The clinical research on fractionated irradiation treatment with X knife in patients of PD

International Nuclear Information System (INIS)

Wei Pengxiang; Chen Xu; Ai Quanshan; Xia Jiyong; Yang Jiongda; Chen Binghuan

2003-01-01

Objective: To explore X knife treatment methods and to seek a new effective way for PD therapy. Methods: Sixteen patients of PD were treated by performing VIM with 2 times of X knife fractionated irradiation (interval, 24 h) to a total dose of 140 Gy, and 8 patients of PD were treated by performing VIM with 3 times of X knife fractionated irradiation (interval, 24 h) to a total of dose of 165 Gy. Results: During 3-24 months follow-up after X knife treatment, tremor was stopped in 19 patients and was relived significantly in 5 patients. Rigidity and bradykinesia of PD were relieved slightly. No complications were observed. Conclusion: To perform VIM with X knife fractionated irradiation can be safely and effectively used to treat PD. The tremor of PD can be relieved slightly

Functional differences between PD-1+ and PD-1- CD4+ effector T cells in healthy donors and patients with glioblastoma multiforme.

Directory of Open Access Journals (Sweden)

Brittany A Goods

Full Text Available Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1 have been highly successful in the treatment of cancer. While PD-1 expression has been widely investigated, its role in CD4+ effector T cells in the setting of health and cancer remains unclear, particularly in the setting of glioblastoma multiforme (GBM, the most aggressive and common form of brain cancer. We examined the functional and molecular features of PD-1+CD4+CD25-CD127+Foxp3-effector cells in healthy subjects and in patients with GBM. In healthy subjects, we found that PD-1+CD4+ effector cells are dysfunctional: they do not proliferate but can secrete large quantities of IFNγ. Strikingly, blocking antibodies against PD-1 did not rescue proliferation. RNA-sequencing revealed features of exhaustion in PD-1+ CD4 effectors. In the context of GBM, tumors were enriched in PD-1+ CD4+ effectors that were similarly dysfunctional and unable to proliferate. Furthermore, we found enrichment of PD-1+TIM-3+ CD4+ effectors in tumors, suggesting that co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial. RNA-sequencing of blood and tumors from GBM patients revealed distinct differences between CD4+ effectors from both compartments with enrichment in multiple gene sets from tumor infiltrating PD-1-CD4+ effectors cells. Enrichment of these gene sets in tumor suggests a more metabolically active cell state with signaling through other co-receptors. PD-1 expression on CD4 cells identifies a dysfunctional subset refractory to rescue with PD-1 blocking antibodies, suggesting that the influence of immune checkpoint inhibitors may involve recovery of function in the PD-1-CD4+ T cell compartment. Additionally, co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial.

Key factors for a high-quality peritoneal dialysis program--the role of the PD team and continuous quality improvement.

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Fang, Wei; Ni, Zhaohui; Qian, Jiaqi

2014-06-01

The proportion of end-stage renal disease (ESRD) patients on peritoneal dialysis (PD) has increased very fast in China over the last decade. Renji Hospital, affiliated with Shanghai Jiaotong University School of Medicine, is a recognized high-quality PD unit with a high PD utilization rate, excellent patient and technique survival (1-year and 5-year patient survival rate of 93% and 71%, and 1-year and 5-year technique survival of 96% and 82%, respectively), low peritonitis rate and a well-documented good quality of life of the treated patients. We believe that a dedicated and experienced PD team, a structured patient training program, continuous patient support, establishing and utilizing standardized protocols, starting PD with low dialysis dose, monitoring key performance indicators (KPIs), and continuous quality improvement (CQI) are the key factors underlying this successful PD program. Copyright © 2014 International Society for Peritoneal Dialysis.

UK Renal Registry 18th Annual Report: Chapter 11 2014 Multisite Dialysis Access Audit in England, Northern Ireland and Wales and 2013 PD One Year Follow-up: National and Centre-specific Analyses.

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Rao, Anirudh; Evans, Rebecca; Wilkie, Martin; Fluck, Richard; Kumwenda, Mick

2016-01-01

Data are presented from the third combined vascular and peritoneal dialysis access audit. In 2014, 53 centres in England, Wales and Northern Ireland (out of 62) returned data on first access from 4,339 incident haemodialysis (HD) patients and 1,090 incident peritoneal dialysis (PD) patients. Of the 5,429 incident patients, 20.1% started dialysis on PD, 27.8% started with an arteriovenous fistula (AVF), 1.0% with an arteriovenous graft (AVG), 27.1% on a tunnelled line (TL) and 24.0% on a non-tunnelled line (NTL). Older patients (565 years) were more likely to start haemodialysis using AVF compared to their younger counterparts (36.2% vs. 32.8%). Thirteen of the nineteen centres (68%) using the physician led percutaneous insertion technique had over 20% of their incident patients starting on PD when compared to only seven out of fourteen centres (50%) which used single technique (open surgical or laparoscopic) for their PD catheter insertion. Wide variations were apparent between centres for use of AVF as the first haemodialysis access ranging from 10–54%. Eight of the 49 centres were achieving close to the 65% target for AV fistula in their incident patients. Length of time known to nephrology services and likelihood of commencing dialysis using either an AVF or a PD catheter are strongly associated. Patients who were known to a nephrologist for over one year were more likely to start dialysis with AVF, as compared to those who were referred between 90–365 days (39.2% vs. 24.6%). Similarly, patients who were known to a nephrologist between 90 days and one year were more likely to start on PD when compared to patients who were referred report demonstrates wide variations in practice between centres across several domains in the provision of dialysis access and further work will be required to understand the underlying reasons.

Basal cell carcinoma: PD-L1/PD-1 checkpoint expression and tumor regression after PD-1 blockade.

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Lipson, Evan J; Lilo, Mohammed T; Ogurtsova, Aleksandra; Esandrio, Jessica; Xu, Haiying; Brothers, Patricia; Schollenberger, Megan; Sharfman, William H; Taube, Janis M

2017-01-01

Monoclonal antibodies that block immune regulatory proteins such as programmed death-1 (PD-1) have demonstrated remarkable efficacy in controlling the growth of multiple tumor types. Unresectable or metastatic basal cell carcinoma, however, has largely gone untested. Because PD-Ligand-1 (PD-L1) expression in other tumor types has been associated with response to anti-PD-1, we investigated the expression of PD-L1 and its association with PD-1 expression in the basal cell carcinoma tumor microenvironment. Among 40 basal cell carcinoma specimens, 9/40 (22%) demonstrated PD-L1 expression on tumor cells, and 33/40 (82%) demonstrated PD-L1 expression on tumor-infiltrating lymphocytes and associated macrophages. PD-L1 was observed in close geographic association to PD-1+ tumor infiltrating lymphocytes. Additionally, we present, here, the first report of an objective anti-tumor response to pembrolizumab (anti-PD-1) in a patient with metastatic PD-L1 (+) basal cell carcinoma, whose disease had previously progressed through hedgehog pathway-directed therapy. The patient remains in a partial response 14 months after initiation of therapy. Taken together, our findings provide a rationale for testing anti-PD-1 therapy in patients with advanced basal cell carcinoma, either as initial treatment or after acquired resistance to hedgehog pathway inhibition.

Corticomuscular coherence during hand gripping with DBS and medication in PD patients

DEFF Research Database (Denmark)

Sridharan, Kousik Sarathy; Højlund, Andreas; Johnsen, Erik Lisbjerg

Deep brain stimulation (DBS) effectively alleviates the motor symptoms in Parkinson’s disease (PD) although its effect mechanism is still unclear. CMC is reduced in PD patients but restorable with medication, while DBS variably affects CMC in advanced PD patients. We recorded magnetoencephalography...... (MEG) from six PD patients performing hand gripping during DBS ON and medicated (levodopa, MED ON) conditions and from ten age-matched healthy controls. Participants performed isotonic contractions (hand gripping) with their right hand, and electromyography (EMG) was recorded from the extensor...... digitorum communis muscle with a belly-tendon montage. We calculated the mean-squared coherence between MEG and the rectified EMG signals. For each group and condition, we selected the maximum CMC value in the beta range (13-30 Hz) within the average of an a priori selection of nine left sensorimotor...

Anti-PD-L1 Treatment Induced Central Diabetes Insipidus.

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Zhao, Chen; Tella, Sri Harsha; Del Rivero, Jaydira; Kommalapati, Anuhya; Ebenuwa, Ifechukwude; Gulley, James; Strauss, Julius; Brownell, Isaac

2018-02-01

Immune checkpoint inhibitors, including anti-programmed cell death protein 1 (PD-1), anti-programmed cell death protein ligand 1 (PD-L1), and anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) monoclonal antibodies, have been widely used in cancer treatment. They are known to cause immune-related adverse events (irAEs), which resemble autoimmune diseases. Anterior pituitary hypophysitis with secondary hypopituitarism is a frequently reported irAE, especially in patients receiving anti-CTLA4 treatment. In contrast, posterior pituitary involvement, such as central diabetes insipidus (DI), is relatively rare and is unreported in patients undergoing PD-1/PD-L1 blockade. We describe a case of a 73-year-old man with Merkel cell carcinoma who received the anti-PD-L1 monoclonal antibody avelumab and achieved partial response. The patient developed nocturia, polydipsia, and polyuria 3 months after starting avelumab. Further laboratory testing revealed central DI. Avelumab was held and he received desmopressin for the management of central DI. Within 6 weeks after discontinuation of avelumab, the patient's symptoms resolved and he was eventually taken off desmopressin. The patient remained off avelumab and there were no signs or symptoms of DI 2 months after the discontinuation of desmopressin. To our knowledge, this is the first report of central DI associated with anti-PD-L1 immunotherapy. The patient's endocrinopathy was successfully managed by holding treatment with the immune checkpoint inhibitor. This case highlights the importance of early screening and appropriate management of hormonal irAEs in subjects undergoing treatment with immune checkpoint inhibitors to minimize morbidity and mortality. Copyright © 2017 Endocrine Society

Chemotherapy treatment is associated with altered PD-L1 expression in lung cancer patients

DEFF Research Database (Denmark)

Rojkó, Lívia; Reiniger, Lilla; Téglási, Vanda

2018-01-01

Objectives: While the predictive value of programmed cell death ligand-1 (PD-L1) protein expression for immune checkpoint inhibitor therapy of lung cancer has been extensively studied, the impact of standard platinum-based chemotherapy on PD-L1 or programmed cell death-1 (PD-1) expression is unkn...... expression of TC in a subset of patients, therefore, rebiopsy and re-evaluation of PD-L1 expression may be necessary for the indication of immune checkpoint inhibitor therapy.......Objectives: While the predictive value of programmed cell death ligand-1 (PD-L1) protein expression for immune checkpoint inhibitor therapy of lung cancer has been extensively studied, the impact of standard platinum-based chemotherapy on PD-L1 or programmed cell death-1 (PD-1) expression...... is unknown. The aim of this study was to determine the changes in PD-L1 expression of tumor cells (TC) and immune cells (IC), in PD-1 expression of IC, and in the amount of stromal mononuclear cell infiltration after platinum-based chemotherapy in patients with lung cancer. Materials and methods: We...

PD_Manager: an mHealth platform for Parkinson's disease patient management.

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Tsiouris, Kostas M; Gatsios, Dimitrios; Rigas, George; Miljkovic, Dragana; Koroušić Seljak, Barbara; Bohanec, Marko; Arredondo, Maria T; Antonini, Angelo; Konitsiotis, Spyros; Koutsouris, Dimitrios D; Fotiadis, Dimitrios I

2017-06-01

PD_Manager is a mobile health platform designed to cover most of the aspects regarding the management of Parkinson's disease (PD) in a holistic approach. Patients are unobtrusively monitored using commercial wrist and insole sensors paired with a smartphone, to automatically estimate the severity of most of the PD motor symptoms. Besides motor symptoms monitoring, the patient's mobile application also provides various non-motor self-evaluation tests for assessing cognition, mood and nutrition to motivate them in becoming more active in managing their disease. All data from the mobile application and the sensors is transferred to a cloud infrastructure to allow easy access for clinicians and further processing. Clinicians can access this information using a separate mobile application that is specifically designed for their respective needs to provide faster and more accurate assessment of PD symptoms that facilitate patient evaluation. Machine learning techniques are used to estimate symptoms and disease progression trends to further enhance the provided information. The platform is also complemented with a decision support system (DSS) that notifies clinicians for the detection of new symptoms or the worsening of existing ones. As patient's symptoms are progressing, the DSS can also provide specific suggestions regarding appropriate medication changes.

Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer

Science.gov (United States)

Brahmer, Julie R.; Tykodi, Scott S.; Chow, Laura Q.M.; Hwu, Wen-Jen; Topalian, Suzanne L.; Hwu, Patrick; Drake, Charles G.; Camacho, Luis H.; Kauh, John; Odunsi, Kunle; Pitot, Henry C.; Hamid, Omid; Bhatia, Shailender; Martins, Renato; Eaton, Keith; Chen, Shuming; Salay, Theresa M.; Alaparthy, Suresh; Grosso, Joseph F.; Korman, Alan J.; Parker, Susan M.; Agrawal, Shruti; Goldberg, Stacie M.; Pardoll, Drew M.; Gupta, Ashok; Wigginton, Jon M.

2013-01-01

BACKGROUND Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host’s immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. METHODS In this multicenter phase 1 trial, we administered intravenous anti–PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti–PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. RESULTS As of February 24, 2012, a total of 207 patients — 75 with non–small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer — had received anti–PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non–small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up. CONCLUSIONS Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non–small-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.) PMID:22658128

The property distance index PD predicts peptides that cross-react with IgE antibodies

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Ivanciuc, Ovidiu; Midoro-Horiuti, Terumi; Schein, Catherine H.; Xie, Liping; Hillman, Gilbert R.; Goldblum, Randall M.; Braun, Werner

2009-01-01

Similarities in the sequence and structure of allergens can explain clinically observed cross-reactivities. Distinguishing sequences that bind IgE in patient sera can be used to identify potentially allergenic protein sequences and aid in the design of hypo-allergenic proteins. The property distance index PD, incorporated in our Structural Database of Allergenic Proteins (SDAP, http://fermi.utmb.edu/SDAP/), may identify potentially cross-reactive segments of proteins, based on their similarity to known IgE epitopes. We sought to obtain experimental validation of the PD index as a quantitative predictor of IgE cross-reactivity, by designing peptide variants with predetermined PD scores relative to three linear IgE epitopes of Jun a 1, the dominant allergen from mountain cedar pollen. For each of the three epitopes, 60 peptides were designed with increasing PD values (decreasing physicochemical similarity) to the starting sequence. The peptides synthesized on a derivatized cellulose membrane were probed with sera from patients who were allergic to Jun a 1, and the experimental data were interpreted with a PD classification method. Peptides with low PD values relative to a given epitope were more likely to bind IgE from the sera than were those with PD values larger than 6. Control sequences, with PD values between 18 and 20 to all the three epitopes, did not bind patient IgE, thus validating our procedure for identifying negative control peptides. The PD index is a statistically validated method to detect discrete regions of proteins that have a high probability of cross-reacting with IgE from allergic patients. PMID:18950868

Is the decline of renal function different before and after the start of dialysis?

NARCIS (Netherlands)

de Jager, Dinanda J.; Halbesma, Nynke; Krediet, Raymond T.; Boeschoten, Elisabeth W.; le Cessie, Saskia; Dekker, Friedo W.; Grootendorst, Diana C.; Apperloo, A. J.; Bijlsma, J. A.; Boekhout, M.; Boer, W. H.; van der Boog, P. J. M.; Büller, H. R.; van Buren, M.; de Charro, F. Th; Doorenbos, C. J.; van den Dorpel, M. A.; van Es, A.; Fagel, W. J.; Feith, G. W.; de Fijter, C. W. H.; Frenken, L. A. M.; van Geelen, J. A. C. A.; Gerlag, P. G. G.; Grave, W.; Gorgels, J. P. M. C.; Huisman, R. M.; Jager, K. J.; Jie, K.; Koning-Mulder, W. A. H.; Koolen, M. I.; Hovinga, T. K. Kremer; Lavrijssen, A. T. J.; Luik, A. J.; van der Meulen, J.; Parlevliet, K. J.; Raasveld, M. H. M.; van der Sande, F. M.; Schonck, M. J. M.; Schuurmans, M. M. J.; Siegert, C. E. H.; Stegeman, C. A.; Stevens, P.; Thijssen, J. G. P.; Valentijn, R. M.; Vastenburg, G. H.; Verburgh, C. A.; Vincent, H. H.; Vos, P. F.

2013-01-01

The presence of glomerular filtration in dialysis patients is associated with improved survival and quality of life. This study explores the time course of the glomerular filtration rate (GFR) between 1 year before and 1 year after the start of haemodialysis (HD) and peritoneal dialysis (PD). This

Expression of PD-1 and PD-L1 in poorly differentiated neuroendocrine carcinomas of the digestive system: a potential target for anti-PD-1/PD-L1 therapy.

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Roberts, Jordan A; Gonzalez, Raul S; Das, Satya; Berlin, Jordan; Shi, Chanjuan

2017-12-01

Poorly differentiated neuroendocrine carcinoma of the digestive system has a dismal prognosis with limited treatment options. This study aimed to investigate expression of the PD-1/PD-L1 pathway in these tumors. Thirty-seven patients with a poorly differentiated neuroendocrine carcinoma of the digestive system were identified. Their electronic medical records, pathology reports, and pathology slides were reviewed for demographics, clinical history, and pathologic features. Tumor sections were immunohistochemically labeled for PD-1 and PD-L1, and expression of PD-1 and PD-L1 on tumor and tumor-associated immune cells was analyzed and compared between small cell and large cell neuroendocrine carcinomas. The mean age of patients was 61 years old with 18 men and 19 women. The colorectum (n=20) was the most common primary site; other primary sites included the pancreaticobiliary system, esophagus, stomach, duodenum, and ampulla. Expression of PD-1 was detected on tumor cells (n=6, 16%) as well as on tumor-associated immune cells (n=23, 63%). The 6 cases with PD-1 expression on tumor cells also had the expression on immune cells. Expression of PD-L1 was visualized on tumor cells in 5 cases (14%) and on tumor-associated immune cells in 10 cases (27%). There was no difference in PD-1 and PD-L1 expression between small cell and large cell neuroendocrine carcinomas. In conclusion, PD-1/PD-L1 expression is a frequent occurrence in poorly differentiated neuroendocrine carcinomas of the digestive system. Checkpoint blockade targeting the PD-1/PD-L1 pathway may have a potential role in treating patients with this disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Retrospective Molecular Epidemiology Study of PD-L1 Expression in Patients with EGFR-Mutant Non-small Cell Lung Cancer.

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Cho, Jong Ho; Zhou, Wei; Choi, Yoon-La; Sun, Jong-Mu; Choi, Hyejoo; Kim, Tae-Eun; Dolled-Filhart, Marisa; Emancipator, Kenneth; Rutkowski, Mary Anne; Kim, Jhingook

2018-01-01

Data are limited on programmed death ligand 1 (PD-L1) expression in epidermal growth factor receptor ( EGFR )-mutant non-small cell lung cancer (NSCLC). We retrospectively evaluated the relationship between PD-L1 expression and recurrence-free survival (RFS) and overall survival in 319 patients with EGFR -mutant NSCLC who were treated at Samsung Medical Center from 2006 to 2014. Membranous PD-L1 expression on tumor cells was measured using the PD-L1 IHC 22C3 pharmDx antibody and reported as tumor proportion score (TPS). Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis. All patients had ≥1 EGFR mutation-54% in exon 19 and 39% in exon 21. Overall, 51% of patients had PD-L1-positive tumors. The prevalence of PD-L1 positivity was higher among patients with stages II-IV versus stage I disease (64% vs. 44%) and among patients with other EGFR mutations (75%) than with L858R mutation (39%) or exon 19 deletion (52%). PD-L1 positivity was associated with shorter RFS, with an adjusted hazard ratio of 1.52 (95% confidence interval [CI], 0.81 to 2.84; median, 18 months) for the PD-L1 TPS ≥ 50% group, 1.51 (95% CI, 1.02 to 2.21; median, 31 months) for the PD-L1 TPS 1%-49% group, and 1.51 (95% CI, 1.05 to 2.18) for the combined PD-L1-positive groups (TPS ≥ 1%) compared with the PD-L1-negative group (median, 35 months). PD-L1 expression is associated with disease stage and type of EGFR mutation. PD-L1 positivity might be associated with worse RFS among patients with surgically treated EGFR -mutant NSCLC.

Interesting case of G6PD deficiency anemia with severe hemolysis

Directory of Open Access Journals (Sweden)

Anupam Chhabra

2013-01-01

Full Text Available Severe hemolysis was observed in a critically ill patient with G6Pd deficiency where the causative trigger could not be identified. We describe one young patient with severe hemolysis treated with two cycles of plasmapheresis which proved to be an effective tool in the treatment. The patient presented with diffuse pain abdomen, vomiting, yellowish discoloration of sclera and skin and acute breathlessness. Hemoglobin 5.4 mg/dl and total (T serum bilirubin 17.08 mg/dl: Direct (D 4.10 mg/dl and Indirect (I 12.98 mg/dl. Subsequently patient started passing black color urine. As the patient developed severe hemolysis and the trigger agent of hemolysis was unknown, two cycles of plasmapheresis were performed with the aim to remove unknown causative agent. Consequently no trace of hemolysis was found and patient stabilized. Plasmapheresis can be used to treat G6PD deficient patients with severe hemolysis due to unidentified trigger agent.

Hypomethylation and up-regulation of PD-1 in T cells by azacytidine in MDS/AML patients

DEFF Research Database (Denmark)

Ørskov, Andreas D; Treppendahl, Marianne B; Skovbo, Anni

2015-01-01

receptor PD-1 is regulated by DNA methylation. In 12 of 27 patients (44%) PD-1 promoter demethylation was observed in sorted peripheral blood T cells isolated over consecutive cycles of treatment with 5-azacytidine (5-aza). The PD-1 promoter demethylation correlated with an increase in PD-1 expression...... HMA treatment can be a possible resistance mechanism, which may be overcome by combination therapy with a PD-1 pathway inhibitor....

CDK4/6 inhibitor PD0332991 in glioblastoma treatment: does it have a future?

Directory of Open Access Journals (Sweden)

Lisette eSchroder

2015-11-01

Full Text Available Glioblastoma is aggressive, highly infiltrating, and the most frequent malignant form of brain cancer. With a median survival time of only 14.6 months, when treated with the standard of care, it is essential to find new therapeutic options. A specific CDK4/6 inhibitor, PD0332991, obtained accelerated approval from the Food and Drug Administration for the treatment of patients with advanced estrogen receptor-positive and HER2-negative breast cancer. Common alterations in the cyclin D1-Cyclin Dependent Kinase 4/6-Retinoblastoma 1 pathway in glioblastoma make PD0332991 also an interesting drug for the treatment of glioblastoma. Promising results in in vitro studies, where patient derived glioblastoma cell lines showed sensitivity to PD0332991, gave motive to start in vivo studies. Outcomes of these studies have been contrasting in terms of PD0332991 efficacy within the brain: more research is necessary to conclude whether CDK4/6 inhibitor can be beneficial in the treatment of glioblastoma.

Dermal fibroblasts from patients with Parkinson’s disease have normal GCase activity and autophagy compared to patients with PD and GBA mutations [version 2; referees: 2 approved

Directory of Open Access Journals (Sweden)

Lucy M Collins

2018-02-01

Full Text Available Background: Recently, the development of Parkinson’s disease (PD has been linked to a number of genetic risk factors, of which the most common is glucocerebrosidase (GBA mutations. Methods: We investigated PD and Gaucher Disease (GD patient derived skin fibroblasts using biochemistry assays. Results: PD patient derived skin fibroblasts have normal glucocerebrosidase (GCase activity, whilst patients with PD and GBA mutations have a selective deficit in GCase enzyme activity and impaired autophagic flux. Conclusions: This data suggests that only PD patients with a GBA mutation have altered GCase activity and autophagy, which may explain their more rapid clinical progression.

Prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency among malaria patients in Upper Myanmar.

Science.gov (United States)

Lee, Jinyoung; Kim, Tae Im; Kang, Jung-Mi; Jun, Hojong; Lê, Hương Giang; Thái, Thị Lam; Sohn, Woon-Mok; Myint, Moe Kyaw; Lin, Khin; Kim, Tong-Soo; Na, Byoung-Kuk

2018-03-16

Glucose-6-phosphate dehydrogenase (G6PD; EC 1.1.1.49) deficiency is one of the most common X-linked recessive hereditary disorders in the world. Primaquine (PQ) has been used for radical cure of P. vivax to prevent relapse. Recently, it is also used to reduce P. falciparum gametocyte carriage to block transmission. However, PQ metabolites oxidize hemoglobin and generate excessive reactive oxygen species which can trigger acute hemolytic anemia in malaria patients with inherited G6PD deficiency. A total of 252 blood samples collected from malaria patients in Myanmar were used in this study. G6PD variant was analysed by a multiplex allele specific PCR kit, DiaPlexC™ G6PD Genotyping Kit [Asian type]. The accuracy of the multiplex allele specific PCR was confirmed by sequencing analysis. Prevalence and distribution of G6PD variants in 252 malaria patients in Myanmar were analysed. Six different types of G6PD allelic variants were identified in 50 (7 females and 43 males) malaria patients. The predominant variant was Mahidol (68%, 34/50), of which 91.2% (31/34) and 8.8% (3/34) were males and females, respectively. Other G6PD variants including Kaiping (18%, 9/50), Viangchan (6%, 3/50), Mediterranean (4%, 2/50), Union (2%, 1/50) and Canton (2%, 1/50) were also observed. Results of this study suggest that more concern for proper and safe use of PQ as a radical cure of malaria in Myanmar is needed by combining G6PD deficiency test before PQ prescription. Establishment of a follow-up system to monitor potential PQ toxicity in malaria patients who are given PQ is also required.

PD-L1 Expression and Survival among Patients with Advanced Non-Small Cell Lung Cancer Treated with Chemotherapy

DEFF Research Database (Denmark)

Sørensen, Steffen Filskov; Zhou, Wei; Dolled-Filhart, Marisa

2016-01-01

with advanced non-small cell lung cancer (NSCLC) treated with chemotherapy are inconsistent. MATERIAL AND METHODS: We evaluated the relationship between PD-L1 expression and overall survival (OS) among 204 patients with advanced NSCLC treated at Aarhus University Hospital, Aarhus, Denmark, from 2007 to 2012. PD......-positive tumors, and 50% had PD-L1 weak-positive tumors. No statistically significant association was found between PD-L1 expression and survival; adjusted hazard ratio of 1.34 (95% confidence interval, 0.88-2.03; median OS, 9.0 months) for the PD-L1 strong-positive group and 1.07 (0.74-1.55; median OS, 9...... by immunohistochemistry to be frequently expressed in patients with advanced NSCLC. However, PD-L1 expression is not a strong prognostic marker in patients with advanced NSCLC treated with chemotherapy....

Visceral fat area is associated with HbA1c but not dialysate-related glucose load in nondiabetic PD patients

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Ho, Li-Chun; Yen, Chung-Jen; Chao, Chia-Ter; Chiang, Chih-Kang; Huang, Jenq-Wen; Hung, Kuan-Yu

2015-08-01

Factors associated with increased visceral fat area (VFA) have been well documented in the general population but rarely explored in nondiabetic individuals on peritoneal dialysis (PD). As glycosylated hemoglobin (HbA1c) is positively correlated with VFA in diabetic patients, we hypothesized that the same correlation would exist in nondiabetic PD patients. We enrolled 105 nondiabetic patients who had undergone chronic PD for more than 3 months. Each subject underwent an abdominal computed tomography (CT) scan, and the umbilicus cut was analyzed for VFA. VFA values, corrected for body mass index and subjected to natural logarithm transformations, were examined to determine whether they were correlated with HbA1c and other parameters. PD dialysates prescribed at the time of enrollment were recorded to calculate glucose load. We found that when 105 nondiabetic PD patients were classified according to tertiles of HbA1c, higher HbA1c was associated with larger VFA. Multiple linear regression analysis revealed that HbA1c was an independent determinant of VFA, while glucose load and other PD-specific factors were not. In summary, HbA1c, but not PD-related glucose load, was positively correlated with VFA in nondiabetic PD patients, suggesting clinical utility of HbA1c in the PD population.

Circulating Tumour DNA for Monitoring Treatment Response to Anti-PD-1 Immunotherapy in Melanoma Patients

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Atsuko Ashida

2017-08-01

Full Text Available Anti-programmed cell death-1 (anti-PD-1 antibody shows high therapeutic efficacy in patients with advanced melanoma. However, assessment of its therapeutic activity can be challenging because of tumour enlargement associated with intratumoural inflammation. Because circulating tumour DNA (ctDNA correlates with tumour burden, we assessed the value of ctDNA levels as an indicator of tumour changes. Quantification of ctDNA (BRAFmutant or NRASmutant levels by droplet digital PCR in 5 patients with BRAF or NRAS mutant melanoma during the treatment course showed dynamic changes corresponding to radiological and clinical alterations. In 3 cases in which the anti-PD-1 antibody was effective, ctDNA levels decreased within 2–4 weeks after treatment initiation. In 2 cases in which the anti-PD-1 antibody was ineffective, ctDNA levels did not decrease after treatment initiation. ctDNA could be a useful biomarker to predict early response to treatment in patients with advanced melanoma treated with anti-PD-1 immunotherapy.

Imipenem in burn patients: pharmacokinetic profile and PK/PD target attainment.

Science.gov (United States)

Gomez, David S; Sanches-Giraud, Cristina; Silva, Carlindo V; Oliveira, Amanda M Ribas Rosa; da Silva, Joao Manoel; Gemperli, Rolf; Santos, Silvia R C J

2015-03-01

Unpredictable pharmacokinetics (PK) in burn patients may result in plasma concentrations below concentrations that are effective against common pathogens. The present study evaluated the imipenem PK profile and pharmacokinetic/pharmacodynamics (PK/PD) correlation in burn patients. Fifty-one burn patients, 38.7 years of age (mean), 68.0 kg, 36.3% total burn surface area (TBSA), of whom 84% (43/51) exhibited thermal injury, 63% inhalation injury and 16% electrical injury (8/51), all of whom were receiving imipenem treatment were investigated. Drug plasma monitoring, PK study (120 sets of plasma levels) and PK/PD correlation were performed in a series of blood samples. Only 250 μl of plasma samples were required for drug plasma measurements using the ultra filtration technique for the purification of biological matrix and quantification using liquid chromatography. Probability of target attainment (PTA) was calculated using a PD target of 40% free drug concentrations above the minimum inhibitory concentration (40%fT>MIC). Significant differences in PK parameters (medians), such as biological half-life (2.2 vs 5.5 h), plasma clearance (16.2 vs 1.4 l h(-1)) and volume of distribution (0.86 vs 0.19 l kg(-1)), were registered in burn patients via comparisons of set periods with normal renal function against periods of renal failure. Correlations between creatinine clearance and total body plasma clearance were also obtained. In addition, the PK profile did not change according to TBSA during sets when renal function was preserved. PTA was >89% for MIC values up to 4 mg l(-1). In conclusion, imipenem efficacy for the control of hospital infection on the basis of PK/PD correlation was guaranteed for burn in patients at the recommended dose regimens for normal renal function (31.1±9.7 mg kg(-1) daily), but the daily dose must be reduced to 17.2±9.7 mg kg(-1) during renal failure to avoid neurotoxicity.

UK Renal Registry 16th annual report: chapter 14 2012 multisite dialysis access audit in England, Northern Ireland and Wales and 2011 PD one year follow-up: national and centre-specific analyses.

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Briggs, Victoria; Pitcher, David; Shaw, Catriona; Fluck, Richard; Wilkie, Martin

2013-01-01

Dialysis access should be timely, minimise complications and maintain functionality. Good functional access is required for renal replacement therapy (RRT) to be successful. The aim of the combined vascular and peritoneal dialysis access audit was to examine practice patterns with respect to dialysis access and highlight variations in practice between renal centres. The UK Renal Registry collected centre-specific information on vascular and peritoneal access outcome measures including patient demographics, dialysis access type (at start of dialysis and three months after start of dialysis), surgical assessment and access functionality. The combined access audit covered incident haemodialysis (HD) and peritoneal dialysis (PD) patients in 2012 from England, Northern Ireland and Wales. Centres who had reported data on incident PD patients for the previous audit in 2011 were additionally asked to provide one year follow up data for this group. Fifty-one centres in England, Wales and Northern Ireland (representing 82% of all centres) returned data on first access from 3,720 incident HD patients and 1,018 incident PD patients. A strong relationship was seen between surgical assessment and the likelihood of starting HD with an arteriovenous fistula (AVF). Type of first access was related to the length of time known to renal services with higher numbers of AVFs and PD catheters used in patients known to renal services for at least one year. Three month and one year outcomes of HD and PD access were poorly reported. This audit provides information on important patient related outcome measures with the potential to lead to an improvement in access provision. This represents an important advance, however data collection remains suboptimal. There is wide practice variation across the England, Wales and Northern Ireland in provision of both HD and PD access which requires further exploration. © 2014 S. Karger AG, Basel.

The Emerging Role of PD-1/PD-L1-Targeting Immunotherapy in the Treatment of Metastatic Urothelial Carcinoma.

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Gwynn, Morgan E; DeRemer, David L

2018-01-01

To summarize and evaluate immunotherapy agents targeting programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) recently approved for the treatment of metastatic urothelial carcinomas (UC). A literature review was performed using PubMed (2012 to June 2017), the American Society of Clinical Oncology abstract databases (2012 to June 2017 Annual Meetings/symposia), and the America Association for Cancer Research symposia (2012 to June 2017). A search using clinicaltrials.gov was conducted to identify studies for atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab. English language phase I to III studies assessing PD-1 and PD-L1 in UC were incorporated. Atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab have demonstrated clinical efficacy with tolerable toxicities in patients with metastatic UC with disease progression following platinum-based chemotherapy. Anti-PD-1/PD-L1 therapies may provide overall survival advantage; these are currently being evaluated in ongoing phase 3 studies. Greater objective response rates seem to be observed in PD-L1-positive patients versus PD-L1-negative patients, but methodologies in this assessment differ among clinical trials. The identification of biomarkers that provide greater insight into patients who positively respond to PD-1/PD-L1 therapies are needed. Treatment options for metastatic UC have expanded to include PD-1/PD-L1 therapies. These agents should be strongly considered as second-line therapy over single-agent chemotherapy for patients who fail or progress after platinum-based treatment.

Hemodialysis versus Peritoneal Dialysis: A Comparison of Survival Outcomes in South-East Asian Patients with End-Stage Renal Disease.

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Fan Yang

Full Text Available Studies comparing patient survival of hemodialysis (HD and peritoneal dialysis (PD have yielded conflicting results and no such study was from South-East Asia. This study aimed to compare the survival outcomes of patients with end-stage renal disease (ESRD who started dialysis with HD and PD in Singapore.Survival data for a maximum of 5 years from a single-center cohort of 871 ESRD patients starting dialysis with HD (n = 641 or PD (n = 230 from 2005-2010 was analyzed using the flexible Royston-Parmar (RP model. The model was also applied to a subsample of 225 propensity-score-matched patient pairs and subgroups defined by age, diabetes mellitus, and cardiovascular disease.After adjusting for the effect of socio-demographic and clinical characteristics, the risk of death was higher in patients initiating dialysis with PD than those initiating dialysis with HD (hazard ratio [HR]: 2.08; 95% confidence interval [CI]: 1.67-2.59; p<0.001, although there was no significant difference in mortality between the two modalities in the first 12 months of treatment. Consistently, in the matched subsample, patients starting PD had a higher risk of death than those starting HD (HR: 1.73, 95% CI: 1.30-2.28, p<0.001. Subgroup analysis showed that PD may be similar to or better than HD in survival outcomes among young patients (≤65 years old without diabetes or cardiovascular disease.ESRD patients who initiated dialysis with HD experienced better survival outcomes than those who initiated dialysis with PD in Singapore, although survival outcomes may not differ between the two dialysis modalities in young and healthier patients. These findings are potentially confounded by selection bias, as patients were not randomized to the two dialysis modalities in this cohort study.

Patient perspectives on the optimal start of renal replacement therapy.

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Henry, Shayna L; Munoz-Plaza, Corrine; Garcia Delgadillo, Jazmine; Mihara, Nichole K; Rutkowski, Mark P

2017-09-01

Healthcare systems and providers are encouraged to prepare their patients with advanced chronic kidney disease (CKD) for a planned start to renal replacement therapies (RRT). Less well understood are the socioemotional experiences surrounding the optimal start of RRT versus suboptimal haemodialysis (HD) starts with a central catheter. To characterise the experiences of patients beginning RRT. Qualitative, semi-structured phone interviews. A total of 168 patients with stage 5 CKD initiating RRT in an integrated, capitated learning healthcare system. Qualitative data from patients were collected as part of a quality improvement initiative to better understand patient-reported themes concerning preparation for RRT, patients' perceptions of their transition to dialysis and why sub-optimal starts for RRT occur within our healthcare system. Dual review and verification was used to identify key phrases and themes within and across each domain, using both deductive a priori codes generated by the interview guide and grounded discovery of emergent themes. From the patient perspective, preparing for RRT is an experience rooted in deep feelings of fear. In addition, a number of key factors contributed to patients' preparation (or failure to prepare) for RRT. While the education provided by our system was viewed as adequate overall, patients often felt that their emotional and psychosocial needs went unmet, regardless of whether or not, they experienced an optimal dialysis start. Future efforts should incorporate additional strategies for helping patients with advanced CKD achieve emotional and psychological safety while preparing for RRT. © 2017 European Dialysis and Transplant Nurses Association/European Renal Care Association.

