagnosis of PG according to DSM-IV criteria, were included in the study and evaluated with a battery of neuropsychological tests: the Wisconsin Card Sorting Test (WCST, the Wechsler Memory Scale revised (WMS-R and the Verbal Associative Fluency Test (FAS. The results obtained in the patients were compared with normative values of matched healthy control subjects. Results The PG patients showed alterations at the WCST only, in particular they had a great difficulty in finding alternative methods of problem-solving and showed a decrease, rather than an increase, in efficiency, as they progressed through the consecutive phases of the test. The mean scores of the other tests were within the normal range. Conclusion Our findings showed that patients affected by PG, in spite of normal intellectual, linguistic and visual-spatial abilities, had abnormalities emerging from the WCST, in particular they could not learn from their mistakes and look for alternative solutions. Our results would seem to confirm an altered functioning of the prefrontal areas which might provoke a sort of cognitive "rigidity" that might predispose to the development of impulsive and/or compulsive behaviors, such as those typical of PG.

  15. Abnormal Spatial Asymmetry of Selective Attention in ADHD

    Chan, Edgar; Mattingley, Jason B.; Huang-Pollock, Cynthia; English, Therese; Hester, Robert; Vance, Alasdair; Bellgrove, Mark A.

    2009-01-01

    Background: Evidence for a selective attention abnormality in children with attention deficit hyperactivity disorder (ADHD) has been hard to identify using conventional methods from cognitive science. This study tested whether the presence of selective attention abnormalities in ADHD may vary as a function of perceptual load and target…

  16. Phenotype abnormality: 46 [Arabidopsis Phenome Database[Archive

    Full Text Available 46 http://metadb.riken.jp/db/SciNetS_ria224i/cria224u1ria224u552i abnormal for trait of behavior.../cria224u2ria224u38i stomatal complex ... abnormal ... response to light stimulus ... behavioral quality

  17. Freud Was Right. . . about the Origins of Abnormal Behavior

    Muris, Peter

    2006-01-01

    Freud's psychodynamic theory is predominantly based on case histories of patients who displayed abnormal behavior. From a scientific point of view, Freud's analyses of these cases are unacceptable because the key concepts of his theory cannot be tested empirically. However, in one respect, Freud was totally right: most forms of abnormal behavior…

  18. Congenital nasal piriform aperture stenosis with vestibular abnormality

    Rajaram, Smitha; Raghavan, Ashok [Sheffield Children' s Hospital, Department of Paediatric Radiology, Sheffield (United Kingdom); Bateman, Neil [Sheffield Children' s Hospital, ENT Department, Sheffield (United Kingdom)

    2008-10-15

    We present a neonate with congenital nasal piriform aperture stenosis associated with an abnormal vestibular aperture. Radiological evaluation with CT is essential to confirm the diagnosis and delineate the anatomy for surgical planning. Extension of the scan field of view to include the petrous temporal bone is essential to identify associated abnormalities of the vestibule. (orig.)

  19. Visualizing how cancer chromosome abnormalities form in living cells

    For the first time, scientists have directly observed events that lead to the formation of a chromosome abnormality that is often found in cancer cells. The abnormality, called a translocation, occurs when part of a chromosome breaks off and becomes attac

  20. A Case of ADHD and a Major Y Chromosome Abnormality

    Mulligan, Aisling; Gill, Michael; Fitzgerald, Michael

    2008-01-01

    Background: ADHD is a common, heritable disorder of childhood. Sex chromosome abnormalities are relatively rare conditions that are sometimes associated with behavioral disorders. Method: The authors present a male child with ADHD and a major de-novo Y chromosome abnormality consisting of deletion of the long arm and duplication of the short arm.…