Impaired Tumor-infiltrating T Cells in Patients with COPD Impacts Lung Cancer Response to PD-1 Blockade.

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Biton, Jérôme; Ouakrim, Hanane; Dechartres, Agnès; Alifano, Marco; Mansuet-Lupo, Audrey; Si, Han; Halpin, Rebecca; Creasy, Todd; Bantsimba-Malanda, Claudie; Arrondeau, Jennifer; Goldwasser, François; Boudou-Rouquette, Pascaline; Fournel, Ludovic; Roche, Nicolas; Burgel, Pierre-Régis; Goc, Jeremy; Devi-Marulkar, Priyanka; Germain, Claire; Dieu-Nosjean, Marie-Caroline; Cremer, Isabelle; Herbst, Ronald; Damotte, Diane

2018-03-08

Patients with chronic obstructive pulmonary disease (COPD) have a higher prevalence of lung cancer. The chronic inflammation associated with COPD probably promotes the earliest stages of carcinogenesis. However, once tumors have progressed to malignancy, the impact of COPD on the tumor immune microenvironment remains poorly defined, and its effects on immune-checkpoint blockers' efficacy are still unknown. To study the impact of COPD on the immune contexture of non-small cell lung cancer (NSCLC). We performed in depth immune profiling of lung tumors by immunohistochemistry and we determined its impact on patients' survival (n=435). Tumor-infiltrating T lymphocyte (TILs) exhaustion by flow cytometry (n=50) was also investigated. The effectiveness of an anti-PD-1 treatment (nivolumab) was evaluated in 39 advanced-stage NSCLC patients. All data were analyzed according to patients' COPD status. Measurments and Main Results: Remarkably, COPD severity is positively correlated with the coexpression of PD-1/TIM-3 by CD8 T cells. In agreement, we observed a loss of CD8 T cell-associated favorable clinical outcome in COPD+ patients. Interestingly, a negative prognostic value of PD-L1 expression by tumor cells was observed only in highly CD8 T cell-infiltrated tumors of COPD+ patients. Finally, data obtained on 39 advanced-stage NSCLC patients treated by an anti-PD-1 antibody showed longer progression free survival in COPD+ patients, and also that the association between the severity of smoking and the response to nivolumab was preferentially observed in COPD+ patients. COPD is associated with an increased sensitivity of CD8 TILs to immune escape mechanisms developed by tumors, thus suggesting a higher sensitivity to PD-1 blockade in patients with COPD.

[Increased expressions of peripheral PD-1+ lymphocytes and CD4+CD25+FOXP3+ T cells in gastric adenocarcinoma patients].

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Li, Hao; Li, Songyan; Hu, Shidong; Zou, Guijun; Hu, Zilong; Wei, Huahua; Wang, Yufeng; Du, Xiaohui

2017-01-01

Objective To detect the frequencies of peripheral programmed death-1 + (PD-1 + ) lymphocytes and CD4 + CD25 + FOXP3 + regulatory T cells in patients with gastric adenocarcinoma. Methods The study enrolled 29 patients with gastric adenocarcinoma and 29 age- and sex-matched healthy controls. Frequencies of PD-1 + lymphocytes and CD4 + CD25 + FOXP3 + regulatory T cells were detected using flow cytometry. Results The number of PD-1 + lymphocytes and CD4 + CD25 + FOXP3 + regulatory T cells in peripheral blood was higher in patients with gastric adenocarcinoma than that in the control group. Moreover, linear correlation analysis indicated a positive correlation between PD-1 expression and frequency of CD4 + CD25 + FOXP3 + regulatory T cells in peripheral blood of the patients. Conclusion Gastric adenocarcinoma patients present with increased PD-1 + lymphocytes and CD4 + CD25 + FOXP3 + regulatory T cells in the peripheral blood.

Human papilloma virus load and PD-1/PD-L1, CD8+ and FOXP3 in anal cancer patients treated with chemoradiotherapy: Rationale for immunotherapy

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Balermpas, Panagiotis; Martin, Daniel; Wieland, Ulrike; Rave-Fränk, Margret; Strebhardt, Klaus; Rödel, Claus; Fokas, Emmanouil; Rödel, Franz

2017-01-01

ABSTRACT We examined the prognostic role of immune markers programmed cell death protein-1 (PD-1) and its ligand (PD-L1), CD8+ tumor-infiltrating lymphocytes (TILs), FOXP3+ Tregs and phosphorylated Caspase-8 (T273) in patients with anal squamous cell cancer (ASCC) treated with standard chemoradiotherapy (CRT). The baseline immunohistochemical expression of immune markers was correlated with clinicopathologic characteristics, and cumulative incidence of local failure, disease-free survival (DFS) and overall survival (OS) in 150 patients, also in the context of human papilloma virus 16 (HPV16) DNA load and p16INK4a expression. After a median follow-up of 40 mo (1–205 mo), the 5-y cumulative incidence of local failure and DFS was 19.4% and 67.2%, respectively. Strong immune marker expression was significantly more common in tumors with high HPV16 viral load. In multivariant analysis, high CD8+ and PD-1+ TILs expression predicted for improved local control (p = 0.023 and p = 0.007, respectively) and DFS (p = 0.020 and p = 0.014, respectively). Also, high p16INK4a (p = 0.011) and PD-L1 (p = 0.033) expression predicted for better local control, whereas high FOXP3+ Tregs (p = 0.050) and phosphorylated Caspase-8 (p = 0.031) expression correlated with superior DFS. Female sex and high HPV16 viral load correlated with favorable outcome for all three clinical endpoints. The present data provide, for the first time, robust explanation for the favorable clinical outcome of HPV16-positive ASCC patients harboring strong immune cell infiltration. Our findings are relevant for treatment stratification with immune PD-1/PD-L1 checkpoint inhibitors to complement CRT and should be explored in a clinical trial. PMID:28405521

PD-1/PD-L blockade in gastrointestinal cancers: lessons learned and the road toward precision immunotherapy

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Junyu Long

2017-08-01

Full Text Available Abstract Gastrointestinal (GI malignancies are the most prevalent tumors worldwide, with increasing incidence and mortality. Although surgical resection, chemotherapy, radiotherapy, and molecular targeted therapy have led to significant advances in the treatment of GI cancer patients, overall survival is still low. Therefore, alternative strategies must be identified to improve patient outcomes. In the tumor microenvironment, tumor cells can escape the host immune response through the interaction of PD-1 and PD-L, which inhibits the function of T cells and tumor-infiltrating lymphocytes while increasing the function of immunosuppressive T regulatory cells. The use of an anti-PD-1/PD-L blockade enables reprogramming of the immune system to efficiently identify and kill tumor cells. In recent years, the efficacy of PD-1/PD-L blockade has been demonstrated in many tumors, and this treatment is expected to be a pan-immunotherapy for tumors. Here, we review the signaling pathway underlying the dysregulation of PD-1/PD-L in tumors, summarize the current clinical data for PD-1/PD-L inhibitors in GI malignancies, and discuss road toward precision immunotherapy in relation to PD-1/PD-L blockade. The preliminary data for PD-1/PD-L inhibitors are encouraging, and the precision immunotherapy of PD-1/PD-L inhibitors will be a viable and pivotal clinical strategy for GI cancer therapy.

PD-1/PD-L blockade in gastrointestinal cancers: lessons learned and the road toward precision immunotherapy.

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Long, Junyu; Lin, Jianzhen; Wang, Anqiang; Wu, Liangcai; Zheng, Yongchang; Yang, Xiaobo; Wan, Xueshuai; Xu, Haifeng; Chen, Shuguang; Zhao, Haitao

2017-08-03

Gastrointestinal (GI) malignancies are the most prevalent tumors worldwide, with increasing incidence and mortality. Although surgical resection, chemotherapy, radiotherapy, and molecular targeted therapy have led to significant advances in the treatment of GI cancer patients, overall survival is still low. Therefore, alternative strategies must be identified to improve patient outcomes. In the tumor microenvironment, tumor cells can escape the host immune response through the interaction of PD-1 and PD-L, which inhibits the function of T cells and tumor-infiltrating lymphocytes while increasing the function of immunosuppressive T regulatory cells. The use of an anti-PD-1/PD-L blockade enables reprogramming of the immune system to efficiently identify and kill tumor cells. In recent years, the efficacy of PD-1/PD-L blockade has been demonstrated in many tumors, and this treatment is expected to be a pan-immunotherapy for tumors. Here, we review the signaling pathway underlying the dysregulation of PD-1/PD-L in tumors, summarize the current clinical data for PD-1/PD-L inhibitors in GI malignancies, and discuss road toward precision immunotherapy in relation to PD-1/PD-L blockade. The preliminary data for PD-1/PD-L inhibitors are encouraging, and the precision immunotherapy of PD-1/PD-L inhibitors will be a viable and pivotal clinical strategy for GI cancer therapy.

Cardiovascular and noncardiovascular mortality among patients starting dialysis

DEFF Research Database (Denmark)

de Jager, Dinanda J; Grootendorst, Diana C; Jager, Kitty J

2009-01-01

CONTEXT: Cardiovascular mortality is considered the main cause of death in patients receiving dialysis and is 10 to 20 times higher in such patients than in the general population. OBJECTIVE: To evaluate if high overall mortality in patients starting dialysis is a consequence of increased cardiov...

UK Renal Registry 17th Annual Report: Chapter 10 2013 Multisite Dialysis Access Audit in England, Northern Ireland and Wales and 2012 PD One Year Follow-up: National and Centre-specific Analyses.

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Rao, Anirudh; Pitcher, David; Fluck, Richard; Kumwenda, Mick

2015-01-01

Dialysis access should be timely, minimize complications and maintain functionality. The aim of the second combined vascular and peritoneal dialysis access audit was to examine practice patterns with respect to dialysis access and highlight variations in practice between renal centres. The UK Renal Registry collected centre-specific information on incident vascular and peritoneal dialysis access outcome measures in patients from England, Wales and Northern Ireland (EW&NI), including patient demographics, dialysis access type (at start of dialysis and three months after start of dialysis), surgical assessment and access functionality. Centres who had reported data on incident PD patients for the previous 2012 audit were additionally asked to provide one year follow up data for this group. The findings were compared to the audit measures stated in Renal Association clinical practice guidelines for dialysis access. Fifty-seven centres in EW&NI (representing 92% of all centres) returned data on first access from 3,663 incident HD patients and 1,022 incident PD patients. A strong relationship was seen between surgical assessment and the likelihood of starting HD with an arteriovenous fistula (AVF). Twenty-four centres were at least two standard deviations below the 65% target for incident patients starting haemodialysis on AVF and only eight centres (14%) were within two standard deviations of the 85% target for prevalent haemodialysis patients on AVF. There was wide practice variation across the UK in provision of both HD and PD access which requires further exploration.

PD-1 Blockade in Advanced Melanoma in Patients with Hepatitis C and/or HIV

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Diwakar Davar

2015-01-01

Full Text Available On the basis of remarkable antitumor activity, programmed death receptor-1 (PD-1 inhibitors pembrolizumab and nivolumab were approved for the treatment of advanced melanoma in the second-line setting following progression on either CTLA-4 inhibitor ipilimumab or BRAF/MEK inhibitors (for BRAF mutated melanoma. Given hypothesized risk of triggering exacerbations of autoimmune diseases and/or chronic viral infections, clinical trials (including regulatory studies evaluating checkpoint blocking antibodies PD-1 and CTLA-4 have excluded patients with autoimmune diseases, chronic hepatitis B/C virus (HBV/HCV, and/or human immunodeficiency virus (HIV infections. Herein, we describe two patients with advanced melanoma and concomitant HCV/HIV infections treated with PD-1 inhibitor pembrolizumab. Patient 2 with HIV/HCV coinfection progressed after 2 doses of pembrolizumab. Patient 1 who had HCV alone was treated with pembrolizumab with initial partial response. HCV viral load remained stable after 9 cycles of pembrolizumab following which 12-week course of HCV-directed therapy was commenced, resulting in prompt reduction of HCV viral load below detectable levels. Response is ongoing and HCV viral load remains undetectable. In both patients, no significant toxicities were observed when pembrolizumab was initiated. We argue for the further investigation of checkpoint inhibition in cancer patients with underlying chronic viral infections in the context of carefully designed clinical trials.

The relationship between the PD-1/PD-L1 pathway and DNA mismatch repair in cervical cancer and its clinical significance

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Feng YC

2018-01-01

Full Text Available Yang-chun Feng,1,2 Wen-li Ji,3 Na Yue,3 Yan-chun Huang,2 Xiu-min Ma1 1Clinical Laboratory Center, The First Affiliated Hospital of Xinjiang Medical University, 2Clinical Laboratory Center, 3Clinical Pathology Center, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi, People’s Republic of China Background: According to recent clinical observations, deficient DNA mismatch repair (dMMR is capable of improving antitumor effects of the PD-1/PD-L1 pathway, suggesting that dMMR may act as a prognostic indicator of PD-1/PD-L1 antibody drugs. In this study, we examined the dMMR and PD-1/PD-L1 expression, as well as explored the correlation of dMMR status with PD-1/PD-L1 expression in cervical cancer patients, in order to optimize cervical cancer patient selection for PD-1/PD-L1 antibody drug treatment, which is helpful to avoid adverse effects and keep costs manageable. Methods: Sixty-six tissue samples from patients with squamous cell carcinoma were collected, and data of their clinical characteristics were also gathered. Based on these samples, the expression levels of MLH1, MSH2, and PD-L1 in cancer cells were tested by immunohistochemical assay (IHC. Moreover, PD-1/PD-L1 expression in tumor-invading lymphocytes (TILs was detected by IHC as well. Six single-nucleotide-repeat markers of microsatellite instability (MSI, including NR-27, MONO-27, BAT-25, NR-24, NR-21, and BAT-26, were tested by capillary electrophoresis sequencer analysis. According to expression of MLH1, MSH2 and the MSI test, all 66 cases were divided into dMMR or proficient DNA mismatch repair (pMMR groups. The comparisons of dMMR and PD-L1 in cancer cells and of PD-1/PD-L1 in TILs were conducted categorized by age, childbearing history, history of abortion, ethnicity, and cancer cell differentiation subgroup. Furthermore, PD-L1 levels in cancer cells and PD-1/PD-L1 in TILs were analyzed and compared in both dMMR and pMMR subgroups. Results: Of the patient samples, 25

Improvement of Freezing of Gait in Patients with Parkinson's Disease by Imagining Bicycling

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Akio Kikuchi

2014-03-01

Full Text Available Freezing of gait (FOG is one of the factors that reduce the quality of life in patients with Parkinson's disease (PD. Imagining bicycling before gait start provided improvement in FOG in 2 PD patients. Imagining and mimicking bicycling after the initiation of gait allowed the rhythmic gait to continue without interruption. We suggest that imagining and mimicking bicycling, which are nonexternal cues, could serve as a helpful therapeutic approach for the intractable freezing and interruption of gait of PD patients.

Overexpression of blood microRNAs 103a, 30b, and 29a in L-dopa-treated patients with PD.

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Serafin, Alice; Foco, Luisa; Zanigni, Stefano; Blankenburg, Hagen; Picard, Anne; Zanon, Alessandra; Giannini, Giulia; Pichler, Irene; Facheris, Maurizio F; Cortelli, Pietro; Pramstaller, Peter P; Hicks, Andrew A; Domingues, Francisco S; Schwienbacher, Christine

2015-02-17

The aims of the present study were to profile the expression of several candidate microRNAs (miRNAs) in blood from L-dopa-treated and drug-naive patients with Parkinson disease (PD) vs unaffected controls and to interpret the miRNA expression data in a biological context. We analyzed RNAs from peripheral blood of 36 L-dopa-treated, 10 drug-naive patients with PD and unaffected controls matched 1:1 by sex and age. We evaluated expression by reverse transcription-quantitative real-time PCR, and we analyzed data using a 2-tailed paired t test. To detect miRNA targets, several miRNA resources were combined to generate an overall score for each candidate gene using weighted rank aggregation. Significant overexpression of miR-103a-3p (p < 0.0001), miR-30b-5p (p = 0.002), and miR-29a-3p (p = 0.005) in treated patients with PD was observed, and promising candidate target genes for these were revealed by an integrated in silico analysis. We revealed 3 candidate biomarkers for PD. miRNAs 30b-5p and 29a-3p replicated a documented deregulation in PD albeit opposite to published data, while for miR-103a-3p, we demonstrated for the first time an overexpression in treated patients with PD. Expression studies in patients and/or in isolated peripheral blood mononuclear cells before and after L-dopa administration are necessary to define the involvement of L-dopa treatment in the observed overexpression. Our in silico analysis to prioritize targets of deregulated miRNAs identified candidate target genes, including genes related to neurodegeneration and PD. Despite the preliminary character of our study, the results provide a rationale for further clarifying the role of the identified miRNAs in the pathogenesis of PD and for validating their diagnostic potential. © 2015 American Academy of Neurology.

Is Peritonitis Risk Increased in Elderly Patients on Peritoneal Dialysis? Report from the French Language Peritoneal Dialysis Registry (RDPLF).

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Duquennoy, Simon; Béchade, Clémence; Verger, Christian; Ficheux, Maxence; Ryckelynck, Jean-Philippe; Lobbedez, Thierry

2016-01-01

♦ This study was carried out to examine whether or not elderly patients on peritoneal dialysis (PD) had an increased risk of peritonitis. ♦ This was a retrospective cohort study based on data from the French Language Peritoneal Dialysis Registry. We analyzed 8,396 incident patients starting PD between January 2003 and December 2010. The end of the observation period was 31 December 2012. Patients were separated into 2 age groups: up to 75 and over of 75 years old. ♦ Among 8,396 patients starting dialysis there were 3,173 patients older than 75. When using a Cox model, no association was found between age greater than 75 years and increased risk of peritonitis (hazard ratio [HR]: 0.97 [0.88 - 1.07]). Diabetes (HR: 1.14 [1.01 - 1.28] and continuous ambulatory PD (HR: 1.13 [1.04 - 1.23]) were significantly associated with a higher risk of peritoneal infection whereas nurse-assisted PD was associated with a lower risk of peritonitis (HR: 0.85 [0.78 - 0.94]. In the analysis restricted to the 3,840 self-care PD patients, there was no association between age older than 75 years and risk of peritonitis. ♦ The risk of peritonitis is not increased in elderly patients on PD in a country where assisted PD is available. Copyright © 2016 International Society for Peritoneal Dialysis.

Type of Referral, Dialysis Start and Choice of Renal Replacement Therapy Modality in an International Integrated Care Setting.

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Belén Marrón

Full Text Available Integrated Care Settings (ICS provide a holistic approach to the transition from chronic kidney disease into renal replacement therapy (RRT, offering at least both types of dialysis.To analyze which factors determine type of referral, modality provision and dialysis start on final RRT in ICS clinics.Retrospective analysis of 626 patients starting dialysis in 25 ICS clinics in Poland, Hungary and Romania during 2012. Scheduled initiation of dialysis with a permanent access was considered as planned RRT start.Modality information (80% of patients and renal education (87% were more frequent (p8.2 ml/min, >2 months between information and RRT initiation and with vascular etiology after adjustment for age and gender. "Optimal care," defined as ICS follow-up >12 months plus modality information and P start, occurred in 23%.Despite the high rate of late referrals, information and education were widely provided. However, NP start was high and related to late referral and may explain the low frequency of PD.

Prevalence of CMMSE defined cognitive impairment among peritoneal dialysis patients and its impact on peritonitis.

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Shea, Yat Fung; Lam, Man-Fai; Lee, Mi Suen Connie; Mok, Ming Yee Maggie; Lui, Sing-Leung; Yip, Terence P S; Lo, Wai Kei; Chu, Leung Wing; Chan, Tak-Mao

2016-02-01

Peritoneal dialysis (PD) exchange procedure is complex. Patients with cognitive impairment (CI) may require assistance. We studied the prevalence of CI among PD patients, its impact on PD-related peritonitis and the outcome of assisted PD. Cantonese version of Mini-Mental State examination (CMMSE) was performed in 151 patients newly started on PD. Data on patient characteristics including demographics, co-morbidities, blood parameters, medications, and number of PD-related peritonitis in the first 6 months were collected. 151 subjects were recruited. The age of studied patients was 60 ± 15.0 years, and 45% were female. The prevalence of CI was 13.9% using education-adjusted cut-off of CMMSE. Patients older than 65-year-old, female, and lower education level were independent risk factors for CI (OR 9.27 p = 0.001, OR 14.84 p = 0.005, and OR 6.10 p = 0.009, respectively). Age greater than 65-year old is an independent risk factor for PD-related peritonitis but CI was not. Patients requiring assisted PD were of older age (p peritonitis (p = 0.07). CI is common among local PD patients. Overall, CI could not be identified as an independent risk factor for PD peritonitis. There is a higher prevalence of CI among assisted PD patients but helpers may not completely eliminate the risk of PD-related peritonitis.

Type of Referral, Dialysis Start and Choice of Renal Replacement Therapy Modality in an International Integrated Care Setting.

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Marrón, Belén; Ostrowski, Janusz; Török, Marietta; Timofte, Delia; Orosz, Attila; Kosicki, Andrzej; Całka, Alicja; Moro, Daniela; Kosa, Dezider; Redl, Jenö; Qureshi, Abdul Rashid; Divino-Filho, Jose Carolino

2016-01-01

Integrated Care Settings (ICS) provide a holistic approach to the transition from chronic kidney disease into renal replacement therapy (RRT), offering at least both types of dialysis. To analyze which factors determine type of referral, modality provision and dialysis start on final RRT in ICS clinics. Retrospective analysis of 626 patients starting dialysis in 25 ICS clinics in Poland, Hungary and Romania during 2012. Scheduled initiation of dialysis with a permanent access was considered as planned RRT start. Modality information (80% of patients) and renal education (87%) were more frequent (pregression analysis, P start (p≤0.05) was associated with early referral, eGFR >8.2 ml/min, >2 months between information and RRT initiation and with vascular etiology after adjustment for age and gender. "Optimal care," defined as ICS follow-up >12 months plus modality information and P start, occurred in 23%. Despite the high rate of late referrals, information and education were widely provided. However, NP start was high and related to late referral and may explain the low frequency of PD.

Prognostic and predictive values of PD-L1 expression in patients with digestive system cancer: a meta-analysis.

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Dai, Cong; Wang, Meng; Lu, Jun; Dai, Zhiming; Lin, Shuai; Yang, Pengtao; Tian, Tian; Liu, Xinghan; Min, Weili; Dai, Zhijun

2017-01-01

PD-L1 has been reported to be expressed in diverse human malignancies. However, the prognostic value of PD-L1 in digestive system cancers remains inconclusive. Therefore, we conducted this meta-analysis to evaluate the prognostic impact of PD-L1 expression in digestive system cancers. We searched the PubMed, Embase, and the Chinese National Knowledge Infrastructure for publications concerning PD-L1 expression in digestive system cancers. Correlations of PD-L1 expression level with overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS) were analyzed. Finally, 32 studies with 7,308 patients were included. Our results show that PD-L1 expression was significantly associated with poorer OS (hazard ratio [HR] =1.44, 95% confidence interval [CI] =1.18-1.76, P digestive system cancers, especially in gastric cancer and pancreatic cancer. In addition, PD-L1 may act as a new parameter for predicting poor prognosis and a promising target for anticancer therapy in digestive system cancers.

Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study.

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Dirix, Luc Y; Takacs, Istvan; Jerusalem, Guy; Nikolinakos, Petros; Arkenau, Hendrik-Tobias; Forero-Torres, Andres; Boccia, Ralph; Lippman, Marc E; Somer, Robert; Smakal, Martin; Emens, Leisha A; Hrinczenko, Borys; Edenfield, William; Gurtler, Jayne; von Heydebreck, Anja; Grote, Hans Juergen; Chin, Kevin; Hamilton, Erika P

2018-02-01

Agents targeting programmed death receptor 1 (PD-1) or its ligand (PD-L1) have shown antitumor activity in the treatment of metastatic breast cancer (MBC). The aim of this study was to assess the activity of avelumab, a PD-L1 inhibitor, in patients with MBC. In a phase 1 trial (JAVELIN Solid Tumor; NCT01772004), patients with MBC refractory to or progressing after standard-of-care therapy received avelumab intravenously 10 mg/kg every 2 weeks. Tumors were assessed every 6 weeks by RECIST v1.1. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Membrane PD-L1 expression was assessed by immunohistochemistry (Dako PD-L1 IHC 73-10 pharmDx). A total of 168 patients with MBC, including 58 patients with triple-negative breast cancer (TNBC), were treated with avelumab for 2-50 weeks and followed for 6-15 months. Patients were heavily pretreated with a median of three prior therapies for metastatic or locally advanced disease. Grade ≥ 3 treatment-related AEs occurred in 13.7% of patients, including two treatment-related deaths. The confirmed objective response rate (ORR) was 3.0% overall (one complete response and four partial responses) and 5.2% in patients with TNBC. A trend toward a higher ORR was seen in patients with PD-L1+ versus PD-L1- tumor-associated immune cells in the overall population (16.7% vs. 1.6%) and in the TNBC subgroup (22.2% vs. 2.6%). Avelumab showed an acceptable safety profile and clinical activity in a subset of patients with MBC. PD-L1 expression in tumor-associated immune cells may be associated with a higher probability of clinical response to avelumab in MBC.

Sleep disturbances in drug naïve Parkinson′s disease (PD patients and effect of levodopa on sleep

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Teresa Ferreira

2014-01-01

Full Text Available Context: Parkinson′s disease (PD is associated with sleep disturbances, attributed to the neurodegenerative process and therapeutic drugs. Studies have found levodopa to increase wakefulness in some patients while increasing sleepiness in others. Aims: To confirm sleep disturbances in drug naïve PD patients and understand the impact of levodopa on their sleep. Materials and Methods: Twenty-three drug naοve PD patients and 31 age-gender matched controls were compared using the Parkinson′s Disease Sleep Scale (PDSS and Epworth Sleepiness Scale (ESS. A polysomnogram objectively compared sleep quality. Of the 23 patients, the 12 initiated on levodopa were reassessed subjectively and through polysomnography after 2 months of therapy. Statistical Analysis: Data was expressed as mean ± standard deviation, median, and range. Continuous variables were analyzed by Student′s T test for normally distributed data and Mann-Whitney U test for skewed data. Discrete variables were compared by Chi Square tests (Pearson Chi square Test or Fisher′s Exact Test. Wilcoxon signed ranks test was applied in the analysis of paired data pre- and post-levodopa. A P value < 0.05 was considered as statistically significant. Statistical analysis of the data was done using the Statistical Package for the Social Sciences (SPSS version 12. Results: Drug naïve PD patients had lower PDSS scores than controls. The sleep architecture changes observed on polysomnogram were reduced NREM Stage III and REM sleep and increased sleep latency and wake after sleep onset time. Following levodopa, improved sleep efficiency with reduced sleep latency and wake after sleep onset time was noted, coupled with improved PDSS scores. However, NREM Stage III and REM sleep duration did not increase. Discussion: PD patients take longer to fall asleep and have difficulty in sleep maintenance. Sleep maintenance is affected by nocturia, REM behavioral disorder, nocturnal cramps, akinesia, and

From DTCA-PD to patient information to health information: the complex politics and semantics of EU health policy.

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Brooks, Eleanor; Geyer, Robert

2012-12-01

Between 2001 and 2011 the pharmaceutical industry, supported by DG Enterprise, was engaged in an ongoing campaign to repeal/amend the European Union (EU) ban on direct-to-consumer advertising of prescription drugs (DTCA-PD). As it became increasingly clear that the ban would not be repealed, DTCA-PD supporters tried to shift the debate away from advertising and towards the provision of 'patient information' and the rights of patients to access such information. Meanwhile, a variety of national and European health organizations, supported by DG SANCO, sought to maintain the ban and oppose the industry-supported 'patient information' campaign. Instead, they promoted a concept of 'health information' that included all aspects of citizens' health, not just pharmaceuticals. This article aims to analyse the transition from DTCA-PD to patient information to health information and examine its implications for EU health policy as a complex policy space. The article examines the emergence and development of EU health policy and the evolution of the DTCA-PD debate through the lens of complexity theory. It analyses the nature of the semantic, political and policy transition and asks why it occurred, what it tells us about EU health policy and future EU health legislation and how it may be understood from a complexity perspective. The article concludes that the complexity framework is ideally suited for the field of public health and, in particular, the DTCA-PD debate. Having successfully shifted the policy-focus of the debate to patients' rights and health information, opponents of the legislation are likely to face their next battle in the realm of cyberspace, where regulatory issues change the nature of advertising. © 2012 Blackwell Publishing Ltd.

Malignant mesothelioma effusions are infiltrated by CD3+ T cells highly expressing PD-L1 and the PD-L1+ tumor cells within these effusions are susceptible to ADCC by the anti-PD-L1 antibody avelumab

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Khanna, Swati; Thomas, Anish; Abate-Daga, Daniel; Zhang, Jingli; Morrow, Betsy; Steinberg, Seth M.; Orlandi, Augusto; Ferroni, Patrizia; Schlom, Jeffrey; Guadagni, Fiorella; Hassan, Raffit

2016-01-01

INTRODUCTION The functional aspects of programmed death 1 (PD-1) and PD ligand 1 (PD-L1) immune checkpoints in malignant mesothelioma have not been studied. METHODS Tumor samples from 65 patients with mesothelioma were evaluated for PD-L1 expression by immunohistochemistry and its prognostic significance. Malignant effusions from patients with pleural and peritoneal mesothelioma were evaluated for PD-1+ and PD-L1+ infiltrating lymphocytes and their role in inducing tumor cell PD-L1 expression. Antibody dependent cellular cytotoxicity (ADCC) of avelumab, a fully humanized IgG1 anti PD-L1 antibody towards primary mesothelioma cell lines was evaluated in presence of autologous and allogeneic NK cells. RESULTS Of 65 pleural and peritoneal mesothelioma tumors examined, 41 (63%) were PD-L1 positive, which was associated with slightly inferior overall survival compared to patients with PD-L1 negative tumors (median 23.0 vs. 33.3 months; p=0.35). The frequency of PD-L1 expression was similar in pleural and peritoneal mesothelioma patients with 62% and 64% of samples positive, respectively. Of nine mesothelioma effusion samples evaluated, the fraction of cells expressing PD-L1 ranged from 12 to 83%. Of 7 patients with paired malignant effusion and peripheral blood mononuclear cells (PBMC) samples, PD-L1 expression was significantly higher on CD3+ T cells present in malignant effusions as compared with PBMC (p=0.016). In addition, CD14+PD-1+ cells were elevated in malignant effusions compared with PBMC (p=0.031). The lymphocytes present in malignant effusions recognized autologous tumor cells and induced IFN-γ-mediated PD-L1 expression on the tumor cell surface. Of the three primary mesothelioma cell lines tested, two were susceptible to avelumab mediated ADCC in presence of autologous NK cells. CONCLUSION The majority of pleural as well as peritoneal mesothelioma express PD-L1. Malignant effusions in this disease are characterized by presence of tumor cells and CD3+ T

Timing of start of dialysis in diabetes mellitus patients: a systematic literature review.

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Nacak, Hakan; Bolignano, Davide; Van Diepen, Merel; Dekker, Friedo; Van Biesen, Wim

2016-02-01

Diabetes mellitus is a frequent cause of the need for renal replacement therapy (RRT). Historically, RRT was started earlier in patients with diabetes, in an attempt to prevent complications of uraemia and diabetes. We did a systematic review to find support for this earlier start of dialysis in patients with versus without diabetes. The MEDLINE, EMBASE and CENTRAL databases were searched for articles about the timing of dialysis initiation in (subgroups of) patients with diabetes and CKD Stage 5. A total of 340 papers were screened and 11 papers were selected to be reviewed. Only three studies showed data of at least one subgroup of patients with diabetes. Two observational studies concluded that start of dialysis with a higher estimated glomerular filtration rate (eGFR) is beneficial with regard to survival, one did not find a difference and six observational studies concluded that start of dialysis with a lower eGFR is associated with better survival in patients with diabetes. The effect of timing of initiation of dialysis did not differ between patients with versus without diabetes. Lastly, one randomized controlled trial (two papers) reported that there was no difference in survival between start at higher versus lower eGFR overall and a P-value for the interaction with diabetes of P = 0.63, indicating no difference between patients with versus without diabetes with regard to the timing of start of dialysis and subsequent mortality on dialysis. There is no difference between early (eGFR) and late (lower eGFR) start of RRT with regard to mortality in patients with versus without diabetes. RRT should thus be initiated based on the same criteria in all patients, irrespective of the presence or absence of diabetes. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Malignant Mesothelioma Effusions Are Infiltrated by CD3+ T Cells Highly Expressing PD-L1 and the PD-L1+ Tumor Cells within These Effusions Are Susceptible to ADCC by the Anti-PD-L1 Antibody Avelumab.

Science.gov (United States)

Khanna, Swati; Thomas, Anish; Abate-Daga, Daniel; Zhang, Jingli; Morrow, Betsy; Steinberg, Seth M; Orlandi, Augusto; Ferroni, Patrizia; Schlom, Jeffrey; Guadagni, Fiorella; Hassan, Raffit

2016-11-01

The functional aspects of programmed death 1 (PD-1) and PD ligand 1 (PD-L1) immune checkpoints in malignant mesothelioma have not been studied. Tumor samples from 65 patients with mesothelioma were evaluated for PD-L1 expression by immunohistochemistry, and its prognostic significance was examined. Malignant effusions from patients with pleural and peritoneal mesothelioma were evaluated for PD-1-positive and PD-L1-positive infiltrating lymphocytes and their role in inducing PD-L1 expression in tumor cells. Antibody-dependent cellular cytotoxicity (ADCC) of avelumab, a fully humanized immunoglobulin G1 anti PD-L1 antibody against primary mesothelioma cell lines, was evaluated in presence of autologous and allogeneic natural killer cells. Of 65 pleural and peritoneal mesothelioma tumors examined, 41 (63%) were PD-L1-positive, which was associated with slightly inferior overall survival compared to patients with PD-L1-negative tumors (median 23.0 versus 33.3 months, p = 0.35). The frequency of PD-L1 expression was similar in patients with pleural and peritoneal mesothelioma, with 62% and 64% of samples testing positive, respectively. In nine mesothelioma effusion samples evaluated, the fraction of cells expressing PD-L1 ranged from 12% to 83%. In seven patients with paired malignant effusion and peripheral blood mononuclear cell (PBMC) samples, PD-L1 expression was significantly higher on CD3-positive T cells present in malignant effusions as compared with PBMCs (p = 0.016). In addition, the numbers of CD14-positive PD-1-positive cells were increased in malignant effusions compared with PBMCs (p = 0.031). The lymphocytes present in malignant effusions recognized autologous tumor cells and induced interferon-γ-mediated PD-L1 expression on the tumor cell surface. Of the three primary mesothelioma cell lines tested, two were susceptible to avelumab-mediated ADCC in the presence of autologous natural killer cells. Most pleural as well as peritoneal mesotheliomas

Young women with PD: a group work experience.

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Posen, J; Moore, O; Tassa, D S; Ginzburg, K; Drory, M; Giladi, N

2000-01-01

Parkinson's Disease (PD) prior to the age of 40 affects between 5-10% of the PD population. The psychosocial changes that patients with early PD encounter, may be more devastating and disabling than the actual motor disability. The paper describes a unique experience in groupwork with young female PD patients treated in the Movement Disorders Unit of the Tel Aviv Sourasky Medical Center. The paper focuses on the special issues which characterized this group's experience: stigma, body and sexual image, and personality traits.

Prognosis of bedridden patients with end-stage renal failure after starting hemodialysis.

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Sugaya, Kimio; Hokama, Asanori; Hayashi, Eiri; Naka, Hidekatsu; Oda, Masami; Nishijima, Saori; Miyazato, Minoru; Hokama, Sanehiro; Ogawa, Yoshihide

2007-06-01

The mean age of starting hemodialysis (HD) in patients with end-stage renal failure is gradually increasing in Japan. It is not uncommon for HD to be commenced in bedridden elderly patients who cannot give informed consent, because of brain damage. However, we have not been able to provide useful advice to their families because there was no relevant information available about the prognosis of bedridden patients on HD. Therefore, we examined the prognosis of bedridden HD patients. Two hundred and nineteen patients who received HD were enrolled. These subjects were divided into five groups; (aged or=80 years at the commencement of HD), and we compared the overall prognosis between bedridden and nonbedridden patients, as well as that for each age group. There were 76 bedridden patients among the 219 HD patients, and the main cause of their bedridden state before starting HD was cerebrovascular disease. The 50% survival time after the start of HD was 120 months for the nonbedridden patients versus 56 months for bedridden patients. However, the mean (+/-SD) age of the bedridden patients was higher than that of nonbedridden patients (70 +/- 13 versus 64 +/- 14 years). In patients under age 50 years at the start of dialysis, the survival rate was lower in the bedridden than in the nonbedridden patients, but there were no differences between survival rates for bedridden and nonbedridden patients in the other four age groups. The prognosis of HD patients is poor compared with the general life expectancy of the Japanese population, but whether these patients are bedridden or not has little influence on their survival.

Relative survival of peritoneal dialysis and haemodialysis patients

DEFF Research Database (Denmark)

Heaf, James G; Wehberg, Sonja

2014-01-01

INTRODUCTION: Epidemiological studies consistently show an initial survival advantage for PD patients compared to HD. It has recently been suggested that this is due to the fact that many HD patients are referred late, and start dialysis on an acute, in-patient basis. The present study was perfor...

Factors Associated with Unplanned Dialysis Starts in Patients followed by Nephrologists: A Retropective Cohort Study.

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Pierre Antoine Brown

Full Text Available The number of patients starting dialysis is increasing world wide. Unplanned dialysis starts (patients urgently starting dialysis in hospital is associated with increased costs and high morbidity and mortality. Risk factors for starting dialysis urgently in hospital have not been well studied. The primary objective of this study was to identify risk factors for unplanned dialysis starts in patients followed in a multidisciplinary chronic kidney disease (CKD clinic. We performed a retrospective cohort study of 649 advanced CKD patients followed in a multidisciplinary CKD clinic at a tertiary care hospital from January 01, 2010 to April 30, 2013. Patients were classified as unplanned start (in hospital or elective start. Multivariable logistic regression was used to identify variables associated with unplanned dialysis initiation. 184 patients (28.4% initiated dialysis, of which 76 patients (41.3% initiated dialysis in an unplanned fashion and 108 (58.7% starting electively. Unplanned start patients were more likely to have diabetes (68.4% versus 51.9%; p = 0.04, CAD (42.1% versus 24.1%; p = 0.02, congestive heart failure (36.8% versus 17.6%; p = 0.01, and were less likely to receive modality education (64.5% vs 89.8%; p < 0.01 or be assessed by a surgeon for access creation (40.8% vesrus 78.7% p < 0.01. On multivariable analysis, higher body mass index (OR 1.07, 95% CI 1.02, 1.13, and a history of congestive heart failure (OR 2.41, 95% CI 1.09, 5.41 were independently associated with an unplanned start. Unplanned dialysis initiation is common among advanced CKD patients, even if they are followed in a multidisciplinary chronic kidney disease clinic. Timely education and access creation in patients at risk may lead to lower costs and less morbidity and mortality.

`Pd20Sn13' revisited: crystal structure of Pd6.69Sn4.31

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Wilhelm Klein

2015-07-01

Full Text Available The crystal structure of the title compound was previously reported with composition `Pd20Sn13' [Sarah et al. (1981. Z. Metallkd, 72, 517–520]. For the original structure model, as determined from powder X-ray data, atomic coordinates from the isostructural compound Ni13Ga3Ge6 were transferred. The present structure determination, resulting in a composition Pd6.69Sn4.31, is based on single crystal X-ray data and includes anisotropic displacement parameters for all atoms as well as standard uncertainties for the atomic coordinates, leading to higher precision and accuracy for the structure model. Single crystals of the title compound were obtained via a solid-state reaction route, starting from the elements. The crystal structure can be derived from the AlB2 type of structure after removing one eighth of the atoms at the boron positions and shifting adjacent atoms in the same layer in the direction of the voids. One atomic site is partially occupied by both elements with a Pd:Sn ratio of 0.38 (3:0.62 (3. One Sn and three Pd atoms are located on special positions with site symmetry 2. (Wyckoff letter 3a and 3b.

Effects of nutritional supplementation for HIV patients starting antiretroviral treatment

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Olsen, Mette Frahm; Abdissa, Alemseged; Kæstel, Pernille

2014-01-01

Objectives: To determine the effects of lipid based nutritional supplements with either whey or soy protein in patients with HIV during the first three months of antiretroviral treatment (ART) and to explore effects of timing by comparing supplementation at the start of ART and after three months....../µL (−2 to 53 cells/µL) were CD4. Effects of the soy containing supplement on immune recovery were not significant. The effects of the two supplements, however, were not significantly different in direct comparison. Exploratory analysis showed that relatively more lean body mass was gained by patients...... with undetectable viral load at three months. Patients receiving delayed supplementation had higher weight gain but lower gains in functional outcomes. Conclusions: Lipid based nutritional supplements improved gain of weight, lean body mass, and grip strength in patients with HIV starting ART. Supplements...

Dialysis access, infections, and hospitalisations in unplanned dialysis start patients

DEFF Research Database (Denmark)

Machowska, Anna; Alscher, Mark Dominik; Vanga, Satyanarayana Reddy

2017-01-01

Introduction: Unplanned dialysis start (UPS) associates with worse clinical outcomes, higher utilisation of healthcare resources, lower chances to select dialysis modality and UPS patients typically commenced in-centre haemodialysis (HD) with central venous catheter (CVC). We evaluated patient ou...

Outcome of Early Initiation of Peritoneal Dialysis in Patients with End-Stage Renal Failure

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Oh, Kook-Hwan; Hwang, Young-Hwan; Cho, Jung-Hwa; Kim, Mira; Ju, Kyung Don; Joo, Kwon Wook; Kim, Dong Ki; Kim, Yon Su; Ahn, Curie

2012-01-01

Recent studies reported that early initiation of hemodialysis may increase mortality. However, studies that assessed the influence of early initiation of peritoneal dialysis (PD) yielded controversial results. In the present study, we evaluated the prognosis of early initiation of PD on the various outcomes of end stage renal failure patients by using propensity-score matching methods. Incident PD patients (n = 491) who started PD at SNU Hospital were enrolled. The patients were divided into 'early starters (n = 244)' and 'late starters (n = 247)' on the basis of the estimated glomerular filtration rate (eGFR) at the start of dialysis. The calculated propensity-score was used for one-to-one matching. After propensity-score-based matching (n = 136, for each group), no significant differences were observed in terms of all-cause mortality (P = 0.17), technique failure (P = 0.62), cardiovascular event (P = 0.96) and composite event (P = 0.86) between the early and late starters. Stratification analysis in the propensity-score quartiles (n = 491) exhibited no trend toward better or poorer survival in terms of all-cause mortality. In conclusion, early commencement of PD does not reduce the mortality risk and other outcomes. Although the recent guidelines suggest that initiation of dialysis at higher eGFR, physicians should not determine the time to initiate PD therapy simply rely on the eGFR alone. PMID:22323864

PD-L1 Expression of Tumor Cells, Macrophages, and Immune Cells in Non-Small Cell Lung Cancer Patients with Malignant Pleural Effusion.

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Tseng, Yen-Han; Ho, Hsiang-Ling; Lai, Chiung-Ru; Luo, Yung-Hung; Tseng, Yen-Chiang; Whang-Peng, Jacqueline; Lin, Yi-Hsuan; Chou, Teh-Ying; Chen, Yuh-Min

2018-03-01

Whether immunohistochemical staining of programmed death ligand 1 (PD-L1) on cells of pleural effusion could be used to predict response to immunotherapy treatment has not been reported. We retrospectively enrolled patients who had undergone malignant pleural effusion drainage and had effusion cell block specimens from 2014 to 2016. Immunohistochemical staining for PD-L1 was performed with tumor cells, immune cells, and macrophages of all cell block specimens. Immunoactivity was scored as 0 for absence of staining and 1+ for faint, 2+ for moderate, and 3+ for intense membranous staining. Patients' clinicopathological characteristics were also collected. PD-L1 expression of pleural effusion tumor cells was associated with the PD-L1 expression of macrophages (p = 0.003) and immune cells (p pleural effusion tumor cells and macrophages. The low intensity of PD-L1 expression in immune cells is associated with the poor survival of patients with lung cancer with malignant pleural effusion. Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease.

Science.gov (United States)

2004-04-01

Treatment with rasagiline mesylate, an irreversible monoamine oxidase type B inhibitor, improves symptoms of early Parkinson disease (PD). Preclinical studies suggest that this compound may also modify the progression of PD. To compare the effects of early and later initiation of rasagiline on progression of disability in patients with PD. Double-blind, parallel-group, randomized, delayed-start clinical trial. Four hundred four subjects with early PD, not requiring dopaminergic therapy, enrolled at 32 sites in the United States and Canada. Subjects were randomized to receive rasagiline, 1 or 2 mg/d, for 1 year or placebo for 6 months followed by rasagiline, 2 mg/d, for 6 months. Change in total Unified Parkinson's Disease Rating Scale score from baseline to 12 months. Three hundred seventy-one subjects were included in the 1-year efficacy analysis. Subjects treated with rasagiline, 2 mg/d, for 1 year had a 2.29-unit smaller increase in mean adjusted total Unified Parkinson's Disease Rating Scale score compared with subjects treated with placebo for 6 months followed by rasagiline, 2 mg/d, for 6 months (P =.01). The mean adjusted difference between the placebo/rasagiline, 2 mg/d, group and those receiving rasagiline, 1 mg/d, for 1 year was -1.82 unit on the Unified Parkinson's Disease Rating Scale score (P =.05). Subjects treated with rasagiline, 2 and 1 mg/d, for 12 months showed less functional decline than subjects whose treatment was delayed for 6 months.

PD-1 expression on peripheral CD8+ TEM/TEMRA subsets closely correlated with HCV viral load in chronic hepatitis C patients

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Zhang Weidong

2010-11-01

Full Text Available Abstract Background Tight correlation between host circulating CD8+ T cell-mediated immune response and control of viral replication is classical characteristic of long-term HCV infection. CD8+ T cell maturation/activation markers are expected to be associated with viral replication and disease progression in chronic HCV infection. The aim of the present study was to explore novel markers on CD8+ T cells with ability to evaluate HCV viral replication and disease progression. Methods PBMCs were isolated from 37 chronic HCV-infected patients and 17 healthy controls. Distributed pattern of CD8+ T cells subsets and expression of PD-1, CD38, HLA-DR and CD127 were analyzed by flow cytometry. The correlation between expression of surface markers and HCV viral load or ALT was studied. Results Declined naïve and increased TEMRA CD8+ T subsets were found in HCV-infected individuals compared with healthy controls. Percentage and MFI of PD-1, CD38 and HLA-DR on all CD8+ T cell subsets were higher in HCV-infected patients than healthy controls. In contrast, CD127 expression on CD8+ TCM showed an opposite trend as PD-1, CD38 and HLA-DR did. In chronic HCV infection, MFI of PD-1 on CD8+ TEM (p Conclusion PD-1 level on peripheral CD8+ TEM/TEMRA was highly correlated with HCV viral load in chronic HCV-infected patients, which made PD-1 a novel indicator to evaluate HCV replication and disease progression in chronic hepatitis C patients.

Psychogenic and neural visual-cue response in PD dopamine dysregulation syndrome.

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Loane, Clare; Wu, Kit; O'Sullivan, Sean S; Lawrence, Andrew D; Woodhead, Zoe; Lees, Andrew J; Piccini, Paola; Politis, Marios

2015-11-01

Dopamine dysregulation syndrome (DDS) in Parkinson's disease (PD) patients refers to the compulsive use of dopaminergic replacement therapy and has serious psycho-social consequences. Mechanisms underlying DDS are not clear although has been linked to dysfunctional brain reward networks. With fMRI, we investigate behavioral and neural response to drug-cues in six PD DDS patients and 12 PD control patients in both the ON and OFF medication state. Behavioral measures of liking, wanting and subjectively 'feeling ON medication' were also collected. Behaviorally, PD DDS patients feel less ON and want their drugs more at baseline compared to PD controls. Following drug-cue exposure, PD DDS patients feel significantly more ON medication, which correlates with significant increases in reward related regions. The results demonstrate that exposure to drug-cues increases the subjective feeling of being 'ON' medication which corresponds to dysfunctional activation in reward related regions in PD DDS patients. These findings should be extended in future studies. Visual stimuli being sufficient to elicit behavioral response through neuroadaptations could have direct implications to the management of addictive behavior. Copyright © 2015 Elsevier Ltd. All rights reserved.

SPECT image analysis using SPM in patients with parkinson's disease and essential tremor : rCBF correlates of immediate surgical outcome following unilateral thalamo-pallidotomy in PD

International Nuclear Information System (INIS)

Kim, Jong Ho; Kim, Nam Bum; Lee, Uhn

2002-01-01

This study investigated alterations in regional cerebral blood flow (rCBF) in patients with PD and essential tremor (ET) using statistical parametric mapping (SPM) and rCBF correlates of immediate surgical outcome following unilateral thalamo-pallidotomy in patients with PD. Noninvasive rCBF measurements using 99m Tc-ethyl cysteinate dimer (ECD) SPECT were performed on 10 PD (60.5±8.7), 10 ET (55.5±17.7) patients and 10 healthy controls (56.2±12.0). Eight patients with PD following unilateral right thalamo-pallidotomy and five following unilateral left thalamo-pallidotomy underwent pre- and post-operative rCBF SPECT both one week before and after surgery. Acquisition were acquired within 30 min, 360 rotations with 90 projections were collected in a 128 x 128 matrix using a dual head gamma camera (Siemens, Multispect II). Data were analyzed using SPM 99. We found definite bilateral decreased rCBF in perfrontal cortex, bilateral increased rCBF in dentate nucleus of superomedial cerebellum in patients with PD and bilateral increased rCBF in lateral aspect of cerebellum in ET, respectively, compared with healthy controls. In addition, rCBF suspiciousely increased bilaterally in left dorsolateral frontal cortex in ET with equivocal clinical significance. Following 8 right and 5 left unilateral thalamo-pallidotomy in PD patients, immediate postop declines in ipsilateral fronto-temporal and temporal cortical perfusion, respectively, as well as pallidothalamic hypoperfusion were significant. SPM analysis showed that significantly decreased rCBF in bilateral perfrontal cortex and increased rCBF in dentate uncleus of superomedial cerebellum in PD and increased bilateral rCBF in lateral aspect of cerebellum in ET. Unilateral thalamo-pallidotomy in PD patients reduced the immediate post-operative rCBF declines in ipsilateral temporal (frontal) cortex as well as pallidothalamic hypoperfusion which is suggestive of thalamo-cortical diaschisis

PD-1 Checkpoint Inhibitor Associated Autoimmune Encephalitis

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Stephanie Schneider

2017-05-01

Full Text Available Objective: To report first-hand narrative experience of autoimmune encephalitis and to briefly review currently available evidence of autoimmune encephalitis in cancer patients treated with immune checkpoint inhibitors. Setting: A case study is presented on the management of a patient who developed autoimmune encephalitis during nivolumab monotherapy occurring after 28 weeks on anti-PD-1 monotherapy (nivolumab 3 mg/kg every 2 weeks for non-small cell lung cancer. Results: No substantial improvement was observed by antiepileptic treatment. After administration of 80 mg methylprednisolone, neurologic symptoms disappeared within 24 h and the patient fully recovered. Conclusions: Immune checkpoint inhibitor treatment can lead to autoimmune encephalitis. Clinical trial data indicate a frequency of autoimmune encephalitis of ≥0.1 to <1% with a higher probability during combined or sequential anti-CTLA-4/anti-PD-1 therapy than during anti-PD-1 or anti-PD-L1 monotherapy. Further collection of evidence and translational research is warranted.

Impulse control disorder in PD: A lateralized monoaminergic frontostriatal disconnection syndrome?

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Premi, E; Pilotto, A; Garibotto, V; Bigni, B; Turrone, R; Alberici, A; Cottini, E; Poli, L; Bianchi, M; Formenti, A; Cosseddu, M; Gazzina, S; Magoni, M; Bertoli, M; Paghera, B; Borroni, B; Padovani, A

2016-09-01

Impulse Control Disorder symptoms (ICD) in Parkinson's disease (PD) has been recently associated by magnetic Resonance imaging with impaired cortico-striatal connectivity, especially between left putamen and frontal associative areas. 84 patients entered the study (21 PD-ICD+ and 64 PD-ICD-) and underwent DATSCAN imaging. The striatal tracer uptake was evaluated using BRASS software (Hermes, Sweden). The whole-brain analysis was performed with Statistical Parametric Mapping (SPM). PD-ICD+ showed a significant reduction of left putaminal and left inferior frontal gyrus tracer uptake compared to PD-ICD-. Functional covariance analysis using left putamen as the seed point showed that, in contrast to ICD-patients, ICD+ patients had no functional covariance with contralateral basal ganglia and ipsilateral cingulate cortex, as index of an impaired inter- and intra-hemispheric dopamine binding in PD-ICD+. the results support and expand the concept of a functional disconnection syndrome linked to ICD symptoms in PD patients through an asymmetric molecular frontostriatal network breakdown with left basal ganglia as central hub. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effective anti-PD-1 therapy in a SUFU-mutated patient with Gorlin-Goltz syndrome.

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Moreira, A; Kirchberger, M C; Toussaint, F; Erdmann, M; Schuler, G; Heinzerling, L

2018-03-30

We present a case of a 77-year-old male patient with more than 50 basal cell carcinomas on the head and upper trunk. The patient did not respond to several lines of treatment, including surgery, imiquimod, retinoids, itraconazole and therapy with the hedgehog inhibitor vismodegib. The patient responded well to an off-label therapy with the anti-PD-1 antibody pembrolizumab after 4 infusions. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Evaluation of continuous ambulatory peritoneal dialysis fluid C-reactive protein in patients with peritonitis.

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Ramanathan, Kumaresan; Padmanabhan, Giri; Vijayaraghavan, Bhooma

2016-05-01

Severe peritonitis causing death is one of the most devastating complications of peritoneal dialysis (PD). Since the predictive value of C-reactive protein (CRP) in PD fluid has not been assessed, the objective of the present study is to evaluate its predictive value and clinical correlation in patients on PD with peritonitis. One hundred and twenty patients on continuous ambulatory PD (CAPD) were enrolled and their serum and fluid CRP (Fl. CRP) were evaluated at the start of CAPD. All patients who developed peritonitis were further evaluated for serum and fluid CRP. The patients were categorized into four groups, namely: normal patients (control group), patients with peritonitis, patients with peritonitis leading to catheter removal, and death due to peritonitis. Sixty-five patients developed peritonitis of whom, catheter removal was performed in eight patients. Five patients died due to peritonitis-related complications. Fl. CRP showed a significant difference among the three groups, unlike S. CRP. Estimation of CRP in the peritoneal fluid may be a useful marker to monitor the onset of peritonitis.

Tenosynovitis in rheumatoid arthritis patients on biologic treatment

DEFF Research Database (Denmark)

Hammer, Hilde Berner; Kvien, Tore K; Terslev, Lene

2017-01-01

, clinical and laboratory assessments were performed when starting biologic DMARD (bDMARD) and after 1, 2, 3, 6 and 12 months including bilateral grey-scale (GS) and power Doppler (PD) semi-quantitatively (0-3) scoring of ECU and TP tendons and 18 joints. Changes from baseline to follow-up were explored...... by Wilcoxon signed rank test, associations by Spearman's rank correlations and responses to treatment by Standardised Response Means (SRMs). RESULTS: 157 patients (mean age/disease duration 52.4/10.2 years) were included. ECU/TP tenosynovitis was frequent (baseline GS/PD pathology in 76/50% of patients...

Prevalence of Cognitive Impairment Among Peritoneal Dialysis Patients, Impact on Peritonitis and Role of Assisted Dialysis.

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Shea, Yat Fung; Lam, Man Fai; Lee, Mi Suen Connie; Mok, Ming Yee Maggie; Lui, Sing-Leung; Yip, Terence P S; Lo, Wai Kei; Chu, Leung Wing; Chan, Tak-Mao

2016-01-01

♦ Chronic renal failure and aging are suggested as risk factors for cognitive impairment (CI). We studied the prevalence of CI among peritoneal dialysis (PD) patients using Montreal Cognitive Assessment (MoCA), its impact on PD-related peritonitis in the first year, and the potential role of assisted PD. ♦ One hundred fourteen patients were newly started on PD between February 2011 and July 2013. Montreal Cognitive Assessment was performed in the absence of acute illness. Data on patient characteristics including demographics, comorbidities, blood parameters, dialysis adequacy, presence of helpers, medications, and the number PD-related infections were collected. ♦ The age of studied patients was 59±15.0 years, and 47% were female. The prevalence of CI was 28.9%. Patients older than 65 years old (odds ratio [OR] 4.88, confidence interval [CI] 1.79 - 13.28 p = 0.002) and with an education of primary level or below (OR 4.08, CI 1.30 - 12.81, p = 0.016) were independent risk factors for CI in multivariate analysis. Patients with PD-related peritonitis were significantly older (p peritonitis among self-care PD patients (OR 2.20, CI 0.65 - 7.44, p = 0.20). When we compared patients with MoCA-defined CI receiving self-care and assisted PD, there were no statistically significant differences between the 2 groups in terms of age, MoCA scores, or comorbidities. There were also no statistically significant differences in 1-year outcome of PD-related peritonitis rates or exit-site infections. ♦ Cognitive impairment is common among local PD patients. Even with CI, peritonitis rate in self-care PD with adequate training is similar to CI patients on assisted PD. Copyright © 2016 International Society for Peritoneal Dialysis.

The role of infection models and PK/PD modelling for optimising care of critically ill patients with severe infections

NARCIS (Netherlands)

Tangden, T.; Martin, V.; Felton, T.W.; Nielsen, E.I.; Marchand, S.; Bruggemann, R.J.M.; Bulitta, J.B.; Bassetti, M.; Theuretzbacher, U.; Tsuji, B.T.; Wareham, D.W.; Friberg, L.E.; Waele, J.J. De; Tam, V.H.; Roberts, J.A.

2017-01-01

Critically ill patients with severe infections are at high risk of suboptimal antimicrobial dosing. The pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in these patients differ significantly from the patient groups from whose data the conventional dosing regimens were developed.

Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study

OpenAIRE

Dirix, Luc Y.; Takacs, Istvan; Jerusalem, Guy; Nikolinakos, Petros; Arkenau, Hendrik-Tobias; Forero-Torres, Andres; Boccia, Ralph; Lippman, Marc E.; Somer, Robert; Smakal, Martin; Emens, Leisha A.; Hrinczenko, Borys; Edenfield, William; Gurtler, Jayne; von Heydebreck, Anja

2017-01-01

Purpose Agents targeting programmed death receptor 1 (PD-1) or its ligand (PD-L1) have shown antitumor activity in the treatment of metastatic breast cancer (MBC). The aim of this study was to assess the activity of avelumab, a PD-L1 inhibitor, in patients with MBC. Methods In a phase 1 trial (JAVELIN Solid Tumor; NCT01772004), patients with MBC refractory to or progressing after standard-of-care therapy received avelumab intravenously 10 mg/kg every 2 weeks. Tumors were assessed every 6 week...

Changes in the gastric potential difference during chemotherapy in patients with metastatic breast cancer

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Fabrin, B; Højgaard, L; Mouridsen, H T

1991-01-01

Nausea and vomiting are frequent side-effects of intravenous cancer chemotherapy. How these complications were related to the gastric mucosal function was investigated by measuring the gastric mucosal potential difference (PD). Eight patients with metastatic breast cancer receiving chemotherapy...... were investigated. The liquid junction-corrected gastric PD and pH were measured with a newly developed microelectrode. The measurements started half an hour before chemotherapy and continued for 4-5 hours. Nausea, vomiting, psychological stress and sleeping episodes were registered. The initial PD...

Fusion of 110Pd with 110Pd

International Nuclear Information System (INIS)

Morawek, W.

1991-07-01

In the framework of this thesis the excitation functions of the systems 110 Pd + 110 Pd and 110 Pd + 104 Ru could be measured. The evaporation-residual-nucleus cross sections is deviating from lighter systems dominated by channels, which arise from evaporation of α particles. In the reaction 110 Pd + 110 Pd no xn channels were observed. In comparison to other reactions qualitatively a strong fusion hindrance of this system is shown. (orig./HSI) [de

Implant R100 Predicts Rectal Bleeding in Prostate Cancer Patients Treated with IG-IMRT to 45 Gy and Pd-103 Implant

OpenAIRE

Matthew Packard; Vladimir Valakh; Russell Fuhrer

2014-01-01

Purpose. To define factors associated with rectal bleeding in patients treated with IG-IMRT followed by Pd-103 seed implant. Methods and Materials. We retrospectively reviewed 61 prostate adenocarcinoma patients from 2002 to 2008. The majority (85.2%) were of NCCN intermediate risk category. All received IG-IMRT to the prostate and seminal vesicles followed by Pd-103 implant delivering a mean D90 of 100.7 Gy. Six patients received 45 Gy to the pelvic nodes and 10 received androgen deprivation...

Effects of Conversion to a Bicarbonate/Lactate-Buffered, Neutral-pH, Low-GDP PD Regimen in Prevalent PD: A 2-Year Randomized Clinical Trial.

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Farhat, Karima; Douma, Caroline E; Ferrantelli, E; Ter Wee, Pieter M; Beelen, Robert H J; van Ittersum, Frans J

2017-01-01

♦ BACKGROUND: The use of pH-neutral peritoneal dialysis (PD) fluids low in glucose degradation products (GDP) may better preserve the peritoneal membrane and have fewer systemic effects. The effects of conversion from conventional to neutral-pH, low-GDP PD fluids in prevalent patients are unclear. Few studies on the role of neutral-pH, low-GDP PD have studied residual renal function, ultrafiltration, peritonitis incidence and technique failure, transport characteristics, and local and systemic markers of inflammation in prevalent PD patients. ♦ METHODS: In a multi-center open-label randomized clinical trial (RCT), we randomly assigned 40 of 78 stable continuous ambulatory PD (CAPD) and automated PD (APD) patients to treatment with bicarbonate/lactate, neutral-pH, low-GDP PD fluid (Physioneal; Baxter Healthcare Corporation, Deerfield, IL, USA) and compared them with 38 patients continuing their current standard lactate-buffered PD fluid (PDF) (Dianeal; Baxter Healthcare Corporation, Deerfield, IL, USA) during 2 years. Primary outcome was residual renal function (RRF) and ultrafiltration (UF) during peritoneal equilibration test (PET); peritonitis incidence was a secondary outcome. Furthermore, clinical parameters as well as several biomarkers in effluents and serum were measured. ♦ RESULTS: During follow-up, RRF did not differ between the groups. In the Physioneal group ultrafiltration (UF) during PET remained more or less stable (-20 mL [confidence interval (CI): -163.5 - 123.5 mL]; p = 0.7 over 24 months), whereas it declined in the Dianeal group (-243 mL [CI: -376.6 to -109.4 mL]; p GDP PD fluids, although there is a possibility that the study was underpowered to detect a difference. Decline in UF during standardized PET was lower after 2 years in the Physioneal group. Copyright © 2017 International Society for Peritoneal Dialysis.

The Concordance between Patients' Renal Replacement Therapy Choice and Definitive Modality: Is It a Utopia?

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Prieto-Velasco, Mario; Quiros, Pedro; Remon, Cesar

2015-01-01

It is desirable for patients to play active roles in the choice of renal replacement therapy (RRT). Patient decision aid tools (PDAs) have been developed to allow the patients to choose the option best suited to their individual needs. An observational, prospective registry was conducted in 26 Spanish hospitals between September 2010 and May 2012. The results of the patients' choice and the definitive RRT modality were registered through the progressive implementation of an Education Process (EP) with PDAs designed to help Chronic Kidney Disease (CKD) patients choose RRT. Patients included in this study: 1044. Of these, 569 patients used PDAs and had made a definitive choice by the end of registration. A total of 88.4% of patients chose dialysis [43% hemodialysis (HD) and 45% peritoneal dialysis (PD)] 3.2% preemptive living-donor transplant (TX), and 8.4% conservative treatment (CT). A total of 399 patients began RRT during this period. The distribution was 93.4% dialysis (53.6% HD; 40% PD), 1.3% preemptive TX and 5.3% CT. The patients who followed the EP changed their mind significantly less often [kappa value of 0.91 (95% CI, 0.86-0.95)] than those who did not follow it, despite starting unplanned treatment [kappa value of 0.85 (95% CI, 0.75-0.95]. A higher agreement between the final choice and a definitive treatment was achieved by the EP and planned patients [kappa value of 0.93 (95% CI, 0.89-0.98)]. Those who did not go through the EP had a much lower index of choosing PD and changed their decision more frequently when starting definitive treatment [kappa value of 0.73 (95% CI, 0.55-0.91)]. Free choice, assisted by PDAs, leads to a 50/50 distribution of PD and HD choice and an increase in TX choice. The use of PDAs, even with an unplanned start, achieved a high level of concordance between the chosen and definitive modality.

Cause-Specific Mortality in HIV-Positive Patients Who Survived Ten Years after Starting Antiretroviral Therapy

DEFF Research Database (Denmark)

Trickey, Adam; May, Margaret T; Vehreschild, Jorg-Janne

2016-01-01

OBJECTIVES: To estimate mortality rates and prognostic factors in HIV-positive patients who started combination antiretroviral therapy between 1996-1999 and survived for more than ten years. METHODS: We used data from 18 European and North American HIV cohort studies contributing to the Antiretro......OBJECTIVES: To estimate mortality rates and prognostic factors in HIV-positive patients who started combination antiretroviral therapy between 1996-1999 and survived for more than ten years. METHODS: We used data from 18 European and North American HIV cohort studies contributing...... to the Antiretroviral Therapy Cohort Collaboration. We followed up patients from ten years after start of combination antiretroviral therapy. We estimated overall and cause-specific mortality rate ratios for age, sex, transmission through injection drug use, AIDS, CD4 count and HIV-1 RNA. RESULTS: During 50,593 person...... years 656/13,011 (5%) patients died. Older age, male sex, injecting drug use transmission, AIDS, and low CD4 count and detectable viral replication ten years after starting combination antiretroviral therapy were associated with higher subsequent mortality. CD4 count at ART start did not predict...

Factors Associated with the Choice of Peritoneal Dialysis in Patients with End-Stage Renal Disease

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Pei-Chun Chiang

2016-01-01

Full Text Available Background. The purpose of this study was to analyze the factors associated with receiving peritoneal dialysis (PD in patients with incident end-stage renal disease (ESRD in a hospital in Southern Taiwan. Methods. The study included all consecutive patients with incident ESRD who participated in a multidisciplinary predialysis education (MPE program and started their first dialysis therapy between January 1, 2008, and June 30, 2013, in the study hospital. We provided small group teaching sessions to advanced CKD patients and their family to enhance understanding of various dialysis modalities. Multivariate logistic regression models were used to analyze the association of patient characteristics with the chosen dialysis modality. Results. Of the 656 patients, 524 (80% chose hemodialysis and 132 chose PD. Our data showed that young age, high education level, and high scores of activities of daily living (ADLs were positively associated with PD treatment. Patients who received small group teaching sessions had higher percentages of PD treatment (30.5% versus 19.5%; P=0.108 and preparedness for dialysis (61.1% versus 46.6%; P=0.090. Conclusion. Young age, high education level, and high ADL score were positively associated with choosing PD. Early creation of vascular access may be a barrier for PD.

Immune-Related Adverse Events Associated with Anti-PD-1/PD-L1 Treatment for Malignancies: A Meta-Analysis

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Peng-Fei Wang

2017-10-01

Full Text Available Background: Treatment of cancers with programmed cell death protein 1 (PD-1 pathway inhibitors can lead to immune-related adverse events (irAEs, which could be serious and even fetal. Therefore, clinicians should be aware of the characteristics of irAEs associated with the use of such drugs.Methods: The MEDLINE, EMBASE, and Cochrane databases were searched to find potential studies using the following strategies: anti-PD-1/PD-L1 treatment; irAEs; and cancer. R© package Meta was used to pool incidence.Results: Forty-six studies representing 12,808 oncologic patients treated with anti-PD-1/PD-L1 agents were included in the meta-analysis. The anti-PD-1/PD-L1 agents included nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and BMS-936559. The tumor types were melanomas, Hodgkin lymphomas, urothelial carcinomas, breast cancers, non-small cell lung cancers, renal cell carcinomas (RCC, colorectal cancers, and others. We described irAEs according to organ systems, namely, the skin (pruritus, rash, maculopapular rash, vitiligo, and dermatitis, endocrine system (hypothyroidism, hyperthyroidism, hypophysitis, thyroiditis, and adrenal insufficiency, digestive system (colitis, diarrhea, pancreatitis, and increased AST/ALT/bilirubin, respiratory system (pneumonitis, lung infiltration, and interstitial lung disease, and urinary system (increased creatinine, nephritis, and renal failure. In patients treated with the PD-1 signaling inhibitors, the overall incidence of irAEs was 26.82% (95% CI, 21.73–32.61; I2, 92.80 in any grade and 6.10% (95% CI, 4.85–7.64; I2, 52.00 in severe grade, respectively. The development of irAEs was unrelated to the dose of anti-PD-1/PD-L1 agents. The incidence of particular irAEs varied when different cancers were treated with different drugs. The incidence of death due to irAEs was around 0.17%.Conclusion: The occurrence of irAEs was organ-specific and related to drug and tumor types.

Blimp-1 impairs T cell function via upregulation of TIGIT and PD-1 in patients with acute myeloid leukemia.

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Zhu, Liuluan; Kong, Yaxian; Zhang, Jianhong; Claxton, David F; Ehmann, W Christopher; Rybka, Witold B; Palmisiano, Neil D; Wang, Ming; Jia, Bei; Bayerl, Michael; Schell, Todd D; Hohl, Raymond J; Zeng, Hui; Zheng, Hong

2017-06-19

T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and programmed cell death protein 1 (PD-1) are important inhibitory receptors that associate with T cell exhaustion in acute myeloid leukemia (AML). In this study, we aimed to determine the underlying transcriptional mechanisms regulating these inhibitory pathways. Specifically, we investigated the role of transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) in T cell response and transcriptional regulation of TIGIT and PD-1 in AML. Peripheral blood samples collected from patients with AML were used in this study. Blimp-1 expression was examined by flow cytometry. The correlation of Blimp-1 expression to clinical characteristics of AML patients was analyzed. Phenotypic and functional studies of Blimp-1-expressing T cells were performed using flow cytometry-based assays. Luciferase reporter assays and ChIP assays were applied to assess direct binding and transcription activity of Blimp-1. Using siRNA to silence Blimp-1, we further elucidated the regulatory role of Blimp-1 in the TIGIT and PD-1 expression and T cell immune response. Blimp-1 expression is elevated in T cells from AML patients. Consistent with exhaustion, Blimp-1 + T cells upregulate multiple inhibitory receptors including PD-1 and TIGIT. In addition, they are functionally impaired manifested by low cytokine production and decreased cytotoxicity capacity. Importantly, the functional defect is reversed by inhibition of Blimp-1 via siRNA knockdown. Furthermore, Blimp-1 binds to the promoters of PD-1 and TIGIT and positively regulates their expression. Our study demonstrates an important inhibitory effect of Blimp-1 on T cell response in AML; thus, targeting Blimp-1 and its regulated molecules to improve the immune response may provide effective leukemia therapeutics.

Blimp-1 impairs T cell function via upregulation of TIGIT and PD-1 in patients with acute myeloid leukemia

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Liuluan Zhu

2017-06-01

Full Text Available Abstract Background T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM domain (TIGIT and programmed cell death protein 1 (PD-1 are important inhibitory receptors that associate with T cell exhaustion in acute myeloid leukemia (AML. In this study, we aimed to determine the underlying transcriptional mechanisms regulating these inhibitory pathways. Specifically, we investigated the role of transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1 in T cell response and transcriptional regulation of TIGIT and PD-1 in AML. Methods Peripheral blood samples collected from patients with AML were used in this study. Blimp-1 expression was examined by flow cytometry. The correlation of Blimp-1 expression to clinical characteristics of AML patients was analyzed. Phenotypic and functional studies of Blimp-1-expressing T cells were performed using flow cytometry-based assays. Luciferase reporter assays and ChIP assays were applied to assess direct binding and transcription activity of Blimp-1. Using siRNA to silence Blimp-1, we further elucidated the regulatory role of Blimp-1 in the TIGIT and PD-1 expression and T cell immune response. Results Blimp-1 expression is elevated in T cells from AML patients. Consistent with exhaustion, Blimp-1+ T cells upregulate multiple inhibitory receptors including PD-1 and TIGIT. In addition, they are functionally impaired manifested by low cytokine production and decreased cytotoxicity capacity. Importantly, the functional defect is reversed by inhibition of Blimp-1 via siRNA knockdown. Furthermore, Blimp-1 binds to the promoters of PD-1 and TIGIT and positively regulates their expression. Conclusions Our study demonstrates an important inhibitory effect of Blimp-1 on T cell response in AML; thus, targeting Blimp-1 and its regulated molecules to improve the immune response may provide effective leukemia therapeutics.

PD-L1 expression associated with worse survival outcome in malignant pleural mesothelioma.

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Nguyen, Bella Hai; Montgomery, Renn; Fadia, Mitali; Wang, Jiali; Ali, Sayed

2018-02-01

There is currently a need to identify prognostic biomarkers to assist in a risk adopted approach in treatment of malignant pleural mesothelioma (MPM). Expression of programmed death ligand 1 (PD-L1) has been studied as a prognostic biomarker in a number of tumors given its central role in antitumoral immune response evasion. Four previously published analyses found PD-L1 positivity to be an adverse survival prognostic factor in MPM. This study aims to further investigate the relationship between PD-L1 expression in mesothelioma tissues and survival outcome. Clinical data of MPM patients from a single institution between 2006 and 2016 were reviewed. Patient's archived tissues were stained with PD-L1 (Clone Ventana SP263). PD-L1 positivity was defined as > 1% membranous staining regardless of intensity. Data from fifty eight patients were analyzed. Median age was 73, majority was male (49, 84%) and had ECOG between 0 and 2 (46, 79%). Most common histopathological subtype was epithelioid (42, 72%), 9 (16%) biphasic subtype and 7 (12%) sarcomatoid. Thirty one patients (53%) received best supportive care and twenty seven patients (47%) received chemotherapy or combination treatment. Forty-two patients had positive PD-L1 expression (72.4%). The median survival time for PD-L1 negative group is 15.5 months and 6 months for the positive group. Positive PD-L1 expression is independently correlated with worse prognosis (HR = 2.02; 95% CI, 1.005-4.057; P-value = 0.0484). Our analysis found a higher percentage of MPM patients with positive PD-L1 (> 1%) compared to other studies. Highly positive PD-L1 expression was associated with statistically significantly lower median survival time. © 2017 John Wiley & Sons Australia, Ltd.

Analyses of the peripheral immunome following multiple administrations of avelumab, a human IgG1 anti-PD-L1 monoclonal antibody.

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Donahue, Renee N; Lepone, Lauren M; Grenga, Italia; Jochems, Caroline; Fantini, Massimo; Madan, Ravi A; Heery, Christopher R; Gulley, James L; Schlom, Jeffrey

2017-01-01

Multiple anti-PD-L1/PD-1 checkpoint monoclonal antibodies (MAb) have shown clear evidence of clinical benefit. All except one have been designed or engineered to omit the possibility to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) as a second potential mode of anti-tumor activity; the reason for this is the concern of lysis of PD-L1 positive immune cells. Avelumab is a fully human IgG1 MAb which has been shown in prior in vitro studies to mediate ADCC versus a range of human tumor cells, and clinical studies have demonstrated anti-tumor activity versus a range of human cancers. This study was designed to investigate the effect on immune cell subsets in the peripheral blood of cancer patients prior to and following multiple administrations of avelumab. One hundred twenty-three distinct immune cell subsets in the peripheral blood of cancer patients ( n  = 28) in a phase I trial were analyzed by flow cytometry prior to and following one, three, and nine cycles of avelumab. Changes in soluble (s) CD27 and sCD40L in plasma were also evaluated. In vitro studies were also performed to determine if avelumab would mediate ADCC of PBMC. No statistically significant changes in any of the 123 immune cell subsets analyzed were observed at any dose level, or number of doses, of avelumab. Increases in the ratio of sCD27:sCD40L were observed, suggesting potential immune activation. Controlled in vitro studies also showed lysis of tumor cells by avelumab versus no lysis of PBMC from five donors. These studies demonstrate the lack of any significant effect on multiple immune cell subsets, even those expressing PD-L1, following multiple cycles of avelumab. These results complement prior studies showing anti-tumor effects of avelumab and comparable levels of adverse events with avelumab versus other anti-PD-1/PD-L1 MAbs. These studies provide the rationale to further exploit the potential ADCC mechanism of action of avelumab as well as other human IgG1 checkpoint

Affinity purification mass spectrometry analysis of PD-1 uncovers SAP as a new checkpoint inhibitor.

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Peled, Michael; Tocheva, Anna S; Sandigursky, Sabina; Nayak, Shruti; Philips, Elliot A; Nichols, Kim E; Strazza, Marianne; Azoulay-Alfaguter, Inbar; Askenazi, Manor; Neel, Benjamin G; Pelzek, Adam J; Ueberheide, Beatrix; Mor, Adam

2018-01-16

Programmed cell death-1 (PD-1) is an essential inhibitory receptor in T cells. Antibodies targeting PD-1 elicit durable clinical responses in patients with multiple tumor indications. Nevertheless, a significant proportion of patients do not respond to anti-PD-1 treatment, and a better understanding of the signaling pathways downstream of PD-1 could provide biomarkers for those whose tumors respond and new therapeutic approaches for those whose tumors do not. We used affinity purification mass spectrometry to uncover multiple proteins associated with PD-1. Among these proteins, signaling lymphocytic activation molecule-associated protein (SAP) was functionally and mechanistically analyzed for its contribution to PD-1 inhibitory responses. Silencing of SAP augmented and overexpression blocked PD-1 function. T cells from patients with X-linked lymphoproliferative disease (XLP), who lack functional SAP, were hyperresponsive to PD-1 signaling, confirming its inhibitory role downstream of PD-1. Strikingly, signaling downstream of PD-1 in purified T cell subsets did not correlate with PD-1 surface expression but was inversely correlated with intracellular SAP levels. Mechanistically, SAP opposed PD-1 function by acting as a molecular shield of key tyrosine residues that are targets for the tyrosine phosphatase SHP2, which mediates PD-1 inhibitory properties. Our results identify SAP as an inhibitor of PD-1 function and SHP2 as a potential therapeutic target in patients with XLP.

The Exosomal/Total α-Synuclein Ratio in Plasma Is Associated With Glucocerebrosidase Activity and Correlates With Measures of Disease Severity in PD Patients

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Silvia Cerri

2018-05-01

Full Text Available Intensive research efforts in the field of Parkinson’s disease (PD are focusing on identifying reliable biomarkers which possibly help physicians in predicting disease onset, diagnosis, and progression as well as evaluating the response to disease-modifying treatments. Given that abnormal alpha-synuclein (α-syn accumulation is a primary component of PD pathology, this protein has attracted considerable interest as a potential biomarker for PD. Alpha-synuclein can be detected in several body fluids, including plasma, where it can be found as free form or in association with exosomes, small membranous vesicles secreted by virtually all cell types. Together with α-syn accumulation, lysosomal dysfunctions seem to play a central role in the pathogenesis of PD, given the crucial role of lysosomes in the α-syn degradation. In particular, heterozygous mutations in the GBA1 gene encoding lysosomal enzyme glucocerebrosidase (GCase are currently considered as the most important risk factor for PD. Different studies have found that GCase deficiency leads to accumulation of α-syn; whereas at the same time, increased α-syn may inhibit GCase function, thus inducing a bidirectional pathogenic loop. In this study, we investigated whether changes in plasma total and exosome-associated α-syn could correlate with disease status and clinical parameters in PD and their relationship with GCase activity. We studied 39 PD patients (mean age: 65.2 ± 8.9; men: 25, without GBA1 mutations, and 33 age-matched controls (mean age: 61.9 ± 6.2; men: 15. Our results showed that exosomes from PD patients contain a greater amount of α-syn compared to healthy subjects (25.2 vs. 12.3 pg/mL, p < 0.001 whereas no differences were found in plasma total α-syn levels (15.7 vs. 14.8 ng/mL, p = 0.53. Moreover, we highlighted a significant increase of plasma exosomal α-syn/total α-syn ratio in PD patients (1.69 vs. 0.89, p < 0.001, which negatively correlates with disease

Clinical characteristics with an impact on ADL functions of PD patients with cognitive impairment indicative of dementia.

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Inga Liepelt-Scarfone

Full Text Available BACKGROUND: Dementia in Parkinson's disease (PD is defined as cognitive decline severe enough to affect activities of daily living function (ADL. The aim of our exploratory study was to compare two groups of PD patients. Both groups had cognitive deficits severe enough to justify diagnosis of dementia, but they differed according to caregivers' rating on ADL dysfunction. Parameters which differed between the two groups were interpreted to affect the caregivers' perception of ADL dysfunction in PD patients with cognitive impairment indicative of Parkinson's disease dementia. METHODOLOGY/PRINCIPAL FINDINGS: Thirty of 131 Parkinson's disease patients fulfilled the Movement Disorders Society Task Force - recommended, cognitive Level-I-criteria for dementia. According to standardized caregiver ratings, volunteers were grouped into 18 patients with (ADL- and 12 without instrumental activities of daily living dysfunction (ADL+. Caregiver activities of daily living function ratings closely correlated with self-estimates of patients and those of physician (p<0.001. ADL- patients performed worse on tests assessing visual-construction (p<0.05 and attention (p=0.03 than ADL+ patients. Moreover, the postural instability and gait disorder subtype was more frequent in ADL- patients (p=0.009. ADL- patients tended to have more communication problems (p=0.05, more anxiety (p=0.05 and showed a tendency to be treated more often with neuroleptics (p=0.049 than ADL+. CONCLUSIONS/SIGNIFICANCE: Results indicate that worse attention, visual-construction abilities, the postural instability and gait disorder subtype, communication problems, medication and presence of anxiety are related to activities of daily living dysfunctions in Parkinson's disease patients with cognitive decline indicative of dementia. Our data suggests that not only cognitive factors but also non-cognitive factors seem to be linked to the diagnosis of Parkinson's disease dementia associated with

Orthostatic Hypotension in Drug-Naïve Patients with Parkinson’s Disease

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Hyo-Jin Bae

2011-05-01

Full Text Available Background and Purpose Orthostatic hypotension (OH is known to be present even in patients with early Parkinson’s disease (PD. To affirm the presence of OH and find correlation between OH and other dysautonomic symptoms in PD, this study has done in newly-diagnosed PD patients. Methods Forty-five non-demented patients with no prior history of treatment for PD were recruited (17 men, 63.8 ± 10.1 years of age. All the patients were evaluated for OH before starting medications. Autonomic symptoms were evaluated with structured questionnaires. Clinical characteristics of PD were evaluated (median Hoehn and Yahr stage 2.0 (1–3, 1.3 ± 1.1 years of disease duration, and comorbid medical conditions that could affect blood pressure were also recorded. Results OH was prevalent, and eighteen patients (40% showed orthostatic hypotension, and twenty-seven (60% did not (normotensive group. There was no significant difference in demographic and clinical characteristics between groups. The presence or severity of symptoms of autonomic dysfunction in the OH group also not differed from those of the normotensive group. Conclusions OH was prevalent even in the early stage of PD, and was not related to presence or severity of any other symptoms of autonomic dysfunction. Our findings suggest that clinicians should pay attention to OH from the early stage of disease.

Assessing the relative potency of (S)- and (R)-warfarin with a new PK-PD model, in relation to VKORC1 genotypes.

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Ferrari, Myriam; Pengo, Vittorio; Barolo, Massimiliano; Bezzo, Fabrizio; Padrini, Roberto

2017-06-01

The purpose of this study is to develop a new pharmacokinetic-pharmacodynamic (PK-PD) model to characterise the contribution of (S)- and (R)-warfarin to the anticoagulant effect on patients in treatment with rac-warfarin. Fifty-seven patients starting warfarin (W) therapy were studied, from the first dose and during chronic treatment at INR stabilization. Plasma concentrations of (S)- and (R)-W and INRs were measured 12, 36 and 60 h after the first dose and at steady state 12-14 h after dosing. Patients were also genotyped for the G>A VKORC1 polymorphism. The PK-PD model assumed a linear relationship between W enantiomer concentration and INR and included a scaling factor k to account for a different potency of (R)-W. Two parallel compartment chains with different transit times (MTT 1 and MTT 2 ) were used to model the delay in the W effect. PD parameters were estimated with the maximum likelihood approach. The model satisfactorily described the mean time-course of INR, both after the initial dose and during long-term treatment. (R)-W contributed to the rac-W anticoagulant effect with a potency of about 27% that of (S)-W. This effect was independent of VKORC1 genotype. As expected, the slope of the PK/PD linear correlation increased stepwise from GG to GA and from GA to AA VKORC1 genotype (0.71, 0.90 and 1.49, respectively). Our PK-PD linear model can quantify the partial pharmacodynamic activity of (R)-W in patients contemporaneously exposed to therapeutic (S)-W plasma levels. This concept may be useful in improving the performance of future algorithms aiming at identifying the most appropriate W maintenance dose.

Imbalance of Circulating Monocyte Subsets and PD-1 Dysregulation in Q Fever Endocarditis: The Role of IL-10 in PD-1 Modulation

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Ka, Mignane B.; Gondois-Rey, Françoise; Capo, Christian; Textoris, Julien; Million, Mathieu; Raoult, Didier; Olive, Daniel; Mege, Jean-Louis

2014-01-01

Q fever endocarditis, a severe complication of Q fever, is associated with a defective immune response, the mechanisms of which are poorly understood. We hypothesized that Q fever immune deficiency is related to altered distribution and activation of circulating monocyte subsets. Monocyte subsets were analyzed by flow cytometry in peripheral blood mononuclear cells from patients with Q fever endocarditis and controls. The proportion of classical monocytes (CD14+CD16− monocytes) was similar in patients and controls. In contrast, the patients with Q fever endocarditis exhibited a decrease in the non-classical and intermediate subsets of monocytes (CD16+ monocytes). The altered distribution of monocyte subsets in Q fever endocarditis was associated with changes in their activation profile. Indeed, the expression of HLA-DR, a canonical activation molecule, and PD-1, a co-inhibitory molecule, was increased in intermediate monocytes. This profile was not restricted to CD16+ monocytes because CD4+ T cells also overexpressed PD-1. The mechanism leading to the overexpression of PD-1 did not require the LPS from C. burnetii but involved interleukin-10, an immunosuppressive cytokine. Indeed, the incubation of control monocytes with interleukin-10 led to a higher expression of PD-1 and neutralizing interleukin-10 prevented C. burnetii-stimulated PD-1 expression. Taken together, these results show that the immune suppression of Q fever endocarditis involves a cross-talk between monocytes and CD4+ T cells expressing PD-1. The expression of PD-1 may be useful to assess chronic immune alterations in Q fever endocarditis. PMID:25211350

Mortality According to CD4 Count at Start of Combination Antiretroviral Therapy Among HIV-infected Patients Followed for up to 15 Years After Start of Treatment

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May, Margaret T; Vehreschild, Jorg-Janne; Trickey, Adam

2016-01-01

BACKGROUND: CD4 count at start of combination antiretroviral therapy (ART) is strongly associated with short-term survival, but its association with longer-term survival is less well characterized. METHODS: We estimated mortality rates (MRs) by time since start of ART (...-4.9, 5-9.9, and ≥10 years) among patients from 18 European and North American cohorts who started ART during 1996-2001. Piecewise exponential models stratified by cohort were used to estimate crude and adjusted (for sex, age, transmission risk, period of starting ART [1996-1997, 1998-1999, 2000......-2001], and AIDS and human immunodeficiency virus type 1 RNA at baseline) mortality rate ratios (MRRs) by CD4 count at start of ART (0-49, 50-99, 100-199, 200-349, 350-499, ≥500 cells/µL) overall and separately according to time since start of ART. RESULTS: A total of 6344 of 37 496 patients died during 359 219...

Patients' perceptions and illness severity at start of antidepressant treatment in general practice

NARCIS (Netherlands)

Van Geffen, Erica C.G.; Heerdink, Eiebert R.; Hugtenburg, Jacqueline G.; Siero, Frans W.; Egberts, Antoine C.G.; Van Hulten, Rolf

2010-01-01

Objectives Patients' perceptions are important to consider when trying to understand why patients often do not follow prescriptions for antidepressant treatment. This study aimed to investigate the influence of patients' perceptions and illness severity at the start on antidepressant-medication-

Central Nervous System Strongyloidiasis and Cryptococcosis in an HIV-Infected Patient Starting Antiretroviral Therapy

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Mónica Rodríguez

2012-01-01

Full Text Available We report a case of Strongyloides stercoralis hyperinfection syndrome with central nervous system involvement, in a patient with late human immunodeficiency virus (HIV infection starting antiretroviral therapy, in whom Strongyloides stercoralis larvae and Cryptococcus neoformans were isolated antemortem from cerebrospinal fluid. Our patient was not from an endemic region for the parasite, so strongyloidiasis was not originally suspected. For this reason, we conclude that Strongyloides stercoralis infection should be suspected in HIV-infected patients starting antiretroviral therapy in order to avoid potential fatal outcomes.

Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013

DEFF Research Database (Denmark)

Trickey, Adam; May, Margaret T.; Vehreschild, Jorg Janne

2017-01-01

Background Health care for people living with HIV has improved substantially in the past two decades. Robust estimates of how these improvements have affected prognosis and life expectancy are of utmost importance to patients, clinicians, and health-care planners. We examined changes in 3 year...... survival and life expectancy of patients starting combination antiretroviral therapy (ART) between 1996 and 2013. Methods We analysed data from 18 European and North American HIV-1 cohorts. Patients (aged ≥16 years) were eligible for this analysis if they had started ART with three or more drugs between...... ART initiation in four calendar periods (1996–99, 2000–03 [comparator], 2004–07, 2008–10). We estimated life expectancy by calendar period of initiation of ART. Findings 88 504 patients were included in our analyses, of whom 2106 died during the first year of ART and 2302 died during the second...

Neurological Complications Associated With Anti-Programmed Death 1 (PD-1) Antibodies.

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Kao, Justin C; Liao, Bing; Markovic, Svetomir N; Klein, Christopher J; Naddaf, Elie; Staff, Nathan P; Liewluck, Teerin; Hammack, Julie E; Sandroni, Paola; Finnes, Heidi; Mauermann, Michelle L

2017-10-01

Neurological complications are an increasingly recognized consequence of the use of anti-programmed death 1 (PD-1) antibodies in the treatment of solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical spectrum and optimum treatment approach are not established. To investigate the frequency, clinical spectrum, and optimum treatment approach to neurological complications associated with anti-PD-1 therapy. This single-center, retrospective cohort study was conducted from either September or December 2014 (the approval dates of the study drugs by the US Food and Drug Administration) to May 19, 2016. All patients receiving anti-PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy Database. Patients with development of neurological symptoms within 12 months of anti-PD-1 therapy were included. Patients with neurological complications directly attributable to metastatic disease or other concurrent cancer-related treatments were excluded. Clinical and pathological characteristics, time to development of neurological symptoms, and modified Rankin Scale (mRS) score. Among 347 patients treated with anti-PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum

CO-induced Pd segregation and the effect of subsurface Pd on CO adsorption on CuPd surfaces

International Nuclear Information System (INIS)

Padama, A A B; Villaos, R A B; Albia, J R; Diño, W A; Nakanishi, H; Kasai, H

2017-01-01

We report results of our study on the adsorption of CO on CuPd surfaces with bulk stoichiometric and nonstoichiometric layers using density functional theory (DFT). We found that the presence of Pd atoms in the subsurface layer promotes the adsorption of CO. We also observed CO-induced Pd segregation on the CuPd surface and we attribute this to the strong CO–Pd interaction. Lastly, we showed that the adsorption of CO promotes Pd–Pd interaction as compared to the pristine surface which promotes strong Cu–Pd interaction. These results indicate that CO adsorption on CuPd surfaces can be tuned by taking advantage of the CO-induced segregation and by considering the role of subsurface Pd atoms. (paper)

Tackling Cancer Resistance by Immunotherapy: Updated Clinical Impact and Safety of PD-1/PD-L1 Inhibitors

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Shifaa M. Abdin

2018-01-01

Full Text Available Cancer therapy has been constantly evolving with the hope of finding the most effective agents with the least toxic effects to eradicate tumors. Cancer immunotherapy is currently among the most promising options, fulfilling this hope in a wide range of tumors. Immunotherapy aims to activate immunity to fight cancer in a very specific and targeted manner; however, some abnormal immune reactions known as immune-related adverse events (IRAEs might occur. Therefore, many researchers are aiming to define the most proper protocols for managing these complications without interfering with the anticancer effect. One of these targeted approaches is the inhibition of the interaction between the checkpoint protein, programmed death-receptor 1 (PD-1, and its ligand, programmed death-ligand 1 (PD-L1, via a class of antibodies known as PD-1/PD-L1 inhibitors. These antibodies achieved prodigious success in a wide range of malignancies, including those where optimal treatment is not yet fully identified. In this review, we have critically explored and discussed the outcome of the latest PD-1 and PD-L1 inhibitor studies in different malignancies compared to standard chemotherapeutic alternatives with a special focus on the clinical efficacy and safety. The approval of the clinical applications of nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab in the last few years clearly highlights the hopeful future of PD-1/PD-L1 inhibitors for cancer patients. These promising results of PD-1/PD-L1 inhibitors have encouraged many ongoing preclinical and clinical trials to explore the extent of antitumor activity, clinical efficacy and safety as well as to extend their applications.

Tackling Cancer Resistance by Immunotherapy: Updated Clinical Impact and Safety of PD-1/PD-L1 Inhibitors.

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Abdin, Shifaa M; Zaher, Dana M; Arafa, El-Shaimaa A; Omar, Hany A

2018-01-25

Cancer therapy has been constantly evolving with the hope of finding the most effective agents with the least toxic effects to eradicate tumors. Cancer immunotherapy is currently among the most promising options, fulfilling this hope in a wide range of tumors. Immunotherapy aims to activate immunity to fight cancer in a very specific and targeted manner; however, some abnormal immune reactions known as immune-related adverse events (IRAEs) might occur. Therefore, many researchers are aiming to define the most proper protocols for managing these complications without interfering with the anticancer effect. One of these targeted approaches is the inhibition of the interaction between the checkpoint protein, programmed death-receptor 1 (PD-1), and its ligand, programmed death-ligand 1 (PD-L1), via a class of antibodies known as PD-1/PD-L1 inhibitors. These antibodies achieved prodigious success in a wide range of malignancies, including those where optimal treatment is not yet fully identified. In this review, we have critically explored and discussed the outcome of the latest PD-1 and PD-L1 inhibitor studies in different malignancies compared to standard chemotherapeutic alternatives with a special focus on the clinical efficacy and safety. The approval of the clinical applications of nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab in the last few years clearly highlights the hopeful future of PD-1/PD-L1 inhibitors for cancer patients. These promising results of PD-1/PD-L1 inhibitors have encouraged many ongoing preclinical and clinical trials to explore the extent of antitumor activity, clinical efficacy and safety as well as to extend their applications.

The combination of anti-KIR monoclonal antibodies with anti-PD-1/PD-L1 monoclonal antibodies could be a critical breakthrough in overcoming tumor immune escape in NSCLC

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He YY

2018-04-01

Full Text Available Yayi He,1,2,* Sangtian Liu,1,* Jane Mattei,3 Paul A Bunn Jr,2 Caicun Zhou,1 Daniel Chan2 1Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China; 2Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 3Oncology Department, Moinhos de Vento Hospital, Porto Alegre, Brazil *These authors contributed equally to this work Background: The anti-programmed death-1 (PD-1/programmed death ligand-1 (PD-L1 monoclonal antibody has a good effect in the treatment of non-small cell lung cancer (NSCLC, but not all PD-1/PD-L1 positive patients can get benefit from it. Compensatory expression of other immune checkpoints may be correlated with the poor efficacy of anti-PD-1/PD-L1 monoclonal antibodies. The inhibitory human leukocyte antigen (HLA/killer cell Ig-like receptor (KIR can effectively block the killing effect of natural killer (NK cells on tumors. Our previous studies have confirmed that high expression of KIR was correlated with poor prognosis of NSCLC. Inhibitory KIR expression was positively correlated with the expression of PD-1. Methods: The expressions of KIR 2D (L1, L3, L4, S4 (BC032422/ADQ31987/NP_002246/NP_036446, Abcam and PD-1 (NAT 105, Cell marque proteins was assessed by immunohis­tochemistry. Results: The expression of inhibitory KIR in tumor cells or tumor infiltrating lymphocytes (TILs is associated with PD-1 expression. Among PD-1 positive patients, 76.3% were KIR 2D (L1, L3, L4, S4 positive on tumor cells, and 74.6% were KIR 2D (L1, L3, L4, S4 positive on TILs. We compared the expression of inhibitory KIR before and after treatment with nivolumab in 11 patients with NSCLC. We found that five (45.5% patients had positive expression of inhibitory KIR in tumor tissue after being treated with anti-PD-1 monoclonal antibodies, two of whom exhibited a significant

Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab.

Science.gov (United States)

Lee, Hyun Tae; Lee, Ju Yeon; Lim, Heejin; Lee, Sang Hyung; Moon, Yu Jeong; Pyo, Hyo Jeong; Ryu, Seong Eon; Shin, Woori; Heo, Yong-Seok

2017-07-17

In 2016 and 2017, monoclonal antibodies targeting PD-L1, including atezolizumab, durvalumab, and avelumab, were approved by the FDA for the treatment of multiple advanced cancers. And many other anti-PD-L1 antibodies are under clinical trials. Recently, the crystal structures of PD-L1 in complex with BMS-936559 and avelumab have been determined, revealing details of the antigen-antibody interactions. However, it is still unknown how atezolizumab and durvalumab specifically recognize PD-L1, although this is important for investigating novel binding sites on PD-L1 targeted by other therapeutic antibodies for the design and improvement of anti-PD-L1 agents. Here, we report the crystal structures of PD-L1 in complex with atezolizumab and durvalumab to elucidate the precise epitopes involved and the structural basis for PD-1/PD-L1 blockade by these antibodies. A comprehensive comparison of PD-L1 interactions with anti-PD-L1 antibodies provides a better understanding of the mechanism of PD-L1 blockade as well as new insights into the rational design of improved anti-PD-L1 therapeutics.

HLA class I antigen processing machinery (APM) component expression and PD-1:PD-L1 pathway activation in HIV-infected head and neck cancers.

Science.gov (United States)

Pai, Sara I; Jack Lee, J; Carey, Thomas E; Westra, William H; Ferrone, Soldano; Moore, Charles; Mosunjac, Marina B; Shin, Dong M; Ferris, Robert L

2018-02-01

Human immunodeficiency virus (HIV)-infected individuals are at increased risk for developing several non-AIDS related malignancies and are often excluded from cancer immunotherapy regimens. To evaluate the immune competence of this cancer patient population, we evaluated HLA class I antigen presenting machinery (APM) component expression and PD-1:PD-L1 pathway upregulation in HIV(+) and HIV(-) head and neck cancers (HNCs). Sixty-two HIV(+) and 44 matched HIV(-) controls diagnosed with HNC between 1991 and 2011 from five tertiary care referral centers in the United States were identified. HLA class I APM component, PD-1, and PD-L1 expression were analyzed by immunohistochemical staining with monoclonal antibodies (mAbs). Clinical data was abstracted from the medical records. There was no significant difference between the cases and controls in LMP2, TAP1, HLA-A and HLA-B/C, as well as PD-1 and PD-L1 expression. Overall, 62% of all subjects had high PD-1 expression and 82% of the subjects expressed PD-L1 within the tumor microenvironment. LMP2, HLA-A and HLA-B/C expression were significantly associated with moderate to high PD-1 expression in the HIV(+) HNC cases (p = .004, p = .026, and p = .006, respectively) but not in the HIV(-) controls. In addition, HLA-A expression was significantly associated with PD-L1 expression in the HIV(+) HNC cases only (p = .029). HIV-infected individuals diagnosed with HNC do not have any detectable defects in HLA class I APM component expression and in PD-1:PD-L1 pathway activation. Given the current successes of HAART therapy in maintaining immune cell counts, HIV(+) patients diagnosed with cancer may benefit from the recently FDA-approved immune checkpoint blockade therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dialysis modality choice in elderly patients with end-stage renal disease

DEFF Research Database (Denmark)

Segall, Liviu; Nistor, Ionuţ; Van Biesen, Wim

2017-01-01

on comprehensive and unbiased information. A multidisciplinary team should review elderly patients starting on dialysis, aiming to identify possible barriers to PD and home HD, including physical, visual, cognitive, psychological and social problems, and to overcome such barriers by adequate care, education...

G6PD Deficiency in an HIV Clinic Setting in the Dominican Republic

Science.gov (United States)

Xu, Julia Z.; Francis, Richard O.; Lerebours Nadal, Leonel E.; Shirazi, Maryam; Jobanputra, Vaidehi; Hod, Eldad A.; Jhang, Jeffrey S.; Stotler, Brie A.; Spitalnik, Steven L.; Nicholas, Stephen W.

2015-01-01

Because human immunodeficiency virus (HIV)-infected patients receive prophylaxis with oxidative drugs, those with glucose-6-phosphate dehydrogenase (G6PD) deficiency may experience hemolysis. However, G6PD deficiency has not been studied in the Dominican Republic, where many individuals have African ancestry. Our objective was to determine the prevalence of G6PD deficiency in Dominican HIV-infected patients and to attempt to develop a cost-effective algorithm for identifying such individuals. To this end, histories, chart reviews, and G6PD testing were performed for 238 consecutive HIV-infected adult clinic patients. The overall prevalence of G6PD deficiency (8.8%) was similar in males (9.3%) and females (8.5%), and higher in Haitians (18%) than Dominicans (6.4%; P = 0.01). By logistic regression, three clinical variables predicted G6PD status: maternal country of birth (P = 0.01) and a history of hemolysis (P = 0.01) or severe anemia (P = 0.03). Using these criteria, an algorithm was developed, in which a patient subset was identified that would benefit most from G6PD screening, yielding a sensitivity of 94.7% and a specificity of 97.2%, increasing the pretest probability (8.8–15.1%), and halving the number of patients needing testing. This algorithm may provide a cost-effective strategy for improving care in resource-limited settings. PMID:26240158

Anti-tumor immunotherapy by blockade of the PD-1/PD-L1 pathway with recombinant human PD-1-IgV.

Science.gov (United States)

Zhang, C; Wu, S; Xue, X; Li, M; Qin, X; Li, W; Han, W; Zhang, Y

2008-01-01

Blockade of the programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway can delay tumor growth and prolong the survival of tumor-bearing mice. The extracellular immunoglobulin (Ig) V domain of PD-1 is important for the interaction between PD-1 and PD-L1, suggesting that PD-1-IgV may be a potential target for anti-tumor immunotherapy. The extracellular sequence of human PD-1-IgV (hPD-1-IgV) was expressed in Escherichia coli and purified. The anti-tumor effect of hPD-1-IgV on tumor-bearing mice was tested. hPD-1-IgV recombinant protein could bind PD-L1 at molecular and cellular levels and enhance Cytotoxic T Lymphocyte (CTL) activity and anti-tumor effect on tumor-bearing mice in vivo. The percentage of CD4(+)CD25(+) T cells in tumor-bearing mice was decreased compared with control mice after administration of the recombinant protein. Our results suggest that inhibition of the interaction between PD-1 and PD-L1 by hPD-1-IgV may be a promising strategy for specific tumor immunotherapy.

Parameters for Pyrethroid Insecticide QSAR and PBPK/PD Models for Human Risk Assessment

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This pyrethroid insecticide parameter review is an extension of our interest in developing quantitative structure–activity relationship–physiologically based pharmacokinetic/pharmacodynamic (QSAR-PBPK/PD) models for assessing health risks, which interest started with the organoph...

Comparison of genotypic resistance profiles and virological response between patients starting nevirapine and efavirenz in EuroSIDA

DEFF Research Database (Denmark)

Bannister, Wendy P; Ruiz, Lidia; Cozzi-Lepri, Alessandro

2008-01-01

OBJECTIVE: To compare virological outcome and genotypic resistance profiles in HIV-1-infected patients starting non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens. METHODS: NNRTI-naive patients were included who started treatment with nevirapine (NVP) or efavirenz (EFV) wi...

Serum Bicarbonate And Survival In Peritoneal Dialysis (Pd: Comparison With Hemodialysis (Hd

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Tania Sharma

2012-06-01

Full Text Available Correction of metabolic acidosis is one of the goals of effective dialysis. The KDOQI guidelines recommend serum bicarbonate >22 meq/L irrespective of dialysis modality. Since the measured bicarbonate reflects the steady state in PD patients and the lowest inter-dialytic value in HD patients, we compared the survival predictability of serum bicarbonate 10,400 PD and 110,951 HD patients treated in DaVita facilities from 7/2001-6/2006 with follow-up through 6/2007. PD patients were substantially less likely to have lower serum bicarbonate (adjusted odds, 22 meq/L for all end-stage renal disease irrespective of dialysis modality.fx1

Systematic review of patient handling activities starting in lying, sitting and standing positions.

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Hignett, Sue

2003-03-01

Over the last 20 years a number of methods have been recommended in professional guidelines for moving patients. This review was undertaken as it was recognized that there was a need for clinical work involving handling patients (systems of work and equipment) to be based on scientific evidence. The aim of this paper is to report the methodology, search strategy and results relating to work involving the care, treatment and transfer of patients starting in lying, sitting and standing positions. An unusual philosophical stance has been taken by appraising studies within a study type rather than comparatively. This facilitated the inclusion of a wide range of study designs (quantitative and qualitative). A string search was run on eight databases and supplemented by other search strategies. A published checklist was selected and inter-rater reliability established before the main review commenced. A systematic process for inclusion, exclusion, appraisal, extraction and synthesis was undertaken. Thirty-two studies were included: nine for activities with the patient starting in a lying position and 23 for the sitting position. No studies were found with respect to patient handling activities starting in a standing position. These data were synthesized into evidence statements. The evidence statements support the use of hoists (for nonweight bearing patients), standaids, sliding sheets (double thickness rollers), lateral transfer boards, walking belts and adjustable height beds and baths. It is suggested that these items should constitute a minimum equipment list for any clinical environment where patient handling takes place on a regular basis. The lack of research relating to patient handling in standing is of particular concern and it is recommended that this area should be a high research priority to address concerns about patient handling in rehabilitation activities.

Global differences in dialysis modality mix: the role of patient characteristics, macroeconomics and renal service indicators.

Science.gov (United States)

van de Luijtgaarden, Moniek W M; Jager, Kitty J; Stel, Vianda S; Kramer, Anneke; Cusumano, Ana; Elliott, Robert F; Geue, Claudia; MacLeod, Alison M; Stengel, Benedicte; Covic, Adrian; Caskey, Fergus J

2013-05-01

An increase in the dialysis programme expenditure is expected in most countries given the continued rise in the number of people with end-stage renal disease (ESRD) globally. Since chronic peritoneal dialysis (PD) therapy is relatively less expensive compared with haemodialysis (HD) and because there is no survival difference between PD and HD, identifying factors associated with PD use is important. Incidence counts for the years 2003-05 were available from 36 countries worldwide. We studied associations of population characteristics, macroeconomic factors and renal service indicators with the percentage of patients on PD at Day 91 after starting dialysis. With linear regression models, we obtained relative risks (RRs) with 95% confidence intervals (CIs). The median percentage of incident patients on PD was 12% (interquartile range: 7-26%). Determinants independently associated with lower percentages of patients on PD were as follows: patients with diabetic kidney disease (per 5% increase) (RR 0.93; 95% CI 0.89-0.97), health expenditure as % gross domestic product (per 1% increase) (RR 0.93; 95% CI 0.87-0.98), private-for-profit share of HD facilities (per 1% increase) (RR 0.996; 95% CI 0.99-1.00; P = 0.04), costs of PD consumables relative to staffing (per 0.1 increase) (RR 0.97; 95% CI 0.95-0.99). The factors associated with a lower percentage of patients on PD include higher diabetes prevalence, higher healthcare expenditures, larger share of private-for-profit centres and higher costs of PD consumables relative to staffing. Whether dialysis modality mix can be influenced by changing healthcare organization and funding requires additional studies.

Implant R100 Predicts Rectal Bleeding in Prostate Cancer Patients Treated with IG-IMRT to 45 Gy and Pd-103 Implant

International Nuclear Information System (INIS)

Packard, M.; Fuhrer, R.; Valakh, V.

2014-01-01

Purpose. To define factors associated with rectal bleeding in patients treated with IG-IMRT followed by Pd-103 seed implant. Methods and Materials. We retrospectively reviewed 61 prostate adenocarcinoma patients from 2002 to 2008. The majority (85.2%) were of NCCN intermediate risk category. All received IG-IMRT to the prostate and seminal vesicles followed by Pd-103 implant delivering a mean D90 of 100.7 Gy. Six patients received 45 Gy to the pelvic nodes and 10 received androgen deprivation. Results. Ten patients (16.4%) developed rectal bleeding: 4 were CTCAE v.3 grade 1, 5 were grade 2, and 1 was grade 3. By univariate analysis, age, stage, Gleason sum, PSA, hormonal therapy, pelvic radiation, postoperative prostate volume, D9, V100, individual source activity, total implanted activity per cm 3 , and duration of interval before implant did not impact rectal bleeding. Implant R100 was higher in patients with rectal bleeding: on average, 0.885 versus 0.396 cm 3 ,(Ρ =0.02) , odds ratio of 2.26 per .5 cm 3 (95% CI, 1.16–4.82). A trend for significance was seen for prostate V200 and total implanted activity. Conclusion. Higher implant R100 was associated with development of rectal bleeding in patients receiving IG-IMRT to 45 Gy followed by Pd-103 implant. Minimizing implant R100 may reduce the rate of rectal bleeding in similar patients.

AB073. Classic infantile-onset Pompe disease: phenotypes and outcomes of 5 Vietnamese patients receiving enzyme replacement therapy

Science.gov (United States)

Nguyen, Khanh Ngoc; Do, Mai Thi Thanh; Can, Ngoc Thi Bich; Hwu, Wuh-Liang; Vu, Dung Chi

2017-01-01

Background Pompe disease (PD) or glycogen storage disease type II is a lysosomal storage disorder, caused by mutations of GAA gene which results in deficiency of acid alpha-glucosidase (GAA) enzyme that involves in metabolism of glycogen in the lysosomes. Its incidence is 1/14,000–1/100,000. PD is divided into three types: classic infantile onset, non-classic infantile onset, and late onset. Early enzyme replacement therapy (ERT) before developing respiratory distress may lead to good outcome. Since 2013, we have identified 16 cases with classic infantile-onset and 5 cases were treated with ERT. Herein, we describe phenotypes and outcomes of five infantile-onset PD patients who received ERT. Methods GAA enzyme assay was done at National Taiwan University Hospital. Results Ages of diagnosis were 12, 38 and 70 days, 5 and 9 months of age. Clinical presentations included macroglossia (5/5), hypertrophic cardiomyopathy (5/5), failure to thrive (5/5), facial weakness and hypotonia (3 patients diagnosed after 70 days of age), respiratory failure (1 patient diagnosed at 9 months of age). All patients had mildly elevated plasma CK (270–380 UI/L) and transaminase (60–260 UI/l). Ages at starting ERT were 28 and 58 days, 3, 6 and 10 months. The time intervals from diagnosis to starting ERT were between 14 days and 1 month. The durations of ERT were 4–22 months. The outcomes were good. All patients had improvement of cardiac functions shown on echocardiography, respiratory status, and motor development. The patient who first received ERT at 10 months of age was reportedly dead at home due to food obstruction at 18 months of age. Current ages of the survivors were 5–24 months. Conclusions Patients with classic infantile-onset PD will have good outcomes if ERT is started early. Newborn screening for this disease is necessary to yield an early diagnosis.

Generation of induced pluripotent stem cells (iPSC) from an atrial fibrillation patient carrying a KCNA5 p.D322H mutation

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Mora, Cristina; Serzanti, Marialaura; Giacomelli, Alessio

2017-01-01

. To investigate the molecular mechanisms underlying AF, we reprogrammed to pluripotency polymorphonucleated leukocytes isolated from the blood of a patient carrying a KCNA5 p.D322H mutation, using a commercially available non-integrating system. The generated iPSCs expressed pluripotency markers...... and differentiated toward cells belonging to the three embryonic germ layers. Moreover, the cells showed a normal karyotype and retained the p.D322H mutation....

Encapsulating peritoneal sclerosis in the era of a multi-disciplinary approach based on biocompatible solutions: the NEXT-PD study.

Science.gov (United States)

Nakayama, Masaaki; Miyazaki, Masanobu; Honda, Kazuho; Kasai, Kenji; Tomo, Tadashi; Nakamoto, Hidetomo; Kawanishi, Hideki

2014-01-01

Encapsulating peritoneal sclerosis (EPS) is a serious complication of peritoneal dialysis (PD). Over the past decade in Japan, a multidisciplinary approach has been adopted to minimize the incidence and improve outcomes of EPS. This strategy includes planned PD discontinuation for high-risk patients and the introduction of biocompatible solutions. This study examined the current clinical status of EPS in representative PD centers in Japan. Patients (n = 1,338) from 55 PD centers in Japan who were using neutral-pH solutions from the initiation of therapy (mean age, 62 years; median PD duration, 32 months; concomitant use of icodextrin, 35.2%; PD and hemodialysis combination therapy, 12.2%) were assessed every 6 months to ascertain the reasons for PD discontinuation and the development of EPS development. Outcomes were also recorded. The study period was from November 2008 to March 2012. There were 727 patients who discontinued PD, including 163 deaths. Among all causes of PD withdrawal except for death, planned PD discontinuation to avoid EPS was utilized in 58 cases (7.1% in total). The strategy was increasingly utilized in proportion to the duration of PD: 0.5% for patients undergoing PD for 8 years. Fourteen patients developed EPS (three cases after PD), which corresponded with an overall incidence of 1.0%. The incidence according to the duration of PD was 0.3% for PD 8 years. In terms of therapy, 11 patients were treated with prednisolone (PSL), and surgical enterolysis was utilized in two cases. Complete remission of abdominal symptoms was achieved in twelve patients (85.7%), and three died due to EPS (mortality rate of 21.4%). Use of the multidisciplinary approach described above reduces the risk of the development of EPS according to PD duration. In cases of de novo EPS cases in Japan, this strategy can also attenuate the clinical course of the condition. Copyright © 2014 International Society for Peritoneal Dialysis.

Effect of permanent 103Pd radioactive seed implantation on brachytherapy of malignant tumor

International Nuclear Information System (INIS)

Chen Ping; Wei Xianzhong; Liu Yanmin; Wu Kaijun; Liang Jianxin; Chen Hanzhang

2003-01-01

Objective: To investigate and assess the brachytherapeutic effectiveness of 103 Pd radioactive seeds in malignant tumor therapy. Methods: 196.1-2127.5 MBq 103 Pd seeds were implanted in 21 confirmed malignant tumor patients. The seeds were evenly scattered in 15/21 patients' tumors and peripherally in the remaining 6 cases' tumors. The size and shape, local recurrence and remote metastasis of the tumors were observed. Results: The brachytherapy of 103 Pd seeds in tumor patients resulted in obvious efficacy. No local recurrence and remote metastasis were observed. 19/21 (90.5%) patients scored 0 and 2/21 (9.5%) of them scored 1 in skin acute radiation morbidity scoring criteria within the observation period. Conclusion: The 103 Pd seeds can be safely used in brachytherapy of malignant tumors with lower or medium sensitivity to radiation therapy

Mild parkinsonian signs in the elderly--is there an association with PD? Crossectional findings in 992 individuals.

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Stefanie Lerche

Full Text Available Mild parkinsonian signs (MPS are common in the elderly population, and have been associated with vascular diseases, mild cognitive impairment and dementia; however their relation to Parkinson's disease (PD is unclear. Hypothesizing that individuals with MPS may reflect a pre-stage of PD, i.e. a stage in which the nigrostriatal system is already affected although to a milder degree than at the time of PD diagnosis, aim of this study was to evaluate the similarities between MPS and PD.The TREND study is a prospective cross-sectional cohort study in individuals >50 years with biennial assessments designed to identify markers for an earlier diagnosis of Parkinson's and Alzheimer's disease. For this substudy 992 individuals were included for analyses (892 controls, 73 MPS individuals, 27 PD patients. Parameters defining risk of PD (sex, age, positive family history, prodromal markers (hyposmia, REM sleep behavior disorder, depression and autonomic failure as well as quantitative fine motor, axial motor and cognitive parameters were compared between the three cohorts.As expected, PD patients differed from controls with regard to 12 of 15 of the assessed parameters. MPS individuals differed significantly from controls in 12 of the PD-associated parameters, but differed from PD only in 5 parameters.This study shows that individuals with MPS share many prodromal and clinical markers of PD with PD patients, implying that either a common dynamic process or similar constitutional factors occur in MPS individuals and PD patients.

UK Renal Registry 15th annual report: Chapter 8 UK multisite peritoneal dialysis access catheter audit for first PD catheters 2011.

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Briggs, Victoria; Pitcher, David; Braddon, Fiona; Fogarty, Damian; Wilkie, Martin

2013-01-01

The central paradigm of effective peritoneal dialysis (PD) is an appropriate standard of PD catheter function. The aim of the project was to develop an effective national PD access audit which would identify an 'appropriate standard' of PD catheter function. The UK Renal Registry collected centre specific information on various PD access outcome measures including catheter functionality and post-insertion complications. The first PD access audit covering England, Northern Ireland and Wales was conducted during April to June 2012 looking at incident dialysis patients in 2011. Forty three data collection spreadsheets were returned from a total of 65 centres describing 917 PD catheter placements. The median age of PD patients was 61 years and 61.5% were male. The proportion of patients initiated on PD in comparison to HD was lower in socially deprived areas. There was a relationship between the timing of nephrology referral and the likelihood of surgical assessment regarding PD catheter placement. Patients with diabetes did not have higher rates of PD catheter failure or of early peritonitis. A comparative PD catheter audit has the potential to provide valuable information on an important patient related outcome measure and lead to an improvement in patient experience. There was wide variation between centres of PD catheter use for late presenting patients. Overall patients were more likely to get a PD catheter if they had been known to the service for more than 1 year. The percutaneous insertion technique was associated with a higher early (less than 2 week) peritonitis rate and more catheter flow problems. Copyright © 2013 S. Karger AG, Basel.

PD-1 and PD-L1 as emerging therapeutic targets in gastric cancer: current evidence

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Tran PN

2017-05-01

Full Text Available Phu N Tran,1* Sarmen Sarkissian,1* Joseph Chao,2 Samuel J Klempner3,4 1Division of Hematology-Oncology, University of California Irvine, Orange, 2Department of Medical Oncology and Developmental Therapeutics, City of Hope, Duarte, 3Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 4The Angeles Clinic and Research Institute, Los Angeles, CA, USA *These authors contributed equally to this work Abstract: Gastric adenocarcinoma is a leading cause of global cancer-related morbidity and mortality, and new therapeutic approaches are needed. Despite the improved outcomes with monoclonal antibodies targeting human epidermal growth factor receptor 2 and vascular endothelial growth factor receptor 2, durable responses are uncommon. Targeting immune checkpoints including PD-1, PD-L1 and CTLA-4 have led to improved survival across several tumor types, frequently characterized by prolonged benefit in responding patients. Tumoral and lymphocyte-derived immunohistochemical staining for PD-1, PD-L1, and tumor mutational burden have shown potential as predictive response biomarkers in several tumor types. Optimal incorporation of immune-mediated therapies into gastric cancer (GC is an area of intense ongoing investigation and benefit has been demonstrated in smaller studies of advanced patients. Important questions of biomarker selection, roles for molecular characterization, optimal combinatorial approaches, and therapeutic sequencing remain. In this study, current data are reviewed for immune checkpoint inhibitors in GC, and putative biomarkers, ongoing trials, and future considerations are discussed. Keywords: immunotherapy, stomach cancer, checkpoint inhibitor, nivolumab, pembrolizumab, tumor mutational burden

Immune recovery after starting ART in HIV-infected patients presenting and not presenting with tuberculosis in South Africa.

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Schomaker, Michael; Egger, Matthias; Maskew, Mhairi; Garone, Daniela; Prozesky, Hans; Hoffmann, Christopher J; Boulle, Andrew; Fenner, Lukas

2013-05-01

We studied the immune response after starting antiretroviral treatment (ART) in 15,646 HIV-infected patients with or without tuberculosis (TB) at presentation in 3 ART programs in South Africa between 2003 and 2010. Patients presenting with TB had similar increases in CD4 cells compared with all other patients (adjusted difference 4.9 cells/µL per 6 months, 95% confidence interval: 0.2 to 9.7). Younger age, advanced clinical stage, female sex, and lower CD4 cell count at ART start were all associated with steeper CD4 slopes. In South Africa, HIV-infected patients presenting with TB experience immune recovery after starting ART that is no worse than in other patients.

[Peritonitis in pediatric patients receiving peritoneal dialysis].

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Jellouli, Manel; Ferjani, Meriem; Abidi, Kamel; Hammi, Yosra; Boutiba, Ilhem; Naija, Ouns; Zarrouk, Chokri; Ben Abdallah, Taieb; Gargah, Tahar

2015-12-01

Peritonitis on catheter of dialysis represents the most frequent complication of the peritoneal dialysis (PD) in the pediatric population. It remains a significant cause of morbidity and mortality. In this study, we investigated the risk factors for peritonitis in children. In this study, we retrospectively collected the records of 85 patients who were treated with PD within the past ten years in the service of pediatrics of the University Hospital Charles-Nicolle of Tunis. Peritonitis rate was 0.75 episode per patient-year. Notably, peritonitis caused by Gram-positive organisms were more common. Analysis of infection risk revealed three significant independent factors: the poor weight (P=0.0045), the non-automated PD (P=0.02) and the short delay from catheter insertion to starting PD (P=0.02). The early onset peritonitis was significantly associated with frequent peritonitis episodes (P=0.0008). The mean duration between the first and second episode of peritonitis was significantly shorter than between PD commencement and the first episode of peritonitis. We revealed a significant association between Gram-negative peritonitis and the presence of ureterostomy (0.018) and between Gram-positive peritonitis and the presence of exit-site and tunnel infections (0.02). Transition to permanent hemodialysis was needed in many children but no death occurred in patients with peritonitis. Considering the important incidence of peritonitis in our patients, it is imperative to establish a targeted primary prevention. Nutritional care must be provided to children to avoid poor weight. The automated dialysis has to be the modality of choice. Copyright © 2015 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.

Limb/trunk lean mass ratio as a risk factor for mortality in peritoneal dialysis patients

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Seok Hui Kang

2012-06-01

Full Text Available Protein energy wasting (PEW is a common problem in dialysis patients. There have been few reports on the effects of regional lean mass distribution for peritoneal dialysis (PD patients. We reviewed the medical records and identified all adults who received PD between May 2001 and May 2011. Five hundred thirty four patients were enrolled. The clinical and laboratory data were collected at 1 and 12 months. Regional lean masses were measured by dual-energy X-ray absorptiometry. The limb/trunk lean mass ratio (LTLM was defined as a value on dividing the sum of four limbs by the trunk lean mass. The mean age at the start of PD was 53.2±14.1 years. Diabetes mellitus (DM was most common underlying disease of end-stage renal disease (49.6%. In males, the low LTLM tertile was associated with low body mass index, creatinine, arm muscle circumference, and high C-reactive protein. In females, the low LTLM tertile was associated with low creatinine and normalized protein equivalent of nitrogen appearance. On both univariate and multivariate analysis adjusted for age, Davies risk index, and residual renal function, initial low LTLM tertile and maintenance of low LTLM were associated with mortality in PD patients. Distribution or change of regional lean mass may be more useful for predicting nutritional status. Initial low LTLM and maintenance of low LTLM were associated with mortality in PD patients. LTLM as a new marker would be useful for predicting the nutritional status and the mortality in patients on PD.

Phenotypic Characteristics of PD-1 and CTLA-4 Expression in Symptomatic Acute Hepatitis A.

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Cho, Hyosun; Kang, Hyojeung; Kim, Chang Wook; Kim, Hee Yeon; Jang, Jeong Won; Yoon, Seung Kew; Lee, Chang Don

2016-03-01

The immunoregulatory molecules programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are associated with the dysfunction of antiviral effector T-cells, which leads to T-cell exhaustion and persistent viral infection in patients with chronic hepatitis C and chronic hepatitis B. Little is known about the role of PD-1 and CTLA-4 in patients with symptomatic acute hepatitis A (AHA). Peripheral blood mononuclear cells were isolated from seven patients with AHA and from six patients with nonviral acute toxic hepatitis (ATH) during the symptomatic and convalescent phases of the respective diseases; five healthy subjects acted as controls. The expression of PD-1 and CTLA-4 on T-cells was measured by flow cytometry. PD-1 and CTLA-4 expression during the symptomatic phase was significantly higher in the T-cells of AHA patients than in those of ATH patients or healthy controls (PD-1 18.3% vs 3.7% vs 1.6%, respectively, p<0.05; CTLA-4 23.5% vs 6.1% vs 5.9%, respectively, p<0.05). The levels of both molecules decreased dramatically during the convalescent phase of AHA, whereas a similar pattern was not seen in ATH. Our findings are consistent with a viral-protective effect of PD-1 and CTLA-4 as inhibitory molecules that suppress cytotoxic T-cells and thereby prevent the destruction of virus-infected hepatocytes in AHA.

Synthesis and characterization of Pd@M(x)Cu(1-x) (M = Au, Pd, and Pt) nanocages with porous walls and a yolk-shell structure through galvanic replacement reactions.

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Xie, Shuifen; Jin, Mingshang; Tao, Jing; Wang, Yucai; Xie, Zhaoxiong; Zhu, Yimei; Xia, Younan

2012-11-19

This paper describes the synthesis of Pd@M(x)Cu(1-x) (M = Au, Pd, and Pt) nanocages with a yolk-shell structure through galvanic replacement reactions that involve Pd@Cu core-shell nanocubes as sacrificial templates and ethylene glycol as the solvent. Compared with the most commonly used templates based on Ag, Cu offers a much lower reduction potential (0.34 versus 0.80 V), making the galvanic reaction more easily to conduct, even at room temperature. Our structural and compositional characterizations indicated that the products were hollow inside, and each one of them contained porous M-Cu alloy walls and a Pd cube in the interior. For the Pd@Au(x)Cu(1-x) yolk-shell nanocages, they displayed broad extinction peaks extending from the visible to the near-IR region. Our mechanistic study revealed that the dissolution of the Cu shell preferred to start from the slightly truncated corners and then progressed toward the interior, because the Cu {100} side faces were protected by a surface capping layer of hexadecylamine. This galvanic approach can also be extended to generating other hollow metal nanostructures by using different combinations of Cu nanostructures and salt precursors. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Peripheral myeloid-derived suppressor and T regulatory PD-1 positive cells predict response to neoadjuvant short-course radiotherapy in rectal cancer patients

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Napolitano, Maria; D'Alterio, Crescenzo; Cardone, Eleonora; Trotta, Anna Maria; Pecori, Biagio; Rega, Daniela; Pace, Ugo; Scala, Dario; Scognamiglio, Giosuè; Tatangelo, Fabiana; Cacciapuoti, Carmela; Pacelli, Roberto; Delrio, Paolo; Scala, Stefania

2015-01-01

Short-course preoperative radiotherapy (SC-RT) followed by total mesorectal excision (TME) is one therapeutic option for locally advanced rectal cancer (LARC) patients. Since radio-induced DNA damage may affect tumor immunogenicity, Myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs) were evaluated in 13 patients undergoing SC-RT and TME for LARC. Peripheral Granulocytic-MDSCs (G-MDSC) [LIN−/HLA-DR−/CD11b+/CD14−/CD15+/CD33+], Monocytic (M-MDSC) [CD14+/HLA-DR−/lowCD11b+/CD33+] and Tregs [CD4+/CD25hi+/FOXP3+- CTLA-4/PD1] basal value was significantly higher in LARC patients compared to healthy donors (HD). Peripheral MDSC and Tregs were evaluated at time 0 (T0), after 2 and 5 weeks (T2-T5) from radiotherapy; before surgery (T8) and 6–12 months after surgery (T9, T10). G-MDSC decreased at T5 and further at T8 while M-MDSC cells decreased at T5; Tregs reached the lowest value at T5. LARC poor responder patients displayed a major decrease in M-MDSC after SC-RT and an increase of Treg-PD-1. In this pilot study MDSCs and Tregs decrease during the SC-RT treatment could represent a biomarker of response in LARC patients. Further studies are needed to confirm that the deepest M-MDSC reduction and increase in Treg-PD1 cells within 5–8 weeks from the beginning of treatment could discriminate LARC patients poor responding to SC-RT. PMID:25823653

Synthesis of 2-vinylic indoles and derivatives via a Pd-catalyzed tandem coupling reaction.

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Fayol, Aude; Fang, Yuan-Qing; Lautens, Mark

2006-09-14

A novel one-step synthesis of valuable 2-vinylic indoles and their tricycle derivatives is described. This reaction, which utilizes a gem-dibromovinyl unit as a readily available starting material, occurs via an efficient Pd-catalyzed tandem Buchwald-Hartwig/Heck reaction.

FOXP3+ Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: Implication for immunotherapy

International Nuclear Information System (INIS)

Ghebeh, Hazem; Barhoush, Eman; Tulbah, Asma; Elkum, Naser; Al-Tweigeri, Taher; Dermime, Said

2008-01-01

Recent studies have demonstrated a direct involvement of B7-H1, PD-1 and FOXP3 molecules in the immune escape of cancer. B7-H1 is an inhibitory molecule that binds to PD-1 on T lymphocytes, while FOXP3 is a marker for regulatory T cells (T regs ). We have previously demonstrated the association of B7-H1-expressing T infiltrating lymphocytes (TIL) with high-risk breast cancer patients while other studies reported the involvement of FOXP3+ T regs as a bad prognostic factor in breast tumors. Although the co-existence between the two types of cells has been demonstrated in vitro and animal models, their relative infiltration and correlation with the clinicopathological parameters of cancer patients have not been well studied. Therefore, we investigated TIL-expressing the B7-H1, PD-1, and FOXP3 molecules, in the microenvironment of human breast tumors and their possible association with the progression of the disease. Using immunohistochemistry, tumor sections from 62 breast cancer patients were co-stained for B7-H1, PD-1 and FOXP3 molecules and their expression was statistically correlated with factors known to be involved in the progression of the disease. A co-existence of B7-H1 + T lymphocytes and FOXP3 + T regs was evidenced by the highly significant correlation of these molecules (P < .0001) and their expression by different T lymphocyte subsets was clearly demonstrated. Interestingly, concomitant presence of FOXP3 + T regs , B7-H1 + and PD-1 + TIL synergistically correlated with high histological grade (III) (P < .001), estrogen receptor negative status (P = .017), and the presence of severe lymphocytic infiltration (P = .022). Accumulation of TIL-expressing such inhibitory molecules may deteriorate the immunity of high-risk breast cancer patients and this should encourage vigorous combinatorial immunotherapeutic approaches targeting T regs and B7-H1/PD-1 molecules

Controlling the size and morphology of Au@Pd core-shell nanocrystals by manipulating the kinetics of seeded growth.

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Li, Jing; Zheng, Yiqun; Zeng, Jie; Xia, Younan

2012-06-25

This article reports a systematic study of the seed-mediated growth of Au@Pd core-shell nanocrystals with a variety of controlled sizes and morphologies. The key to the success of this synthesis is to manipulate the reaction kinetics by tuning a set of reaction parameters, including the type and concentration of capping agent, the amount of ascorbic acid used as the reducing agent, and the injection rate used for the precursor solution. Starting from Au nanospheres of 11 nm in diameter as the seeds, Au@Pd core-shell nanocrystals with a number of morphologies, including octahedra, concave octahedra, rectangular bars, cubes, concave cubes, and dendrites, could all be obtained by simply altering the reaction rate. For the first time, it was possible to generate Au@Pd nanocrystals with concave structures on the surfaces while their sizes were kept below 20 nm. In addition, the as-prepared Au@Pd nanocubes can be used as seeds to generate Au@Pd@Au and Au@Pd@Au@Pd nanocrystals with multishelled structures. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PD-1/PD-L signaling pathway in chronic hepatitis B

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TAO Lilin

2016-12-01

Full Text Available Hepatitis B is one of the major diseases that affect the health of Chinese people, and chronic hepatitis B virus (HBV infection can lead to disease progression. Programmed death-1 (PD-1 discovered in recent years is an important coordinated stimulus molecule which belongs to the B7/CD28 family. After its binding with programmed death ligand (PD-L, it can regulate the activation, differentiation, and proliferation of T lymphocytes. PD-1 and its ligand are differently expressed in different stages of chronic HBV infection. The interaction between PD-1 and its ligand in different immune cells induces immune tolerance in human body and finally leads to the chronicity of HBV infection. Blocking the PD-1/PD-L signaling pathway through different ways can improve T cell exhaustion, suggesting that this might be one of the directions of antiviral therapy in future.

Increased Expression and Modulated Regulatory Activity of Coinhibitory Receptors PD-1, TIGIT, and TIM-3 in Lymphocytes From Patients With Systemic Sclerosis.

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Fleury, Michelle; Belkina, Anna C; Proctor, Elizabeth A; Zammitti, Christopher; Simms, Robert W; Lauffenburger, Douglas A; Snyder-Cappione, Jennifer E; Lafyatis, Robert; Dooms, Hans

2018-04-01

Immune dysfunction is an important component of the disease process underlying systemic sclerosis (SSc), but the mechanisms contributing to altered immune cell function in SSc remain poorly defined. This study was undertaken to measure the expression and function of the coinhibitory receptors (co-IRs) programmed cell death 1 (PD-1), T cell immunoglobulin and ITIM domain (TIGIT), T cell immunoglobulin and mucin domain 3 (TIM-3), and lymphocyte activation gene 3 (LAG-3) in lymphocyte subsets from the peripheral blood of patients with SSc. Co-IR expression levels on subsets of immune cells were analyzed using a 16-color flow cytometry panel. The functional role of co-IRs was determined by measuring cytokine production after in vitro stimulation of SSc and healthy control peripheral blood mononuclear cells (PBMCs) in the presence of co-IR-blocking antibodies. Supernatants from cultures of stimulated PBMCs were added to SSc fibroblasts, and their impact on fibroblast gene expression was measured. Mathematical modeling was used to reveal differences between co-IR functions in SSc patients and healthy controls. Levels of the co-IRs PD-1 and TIGIT were increased, and each was coexpressed, in distinct T cell subsets from SSc patients compared to healthy controls. Levels of TIM-3 were increased in SSc natural killer cells. PD-1, TIGIT, and TIM-3 antibody blockade revealed patient-specific roles of each of these co-IRs in modulating activation-induced T cell cytokine production. In contrast to healthy subjects, blockade of TIGIT and TIM-3, but not PD-1, failed to reverse inhibited cytokine production in SSc patients, indicating that enhanced T cell exhaustion is present in SSc. Finally, cytokines secreted in anti-TIM-3-treated PBMC cultures distinctly changed the gene expression profile in SSc fibroblasts. The altered expression and regulatory capacity of co-IRs in SSc lymphocytes may contribute to disease pathophysiology by modulating the cytokine-mediated cross-talk of

[Satisfaction of patients with type 2 diabetes mellitus after starting treatment with insulin].

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Mancera-Romero, J; Carramiñana-Barrera, F; Muñoz-González, L; Guillén-Álvarez, P; Murillo-García, D; Sánchez-Pérez, M R

2016-01-01

The objective of this study is to evaluate if overcoming the barrier of starting treatment with insulin can lead to better clinical control and a higher level of patient satisfaction with their treatment. This is an observational, multicentre study of patients diagnosed with DM2 who attended primary care centres with poor glycaemic control (A1c≥8%) under treatment with oral antidiabetic drugs (OADs), and who were given motivational treatment to overcome their fear of injections, and started treatment with insulin. The level of satisfaction with the treatment was evaluated using the Diabetes Treatment Satisfaction Questionnaire (DTSQ). The questionnaire was used before initiating the treatment with insulin and in the follow-up visit (3-4 months from the beginning of treatment with basal insulin). A total of 573 patients with a mean age of 64±10 years were recruited. The overall mean score from the DTSQs satisfaction questionnaire was 18.3±6.3, and the change of treatment led to an improvement in patient satisfaction compared to the previous treatment (DTSQc mean score 8.8±5.9). A1c dropped from an initial value of 8.7% (SD 0.8) to 7.5% (SD 0.7) (P<.001). The frequency of hyperglycaemic episodes perceived by the patients was significantly lower after they overcame their fear of injections (35.6% compared to 11.5%; P<.001), but no statistically significant differences were found in the frequency of hypoglycaemic episodes (32% compared to 35%; P=.059). In patients with DM2 poorly controlled with OADs, overcoming a fear of injections and starting treatment with insulin was associated with an overall improvement in satisfaction with the new treatment, and decreased the perception of hyperglycaemic episodes. Glycaemic control and the metabolic profile of the patients also improved to a statistically significant degree with the change of treatment. Copyright © 2015 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S

CD3+/CD8+ T-cell density and tumoral PD-L1 predict survival irrespective of rituximab treatment in Chinese diffuse large B-cell lymphoma patients.

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Shi, Yunfei; Deng, Lijuan; Song, Yuqin; Lin, Dongmei; Lai, Yumei; Zhou, LiXin; Yang, Lei; Li, Xianghong

2018-05-10

To investigate the prognostic value of tumor-infiltrating T-cell density and programmed cell death ligand-1 (PD-L1) expression in diffuse large B cell lymphoma (DLBCL). One-hundred-twenty-five Chinese DLBCL patients were enrolled in our study and provided samples; 76 of all cases were treated with rituximab (R). Tumor tissues were immunostained and analyzed for CD3+ and CD8+ tumor-infiltrating T-cell density, tumoral PD-L1, and microenvironmental PD-L1 (mPD-L1). The density of CD3 was rated as high in 33.6% cases, while 64.0% of DLBCLs were classified as high CD8 density. Of all cases, 16.8% were PD-L1+. Of the remaining PD-L1-DLBCLs, 29.8% positively expressed mPD-L1. Both CD3 high density and CD8 high density were associated with mPD-L1 positivity (P = 0.001 and P = 0.0001). In multivariate analysis, independently, high CD3 density predicted better OS (P = 0.023), while CD8 high density and PD-L1 positivity were both associated with prolonged PFS (P = 0.013 and P = 0.036, respectively). Even in the subgroup treated with R, univariate analyses indicated that high CD3 density and PD-L1 positivity were associated with better OS (P = 0.041) and PFS (P = 0.033), respectively. The infiltrating densities of CD3+ T-cells, CD8+ T-cells, and PD-L1 expression are predictive of survival in DLBCLs, irrespective of R usage.

Psychosocial Factors Predict Nonadherence to PD Treatment: A Hong Kong Survey.

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Fung, Timothy K F; Ng, Yu Leung; Lam, Man Fai; Lee, Kelvin K W

2017-01-01

♦ BACKGROUND: Nonadherence to hand hygiene and aseptic regimen, dialysis environment guidelines, and catheter and exit-site care guidelines are risk factors of peritonitis. However, little is known about the psychosocial factors that account for the nonadherent behavior of patients undergoing peritoneal dialysis (PD). Applying the health belief model, this study seeks to enhance the understanding of psychosocial influences on patients' nonadherent behavior to the 3 regimen components. ♦ METHODS: Through referrals by 7 Hong Kong renal patient support groups, we surveyed patients undergoing PD treatment. ♦ RESULTS: A total of 244 Hong Kong PD patients completed the questionnaires. About 90% of the patients reported no deviation from catheter and exit-site care guidelines. However, the nonadherence rates of hand hygiene and aseptic regimen and of dialysis environment guidelines were 30.3% and 23%, respectively. Longer time on PD treatment and lower family monthly income were associated with nonadherence to dialysis environment guidelines. Employed patients tended toward nonadherence to catheter and exit-site care guidelines twice as much as unemployed patients. Of the 5 health beliefs, perceived benefits, perceived barriers, and efficacy belief were significant predictors of nonadherence to the 3 regimen components. ♦ CONCLUSIONS: The findings of this study inform the design of intervention to change patients' behavior in regimen nonadherence for preventing peritonitis. To identify the target audience for adherence intervention based on the 3 regimen components, the results suggest dividing patients into subgroups according to their sociodemographic background. To foster behavioral change, health communicators should address patients' health beliefs when formulating intervention strategies. Copyright © 2017 International Society for Peritoneal Dialysis.

Effect of center practices on the choice of the first dialysis modality for children and young adults.

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Hogan, Julien; Ranchin, Bruno; Fila, Marc; Harambat, Jérome; Krid, Saoussen; Vrillon, Isabelle; Roussey, Gwenaelle; Fischbach, Michel; Couchoud, Cécile

2017-04-01

Peritoneal dialysis (PD) remains the modality of choice in children, but there is no clear evidence to support a better outcome in children treated with PD. We aimed to assess factors that have an impact on the choice of dialysis modality in children and young adults in France and sought to determine the roles of medical factors and center practices. We included all patients aged dialysis modality. We included 806 patients starting RRT in 177 centers, 23 of which were specialized pediatric centers. Six hundred and one patients (74.6 %) started with hemodialysis (HD), whereas 205 (25.4 %) started with PD. A greater probability of PD was found in younger children, whereas starting the treatment in an emergency setting was associated with a low use of PD. We found a significant variability among centers that accounted for 43 % of the total variability. The probability of PD was higher in adult centers and was proportional to the rate of PD in the center. Center practices are a major factor in the choice of dialysis modality. This raises concerns about patient and family choices and to what extent doctors may influence the final decision. Further pediatric studies focusing on children's and parents' wishes are needed to provide care as close as possible to patients' and families' expectations.

RAC1 P29S regulates PD-L1 expression in melanoma

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Vu, Ha Linh; Rosenbaum, Sheera; Purwin, Timothy J.; Davies, Michael A.; Aplin, Andrew E.

2015-01-01

Summary Whole exome sequencing of cutaneous melanoma has led to the detection of P29 mutations in RAC1 in 5–9% of samples, but the role of RAC1 P29 mutations in melanoma biology remains unclear. Using reverse phase protein array analysis to examine the changes in protein/phospho-protein expression, we identified cyclin B1, PD-L1, Ets-1, and Syk as being selectively upregulated with RAC1 P29S expression and downregulated with RAC1 P29S depletion. Using the melanoma patient samples in TCGA, we found PD-L1 expression to be significantly increased in RAC1 P29S patients compared to RAC1 WT as well as other RAC1 mutants. The finding that PD-L1 is upregulated suggests that oncogenic RAC1 P29S may promote suppression of the antitumor immune response. This is a new insight into the biological function of RAC1 P29S mutations with potential clinical implications as PD-L1 is a candidate biomarker for increased benefit from treatment with anti-PD1 or anti-PD-L1 antibodies. PMID:26176707

Independent Validation of the SEND-PD and Correlation with the MDS-UPDRS Part IA

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Mayela Rodríguez-Violante

2014-01-01

Full Text Available Introduction. Neuropsychiatric symptoms in Parkinson’s disease can be assessed by the MDS-UPDRS part IA. The Scale for Evaluation of Neuropsychiatric Disorders in Parkinson’s disease (SEND-PD has been recently developed to assess the severity of some neuropsychiatric symptoms. The objective of this study is to compare the performance of the SEND-PD with the corresponding items of the MDS-UPDRS part IA. Methods. Patients with Parkinson’s disease were evaluated using the MDS-UPDRS and the SEND-PD by independent raters. Partial SEND-PD and neuropsychiatric MDS-UPDRS part IA were constructed with equivalent items for comparison. Results. A total of 260 consecutive patients were included. Overall, 61.2% of the patients did not report any psychotic symptom and 83.5% did not report any ICD symptom. On the other hand, 78.5% of the patients did report at least one symptom related to apathy, depression, or anxiety. The partial SEND-PD score was 2.9±3.1 (range from 0 to 16. The neuropsychiatric MDS-UPDRS part IA score was 2.9±3 (range from 0 to 14. The correlation coefficient between corresponding items ranged from 0.67 to 0.98 and between both summary indexes was rs=0.93 (all, P<0.001. Conclusion. A high association between equivalent items of the SEND-PD and the MDS-UPDRS was found.

The patients’ perspective: Results of a survey assessing knowledge about and attitudes toward depression in PD

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Irene Hegeman Richard

2007-01-01

Full Text Available Irene Hegeman Richard1, Kori A LaDonna1, Rosanne Hartman2, Carol Podgorski1, Roger Kurlan1, SAD-PD Study Group31University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; 2Canisius College, Buffalo, NY, USA; 3Please see Appendix for members of the SAD-PD Study GroupAbstract: We report results of a survey assessing patients’ knowledge about and attitudes towards depression in Parkinson’s disease (PD. 345 patients from 8 tertiary care centers responded (43% response rate. Overall, patients were relatively knowledgeable about depression and its occurrence in PD. However, many patients believed that depression is a normal reaction to the illness. While many respondents would be reluctant to initiate a discussion of depression during a clinical evaluation, most would feel comfortable talking about depression with their physician if he or she asked them questions about their mood. Based on the results of this survey, we recommend the following approach for physicians: (1 inform PD patients that, although a frequent occurrence, depression need not be accepted as a “normal reaction” to PD; and (2 routinely inquire about depressive symptoms rather than waiting for the patient to spontaneously report them.Keywords: depression, Parkinson’s disease, survey

Influence of surface melting effects and availability of reagent ions on LDI-MS efficiency after UV laser irradiation of Pd nanostructures.

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Silina, Yuliya E; Koch, Marcus; Volmer, Dietrich A

2015-03-01

In this study, the influence of surface morphology, reagent ions and surface restructuring effects on atmospheric pressure laser desorption/ionization (LDI) for small molecules after laser irradiation of palladium self-assembled nanoparticular (Pd-NP) structures has been systematically studied. The dominant role of surface morphology during the LDI process, which was previously shown for silicon-based substrates, has not been investigated for metal-based substrates before. In our experiments, we demonstrated that both the presence of reagent ions and surface reorganization effects--in particular, melting--during laser irradiation was required for LDI activity of the substrate. The synthesized Pd nanostructures with diameters ranging from 60 to 180 nm started to melt at similar temperatures, viz. 890-898 K. These materials exhibited different LDI efficiencies, however, with Pd-NP materials being the most effective surface in our experiments. Pd nanostructures of diameters >400-800 nm started to melt at higher temperatures, >1000 K, making such targets more resistant to laser irradiation, with subsequent loss of LDI activity. Our data demonstrated that both melting of the surface structures and the presence of reagent ions were essential for efficient LDI of the investigated low molecular weight compounds. This dependence of LDI on melting points was exploited further to improve the performance of Pd-NP-based sampling targets. For example, adding sodium hypophosphite as reducing agent to Pd electrolyte solutions during synthesis lowered the melting points of the Pd-NP materials and subsequently gave reduced laser fluence requirements for LDI. Copyright © 2015 John Wiley & Sons, Ltd.

Recovery of high-purity metallic Pd from Pd(II)-sorbed biosorbents by incineration.

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Won, Sung Wook; Lim, Areum; Yun, Yeoung-Sang

2013-06-01

This work reports a direct way to recover metallic palladium with high purity from Pd(II)-sorbed polyethylenimine-modified Corynebacterium glutamicum biosorbent using a combined method of biosorption and incineration. This study is focused on the incineration part which affects the purity of recovered Pd. The incineration temperature and the amount of Pd loaded on the biosorbent were considered as major factors in the incineration process, and their effects were examined. The results showed that both factors significantly affected the enhancement of the recovery efficiency and purity of the recovered Pd. SEM-EDX and XRD analyses were used to confirm that Pd phase existed in the ash. As a result, the recovered Pd was changed from PdO to zero-valent Pd as the incineration temperature was increased from 600 to 900°C. Almost 100% pure metallic Pd was recovered with recovery efficiency above 99.0% under the conditions of 900°C and 136.9 mg/g. Copyright © 2013 Elsevier Ltd. All rights reserved.

Immuno-Oncology Biomarkers for Gastric and Gastroesophageal Junction Adenocarcinoma: Why PD-L1 Testing May Not Be Enough.

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Weinberg, Benjamin A; Xiu, Joanne; Hwang, Jimmy J; Shields, Anthony F; Salem, Mohamed E; Marshall, John L

2018-04-27

The treatment of patients with advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinomas has been transformed by the U.S. Food and Drug Administration approval of pembrolizumab. Tumor and adjacent tissue must stain positively for the programmed cell death ligand 1 (PD-L1) protein by companion diagnostic testing. However, some patients with PD-L1-negative tumors also benefit from pembrolizumab. High microsatellite instability (MSI) and tumor mutational load (TML) are positive predictive biomarkers for immune checkpoint inhibition (ICI) in other tumors. We sought to identify more patients who could benefit from ICI using alternative PD-L1 thresholds, MSI, and TML. Tumor specimens underwent next-generation sequencing (NGS) and PD-L1 testing using immunohistochemistry. NGS was used to determine TML and MSI. We profiled 581 G/GEJ adenocarcinoma specimens. PD-L1 staining was scored for intensity (0, none; 1+, weak; 2+, moderate; 3+, strong). Using 2+ staining at a 5% threshold, 9.3% of tumors were PD-L1 positive, and using 1+ staining at 1%, 16.2% were PD-L1 positive. 6.9% of tumors had high MSI. High TML (≥17 mutations per megabase) was seen in 6.9%, and medium TML (≥7) was seen in 56.5% of tumors. Thirty (5.2%) PD-L1-negative tumors at the 1+, 1% threshold had high TML or high MSI. Primary tumors had higher rates of high TML (8.8% vs. 3.9%; p  = .0377) and high MSI (8.5% vs. 3.9%; p  = .0471) than metastases. PD-L1 testing alone fails to detect patients who may benefit from ICI. Lower PD-L1 thresholds and TML testing should be considered in future clinical trials. Pembrolizumab is approved by the U.S. Food and Drug Administration for patients with refractory gastric and gastroesophageal cancers if the tumor and adjacent tissue stain positively for the programmed cell death ligand 1 (PD-L1) protein by companion diagnostic testing. Tumor mutational load, microsatellite instability (MSI), and alternative PD-L1 testing thresholds may serve as

Investigating unexpected magnetism of mesoporous silica-supported Pd and PdO nanoparticles

KAUST Repository

Song, Hyon Min

2015-01-13

The synthesis and magnetic behavior of matrix-supported Pd and PdO nanoparticles (NPs) are described. Mesoporous silica with hexagonal columnal packing is selected as a template, and the impregnation method with thermal annealing is used to obtain supported Pd and PdO NPs. The heating rate and the annealing conditions determine the particle size and the phase of the NPs, with a fast heating rate of 30 °C/min producing the largest supported Pd NPs. Unusual magnetic behaviors are observed. (1) Contrary to the general belief that smaller Pd NPs or cluster size particles have higher magnetization, matrix-supported Pd NPs in this study maintain the highest magnetization with room temperature ferromagnetism when the size is the largest. (2) Twin boundaries along with stacking faults are more pronounced in these large Pd NPs and are believed to be the reason for this high magnetization. Similarly, supported PdO NPs were prepared under air conditions with different heating rates. Their phase is tetragonal (P42/mmc) with cell parameters of a = 3.050 Å and c = 5.344 Å, which are slightly larger than in the bulk phase (a = 3.03 Å, c = 5.33 Å). Faster heating rate of 30 °C/min also produces larger particles and larger magnetic hysteresis loop, although magnetization is smaller and few twin boundaries are observed compared to the supported metallic Pd NPs.

Theoretical analysis of hydrogen chemisorption on Pd(111), Re(0001) and PdML/Re(0001), ReML/Pd(111) pseudomorphic overlayers

DEFF Research Database (Denmark)

Pallassana, Venkataraman; Neurock, Matthew; Hansen, Lars Bruno

1999-01-01

not appear to provide an independent parameter for assessing surface reactivity. The weak chemisorption of hydrogen on the Pd-ML/Re(0001) surface relates to substantial lowering of the d-band center of Pd, when it is pseudomorphically deposited as a monolayer on a Re substrate. [S0163-1829(99)00331-2].......Gradient-corrected density-functional theory (DFT-GGA) periodic slab calculations have been used to analyze the binding of atomic hydrogen on monometallic Pd(111), Re(0001), and bimetallic Pd-mL/Re(0001) [pseudomorphic monolayer of Pd(111) on Re(0001)] and Re-ML/Pd(111) surfaces. The computed...

Longitudinal fluctuations in PD1 and PD-L1 expression in association with changes in anti-viral immune response in chronic hepatitis B

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Wenjin Zhang

2012-08-01

Full Text Available Abstract Background Controversy exists regarding the role of PD1 and its ligand PD-L1 in chronic hepatitis B infection. In some studies, persistent HBV infection has been attributed to high levels of PD-1 and PD-L1 expression on HBV-specific T-cells and antigen-presenting cells (APCs respectively. Other studies revealed that the up-regulation of PD-1 and PD-L1 during an acute inflammation phase is required to offset increasing positive co-stimulatory signals to avoid severe damage by an over-vigorous immune response. Methods Fifteen chronic hepatitis B patients, with inflammatory flare episode, were recruited prospectively. Based on serum HBV-DNA, HBsAg load, and ALT values, inflammatory flare episode were divided into initial, climax, decline and regression phase. Blood sample and liver biopsy tissues from each individual were taken in these 4 phases respectively. Circulating and intra-hepatic PD1 and PD-L1 expression levels were monitored throughout the inflammatory flare episode by flow cytometry and immunostaining and these expression levels were related to the HBV-specific T-cell changes, expression of pro-inflammatory cytokines, HBV-DNA replication and HBV antigen load. Results ]The levels of PD-1 and PD-L1 expressions were significantly up-regulated in the inflammation ascending phase, initial and climax period and in parallel with HBV-specific colon expansion. It showed increasing the level of serum ALT and decreasing the HBV-DNA loads. As the level of inflammation reduced, the circulating and intra-hepatic PD1 and circulating PD-L1 decreased progressively in concordance with serum ALT, HBV-DNA and HBsAg loads decreased except intra-hepatic PD-1 expression. Intra-hepatic PD-L1 expression did not decrease significantly during the regression phase of inflammation compared to that in prior period. The intra-hepatic PD-L1 expression remained relatively on higher level when serum HBV-DNA load and ALT decreased to approximately normal range

PD-1/PD-L1 Inhibitors for Immuno-oncology: From Antibodies to Small Molecules.

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Geng, Qiaohong; Jiao, Peifu; Jin, Peng; Su, Gaoxing; Dong, Jinlong; Yan, Bing

2018-02-12

The recent regulatory approvals of immune checkpoint protein inhibitors, such as ipilimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab ushered a new era in cancer therapy. These inhibitors do not attack tumor cells directly but instead mobilize the immune system to re-recognize and eradicate tumors, which endows them with unique advantages including durable clinical responses and substantial clinical benefits. PD-1/PD-L1 inhibitors, a pillar of immune checkpoint protein inhibitors, have demonstrated unprecedented clinical efficacy in more than 20 cancer types. Besides monoclonal antibodies, diverse PD- 1/PD-L1 inhibiting candidates, such as peptides, small molecules have formed a powerful collection of weapons to fight cancer. The goal of this review is to summarize and discuss the current PD-1/PD-L1 inhibitors including candidates under clinical development, their molecular interactions with PD-1 or PD-L1, the disclosed structureactivity relationships of peptides and small molecules as inhibitors. Current PD-1/PD-L1 inhibitors under clinical development are exclusively dominated by antibodies. The molecular interactions of therapeutic antibodies with PD-1 or PD-L1 have been gradually elucidated for the design of novel inhibitors. Various peptides and traditional small molecules have been investigated in preclinical model to discover novel PD-1/PD-L1 inhibitors. Peptides and small molecules may play an important role in immuno-oncology because they may bind to multiple immune checkpoint proteins via rational design, opening opportunity for a new generation of novel PD-1/PD-L1 inhibitors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Multiplexed Immunofluorescence Reveals Potential PD-1/PD-L1 Pathway Vulnerabilities in Craniopharyngioma.

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Coy, Shannon; Rashid, Rumana; Lin, Jia-Ren; Du, Ziming; Donson, Andrew M; Hankinson, Todd C; Foreman, Nicholas K; Manley, Peter E; Kieran, Mark W; Reardon, David A; Sorger, Peter K; Santagata, Sandro

2018-03-02

Craniopharyngiomas are neoplasms of the sellar/parasellar region that are classified into adamantinomatous (ACP) and papillary (PCP) subtypes. Surgical resection of craniopharyngiomas is challenging, and recurrence is common, frequently leading to profound morbidity. BRAF V600E mutations render PCP susceptible to BRAF/MEK inhibitors, but effective targeted therapies are needed for ACP. We explored the feasibility of targeting the PD-1/PD-L1 immune checkpoint pathway in ACP and PCP. We mapped and quantified PD-L1 and PD-1 expression in ACP and PCP resections using immunohistochemistry, immunofluorescence, and RNA in situ hybridization. We used tissue-based cyclic immunofluorescence (t-CyCIF) to map the spatial distribution of immune cells and characterize cell cycle and signaling pathways in ACP tumor cells which intrinsically express PD-1. All ACP (15±14% of cells, n=23, average±S.D.) and PCP (35±22% of cells, n=18) resections expressed PD-L1. In ACP, PD-L1 was predominantly expressed by tumor cells comprising the cyst-lining. In PCP, PD-L1 was highly-expressed by tumor cells surrounding the stromal fibrovascular cores. ACP also exhibited tumor cell-intrinsic PD-1 expression in whorled epithelial cells with nuclear-localized beta-catenin. These cells exhibited evidence of elevated mTOR and MAPK signaling. Profiling of immune populations in ACP and PCP showed a modest density of CD8+ T-cells. ACP exhibit PD-L1 expression in the tumor cyst-lining and intrinsic PD-1 expression in cells proposed to comprise an oncogenic stem-like population. In PCP, proliferative tumor cells express PD-L1 in a continuous band at the stromal-epithelial interface. Targeting PD-L1 and/or PD-1 in both subtypes of craniopharyngioma might therefore be an effective therapeutic strategy.

Effects of starting hemodialysis with an arteriovenous fistula or central venous catheter compared with peritoneal dialysis: a retrospective cohort study

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Coentrão Luis

2012-08-01

Full Text Available Abstract Background Although several studies have demonstrated early survival advantages with peritoneal dialysis (PD over hemodialysis (HD, the reason for the excess mortality observed among incident HD patients remains to be established, to our knowledge. This study explores the relationship between mortality and dialysis modality, focusing on the role of HD vascular access type at the time of dialysis initiation. Methods A retrospective cohort study was performed among local adult chronic kidney disease patients who consecutively initiated PD and HD with a tunneled cuffed venous catheter (HD-TCC or a functional arteriovenous fistula (HD-AVF in our institution in the year 2008. A total of 152 patients were included in the final analysis (HD-AVF, n = 59; HD-TCC, n = 51; PD, n = 42. All cause and dialysis access-related morbidity/mortality were evaluated at one year. Univariate and multivariate analysis were used to compare the survival of PD patients with those who initiated HD with an AVF or with a TCC. Results Compared with PD patients, both HD-AVF and HD-TCC patients were more likely to be older (pp = 0.017 and cardiovascular disease (p = 0.020. Overall, HD-TCC patients were more likely to have clinical visits (p = 0.069, emergency room visits (ppvs. 0.93 vs. 0.64, per patient-year; pvs. 0.07 vs. 0.14, per patient-year; p = 0.034 than HD-AVF and PD patients, respectively. The survival rates at one year were 96.6%, 74.5% and 97.6% for HD-AVF, HD-TCC and PD groups, respectively (pp = 0.024. Conclusion Our results suggest that HD vascular access type at the time of renal replacement therapy initiation is an important modifier of the relationship between dialysis modality and survival among incident dialysis patients.

Testing the START Triage Protocol: Can It Improve the Ability of Nonmedical Personnel to Better Triage Patients During Disasters and Mass Casualties Incidents ?

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Badiali, Stefano; Giugni, Aimone; Marcis, Lucia

2017-06-01

START (Simple Triage and Rapid Treatment) triage is a tool that is available even to nonmedical rescue personnel in case of a disaster or mass casualty incident (MCI). In Italy, no data are available on whether application of the START protocol could improve patient outcomes during a disaster or MCI. We aimed to address whether "last-minute" START training of nonmedical personnel during a disaster or MCI would result in more effective triage of patients. In this case-control study, 400 nonmedical ambulance crew members were randomly assigned to a non-START or a START group (200 per group). The START group received last-minute START training. Each group examined 6000 patients, obtained from the Emergo Train System (ETS Italy, Bologna, Italy) victims database, and assigned patients a triage code (black-red-yellow-green) along with a reason for the assignment. Each rescuer triaged 30 patients within a 30-minute time frame. Results were analyzed according to Fisher's exact test for a P valueSTART group completed the evaluations in 15 minutes, whereas the non-START group took 30 minutes. The START group correctly triaged 94.2% of their patients, as opposed to 59.83% of the non-START group (PSTART group versus 13.67% and 26.5% for the non-START group. The non-START group had 458 "preventable deaths" on 6000 cases because of incorrect triage, whereas the START group had 91. Even a "last-minute" training on the START triage protocol allows nonmedical personnel to better identify and triage the victims of a disaster or MCI, resulting in more effective and efficient medical intervention. (Disaster Med Public Health Preparedness. 2017;11:305-309).

Hypothyroidism in Cancer Patients on Immune Checkpoint Inhibitors with anti-PD1 Agents: Insights on Underlying Mechanisms.

Science.gov (United States)

Alhusseini, M; Samantray, J

2017-04-01

Background: Immune therapy using monoclonal antibodies against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death 1 receptor (PD-1) for various cancers have been reported to cause thyroid dysfunction. Little is known, however, about the underlying pathogenic mechanisms and the course of hypothyroidism that subsequently develops. In this report, we use the change in thyroglobulin and thyroid antibody levels in patients on immune therapy who develop hypothyroidism to better understand its pathogenesis as well as examine the status of hypothyroidism in the long term. Methods: We report a case series of 10 patients who developed hypothyroidism after initiation of immune therapy (either anti-PD-1 alone or in combination with anti-CTLA-4). Available thyroid antibodies including anti-thyroglobulin (anti-Tg), anti-thyroid peroxidase (anti-TPO), and thyroid stimulating immunoglobulin (TSI) were noted during the initial thyroiditis phase as well as the hypothyroid phase. Persistence or remission of hypothyroidism was noted at 6 months. Summary: During the thyroiditis phase, 50% of the patients had elevated Tg titers, 40% had elevated anti-Tg, and 40% had elevated TSI. All of these titers decreased during the hypothyroid phase. Permanent hypothyroidism was noted in 80% of the cases. Conclusion: Hypothyroidism following initiation of immune therapy has immunologic and non-immunologic mediated mechanisms and is likely to be persistent. © Georg Thieme Verlag KG Stuttgart · New York.

PD-L1 expression in EBV-negative diffuse large B-cell lymphoma: clinicopathologic features and prognostic implications.

Science.gov (United States)

Xing, Wei; Dresser, Karen; Zhang, Rui; Evens, Andrew M; Yu, Hongbo; Woda, Bruce A; Chen, Benjamin J

2016-09-13

Programmed cell death ligand 1 (PD-L1) is a cell surface glycoprotein that regulates the cellular immune response and serves as a targetable immune checkpoint molecule. PD-L1 is expressed on tumor cells and the immune microenvironment of several human malignancies, including a subset of aggressive lymphomas. We sought to investigate further the clinical and pathologic features of EBV-negative diffuse large B-cell lymphoma (DLBCL) cases that express PD-L1. Immunohistochemical staining using an anti-PD-L1 monoclonal antibody was performed on DLBCL cases from 86 patients. These patients received standard chemotherapy treatment and were followed for up to 175 months. Overall, 14 cases (16%) were considered positive for PD-L1 in tumor cells. In comparison with PD-L1 negative cases, PD-L1 positive cases had a higher rate of non-GCB type (71% vs. 30%, P=0.0060), and higher Ann Arbor stage (II-IV) (100% vs. 73%, P=0.0327). No significant differences were seen in the immunohistochemical expression of BCL2, MYC, or Ki67. Patients with tumors expressing PD-L1 demonstrated inferior overall survival (OS) upon long term follow up (P=0.0447). Both age/sex-adjusted and multivariate analyses identified PD-L1 as an independent predictor for OS (P=0.0101 and P=0.0424). There was no significant difference, however, in terms of remission rates after first treatment, relapse rates, and progression free survival between the groups. Identification of DLBCL cases that express PD-L1 may serve to select a subset of patients that could further benefit from targeted immunotherapy.

Pd-nanoparticles cause increased toxicity to kiwifruit pollen compared to soluble Pd(II)

International Nuclear Information System (INIS)

Speranza, Anna; Leopold, Kerstin; Maier, Marina; Taddei, Anna Rita; Scoccianti, Valeria

2010-01-01

In the present study, endpoints including in vitro pollen performance (i.e., germination and tube growth) and lethality were used as assessments of nanotoxicity. Pollen was treated with 5-10 nm-sized Pd particles, similar to those released into the environment by catalytic car exhaust converters. Results showed Pd-nanoparticles altered kiwifruit pollen morphology and entered the grains more rapidly and to a greater extent than soluble Pd(II). At particulate Pd concentrations well below those of soluble Pd(II), pollen grains experienced rapid losses in endogenous calcium and pollen plasma membrane damage was induced. This resulted in severe inhibition and subsequent cessation of pollen tube emergence and elongation at particulate Pd concentrations as low as 0.4 mg L -1 . Particulate Pd emissions related to automobile traffic have been increasing and are accumulating in the environment. This could seriously jeopardize in vivo pollen function, with impacts at an ecosystem level. - Nanoparticulate Pd - which resembles emissions from automobile catalysts - affects pollen to a higher extent than soluble Pd.

Pd-nanoparticles cause increased toxicity to kiwifruit pollen compared to soluble Pd(II)

Energy Technology Data Exchange (ETDEWEB)

Speranza, Anna, E-mail: anna.speranza@unibo.i [Dipartimento di Biologia, Universita di Bologna, via Irnerio 42, 40126 Bologna (Italy); Leopold, Kerstin, E-mail: kerstin.leopold@lrz.tu-muenchen.d [Arbeitsgruppe fuer Analytische Chemie, Technische Universitaet Muenchen, Garching (Germany); Maier, Marina, E-mail: marina.maier@ch.tum.d [Arbeitsgruppe fuer Analytische Chemie, Technische Universitaet Muenchen, Garching (Germany); Taddei, Anna Rita, E-mail: artaddei@unitus.i [CIME, Universita della Tuscia, Viterbo (Italy); Scoccianti, Valeria, E-mail: valeria.scoccianti@uniurb.i [Dipartimento di Scienze dell' Uomo, dell' Ambiente e della Natura, Universita di Urbino ' Carlo Bo' , Urbino (Italy)

2010-03-15

In the present study, endpoints including in vitro pollen performance (i.e., germination and tube growth) and lethality were used as assessments of nanotoxicity. Pollen was treated with 5-10 nm-sized Pd particles, similar to those released into the environment by catalytic car exhaust converters. Results showed Pd-nanoparticles altered kiwifruit pollen morphology and entered the grains more rapidly and to a greater extent than soluble Pd(II). At particulate Pd concentrations well below those of soluble Pd(II), pollen grains experienced rapid losses in endogenous calcium and pollen plasma membrane damage was induced. This resulted in severe inhibition and subsequent cessation of pollen tube emergence and elongation at particulate Pd concentrations as low as 0.4 mg L{sup -1}. Particulate Pd emissions related to automobile traffic have been increasing and are accumulating in the environment. This could seriously jeopardize in vivo pollen function, with impacts at an ecosystem level. - Nanoparticulate Pd - which resembles emissions from automobile catalysts - affects pollen to a higher extent than soluble Pd.

Frequency of G6PD Mediterranean in individuals with and without malaria in Southern Pakistan.

Science.gov (United States)

Moiz, Bushra; Arshad, Haroon Muhammad; Raheem, Ahmed; Hayat, Hasan; Karim Ghanchi, Najia; Beg, M Asim

2017-10-24

Pakistan has an estimated annual burden of 1.5 million malaria cases. The current situation calls for an effective malaria control and eradication programme in this country. Currently, primaquine is an attractive option for eliminating reservoirs of Plasmodium vivax hypnozoites and killing gametocytes of Plasmodium falciparum. However, this drug causes haemolysis in individuals who are glucose-6-phosphate (G6PD) deficient. It is important to map G6PD deficiency and malaria distribution in Pakistan to design an effective malaria eradication regimen. Frequency of G6PD deficiency (G6PDd) in malaria patients has not been reported from Pakistan in any meaningful way. The purpose of this study was to evaluate the frequency of G6PD c.563C>T (G6PD Mediterranean) in male individuals with and without falciparum malaria. Two hundred and ten archived DNA samples from males (110 from falciparum malaria patients and 100 from healthy individuals) were utilized in this study. Healthy blood donors were selected based on stringent pre-defined criteria. Patients were confirmed for malaria parasites on microscopy and or immune chromatographic assay detecting P. falciparum histidine-rich protein 2. Parasitaemia was also computed. DNA samples were tested for G6PD c.563C>T mutation through PCR-RFLP according to the previously defined protocol and its allelic frequency was computed. G6PD c.563C>T was observed in four of 110 patients with falciparum malaria and in two of 100 healthy donors. Mean (± SD) haemoglobin, median (IQR) platelet and median (IQR) parasite count in G6PD-deficient malaria-patients were 8.9 ± 0.9 g/dL, 124 × 109/L (IQR 32, 171) and 57,920/μL of blood (IQR 12,920, 540,000) respectively. Cumulative allelic frequency for G6PD 563c.C>T was 0.0285 detected in 6 of 210 X-chromosomes in Southern Pakistan. Frequency for this G6PD allele was 0.0364 in malaria-patients and 0.0200 in healthy individuals. Large studies including females are needed to elucidate the true

Glucose-6-phosphate dehydrogenase (G6PD mutations and haemoglobinuria syndrome in the Vietnamese population

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Day Nick

2009-07-01

Full Text Available Abstract Background In Vietnam the blackwater fever syndrome (BWF has been associated with malaria infection, quinine ingestion and G6PD deficiency. The G6PD variants within the Vietnamese Kinh contributing to the disease risk in this population, and more generally to haemoglobinuria, are currently unknown. Method Eighty-two haemoglobinuria patients and 524 healthy controls were screened for G6PD deficiency using either the methylene blue reduction test, the G-6-PDH kit or the micro-methaemoglobin reduction test. The G6PD gene variants were screened using SSCP combined with DNA sequencing in 82 patients with haemoglobinuria, and in 59 healthy controls found to be G6PD deficient. Results This study confirmed that G6PD deficiency is strongly associated with haemoglobinuria (OR = 15, 95% CI [7.7 to 28.9], P G6PD variants were identified in the Vietnamese population, of which two are novel (Vietnam1 [Glu3Lys] and Vietnam2 [Phe66Cys]. G6PD Viangchan [Val291Met], common throughout south-east Asia, accounted for 77% of the variants detected and was significantly associated with haemoglobinuria within G6PD-deficient ethnic Kinh Vietnamese (OR = 5.8 95% CI [114-55.4], P = 0.022. Conclusion The primary frequency of several G6PD mutations, including novel mutations, in the Vietnamese Kinh population are reported and the contribution of G6PD mutations to the development of haemoglobinuria are investigated.

Interval Between Hysterectomy and Start of Radiation Treatment Is Predictive of Recurrence in Patients With Endometrial Carcinoma

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Cattaneo, Richard [Department of Radiation Oncology, Henry Ford Hospital, Detroit, Michigan (United States); Hanna, Rabbie K. [Division of Gynecologic Oncology, Department of Women' s Health Services, Henry Ford Hospital, Detroit, Michigan (United States); Jacobsen, Gordon [Public Health Science, Henry Ford Hospital, Detroit, Michigan (United States); Elshaikh, Mohamed A., E-mail: melshai1@hfhs.org [Department of Radiation Oncology, Henry Ford Hospital, Detroit, Michigan (United States)

2014-03-15

Purpose: Adjuvant radiation therapy (RT) has been shown to improve local control in patients with endometrial carcinoma. We analyzed the impact of the time interval between hysterectomy and RT initiation in patients with endometrial carcinoma. Methods and Materials: In this institutional review board-approved study, we identified 308 patients with endometrial carcinoma who received adjuvant RT after hysterectomy. All patients had undergone hysterectomy, oophorectomy, and pelvic and para-aortic lymph node evaluation from 1988 to 2010. Patients' demographics, pathologic features, and treatments were compared. The time interval between hysterectomy and the start of RT was calculated. The effects of time interval on recurrence-free (RFS), disease-specific (DSS), and overall survival (OS) were calculated. Following univariate analysis, multivariate modeling was performed. Results: The median age and follow-up for the study cohort was 65 years and 72 months, respectively. Eighty-five percent of the patients had endometrioid carcinoma. RT was delivered with high-dose-rate brachytherapy alone (29%), pelvic RT alone (20%), or both (51%). Median time interval to start RT was 42 days (range, 21-130 days). A total of 269 patients (74%) started their RT <9 weeks after undergoing hysterectomy (group 1) and 26% started ≥9 weeks after surgery (group 2). There were a total of 43 recurrences. Tumor recurrence was significantly associated with treatment delay of ≥9 weeks, with 5-year RFS of 90% for group 1 compared to only 39% for group 2 (P<.001). On multivariate analysis, RT delay of ≥9 weeks (P<.001), presence of lymphovascular space involvement (P=.001), and higher International Federation of Gynecology and Obstetrics grade (P=.012) were independent predictors of recurrence. In addition, RT delay of ≥9 weeks was an independent significant predictor for worse DSS and OS (P=.001 and P=.01, respectively). Conclusions: Delay in administering adjuvant RT after

Severe acute haemolytic anaemia associated with severe methaemoglobinaemia in a G6PD-deficient man.

Science.gov (United States)

Rehman, Abdul; Shehadeh, Mohanad; Khirfan, Diala; Jones, Akhnuwhkh

2018-03-28

Methaemoglobin is a form of haemoglobin in which the ferrous (Fe 2+ ) ion contained in the iron-porphyrin complex of haem is oxidised to its ferric (Fe 3+ ) state. Methaemoglobinaemia, the presence of methaemoglobin in the blood, is most commonly treated with methylene blue. However, methylene blue cannot be used in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency as it is ineffective in such patients and it can worsen G6PD deficiency haemolysis. We report the case of a 30-year-old man who presented with clinical features of G6PD deficiency-associated haemolysis and was found to have severe methaemoglobinaemia (35%). He was administered blood transfusions and intravenous ascorbic acid. His methaemoglobinaemia resolved within 24 hours. This case demonstrates the successful management of a patient with severe methaemoglobinaemia in the setting of G6PD deficiency haemolysis. Emergency physicians should be aware of the possible co-occurrence of severe methaemoglobinaemia in a patient with G6PD deficiency haemolysis. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Magnetotransport in Pd-rich PdFe alloys

Czech Academy of Sciences Publication Activity Database

Kudrnovský, Josef; Drchal, Václav; Turek, Ilja

2013-01-01

Roč. 26, č. 5 (2013), s. 1749-1752 ISSN 1557-1939 R&D Projects: GA ČR(CZ) GAP204/11/1228 Institutional support: RVO:68378271 ; RVO:68081723 Keywords : galvanomagnetic transport * Pd-rich PdFe * long-range order * effect of temperature * anisotropic magnetoresistance Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 0.930, year: 2013

[DIETARY INTAKE AND NUTRITIONAL STATUS IN ONCOLOGY PATIENTS WHO START TREATMENT WITH TYROSINE KINASE INHIBITORS].

Science.gov (United States)

Higuera-Pulgar, Isabel; Ribed, Almudena; Carrascal-Fabian, M Luisa; Bretón-Lesmes, Irene; Romero-Jiménez, Rosa M; Cuerda-Compes, Cristina; Velasco-Gimeno, Cristina; Camblor-Álvarez, Miguel; García-Peris, Pilar

2015-09-01

in recent years, researching about new oral antineoplastics has progressed while its impact on dietary intake and nutritional status (NS) hasn't developed enough yet. dietary intake and NS assessment in patients who start treatment with tyrosine kinase inhibitors (TKI) and evaluate its impact on them. an observational, prospective-six-months study, in which were included patients starting treatment with TKI. The intake was evaluated by a 24 h dietary record and a food frequency questionnaire. The NS was evaluated by anthropometric measurements and the patient-generated Global Subjective Assessment (PG-GSA); the results were compared with the Spanish references (SENC-semFYC, 2007 and O. Moreiras, 2013). Friedman test, χ2, Wilcoxon, Kruskal-Wallis and Mann-Whitney were used in the statistical analysis. Significance p Weight loss was no significant, although a high percentage of the energy and protein requirements hadn't been reached. The caloric intake was positively related with the number of meals. Dietary habits did not change during treatment. dietary intake did not reach nutritional requirements at baseline. The TKI don't seem to affect the patient's intake and nutritional status. The research about these parameters before starting treatment could prevent future complications and it would guide the dietary advice. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Prognostic Value of PD-L1 in Breast Cancer: A Meta-Analysis.

Science.gov (United States)

Wang, Changjun; Zhu, Hanjiang; Zhou, Yidong; Mao, Feng; Lin, Yan; Pan, Bo; Zhang, Xiaohui; Xu, Qianqian; Huang, Xin; Sun, Qiang

2017-07-01

Programmed cell death 1 ligand 1 (PD-L1) is a promising therapeutic target for cancer immunotherapy. However, the correlation between PD-L1 and breast cancer survival remains unclear. Here, we present the first meta-analysis to investigate the prognostic value of PD-L1 in breast cancer. We searched Pubmed, Embase, and Cochrane Central Register of Controlled Trials databases for relevant studies evaluating PD-L1 expression and breast cancer survival. Fixed- and random-effect meta-analyses were conducted based on heterogeneity of included studies. Publication bias was evaluated by funnel plot and Begg's test. Overall, nine relevant studies with 8583 patients were included. PD-L1 overexpression was found in 25.8% of breast cancer patients. PD-L1 (+) associated with several high-risk prognostic indicators, such as ductal cancer (p = 0.037), high tumor grade (p = 0.000), ER negativity (p = 0.000), PR negativity (p = 0.000), HER2 positivity (p = 0.001) and aggressive molecular subtypes (HER2-rich and Basal-like p = 0.000). PD-L1 overexpression had no significant impact on metastasis-free survival (HR 0.924, 95% CI = 0.747-1.141, p = 0.462), disease-free survival (HR 1.122, 95% CI = 0.878-1.434, p = 0.357) and overall specific survival (HR 0.837, 95% CI = 0.640-1.093, p = 0.191), but significantly correlated with shortened overall survival (HR 1.573, 95% CI = 1.010-2.451, p = 0.045). PD-L1 overexpression in breast cancer associates with multiple clinicopathological parameters that indicated poor outcome, and may increase the risk for mortality. Further standardization of PD-L1 assessment assay and well-controlled clinical trials are warranted to clarify its prognostic and therapeutic value. © 2017 Wiley Periodicals, Inc.

103PD brachytherapy and external beam irradiation for clinically localized, high-risk prostatic carcinoma

International Nuclear Information System (INIS)

Dattoli, Michael; Wallner, Kent; Sorace, Richard; Koval, John; Cash, Jennifer; Acosta, Rudolph; Brown, Charles; Etheridge, James; Binder, Michael; Brunelle, Richard; Kirwan, Novelle; Sanchez, Servando; Stein, Douglas; Wasserman, Stuart

1996-01-01

Purpose: To summarize biochemical failure rates and morbidity of external beam irradiation (EBRT) combined with palladium ( 103 Pd) boost for clinically localized high-risk prostate carcinoma. Methods and Materials: Seventy-three consecutive patients with stage T2a-T3 prostatic carcinoma were treated from 1991 through 1994. Each patient had at least one of the following risk factors for extracapsular disease extension: Stage T2b or greater (71 patients), Gleason score 7-10 (40 patients), prostate specific antigen (PSA) >15 (32 patients), or elevated prostatic acid phosphatase (PAP) (17 patients). Patients received 41 Gy EBRT to a limited pelvic field, followed 4 weeks later by a 103 Pd boost (prescription dose: 80 Gy). Biochemical failure was defined as a PSA greater than 1.0 ng/ml (normal 103 Pd brachytherapy for clinically localized, high-risk prostate cancer compare favorably with that reported after conventional dose EBRT alone. Morbidity has been acceptable

PD-L1 inhibition with avelumab for metastatic Merkel cell carcinoma.

Science.gov (United States)

Gaiser, Maria Rita; Bongiorno, Michelle; Brownell, Isaac

2018-04-01

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer that lacks durable responses to traditional chemotherapy. Areas covered: After MCC was shown to be an immunogenic tumor, small trials revealed high objective response rates to PD-1/PD-L1 checkpoint inhibitors. The JAVELIN Merkel 200 (NCT02155647) trial tested the use of avelumab, a human IgG1 monoclonal antibody against PD-L1, in metastatic MCC. Avelumab recently became the first approved drug for metastatic MCC. Expert commentary: By conducting broad phase I studies assessing the safety of avelumab and a small phase II study demonstrating efficacy in this rare orphan tumor type, avelumab gained accelerated approval for the treatment of metastatic MCC. Additional studies are needed to determine how the antibody-dependent cellular cytotoxicity (ADCC) competent Fc region of avelumab contributes to disease control. Remaining questions: Longer follow-up will determine the durability of checkpoint blockade in controlling metastatic MCC. Additional studies will assess the utility and safety of adjuvant checkpoint blockade in patients with excised MCC. How to increase response rates by combining PD-1/PD-L1 blockade with other treatment approaches needs to be explored. In addition, treatment options for MCC patients who fail or do not respond to avelumab need to be identified.

Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression.

LENUS (Irish Health Repository)

Guo, Yanxia

2018-01-01

Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development. We demonstrate that the expression of PD-1 was increased in early and established RA synovial tissue compared to normal and OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and PD-L2, was increased at all the stages of RA disease progression, namely arthralgia, IA\\/undifferentiated arthritis, early RA and established RA. Further, we show that RA patients expressed PD-1 on a majority of synovial tissue infiltrating CD4+ and CD8+ T cells. Moreover, enrichment of Nivolumab gene signature was observed in IA and RA, indicating that the PD-1 pathway was downregulated during RA disease progression. Furthermore, serum soluble (s) PD-1 levels were increased in autoantibody positive early RA patients. Interestingly, most of the early RA synovium tissue sections showed negative PD-L1 staining by immunohistochemistry. Therefore, downregulation in PD-1 inhibitory signaling in RA could be attributed to increased serum sPD-1 and decreased synovial tissue PD-L1 levels. Taken together, these data suggest that agonistic PD1 antibody-based therapeutics may show efficacy in RA treatment and interception.

Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression.

Science.gov (United States)

Guo, Yanxia; Walsh, Alice M; Canavan, Mary; Wechalekar, Mihir D; Cole, Suzanne; Yin, Xuefeng; Scott, Brittney; Loza, Mathew; Orr, Carl; McGarry, Trudy; Bombardieri, Michele; Humby, Frances; Proudman, Susanna M; Pitzalis, Costantino; Smith, Malcolm D; Friedman, Joshua R; Anderson, Ian; Madakamutil, Loui; Veale, Douglas J; Fearon, Ursula; Nagpal, Sunil

2018-01-01

Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development. We demonstrate that the expression of PD-1 was increased in early and established RA synovial tissue compared to normal and OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and PD-L2, was increased at all the stages of RA disease progression, namely arthralgia, IA/undifferentiated arthritis, early RA and established RA. Further, we show that RA patients expressed PD-1 on a majority of synovial tissue infiltrating CD4+ and CD8+ T cells. Moreover, enrichment of Nivolumab gene signature was observed in IA and RA, indicating that the PD-1 pathway was downregulated during RA disease progression. Furthermore, serum soluble (s) PD-1 levels were increased in autoantibody positive early RA patients. Interestingly, most of the early RA synovium tissue sections showed negative PD-L1 staining by immunohistochemistry. Therefore, downregulation in PD-1 inhibitory signaling in RA could be attributed to increased serum sPD-1 and decreased synovial tissue PD-L1 levels. Taken together, these data suggest that agonistic PD1 antibody-based therapeutics may show efficacy in RA treatment and interception.

Effect of assistance on peritonitis risk in diabetic patients treated by peritoneal dialysis: report from the French Language Peritoneal Dialysis Registry.

Science.gov (United States)

Benabed, Anais; Bechade, Clemence; Ficheux, Maxence; Verger, Christian; Lobbedez, Thierry

2016-04-01

Diabetic patients treated by peritoneal dialysis (PD) have been reported to be at an increased risk of peritonitis. This has been attributed to impairment in host defense, visual impairment, disability and muscle wasting, which could compromise ability to safely perform catheter connections. This study aimed to evaluate whether assisted PD is associated with a lower risk of peritonitis in diabetic patients. This was a retrospective study based on data from the French Language Peritoneal Dialysis Registry. We included diabetic patients starting PD between 1 January 2002 and 31 December 2012. The end of the observation period was 31 December 2013. Using complementary regression analysis (Fine and Gray, Hurdle models), we assessed the relationship between peritonitis occurrence, peritonitis number over time and the type of assisted PD. Of the 3598 diabetic patients, there were 2040 patients on nurse-assisted PD. These patients were older, more comorbid and more frequently on continuous ambulatory peritoneal dialysis (CAPD). In the multivariate analysis, nurse assistance was associated with a reduced risk of peritonitis in the Fine and Gray [subdistribution hazard ratio: 0.78 (95% confidence interval, CI, 0.68-0.89)] and in the first component of the Hurdle models [rate ratio: 0.82 (95% CI 0.71-0.93)], but not a lower incidence of peritonitis after an initial episode [rate ratio: 0.82 (95% CI 0.95-1.38)]. Transplant failure, glomerulonephritis and CAPD were associated with an increased risk. In France, nurse-assisted PD is associated with a lower risk of peritonitis in diabetic patients treated by PD but not a lower incidence of peritonitis. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Expression of TLR4 in Non-Small Cell Lung Cancer Is Associated with PD-L1 and Poor Prognosis in Patients Receiving Pulmonectomy

Directory of Open Access Journals (Sweden)

Xiubao Ren

2017-04-01

Full Text Available Currently, the effect of inflammation on tumorigenesis and progression has been widely noted. As a member of pattern recognition receptors, toll-like receptor 4 (TLR4 plays a pivotal role in tumor immune microenvironment and has been increasingly investigated. In the present study, we evaluated TLR4 expression and its association with programmed cell death ligand 1 (PD-L1 in non-small cell lung cancer (NSCLC tissues and assessed the predicting value of TLR4 on postoperative outcome. A total of 126 NSCLC patients receiving complete pulmonary resection and systematic lymph node dissection between April 2008 and August 2014 were enrolled. All the patients had integrated clinicopathological records and follow-up data. TLR4 and PD-L1 expression on NSCLC samples were determined by immunohistochemistry, and serum soluble TLR4 (sTLR4 levels were measured by enzyme-linked immunosorbent assay. Results showed that TLR4 expression level in cancer tissue was significantly higher than that in para-cancer tissue. Elevated TLR4 expression was significantly associated with histological type (adenocarcinoma higher than squamous cell carcinoma, P = 0.041, increased clinical TNM stage (P < 0.001, and presence of lymphatic invasion (P < 0.001. Besides, TLR4 expression level in cancer samples was inversely correlated with serum sTLR4 level in patients with early-stage NSCLC (r = −0.485, P = 0.003. TLR4 expression level was also positively correlated with the PD-L1 expression level (r = 0.545, P < 0.0001. Multivariate analysis showed that expression level of TLR4 was an independent prognostic factor and TLR4 overexpression indicated a poor overall survival and disease-free survival. Taken together, we conclude that expression of TLR4 in lung cancer is associated with PD-L1 and could predict the outcome of patients with NSCLC receiving pulmonary resection for cancer.

Programmed Death Ligand 1 (PD-L1 Tumor Expression Is Associated with a Better Prognosis and Diabetic Disease in Triple Negative Breast Cancer Patients

Directory of Open Access Journals (Sweden)

Gerardo Botti

2017-02-01

Full Text Available Triple Negative Breast Cancers (TNBC subtype is an aggressive disease with poor clinical outcome. The only treatment available is surgery followed by chemotherapy or radiotherapy. Programmed death-ligand 1 (PD-L1 is a trans-membrane protein expressed on a wide variety of cells including immune cells, epithelial and vascular endothelial cells. Recently, PD-1/PD-L1 pathway signaling was described as an adaptive immune resistance mechanism enacted by the tumor cells to evade the immune response. Its presence on tumor cell membranes, acquired for this reason, through time, is an important prognostic value. However, data available in the literature about PD-L1 immunohistochemical expression in breast cancer are often discordant and not uniform, probably for the use of different antibodies clones and the high molecular heterogeneity of the different tumor types. The absence of target therapies, in particular for TNBC, has shifted the clinical attention mainly on the role of PD-L1 in this subtype of breast cancer. In this study, we evaluated tumor and TIL (tumor infiltrating lymphocytes PDL-1 expression in a series of TNBC, included in Tissue Micro Arrays (TMAs, to define its real prognostic value, optimizing immunohistochemistry method with an “approved for diagnostic assay” antibody. PD-L1 expression directly correlated with proliferation index (Ki-67, glycemia, the presence of diabetes and indirectly with menopausal status, presence of lymph node metastasis and relapse. The analysis of Kaplan–Meier showed that an increased PD-L1 expression was strongly associated with better disease-free survival (DFS but not correlated with overall survival (OS. Our data confirmed that PD-L1 could be an important marker for prognostic stratification and for planning immune checkpoint inhibitors therapies in patients with TNBC.

Structure characterization of Pd/Co/Pd tri-layer films epitaxially grown on MgO single-crystal substrates

Energy Technology Data Exchange (ETDEWEB)

Tobari, Kousuke, E-mail: tobari@futamoto.elect.chuo-u.ac.jp; Ohtake, Mitsuru; Nagano, Katsumasa; Futamoto, Masaaki

2011-09-30

Pd/Co/Pd tri-layer films were prepared on MgO substrates of (001), (111), and (011) orientations at room temperature by ultra high vacuum rf magnetron sputtering. The detailed film structures around the Co/Pd and the Pd/Co interfaces are investigated by reflection high energy electron diffraction. Pd layers of (001){sub fcc}, (111){sub fcc}, and (011){sub fcc} orientations epitaxially grow on the respective MgO substrates. Strained fcc-Co(001) single-crystal layers are formed on the Pd(001){sub fcc} layers by accommodating the fairly large lattice mismatch between the Co and the Pd layers. On the Co layers,, Pd polycrystalline layers are formed. When Co films are formed on the Pd(111){sub fcc} and the Pd(011){sub fcc} layers, atomic mixing is observed around the Co/Pd interfaces and fcc-CoPd alloy phases are coexisting with Co crystals. The Co crystals formed on the Pd(111){sub fcc} layers consist of hcp(0001) + fcc(111) and Pd(111){sub fcc} epitaxial layers are formed on the Co layers. Co crystals epitaxially grow on the Pd(011){sub fcc} layers with two variants, hcp(11-bar 00) and fcc(111). On the Co layers, Pd(011){sub fcc} epitaxial layers are formed.

PD Lab

NARCIS (Netherlands)

Bilow, Marcel; Entrop, Alexis Gerardus; Lichtenberg, Jos; Stoutjesdijk, Pieter

2015-01-01

PD Lab explores the applications of building sector related product development. PD lab investigates and tests digital production technologies like CNC milled wood connections. It will also act as a platform in its wider meaning to investigate the effects and influences of file to factory

Investigating unexpected magnetism of mesoporous silica-supported Pd and PdO nanoparticles

KAUST Repository

Song, Hyon Min; Zink, Jeffrey I.; Khashab, Niveen M.

2015-01-01

supported Pd and PdO NPs. The heating rate and the annealing conditions determine the particle size and the phase of the NPs, with a fast heating rate of 30 °C/min producing the largest supported Pd NPs. Unusual magnetic behaviors are observed. (1) Contrary

Movements in Parties: OccupyPD

Directory of Open Access Journals (Sweden)

Donatella della Porta

2015-03-01

Full Text Available When the United States activists called for people to Occupy#everywhere, it is unlikely they were thinking of the headquarters of the Italian centre-left party. Parties and movements are often considered to be worlds apart. In reality, parties have been relevant players in movement politics, and movements have influenced parties, often through the double militancy of many of their members. OccupyPD testifies to a continuous fluidity at the movement-party border, but also to a blockage in the party’s interactions with society that started long before the economic crisis but drastically accelerated with it. In this paper we present the OccupyPD Movement as a case of interaction between party politics and social movement politics, and in particular between the base membership of a centre-left party and the broader anti-austerity movement that diffused from the US to Europe adopting similar forms of actions and claims. Second, by locating it within the context of the economic and democratic crisis that erupted in 2007, we understand its emergence as a reaction towards politics in times of crisis of responsibility, by which we mean a drastic drop in the capacity of the government to respond to citizens’ requests. To fulfil this double aim, we bridge social movement studies with research on party change, institutional trust and democratic theory, looking at some political effects of the economic crisis in terms of a specific form of legitimacy crisis, as well as citizens’ responses to it, with a particular focus on the political meaning of recent anti-austerity protests. In this analysis, we refer to both quantitative and qualitative data from secondary liter-ature and original in-depth interviews carried out with a sample of OccupyPD activists.

Cytotoxicity of Pd nanostructures supported on PEN: Influence of sterilization on Pd/PEN interface

Energy Technology Data Exchange (ETDEWEB)

Polívková, M., E-mail: polivkoa@vscht.cz [Department of Solid State Engineering, University of Chemistry and Technology Prague, 166 28 Prague (Czech Republic); Siegel, J. [Department of Solid State Engineering, University of Chemistry and Technology Prague, 166 28 Prague (Czech Republic); Rimpelová, S. [Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, 166 28 Prague (Czech Republic); Hubáček, T. [Institute of Hydrobiology, Biology Centre of the AS CR, 370 05 Ceske Budejovice (Czech Republic); Kolská, Z. [Materials Centre of Usti n. L., J.E. Purkyne University, 400 96 Usti nad Labem (Czech Republic); Švorčík, V. [Department of Solid State Engineering, University of Chemistry and Technology Prague, 166 28 Prague (Czech Republic)

2017-01-01

Non-conventional antimicrobial agents, such as palladium nanostructures, have been increasingly used in the medicinal technology. However, experiences uncovering their harmful and damaging effects to human health have begun to appear. In this study, we have focused on in vitro cytotoxicity assessment of Pd nanostructures supported on a biocompatible polymer. Pd nanolayers of variable thicknesses (ranging from 1.1 to 22.4 nm) were sputtered on polyethylene naphthalate (PEN). These nanolayers were transformed by low-temperature post-deposition annealing into discrete nanoislands. Samples were characterized by AFM, XPS, ICP-MS and electrokinetic analysis before and after annealing. Sterilization of samples prior to cytotoxicity testing was done by UV irradiation, autoclave and/or ethanol. Among the listed sterilization techniques, we have chosen the gentlest one which had minimal impact on sample morphology, Pd dissolution and overall Pd/PEN interface quality. Cytotoxic response of Pd nanostructures was determined by WST-1 cell viability assay in vitro using three model cell lines: mouse macrophages (RAW 264.7) and two types of mouse embryonic fibroblasts (L929 and NIH 3T3). Finally, cell morphology in response to Pd/PEN was evaluated by means of fluorescence microscopy. - Highlights: • Annealing of Pd nanolayers on PEN resulted to Pd aggregation and formation of discrete nanoislands. • UV treatment was found as the gentlest sterilization method in term of physicochemical properties of Pd/PEN interface. • Autoclaving and chemical sterilization by ethanol resulted into remarkable changes of Pd/PEN interface. • Cytotoxicity of Pd samples was insignificant. • Pd nanostructures are potentially applicable as health-unobjectionable antibacterial coatings of medical devices.

Aqueous phase hydrogenation of phenol catalyzed by Pd and PdAg on ZrO 2

Energy Technology Data Exchange (ETDEWEB)

Resende, Karen A.; Hori, Carla E.; Noronha, Fabio B.; Shi, Hui; Gutierrez, Oliver Y.; Camaioni, Donald M.; Lercher, Johannes A.

2017-11-01

Hydrogenation of phenol in aqueous phase was studied over a series of ZrO2-supported Pd catalysts in order to explore the effects of particle size and of Ag addition on the activity of Pd. Kinetic assessments were performed in a batch reactor, on monometallic Pd/ZrO2 samples with different Pd loadings (0.5%, 1% and 2%), as well as on a 1% PdAg/ZrO2 sample. The turnover frequency (TOF) increases with the Pd particle size. The reaction orders in phenol and H2 indicate that the surface coverages by phenol, H2 and their derived intermediates are higher on 0.5% Pd/ZrO2 than on other samples. The activation energy was the lowest on the least active sample (0.5% Pd/ZrO2), while being identical on 1% and 2% Pd/ZrO2 catalysts. Thus, the significantly lower activity of the small Pd particles (1-2 nm on average) in 0.5%Pd/ZrO2 is explained by the unfavorable activation entropies for the strongly bound species. The presence of Ag increases considerably the TOF of the reaction by decreasing the Ea and increasing the coverages of phenol and H2.

Tumoral immune-infiltrate (IF), PD-L1 expression and role of CD8/TIA-1 lymphocytes in localized osteosarcoma patients treated within protocol ISG-OS1.

Science.gov (United States)

Palmerini, Emanuela; Agostinelli, Claudio; Picci, Piero; Pileri, Stefano; Marafioti, Teresa; Lollini, Pier-Luigi; Scotlandi, Katia; Longhi, Alessandra; Benassi, Maria Serena; Ferrari, Stefano

2017-12-19

We hypothesized that immune-infiltrates were associated with superior survival, and examined a primary osteosarcoma tissue microarrays (TMAs) to test this hypothesis. 129 patients (pts) with localized osteosarcoma treated within protocol ISG-OS1 were included in the study. Clinical characteristics, expression of CD8, CD3, FOXP3, CD20, CD68/CD163 (tumor associated macrophage, TAM), Tia-1 (cytotoxic T cell), CD303 (plasmacytoid dendritic cells: pDC), Arginase-1 (myeloid derived suppressor cells: MDSC), PD-1 on immune-cells (IC), and PD-L1 on tumoral cells (TC) and IC were analysed and correlated with outcome. Most of the cases presented tumor infiltrating lymphocytes (TILs) (CD3+ 90%; CD8+ 86%). Tia-1 was detected in 73% of the samples. PD-L1 expression was found in 14% patients in IC and 0% in TC; 22% showed PD-1 expression in IC.With a median follow-up of 8 years (range 1-13), the 5-year overall survival (5-year OS) was 74% (95% CI 64-85). Univariate analysis showed better 5-year OS for: a) pts with a good histologic response to neoadjuvant chemotherapy (p = 0.0001); b) pts with CD8/Tia1 tumoral infiltrates (p = 0.002); c) pts with normal alkaline phosphatas (sALP) (p = 0.04). After multivariate analysis, histologic response (p = 0.007) and CD8/Tia1 infiltration (p = 0.01) were independently correlated with survival. In the subset of pts with CD8+ infiltrate, worse (p 0.02) OS was observed for PD-L1(IC)+ cases. Our findings support the hypothesis that CD8/Tia1 infiltrate in tumor microenvironment at diagnosis confers superior survival for pts with localized osteosarcoma, while PD-L1 expression is associated with worse survival.

High-temperature stability of Au/Pd/Cu and Au/Pd(P)/Cu surface finishes

Science.gov (United States)

Ho, C. E.; Hsieh, W. Z.; Lee, P. T.; Huang, Y. H.; Kuo, T. T.

2018-03-01

Thermal reliability of Au/Pd/Cu and Au/Pd(4-6 wt.% P)/Cu trilayers in the isothermal annealing at 180 °C were investigated by X-ray photoelectron spectroscopy (XPS), time-of-flight secondary ion mass spectrometry (TOF-SIMS), and transmission electron microscopy (TEM). The pure Pd film possessed a nanocrystalline structure with numerous grain boundaries, thereby facilitating the interdiffusion between Au and Cu. Out-diffusion of Cu through Pd and Au grain boundaries yielded a significant amount of Cu oxides (CuO and Cu2O) over the Au surface and gave rise to void formation in the Cu film. By contrast, the Pd(P) film was amorphous and served as a good diffusion barrier against Cu diffusion. The results of this study indicated that amorphous Pd(P) possessed better oxidation resistance and thermal reliability than crystalline Pd.

MIS gas sensors based on porous silicon with Pd and WO{sub 3}/Pd electrodes

Energy Technology Data Exchange (ETDEWEB)

Solntsev, V.S. [Institute of Semiconductor Physics, National Academy of Science of Ukraine, 03028, Kiev (Ukraine); Gorbanyuk, T.I., E-mail: tatyanagor@mail.r [Institute of Semiconductor Physics, National Academy of Science of Ukraine, 03028, Kiev (Ukraine); Litovchenko, V.G.; Evtukh, A.A. [Institute of Semiconductor Physics, National Academy of Science of Ukraine, 03028, Kiev (Ukraine)

2009-09-30

Pd and WO{sub 3}/Pd gate metal-oxide-semiconductor (MIS) gas sensitive structures based on porous silicon layers are studied by the high frequency C(V) method. The chemical compositions of composite WO{sub 3}/Pd electrodes are characterized by secondary-ion mass spectrometry (SIMS). The atomic force microscopy (AFM) was used for morphologic studies of WO{sub 3}/Pd films. As shown in the experiments, WO{sub 3}/Pd structures are more sensitive and selective to the adsorption of hydrogen sulphide compared to Pd gate. The analyses of kinetic characteristics allow us to determine the response and characteristic times for these structures. The response time of MIS-structures with thin composite WO{sub 3}/Pd electrodes (the thickness of Pd is about 50 nm with WO{sub 3} clusters on its surface) is slower compared to the structures with Pd electrodes. Slower sensor responses of WO{sub 3}-based gas sensors may be associated with different mechanism of gas sensitivity of given structures. The enhanced sensitivity and selectivity to H{sub 2}S action of WO{sub 3}/Pd MIS-structures can also be explained by the chemical reaction that occurs at the catalytic active surface of gate electrodes. The possible mechanisms of enhanced sensitivity and selectivity to H{sub 2}S adsorption of MIS gas sensors with WO{sub 3}/Pd composite gate electrodes compared to pure Pd have been analyzed.

Suicidal behavior among Turkish patients with Parkinson’s disease

Directory of Open Access Journals (Sweden)

Ozdilek B

2014-03-01

Full Text Available Betul Ozdilek,1 Bulent Kadri Gultekin21Department of Neurology, 2Department of Psychiatry, Erenkoy Mental Health and Neurology Training and Research Hospital, Istanbul, TurkeyObjective: To investigate the predictors of suicidal ideation and attempts among Turkish Parkinson’s disease (PD patients.Materials and methods: The study comprised 120 patients with PD. Clinical findings were obtained by using the Unified Parkinson’s Disease Rating Scale. Disease severity was measured by the Hoehn and Yahr staging scale, and the Schwab and England Activities of Daily Living scale was used for patient disability. Psychiatric evaluation was performed by the same psychiatrist using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM-IV Axis I Disorders. Severity of depression was measured with the Hamilton Depression Rating Scale. Suicidal ideation and attempts were considered positive if experienced during the patient’s lifetime. The Suicide Probability Scale was used to assess the risk of suicide. Data were analyzed by logistic regression models to identify variables associated with suicidal ideation and attempts.Results: Based on logistic regression analysis, education level, age of disease onset, disease duration, depression, and history of impulse-control disorder (ICD behaviors were significant predictors of suicidal ideation. The risk rate in the presence of depression and history of ICD behaviors was increased by 5.92 and 4.97, respectively. Additionally, lifetime prevalence of suicidal ideation was found in 11.6% (14 of 120 of PD patients, although no patient had ever attempted suicide.Conclusion: Turkish patients with PD who exhibit a high risk for suicidal ideation also experience disease starting at an earlier age, longer disease duration, presence of depression, and ICD behaviors, and should be monitored carefully.Keywords: Parkinson’s disease, suicidal behavior, risk factors

One-pot synthesis of Pd-Pt@Pd core-shell nanocrystals with enhanced electrocatalytic activity for formic acid oxidation

KAUST Repository

Yuan, Qiang; Huang, Dabing; Wang, Honghui; Zhou, Zhiyou; Wang, Qingxiao

2014-01-01

Well-defined Pd-Pt@Pd core-shell nanocrystals with a Pd-Pt alloy core and a conformal Pd shell of ~2-3 nm were directly synthesized through a one-pot, aqueous solution approach without any preformed Pd or Pt seeds. These Pd-Pt@Pd core

A comparative study of PD-L1 immunohistochemical assays with four reliable antibodies in thymic carcinoma.

Science.gov (United States)

Sakane, Tadashi; Murase, Takayuki; Okuda, Katsuhiro; Takino, Hisashi; Masaki, Ayako; Oda, Risa; Watanabe, Takuya; Kawano, Osamu; Haneda, Hiroshi; Moriyama, Satoru; Saito, Yushi; Yamada, Takeshi; Nakanishi, Ryoichi; Inagaki, Hiroshi

2018-01-23

Currently, four immunohistochemical assays are registered with the US Food and Drug Administration to detect the expression of PD-L1. We investigated the PD-L1 expression in thymic carcinomas using these four diagnostic assays. The cases of 53 patients were reviewed and their specimens were subjected to four PD-L1 assays with different antibodies (SP142, SP263, 22C3, and 28-8). The PD-L1 expression in tumor cells (TCs) and immune cells (ICs) was evaluated. In TCs, the four assays showed similar scores in each case. Histopathologically, high TC scores were observed in squamous cell carcinomas (SqCCs). Meanwhile, there were no significant relationships among the IC scores in the four assays. In SqCCs, the high expression of PD-L1 (defined as ≥50% TC score) in TCs tended to be associated with early stage cancer. The patients with high expression levels of PD-L1 tended to show longer overall survival in the 22C3 assays (p=0.0200). In thymic carcinomas, the staining pattern showed high concordance among the four assays when TCs - rather than ICs - were stained. High PD-L1 positivity in TCs, especially in SqCCs, indicated that PD-1/PD-L1 targeted therapy may be a promising therapeutic approach.

[Inappropriate prescription in older patients: the STOPP/START criteria].

LENUS (Irish Health Repository)

Delgado Silveira, Eva

2009-09-01

Older people are a heterogeneous group of patients, often with multiple comorbidities for which they are prescribed a large number of drugs, leading to an increased risk of adverse drug reactions (ADR) and drug interactions. This risk is compounded by physiological age-related changes in physiology, changes in drug pharmacokinetics and pharmacodynamics, as well as by disease-related, functional and social issues. Inappropriate prescription of drugs is common in the older individuals and contributes to the increased risk of ADR. Several tools have been developed to detect potentially inappropriate prescription, the most frequently used in Spain being Beers\\' criteria. However, the value of these criteria is limited, especially as they were developed in a different healthcare system. In this article, the Spanish version of a new tool to detect potentially inappropriate prescriptions-STOPP (Screening Tool of Older Person\\'s Prescriptions) and START (Screening Tool to Alert doctors to Right i.e. appropriate, indicated Treatment) criteria-is presented. The creation, development, reliability, and use of these criteria in routine practice is described and discussed. These criteria have shown better sensitivity than Beers\\' criteria in detecting prescription problems and have the added value of being able to detect not only inappropriate prescription of some drugs, but also the omission of well indicated drugs. The STOPP\\/START criteria could become a useful screening tool to improve prescription in older people.

Expression of PD-L1 and presence of CD8-positive T cells in pre-treatment specimens of locally advanced cervical cancer.

Science.gov (United States)

Enwere, Emeka K; Kornaga, Elizabeth N; Dean, Michelle; Koulis, Theodora A; Phan, Tien; Kalantarian, Maria; Köbel, Martin; Ghatage, Prafull; Magliocco, Anthony M; Lees-Miller, Susan P; Doll, Corinne M

2017-04-01

Several of the cancer immunotherapies under investigation or in clinical use target the programmed death-ligand 1/programmed death-1 (PD-L1/PD-1) signaling axis. PD-L1 expression in tumor samples has been used as a predictive marker for response to these therapeutics, and may also have independent prognostic utility when assessed along with immune cell markers. Our objectives were to assess the expression of PD-L1 in tumor specimens from a uniformly treated patient cohort with locally advanced cervical cancer, and to determine its prognostic significance along with the density of tumor-infiltrating T cells. We identified 120 patients with locally advanced cervical cancer treated with radical chemoradiotherapy, and built tissue microarrays from their formalin-fixed, paraffin-embedded pre-treatment biopsies. We used conventional brightfield and fluorescence immunohistochemistry to detect PD-L1, and quantified protein expression using both manual pathologist scoring and automated software analysis. We also evaluated the effect of PD-L1 expression in tumors, along with the presence and density of intra-tumoral CD8 + T cells, on patient survival outcomes. Approximately 96% of the tumor samples expressed PD-L1, as determined using quantitative software analysis. Neither expression of PD-L1 nor density of CD8 + T cells was associated with progression-free or overall survival. However, there was a trend towards worse progression-free survival in patients whose tumors expressed PD-L1 but lacked CD8 + T cells (hazard ratio=0.43 (0.18-1.01), P=0.053). Nevertheless, the high percentage of cervical cancer tumor samples expressing PD-L1 suggests that anti-PD-L1 or anti-PD-1 therapies are potential treatment options for this patient population.

Parental discussion of G6PD deficiency and child health: implications for clinical practice.

Science.gov (United States)

Guan, Yue; Roter, Debra L; Huang, Aichu; Erby, Lori A H; Chien, Yin-Hsiu; Hwu, Wuh-Liang

2014-03-01

Parents are encouraged to discuss self-care with children affected by G6PD deficiency; however, little is known about the extent or impact of these discussions on the physical and psychosocial health of these children. The purpose of this study was to examine the nature of parental-child discussions of G6PD deficiency self-care and their relationship to child health. A quantitative cross-sectional survey of 178 Taiwanese parents of children with G6PD deficiency was conducted. The extent of parental-child self-care discussions was assessed in regards to coverage of nine key topics. Parent's G6PD deficiency status, knowledge of haemolytic anaemia symptoms and reported G6PD deficiency education from providers were examined as correlates of parental discussion. Child health was assessed with the child health questionnaire-parent form (Chinese version) and a 13-item haemolytic anaemia symptom list. Self-care discussions were positively correlated with parental G6PD deficiency status (β=2.08, p=0.03), accurate identification of haemolytic anaemia symptoms (β=0.18, p=0.01), the thoroughness and clarity of patient education (β=0.14, pchild age (β=1.04, pchild health (β=1.18, pchild G6PD deficiency self-care discussions are associated with better child health, and parental involvement in these discussions is facilitated by the thoroughness and clarity of patient education received from providers.

Magnetic characteristics of CoPd and FePd antidot arrays on nanoperforated Al_2O_3 templates

International Nuclear Information System (INIS)

Maximenko, A.; Fedotova, J.; Marszałek, M.; Zarzycki, A.; Zabila, Y.

2016-01-01

Hard magnetic antidot arrays show promising results in context of designing of percolated perpendicular media. In this work the technology of magnetic FePd and CoPd antidot arrays fabrication is presented and correlation between surface morphology, structure and magnetic properties is discussed. CoPd and FePd antidot arrays were fabricated by deposition of Co/Pd and Fe/Pd multilayers (MLs) on porous anodic aluminum oxide templates with bowl-shape cell structure with inclined intercellular regions. FePd ordered L1_0 structure was obtained by successive vacuum annealing at elevated temperatures (530 °C) and confirmed by XRD analysis. Systematic analysis of magnetization curves evidenced perpendicular magnetic anisotropy of CoPd antidot arrays, while FePd antidot arrays revealed isotropic magnetic anisotropy with increased out-of-plane magnetic contribution. MFM images of antidots showed more complicated contrast, with alternating magnetic dots oriented parallel and antiparallel to tip magnetization moment. - Highlights: • CoPd and FePd antidots were fabricated on porous anodic aluminum oxide templates. • CoPd antidot arrays have perpendicular magnetic anisotropy. • FePd antidot arrays revealed isotropic magnetic behavior. • The complex morphology of nanoporous template resulted in a complex magnetic domains image.

A Regional PD Strategy for EPR Systems: Evidence-Based IT Development

DEFF Research Database (Denmark)

Simonsen, Jesper; Hertzum, Morten

2006-01-01

One of the five regions in Denmark has initiated a remark-able and alternative strategy for the development of Elec-tronic Patient Record (EPR) systems. This strategy is driven by Participatory Design (PD) experiments and based on evidence of positive effects on the clinical practice when using EPR...... systems. We present this PD strategy and our related research on evidence-based IT development. We report from a newly completed PD experiment with EPR in the region conducted through a close collaboration compris-ing a neurological stroke unit, the region’s EPR unit, the vendor, as well as the authors....

Asymptomatic Effluent Protozoa Colonization in Peritoneal Dialysis Patients.

Science.gov (United States)

Simões-Silva, Liliana; Correia, Inês; Barbosa, Joana; Santos-Araujo, Carla; Sousa, Maria João; Pestana, Manuel; Soares-Silva, Isabel; Sampaio-Maia, Benedita

Currently, chronic kidney disease (CKD) is a global health problem. Considering the impaired immunity of CKD patients, the relevance of infection in peritoneal dialysis (PD), and the increased prevalence of parasites in CKD patients, protozoa colonization was evaluated in PD effluent from CKD patients undergoing PD. Overnight PD effluent was obtained from 49 asymptomatic stable PD patients. Protozoa analysis was performed microscopically by searching cysts and trophozoites in direct wet mount of PD effluent and after staining smears. Protozoa were found in PD effluent of 10.2% of evaluated PD patients, namely Blastocystis hominis, in 2 patients, and Entamoeba sp., Giardia sp., and Endolimax nana in the other 3 patients, respectively. None of these patients presented clinical signs or symptoms of peritonitis at the time of protozoa screening. Our results demonstrate that PD effluent may be susceptible to asymptomatic protozoa colonization. The clinical impact of this finding should be further investigated. Copyright © 2016 International Society for Peritoneal Dialysis.

One-pot synthesis of Pd-Pt@Pd core-shell nanocrystals with enhanced electrocatalytic activity for formic acid oxidation

KAUST Repository

Yuan, Qiang

2014-01-01

Well-defined Pd-Pt@Pd core-shell nanocrystals with a Pd-Pt alloy core and a conformal Pd shell of ~2-3 nm were directly synthesized through a one-pot, aqueous solution approach without any preformed Pd or Pt seeds. These Pd-Pt@Pd core-shell nanocrystals show an enhanced electrocatalytic activity for formic acid oxidation compared with commercial Pd black. This journal is © 2014 The Royal Society of Chemistry.

PD-1hiTIM-3+ T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation

International Nuclear Information System (INIS)

Kong, Y; Zhang, J; Claxton, D F; Ehmann, W C; Rybka, W B; Zhu, L; Zeng, H; Schell, T D; Zheng, H

2015-01-01

Prognosis of leukemia relapse post allogeneic stem cell transplantation (alloSCT) is poor and effective new treatments are urgently needed. T cells are pivotal in eradicating leukemia through a graft versus leukemia (GVL) effect and leukemia relapse is considered a failure of GVL. T-cell exhaustion is a state of T-cell dysfunction mediated by inhibitory molecules including programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3). To evaluate whether T-cell exhaustion and inhibitory pathways are involved in leukemia relapse post alloSCT, we performed phenotypic and functional studies on T cells from peripheral blood of acute myeloid leukemia patients receiving alloSCT. Here we report that PD-1 hi TIM-3 + cells are strongly associated with leukemia relapse post transplantation. Consistent with exhaustion, PD-1 hi TIM-3 + T cells are functionally deficient manifested by reduced production of interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). In addition, these cells demonstrate a phenotype consistent with exhausted antigen-experienced T cells by losing T N and T EMRA subsets. Importantly, increase of PD-1 hi TIM-3 + cells occurs before clinical diagnosis of leukemia relapse, suggesting their predictive value. Results of our study provide an early diagnostic approach and a therapeutic target for leukemia relapse post transplantation

Increased frequency and range of sexual behavior in a patient with Parkinson's disease after use of pramipexole: a case report.

Science.gov (United States)

Munhoz, Renato P; Fabiani, Giorgio; Becker, Nilson; Teive, Hélio A G

2009-04-01

Several recent reports have linked the use of dopamine agonists (DAs) to a variety of compulsive behaviors in patients with Parkinson's disease (PD). These inappropriate behaviors may include pathological gambling, compulsive shopping, and hypersexuality. To report the case of a patient with increased range of sexual behavior after use of pramipexole, a DA. A 67-year-old man with a 7-year diagnosis of PD treated with levodopa and pramipexole presented with a dramatic change in sexual behavior after an increase in DA dose. The patient, who historically was a very shy and conservative person, started to present increased frequency of sexual intercourse with his wife, during which he began speaking obscenities with an extreme preference for anal intercourse, preferences never requested before. After pramipexole was withdrawn, complete remission was observed with return to his usual sexual behavior. Hypersexuality and paraphilias are complications not uncommonly found in patients with PD under dopaminergic treatment. Further studies are needed for the understanding of this complex complication, and particularly the most prevalent relationship between pathological hypersexuality and use of DAs.

Predictors of work disability after start of anti-TNF therapy in a national cohort of Swedish patients with rheumatoid arthritis: does early anti-TNF therapy bring patients back to work?

Science.gov (United States)

Olofsson, T; Petersson, I F; Eriksson, J K; Englund, M; Nilsson, J A; Geborek, P; Jacobsson, L T H; Askling, J; Neovius, M

2017-07-01

To examine predictors of work ability gain and loss after anti-tumour necrosis factor (TNF) start, respectively, in working-age patients with rheumatoid arthritis (RA) with a special focus on disease duration. Patients with RA, aged 19-62 years, starting their first TNF inhibitor 2006-2009 with full work ability (0 sick leave/disability pension days during 3 months before bio-start; n=1048) or no work ability (90 days; n=753) were identified in the Swedish biologics register (Anti-Rheumatic Treatment In Sweden, ARTIS) and sick leave/disability pension days retrieved from the Social Insurance Agency. Outcome was defined as work ability gain ≥50% for patients without work ability at bio-start and work ability loss ≥50% for patients with full work ability, and survival analyses conducted. Baseline predictors including disease duration, age, sex, education level, employment, Health Assessment Questionnaire, Disease Activity Score 28 and relevant comorbidities were estimated using Cox regression. During 3 years after anti-TNF start, the probability of regaining work ability for totally work-disabled patients was 35% for those with disease duration start, disease duration did not predict work ability loss. Baseline disability pension was also a strong predictor of work ability gain after treatment start. A substantial proportion of work-disabled patients with RA who start anti-TNF therapy regain work ability. Those initiating treatment within 5 years of symptom onset have a more than doubled 3-year probability of regaining work ability compared with later treatment starts. This effect seems largely due to the impact of disease duration on disability pension status. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Immuno-inhibitory PD-L1 can be induced by a peptidoglycan/NOD2 mediated pathway in primary monocytic cells and is deficient in Crohn's patients with homozygous NOD2 mutations.

Science.gov (United States)

Hewitt, Rachel E; Pele, Laetitia C; Tremelling, Mark; Metz, Andrew; Parkes, Miles; Powell, Jonathan J

2012-05-01

Peptidoglycan (PGN) is a ubiquitous bacterial membrane product that, despite its well known pro-inflammatory properties, has also been invoked in immuno-tolerance of the gastrointestinal tract. PGN-induced mucosal IL-10 secretion and downregulation of Toll like receptors are potential mechanisms of action in the gut but there are few data on tolerogenic adaptive immune responses and PGN. Here, using blood-derived mononuclear cells, we showed that PGN induced marked cell surface expression of PD-L1 but not PD-L2 or CD80/CD86, and specifically in the CD14(+) monocytic fraction. This was reproduced at the gene level with rapid induction (<4 h) and, unlike for LPS stimulation, was still sustained at 24 h. Using transfected and native muramyl dipeptide (MDP), which is a cleavage product of PGN and a specific NOD2 agonist, in assays with wild type cells or those from patients with Crohn's disease carrying the Leu1007 frameshift mutation of NOD2, we showed that (i) both NOD2 dependent and independent signalling (appearing TLR2 mediated) occurred for PGN upregulation of PD-L1 (ii) upregulation is lost in response to MDP in patients with the homozygous mutation and (iii) PD-L1 upregulation was unaffected in patients with heterozygous mutations as previously reported for cytokine responses to MDP. The uptake of PGN and its cleavage products by the intestinal mucosa is well recognised and further work should consider PD-L1 upregulation as one potential mechanism of the commensal flora-driven intestinal immuno-tolerance. Indeed, recent work has shown that loss of PD-L1 signalling in the gut breaks CD8(+) T cell tolerance to self antigen and leads to severe autoimmune enteritis. Copyright © 2012 Elsevier Inc. All rights reserved.

Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy.

Science.gov (United States)

Hofmann, Lars; Forschner, Andrea; Loquai, Carmen; Goldinger, Simone M; Zimmer, Lisa; Ugurel, Selma; Schmidgen, Maria I; Gutzmer, Ralf; Utikal, Jochen S; Göppner, Daniela; Hassel, Jessica C; Meier, Friedegund; Tietze, Julia K; Thomas, Ioannis; Weishaupt, Carsten; Leverkus, Martin; Wahl, Renate; Dietrich, Ursula; Garbe, Claus; Kirchberger, Michael C; Eigentler, Thomas; Berking, Carola; Gesierich, Anja; Krackhardt, Angela M; Schadendorf, Dirk; Schuler, Gerold; Dummer, Reinhard; Heinzerling, Lucie M

2016-06-01

Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential. In total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis. Anti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Structure and transformation behaviour of a rapidly solidified Al-Y-Ni-Co-Pd alloy

International Nuclear Information System (INIS)

Louzguine-Luzgin, D.V.; Inoue, A.

2005-01-01

An as-solidified structure and transformation behaviour on heating of the rapidly solidified Al-Y-Ni-Co-Pd alloy was studied by X-ray diffractometry (XRD), transmission electron microscopy (TEM), differential scanning and isothermal calorimetries. The Al-Y-Ni-Co-Pd ribbon samples have been produced by the melt spinning technique and heat treated using a differential scanning calorimeter (DSC). The addition of Pd to Al-Y-Ni-Co alloys caused disappearance of the supercooled liquid region as well as the formation of the highly dispersed primary α-Al nanoparticles about 3-7 nm in size homogeneously embedded in the glassy matrix upon solidification. An extremely high density of precipitates of the order of 10 24 m -3 is obtained. These particles start growing at the temperature below a glass-transition temperature. The results presented in this paper indicate that some of so-called 'marginal' glass-formers in as-solidified state are actually not glassy alloys with pre-existed nuclei but crystal-glassy nanocomposites

Progress of PD-1/PD-L1 Inhibitors in Non-small Cell Lung Cancer

Directory of Open Access Journals (Sweden)

Zhansheng JIANG

2017-02-01

Full Text Available Pembrolizumab, an inhibitor target programmed death 1 (PD-1, was approved into the first line therapy in advanced non-small cell lung cancer (NSCLC. It was a milestone that immune checkpoints drugs have played an important role in the treatment system of NSCLC. The results of clinical trials revealed the superiority of PD-1/programmed death ligand 1 (PD-L1 inhibitors compared with chemotherapy in first-line, second-line and multidrug resistance phase therapy. Objective response rate (ORR was up to 80% with pembrolizumab plus chemotherapy, and progression-free survival (PFS with single pembrolizumab in first line was nearly 1 year (10.3 months, the hazard ratio for death fell by 40%. Overall survival (OS was more or less 1 year with single drug pembrolizumab, nivolumab and atezolizumab for second line therapy. PD-L1 expression was a predictor of PD-1/PD-L1 inhibitors. The positive rate of PD-L1 (more than 1% in advanced NSCLC was about 60% with little difference between the tissue types. However, there was no gold standard test of PD-L1 expression.

Improved ethanol electrooxidation performance by shortening Pd-Ni active site distance in Pd-Ni-P nanocatalysts

Science.gov (United States)

Chen, Lin; Lu, Lilin; Zhu, Hengli; Chen, Yueguang; Huang, Yu; Li, Yadong; Wang, Leyu

2017-01-01

Incorporating oxophilic metals into noble metal-based catalysts represents an emerging strategy to improve the catalytic performance of electrocatalysts in fuel cells. However, effects of the distance between the noble metal and oxophilic metal active sites on the catalytic performance have rarely been investigated. Herein, we report on ultrasmall (~5 nm) Pd-Ni-P ternary nanoparticles for ethanol electrooxidation. The activity is improved up to 4.95 A per mgPd, which is 6.88 times higher than commercial Pd/C (0.72 A per mgPd), by shortening the distance between Pd and Ni active sites, achieved through shape transformation from Pd/Ni-P heterodimers into Pd-Ni-P nanoparticles and tuning the Ni/Pd atomic ratio to 1:1. Density functional theory calculations reveal that the improved activity and stability stems from the promoted production of free OH radicals (on Ni active sites) which facilitate the oxidative removal of carbonaceous poison and combination with CH3CO radicals on adjacent Pd active sites.

When antithyroid drugs must be started in patients with hyperemesis gravidarum

International Nuclear Information System (INIS)

Farzad, N.; Akbar, A.; Naser, A.; Majid, M.

2009-01-01

To find out role of anti-thyroid drugs in patients with Hyperemesis gravidarum and thyroid dysfunction. One hundred thirty five patients with hyperemesis gravidarum who were admitted to obstetric and gynecology hospital were enrolled in this study. Thirty two patients were excluded because of diabetes mellitus and thyroid diseases. Hence, one hundred three patients underwent investigations including thyroid function test and beta-hCG (Human chorionic gonadotropin). Thirty five women were found with abnormal thyroid function test with FT4I (Free Thyroxin Index) 4.74 +- 0.54 and in another group (68 women) was 2.9 +- 0.39 (P<0.0001). B-hCG in first group was 59406 +-14899 miu/ml and in second group was 6750 +- m 3476 miu/mL (P<0.0001). In five patients PTU (propylthiouracil) was started due to severe sign and symptoms of hyperthyroidism. Thyroid function test was rechecked for all of 35 patients after four weeks routine therapy for hyperemesis gravidarum. Thyroid function test was normalized in 11 patients with hyperemesis graridarum but remained abnormal in 22 patients. In our study thyroid dysfunction in hyperemesis gravidarum was 35% and, 20% of patients needed anti-thyroid therapy. Routine assessment of thyroid function is necessary for women with hyperemesis gravidarum especially in patients with clinical features of hyperthyroidism. We must consider PTU (propylthouracil) in hyperemesis gravidarum with severe weight loss, vomiting and biochemical hyperthyroidism. (author)

Acute Malaria Induces PD1+CTLA4+ Effector T Cells with Cell-Extrinsic Suppressor Function.

Directory of Open Access Journals (Sweden)

Maria Sophia Mackroth

2016-11-01

Full Text Available In acute Plasmodium falciparum (P. falciparum malaria, the pro- and anti-inflammatory immune pathways must be delicately balanced so that the parasitemia is controlled without inducing immunopathology. An important mechanism to fine-tune T cell responses in the periphery is the induction of coinhibitory receptors such as CTLA4 and PD1. However, their role in acute infections such as P. falciparum malaria remains poorly understood. To test whether coinhibitory receptors modulate CD4+ T cell functions in malaria, blood samples were obtained from patients with acute P. falciparum malaria treated in Germany. Flow cytometric analysis showed a more frequent expression of CTLA4 and PD1 on CD4+ T cells of malaria patients than of healthy control subjects. In vitro stimulation with P. falciparum-infected red blood cells revealed a distinct population of PD1+CTLA4+CD4+ T cells that simultaneously produced IFNγ and IL10. This antigen-specific cytokine production was enhanced by blocking PD1/PDL1 and CTLA4. PD1+CTLA4+CD4+ T cells were further isolated based on surface expression of PD1 and their inhibitory function investigated in-vitro. Isolated PD1+CTLA4+CD4+ T cells suppressed the proliferation of the total CD4+ population in response to anti-CD3/28 and plasmodial antigens in a cell-extrinsic manner. The response to other specific antigens was not suppressed. Thus, acute P. falciparum malaria induces P. falciparum-specific PD1+CTLA4+CD4+ Teffector cells that coproduce IFNγ and IL10, and inhibit other CD4+ T cells. Transient induction of regulatory Teffector cells may be an important mechanism that controls T cell responses and might prevent severe inflammation in patients with malaria and potentially other acute infections.

Influence of Pd-precursor on the acetoxylation activity of Pd-Sb/TiO{sub 2} catalysts

Energy Technology Data Exchange (ETDEWEB)

Ben-homeid, A. [Benghazi Univ. (Libyan Arab Jamahiriya). Chemistry Dept.; Kalevaru, V.N.; Radnik, J.; Luecke, B.; Martin, A. [Leibniz-Institut fuer Katalyse e.V. an der Universitaet Rostock (Germany)

2013-11-01

The impact of palladium precursors (e.g. chloride-PdCl{sub 2}; acetate-Pd(OAc){sub 2}; nitrate-Pd(NO{sub 3}){sub 2}) on the catalytic properties of Pd-Sb/TiO{sub 2} catalysts used for acetoxylation of toluene has been investigated. The catalysts were characterized by different techniques such as N{sub 2}-adsorption (BET-surface area and pore volume), XRD, TEM, CO-Chemisorption and XPS for better understanding of the catalytic properties of the catalysts. The acetate and nitrate-type precursors exhibited higher surface areas, pore volumes and higher dispersion of Pd, but displayed poor performance compared to chloride precursor. TEM analysis indicated that the size of Pd particles depended upon the nature of Pd-precursor. Among the three, chloride precursor exhibited bigger Pd particles. XPS results revealed that all the fresh catalysts irrespective of Pd-precursor contained Pd in oxidized state (i.e. Pd{sup +2}), while in the spent catalysts such oxidized Pd species were reduced. The catalytic performance was found to depend strongly on the nature of precursor used. Among the three, the catalysts prepared from chloride-type precursor showed much higher overall catalytic activity (68%) than those of nitrate and/or acetate type precursors. Moreover, these two precursors (acetate and nitrate) gave higher total oxidation products due to oxidative decomposition of mainly acetic acid. Furthermore, the catalyst prepared from Cl-precursor revealed easy deactivation due to coke deposition and also due to loss of Pd in the near-surface-region. (orig.)

Epidemiology and Management of Patients With Acute Coronary Syndromes in Contemporary Real-World Practice: Evolving Trends From the EYESHOT Study to the START-ANTIPLATELET Registry.

Science.gov (United States)

Calabrò, Paolo; Gragnano, Felice; di Maio, Marco; Patti, Giuseppe; Antonucci, Emilia; Cirillo, Plinio; Gresele, Paolo; Palareti, Gualtiero; Pengo, Vittorio; Pignatelli, Pasquale; Pennacchi, Mauro; Granatelli, Antonino; De Servi, Stefano; De Luca, Leonardo; Marcucci, Rossella

2018-01-01

The epidemiology and management of patients with acute coronary syndromes (ACSs) have evolved. We aimed to describe recent demographics and therapeutic changes in the Italian ACS population. We analyzed data from 2 multicenter consecutive Italian registries (the EYESHOT [EmploYEd antithrombotic therapies in patients with acute coronary Syndromes HOspitalised in iTalian cardiac care units] and START-ANTIPLATELET registries) enrolling patients with ACS between December 2013 and June 2016. An overall population of 3756 patients with ACS was enrolled: 2585 in the EYESHOT and 1171 in the START-ANTIPLATELET. Compared with the EYESHOT, patients in the START-ANTIPLATELET registry presented more frequently with ST-segment elevation myocardial infarction and were more often smokers and dyslipidemic (all P START-ANTIPLATELET (all P START-ANTIPLATELET compared with the EYESHOT. The START-ANTIPLATELET and EYESHOT registries provide consecutive snapshots in the contemporary management of patients with ACS in Italy, showing important changes in both demographic characteristics and treatment strategies.

Specific brainstem and cortico-spinal reflex abnormalities in coexisting essential tremor and Parkinson's disease (ET-PD).

Science.gov (United States)

Yavuz, D; Gündüz, A; Ertan, S; Apaydın, H; Şifoğlu, A; Kiziltan, G; Kiziltan, M E

2015-05-01

We aimed to analyze functional changes at brainstem and spinal levels in essential tremor (ET), Parkinson's disease (PD) and coexisting essential tremor and Parkinson's disease (ET-PD). Age- and gender-matched patients with tremor (15 ET, 7 ET with resting tremor, 25 ET-PD and 10 PD) and 12 healthy subjects were enrolled in the study. Diagnosis was established according to standardized clinical criteria. Electrophysiological studies included blink reflex (BR), auditory startle reaction (ASR) and long latency reflex (LLR). Blink reflex was normal and similar in all groups. Probability of ASR was significantly lower in ET-PD group whereas it was similar to healthy subjects in ET and PD (PET, PD and ET-PD groups. LLR III was far more common in the PD group (n=3, 13.6% in ET; n=4, 16.0% in ET-PD and n=7, 46.7% in PD; p=0.037). Despite the integrity of BR pathways, ASR and LLR show distinctive abnormalities in ET-PD. In our opinion, our electrophysiological findings support the hypothesis that ET-PD is a distinct entity. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Production of verbs related to body movement in amyotrophic lateral sclerosis (ALS) and Parkinson's Disease (PD).

Science.gov (United States)

Cousins, Katheryn A Q; Ash, Sharon; Grossman, Murray

2018-03-01

Theories of grounded cognition propose that action verb knowledge relies in part on motor processing regions, including premotor cortex. Accordingly, impaired action verb knowledge in patients with amyotrophic lateral sclerosis (ALS) and Parkinson's Disease (PD) is thought to be due to motor system degeneration. Upper motor neuron disease in ALS degrades the motor cortex and related pyramidal motor system, while disease in PD is centered in the basal ganglia and can spread to frontostriatal areas that are important to language functioning. These anatomical distinctions in disease may yield subtle differences in the action verb impairment between patient groups. Here we compare verbs where the body is the agent of the action to verbs where the body is the theme. To examine the role of motor functioning in body verb production, we split patient groups into patients with high motor impairment (HMI) and those with low motor impairment (LMI), using disease-specific measures of motor impairment. Regression analyses assessed how verb production in ALS and PD was related to motor system atrophy. We find a dissociation between agent- and theme-body verbs in ALS: ALS HMI were impaired for agent body verbs but not theme verbs, compared to ALS LMI. This dissociation was not present in PD patients, who instead show depressed production for all body verbs. Although patients with cognitive impairment were excluded from this study, cognitive performance significantly correlated with the production of theme verbs in ALS and cognitive/stative verbs in PD. Finally, regression analyses related the agent-theme dissociation in ALS to grey matter atrophy of premotor cortex. These findings support the view that motor dysfunction and disease in premotor cortex contributes to the agent body verb deficit in ALS, and begin to identify some distinct characteristics of impairment for verbs in ALS and PD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Changes in geriatric nutritional risk index and risk of major adverse cardiac and cerebrovascular events in incident peritoneal dialysis patients

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Mi Jung Lee

2017-12-01

Full Text Available Background: Geriatric nutritional risk index (GNRI is a validated nutritional assessment method, and lower GNRI values are closely associated with adverse clinical outcomes in dialysis patients. This study investigated the impact of changes in GNRI during the first year of dialysis on cardiovascular outcomes in incident peritoneal dialysis (PD patients. Methods: We reviewed medical records in 133 incident PD patients to determine GNRI at the start of PD and after 12 months. Patients were categorized into improved (delta GNRI > 0 and worsening/stationary (delta GNRI ≤ 0 groups. The primary outcome was major adverse cardiac and cerebrovascular events (MACCEs. Results: During a mean follow-up of 51.1 months, the primary outcome was observed in 42 patients (31.6%. The baseline GNRI at PD initiation was not significantly associated with MACCEs (log-rank test, P = 0.40. However, the cumulative event-free rate was significantly lower in the worsening or stationary GNRI group than in the improved group (log-rank test, P = 0.004. Multivariate Cox analysis revealed that a worsening or stationary GNRI was independently associated with higher risk for MACCEs (hazard ratio, 2.47; 95% confidence interval, 1.15–5.29; P = 0.02. In subgroup analysis, patients with worsening or stationary GNRI were at significantly greater risk for MACCEs in both the lower (P = 0.04 and higher (P = 0.01 baseline GNRI groups. Conclusion: Baseline GNRI was not associated with MACCEs, but patients with deteriorating or stationary nutritional status were at significantly greater risk for MACCEs, suggesting that serial monitoring of nutritional status is important to stratify cardiovascular risk in incident PD patients.

Pain Correlates with Sleep Disturbances in Parkinson's Disease Patients.

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Fu, Yun-Ting; Mao, Cheng-Jie; Ma, Li-Jing; Zhang, Hui-Jun; Wang, Yi; Li, Jie; Huang, Jun-Ying; Liu, Jun-Yi; Liu, Chun-Feng

2018-01-01

Both sleep disorders and pain decrease quality of life in patients with Parkinson's disease (PD). However, little is known about the relationship between objective sleep disturbances and pain in patients with PD. This study aimed to (1) examine the clinical characteristics of pain in PD patients and (2) explore the correlation between pain and sleep disturbances in PD patients. Parkinson's disease patients (N = 144) underwent extensive clinical evaluations of motor and nonmotor symptoms and characteristics of pain. Overnight video-polysomnography was also conducted. Clinical characteristics and sleep parameters were compared between PD patients with or without pain. Pain was reported by 75 patients (52.1%), with 49 (65.3%) reporting pain of at least moderate severity. PD patients with pain were older and had longer disease duration, more severe PD symptoms as assessed by Hoehn and Yahr stage and the Unified Parkinson's Disease Rating Scale, and higher L-dopa equivalent daily dose compared with PD patients without pain. PD patients with pain also showed significantly decreased sleep efficiency (57.06% ± 15.84% vs. 73.80% ± 12.00%, P daily living, depressed mood, higher percentage of N1 sleep, and lower sleep efficiency were independent predictors of pain in patients with PD. Musculoskeletal pain is the most common type of pain in patients with PD. Disrupted sleep continuity, altered sleep architecture, depressed mood, and compromised activities of daily living may be associated with pain in patients with PD. © 2017 World Institute of Pain.

Lactoferricin B reverses cisplatin resistance in head and neck squamous cell carcinoma cells through targeting PD-L1.

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Zhang, Pei; Liu, Jinzhong; Li, Wenlu; Li, Shanshan; Han, Xinguang

2018-05-15

Head and neck squamous cell carcinoma (HNSCC) ranks among the top most common cancers with a poor prognosis. The mechanism of chemoresistance is still not well known. This study is to investigate the programmed death-ligand 1 (PD-L1) expression in HNSCC, and test the effect of lactoferricin B (LfcinB) on chemoresistance and its mechanism. We analyzed 510 HNSCC patients in TCGA database and investigated how CD274 expression was related to patient prognosis. PD-L1 was verified from HNSCC samples at local hospital with immunohistochemistry. PD-L1 expression in the acquired cisplatin-resistant HNSCC cells was examined by PCR and WB in order to test PD-L1-induced chemoresistance. LfcinB inoculation in cisplatin-resistant HNSCC cells and in the nude mice was introduced to test the effect of LfcinB on targeting cisplatin resistance and its mechanism. High CD274 mRNA (>125 FPKM) from TCGA database had a significantly reduced 5-year survival rate, and a lower 5-year survival rate in the chemotherapy and radiotherapy-treated patients (P < .05). PD-L1 overexpression was further supported from analysis of 40 HNSCC specimens. PD-L1 and IL-6 in the established cisplatin-resistant HNSCC cells were shown significantly higher (P < .05). IL-6 and PD-L1 expression were partially inhibited by the anti-IL-6/STAT3 antibody. LfcinB displayed a direct cytotoxic effect on cisplatin-resistant HNSCC cells and HNSCC xenografts of cisplatin-resistant cells in the nude mice displayed significant reduction in tumor volume after LfcinB injection (P < .05). Besides, the increase of IL-6 and PD-L1 in cisplatin-resistant HNSCC cells was abolished in vitro by LfcinB (P < .05). PD-L1 expression in HNSCC cells correlates with poor prognosis and chemoresistance, and LfcinB might provide therapeutic potential in HNSCC patients through modulating IL-6 and PD-L1. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Applications of the pharmacokinetic/pharmacodynamic (PK/PD) analysis of antimicrobial agents.

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Asín-Prieto, Eduardo; Rodríguez-Gascón, Alicia; Isla, Arantxazu

2015-05-01

The alarming increase of resistance against multiple currently available antibiotics is leading to a rapid lose of treatment options against infectious diseases. Since the antibiotic resistance is partially due to a misuse or abuse of the antibiotics, this situation can be reverted when improving their use. One strategy is the optimization of the antimicrobial dosing regimens. In fact, inappropriate drug choice and suboptimal dosing are two major factors that should be considered because they lead to the emergence of drug resistance and consequently, poorer clinical outcomes. Pharmacokinetic/pharmacodynamic (PK/PD) analysis in combination with Monte Carlo simulation allows to optimize dosing regimens of the antibiotic agents in order to conserve their therapeutic value. Therefore, the aim of this review is to explain the basis of the PK/PD analysis and associated techniques, and provide a brief revision of the applications of PK/PD analysis from a therapeutic point-of-view. The establishment and reevaluation of clinical breakpoints is the sticking point in antibiotic therapy as the clinical use of the antibiotics depends on them. Two methodologies are described to establish the PK/PD breakpoints, which are a big part of the clinical breakpoint setting machine. Furthermore, the main subpopulations of patients with altered characteristics that can condition the PK/PD behavior (such as critically ill, elderly, pediatric or obese patients) and therefore, the outcome of the antibiotic therapy, are reviewed. Finally, some recommendations are provided from a PK/PD point of view to enhance the efficacy of prophylaxis protocols used in surgery. Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

PD-L1 blockade with avelumab: A new paradigm for treating Merkel cell carcinoma.

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Barkdull, Savannah; Brownell, Isaac

2017-12-02

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer. Until recently, no durable treatment options were available for patients with advanced disease. As an immunogenic cancer, MCC was hypothesized to be a candidate for PD-L1/PD-1 targeted therapy. On March 23, 2017 the US Food and Drug Administration granted accelerated approval for avelumab, an anti-PD-L1 monoclonal antibody, for the treatment of metastatic MCC on the basis of the JAVELIN Merkel 200 trial. Here we examine the results and implications of this pivotal study, published in Lancet Oncology by Kaufman et al., as well as current developments in the use of immune-checkpoint therapies for treating patients with MCC.

Targeting the upstream transcriptional activator of PD-L1 as an alternative strategy in melanoma therapy.

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Zhu, Bo; Tang, Liming; Chen, Shuyang; Yin, Chengqian; Peng, Shiguang; Li, Xin; Liu, Tongzheng; Liu, Wei; Han, Changpeng; Stawski, Lukasz; Xu, Zhi-Xiang; Zhou, Guangbiao; Chen, Xiang; Gao, Xiumei; Goding, Colin R; Xu, Nan; Cui, Rutao; Cao, Peng

2018-05-22

Programmed cell death ligand 1 (PD-L1) interacts with programmed cell death protein-1 (PD-1) as an immune checkpoint. Reactivating the immune response by inhibiting PD-L1 using therapeutic antibodies provides substantial clinical benefits in many, though not all, melanoma patients. However, transcriptional suppression of PD-L1 expression as an alternative therapeutic anti-melanoma strategy has not been exploited. Here we provide biochemical evidence demonstrating that ultraviolet radiation (UVR) induction of PD-L1 in skin is directly controlled by nuclear factor E2-related transcription factor 2 (NRF2). Depletion of NRF2 significantly induces tumor infiltration by both CD8 + and CD4 + T cells to suppress melanoma progression, and combining NRF2 inhibition with anti-PD-1 treatment enhanced its anti-tumor function. Our studies identify a critical and targetable PD-L1 upstream regulator and provide an alternative strategy to inhibit the PD-1/PD-L1 signaling in melanoma treatment.

Crystal clear: visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies

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Shuguang Tan

2016-11-01

Full Text Available Abstract Antibody-based PD-1/PD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre-existing T-cell function to modulate antitumor immunity. In this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-1/PD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural information will benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.

Magnetic characteristics of CoPd and FePd antidot arrays on nanoperforated Al2O3 templates

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Maximenko, A.; Fedotova, J.; Marszałek, M.; Zarzycki, A.; Zabila, Y.

2016-02-01

Hard magnetic antidot arrays show promising results in context of designing of percolated perpendicular media. In this work the technology of magnetic FePd and CoPd antidot arrays fabrication is presented and correlation between surface morphology, structure and magnetic properties is discussed. CoPd and FePd antidot arrays were fabricated by deposition of Co/Pd and Fe/Pd multilayers (MLs) on porous anodic aluminum oxide templates with bowl-shape cell structure with inclined intercellular regions. FePd ordered L10 structure was obtained by successive vacuum annealing at elevated temperatures (530 °C) and confirmed by XRD analysis. Systematic analysis of magnetization curves evidenced perpendicular magnetic anisotropy of CoPd antidot arrays, while FePd antidot arrays revealed isotropic magnetic anisotropy with increased out-of-plane magnetic contribution. MFM images of antidots showed more complicated contrast, with alternating magnetic dots oriented parallel and antiparallel to tip magnetization moment.

Vibrotactile neurofeedback balance training in patients with Parkinson's disease: reducing the number of falls.

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Rossi-Izquierdo, Marcos; Ernst, Arne; Soto-Varela, Andrés; Santos-Pérez, Sofía; Faraldo-García, Ana; Sesar-Ignacio, Angel; Basta, Dietmar

2013-02-01

The aim of this study was to assess effectiveness of balance training with a vibrotactile neurofeedback system in improving overall stability in patients with Parkinson's disease (PD). Ten patients diagnosed with idiopathic PD were included. Individualization of the rehabilitation program started with a body sway analysis of stance and gait tasks (Standard Balance Deficit Test, SBDT) by using the diagnostic tool of the applied device (Vertiguard(®)-RT). Those tasks with the poorest outcome as related to age- and gender-related controls were included in the training program (not more than six tasks). Improvement of postural stability was assessed by performing SBDT, Sensory Organization Test (SOT) of Computerized Dynamic Posturography (CDP), Dizziness Handicap Inventory (DHI), activity-specific balance confidence scale and recording the number of falls over the past three months. Furthermore, scores of SOT and DHI of 10 PD patients previously trained in an earlier study (by using CDP) were compared with results of those in the present study. After neurofeedback training (NFT), there was a statistically significant improvement in body sway (calculated over all training tasks), number of falls, and scores of SOT, DHI and ABC. In comparison with CDP-training, a statistically significant higher increase of SOT score was observed for patients after NFT with the Vertiguard-RT device compared to CDP training. Our results showed that a free-field vibrotactile NFT with Vertiguard(®)-RT device can improve balance in PD patients in everyday life conditions very effectively, which might led in turn to a reduction of falls. Copyright © 2012 Elsevier B.V. All rights reserved.

Neonatal nucleated red blood cells in G6PD deficiency.

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Yeruchimovich, Mark; Shapira, Boris; Mimouni, Francis B; Dollberg, Shaul

2002-05-01

The objective of this study is to study the absolute number of nucleated red blood cells (RBC) at birth, an index of active fetal erythropoiesis, in infants with G6PD deficiency and in controls. We tested the hypothesis that hematocrit and hemoglobin would be lower, and absolute nucleated RBC counts higher, in the G6PD deficient and that these changes would be more prominent in infants exposed passively to fava bean through maternal diet. Thirty-two term infants with G6PD deficiency were compared with 30 term controls. Complete blood counts with manual differential counts were obtained within 12 hours of life. Absolute nucleated RBC and corrected leukocyte counts were computed from the Coulter results and the differential count. G6PD deficient patients did not differ from controls in terms of gestational age, birth weight, or Apgar scores or in any of the hematologic parameters studied, whether or not the mother reported fava beans consumption in the days prior to delivery. Although intrauterine hemolysis is possible in G6PD deficient fetuses exposed passively to fava beans, our study supports that such events must be very rare.

PD-L1 expression is associated with p16INK4A expression in non-oropharyngeal head and neck squamous cell carcinoma

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Chen, San-Chi; Chang, Peter Mu-Hsin; Wang, Hsiao-Jung; Tai, Shyh-Kuan; Chu, Pen-Yuan; Yang, Muh-Hwa

2018-01-01

PD-L1 expression is critical in helping tumor cells evade the immune system. However, the level of PD-L1 expression in non-oropharyngeal head and neck squamous cell carcinoma (non-OPHNSCC) and its association with patient prognosis remains unclear. A retrospective clinicopathological analysis was performed on 106 patients with non-OPHNSCC diagnosed between 2007 and 2014. In the current study, tissue arrays from paraffin-embedded non-OPHNSCC samples obtained from patients were constructed, and PD-L1 and p16INK4A expression were determined using immunohistochemistry. Systemic inflammatory factors, including C-reactive protein, serum white blood cell, neutrophil, monocyte and lymphocyte counts were also analyzed. The current study demonstrated that PD-L1 was overexpressed in 32.1% (34/106) and p16INK4A in 20.8% (22/106) of patients. The expression of PD-L1 was associated with p16INK4A expression (P<0.01) but was not associated with levels of systemic inflammatory factors. Tumor stage was determined to be a significant prognostic value (stage I/II vs. III/IV, P=0.03), however, PD-L1, p16INK4A or other clinicopathological factors were not. The current study identified an association between PD-L1 and p16INK4A expression in non-OPHNSCC. This may facilitate the development of anti-PD1/PDL1 therapies to treat patients with head and neck cancer. PMID:29434933

Should patients with esophageal atresia be submitted to esophageal substitution before they start walking?

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Tannuri, U; Tannuri, A C A

2011-01-01

Esophagocoloplasty and gastric transposition are two major methods for esophageal substitution in children with esophageal atresia, and there is broad agreement that these operations should not be performed before the children start walking. However, there are some reported advantages of performing such operations in the first months of life or in the neonatal period. In this study, we compared our experience with esophageal substitution procedures performed in walking children with esophageal atresia, with the outcomes of children who had the operation before the third month of life reported in the literature. The purpose of this study was to establish if we have to wait until the children start walking before indicating the esophageal replacement procedure. From February 1978 to October 2009, 129 children with esophageal atresia underwent esophageal replacement in our hospital (99 colonic interpositions and 30 gastric transpositions). The records of these patients were reviewed for data regarding demographics, complications (leaks, graft failures, strictures, and graft torsion), and mortality and compared with those reported in the two main articles on esophageal replacement in the neonatal period or in patients less than 3 months of age. The main complication of our casuistic was cervical anastomosis leakage, which sealed spontaneously in all except in four patients. One patient of the esophagocoloplasty group developed graft necrosis and three patients in the gastric transposition group had gastric outlet obstruction, secondary to axial torsion of the stomach placed in the retrosternal space. The long-term outcome of the patients in both groups was considered good to excellent in terms of normal weight gain, absence of dysphagia, and other gastrointestinal symptoms. The comparisons of the main complications and mortality rates in walking children with esophageal substitutions performed in the first months of life showed that the incidences of cervical

Satisfaction with care in peritoneal dialysis patients.

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Kirchgessner, J; Perera-Chang, M; Klinkner, G; Soley, I; Marcelli, D; Arkossy, O; Stopper, A; Kimmel, P L

2006-10-01

Patient satisfaction is an important aspect of dialysis care, only recently evaluated in clinical studies. We developed a tool to assess peritoneal dialysis (PD) customer satisfaction, and sought to evaluate and validate the Customer Satisfaction Questionnaire (CSQ), quantifying PD patient satisfaction. The CSQ included questions regarding administrative issues, Delivery Service, PD Training, Handling Requests, and transportation. The study was performed using interviews in all Hungarian Fresenius Medical Care dialysis centers offering PD. CSQ results were compared with psychosocial measures to identify if patient satisfaction was associated with perception of social support and illness burden, or depression. We assessed CSQ internal consistency and validity. Factor analysis explored potential underlying dimensions of the CSQ. One hundred and thirty-three patients treated with PD for end-stage renal disease for more than 3 months were interviewed. The CSQ had high internal consistency. There was high patient satisfaction with customer service. PD patient satisfaction scores correlated with quality of life (QOL) and social support measures, but not with medical or demographic factors, or depressive affect. The CSQ is a reliable tool to assess PD customer satisfaction. PD patient satisfaction is associated with perception of QOL. Efforts to improve customer satisfaction may improve PD patients' quantity as well as QOL.

Elevated frequencies of CD8 T cells expressing PD-1, CTLA-4 and Tim-3 within tumour from perineural squamous cell carcinoma patients.

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Linedale, Richard; Schmidt, Campbell; King, Brigid T; Ganko, Annabelle G; Simpson, Fiona; Panizza, Benedict J; Leggatt, Graham R

2017-01-01

Perineural spread of tumour cells along cranial nerves is a severe complication of primary cutaneous squamous cell carcinomas of the head and neck region. While surgical excision of the tumour is the treatment of choice, removal of all the tumour is often complicated by the neural location and recurrence is frequent. Non-invasive immune treatments such as checkpoint inhibitor blockade may be useful in this set of tumours although little is understood about the immune response to perineural spread of squamous cell carcinomas. Immunohistochemistry studies suggest that perineural tumour contains a lymphocyte infiltrate but it is difficult to quantitate the different proportions of immune cell subsets and expression of checkpoint molecules such as PD-1, Tim-3 and CTLA-4. Using flow cytometry of excised perineural tumour tissue, we show that a T cell infiltrate is prominent in addition to less frequent B cell, NK cell and NKT cell infiltrates. CD8 T cells are more frequent than other T cells in the tumour tissue. Amongst CD8 T cells, the frequency of Tim-3, CTLA-4 and PD-1 expressing cells was significantly greater in the tumour relative to the blood, a pattern that was repeated for Tim-3, CTLA-4 and PD-1 amongst non-CD8 T cells. Using immunohistochemistry, PD-1 and PD-L1-expression could be detected in close proximity amongst perineural tumour tissue. The data suggest that perineural SCC contains a mixture of immune cells with a predominant T cell infiltrate containing CD8 T cells. Elevated frequencies of tumour-associated Tim-3+, CTLA-4+ and PD-1+ CD8 T cells suggests that a subset of patients may benefit from local antibody blockade of these checkpoint inhibitors.

Elevated frequencies of CD8 T cells expressing PD-1, CTLA-4 and Tim-3 within tumour from perineural squamous cell carcinoma patients.

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Richard Linedale

Full Text Available Perineural spread of tumour cells along cranial nerves is a severe complication of primary cutaneous squamous cell carcinomas of the head and neck region. While surgical excision of the tumour is the treatment of choice, removal of all the tumour is often complicated by the neural location and recurrence is frequent. Non-invasive immune treatments such as checkpoint inhibitor blockade may be useful in this set of tumours although little is understood about the immune response to perineural spread of squamous cell carcinomas. Immunohistochemistry studies suggest that perineural tumour contains a lymphocyte infiltrate but it is difficult to quantitate the different proportions of immune cell subsets and expression of checkpoint molecules such as PD-1, Tim-3 and CTLA-4. Using flow cytometry of excised perineural tumour tissue, we show that a T cell infiltrate is prominent in addition to less frequent B cell, NK cell and NKT cell infiltrates. CD8 T cells are more frequent than other T cells in the tumour tissue. Amongst CD8 T cells, the frequency of Tim-3, CTLA-4 and PD-1 expressing cells was significantly greater in the tumour relative to the blood, a pattern that was repeated for Tim-3, CTLA-4 and PD-1 amongst non-CD8 T cells. Using immunohistochemistry, PD-1 and PD-L1-expression could be detected in close proximity amongst perineural tumour tissue. The data suggest that perineural SCC contains a mixture of immune cells with a predominant T cell infiltrate containing CD8 T cells. Elevated frequencies of tumour-associated Tim-3+, CTLA-4+ and PD-1+ CD8 T cells suggests that a subset of patients may benefit from local antibody blockade of these checkpoint inhibitors.

Measurement of benzenethiol adsorption to nanostructured Pt, Pd, and PtPd films using Raman spectroelectrochemistry.

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Pomfret, Michael B; Pietron, Jeremy J; Owrutsky, Jeffrey C

2010-05-04

Raman spectroscopy and electrochemical methods were used to study the behavior of the model adsorbate benzenethiol (BT) on nanostructured Pt, Pd, and PtPd electrodes as a function of applied potential. Benzenethiol adsorbs out of ethanolic solutions as the corresponding thiolate, and voltammetric stripping data reveal that BT is oxidatively removed from all of the nanostructured metals upon repeated oxidative and reductive cycling. Oxidative stripping potentials for BT increase in the order Pt oxidizing potentials via cleavage of the Pt-S bond. In contrast, on nanoscale Pd and PtPd, BT is irreversibly lost due to cleavage of BT C-S bonds at oxidizing potentials, which leaves adsorbed sulfur oxides on Pd and PtPd films and effects the desulfurization of BT. While Pd and PtPd films are less sulfur-resistant than Pt films, palladium oxides, which form at higher potentials than Pt oxides, oxidatively desulfurize BT. In situ spectroelectrochemical Raman spectroscopy provides real-time, chemically specific information that complements the cyclic voltammetric data. The combination of these techniques affords a powerful and convenient method for guiding the development of sulfur-tolerant PEMFC catalysts.

Structural Biology of the Immune Checkpoint Receptor PD-1 and Its Ligands PD-L1/PD-L2

NARCIS (Netherlands)

Zak, Krzysztof M.; Grudnik, Przemyslaw; Magiera, Katarzyna; Dömling, Alexander; Dubin, Grzegorz; Holak, Tad A.

2017-01-01

Cancer cells can avoid and suppress immune responses through activation of inhibitory immune checkpoint proteins, such as PD-1, PD-L1, and CTLA-4. Blocking the activities of these proteins with monoclonal antibodies, and thus restoring T cell function, has delivered breakthrough therapies against

Illustrative cases for monitoring by quantitative analysis of BRAF/NRAS ctDNA mutations in liquid biopsies of metastatic melanoma patients who gained clinical benefits from anti-PD1 antibody therapy.

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Seremet, Teofila; Planken, Simon; Schreuer, Max; Jansen, Yanina; Delaunoy, Mélanie; El Housni, Hakim; Lienard, Danielle; Del Marmol, Véronique; Heimann, Pierre; Neyns, Bart

2018-02-01

Anti-programmed death 1 (PD-1) monoclonal antibodies improve the survival of metastatic melanoma patients. Predictive or monitoring biomarkers for response to this therapy could improve the clinical management of these patients. To date, no established biomarkers are available for monitoring the response to immunotherapy. Tumor- specific mutations in circulating tumor DNA (ctDNA) such as BRAF and NRAS mutations for melanoma patients have been proposed for monitoring of immunotherapy response. We present seven illustrative cases for the use of ctDNA BRAF and NRAS mutations' monitoring in plasma. The cases described exemplify four distinct clinical benefit patterns: rapid and durable complete response (CR), early progression, followed by CR, CR followed by early progression after interrupting treatment and long-term disease stabilization. These representative cases suggest that comprehensive BRAF/NRAS ctDNA monitoring during anti-PD1 therapy is informative and can be of added value for the monitoring of melanoma patients gaining clinical benefit on anti-PD1 treatment. An important advantage of our approach is that using the cartridge system on the Idylla platform for mutation analysis, the results become available the same day 2 h after plasma collection. Therefore, in the future, the ctDNA level can be an element in the clinical management of the patients.

Glycerol electro-oxidation in alkaline medium using Pd/C and PdSn/C electrocatalysts prepared by electron beam irradiation

International Nuclear Information System (INIS)

Geraldes, Adriana Napoleao; Silva, Dionisio Fortunato da; Pino, Eddy Segura; Spinace, Estevan Vitorio; Oliveira Neto, Almir; Linardi, Marcelo; Santos, Mauro Coelhos dos

2013-01-01

Carbon-supported metal nanoparticles were prepared for fuel cell applications by radiation-induced reduction of metal ions precursors. Pd/C and PdSn/C electrocatalysts (Pd:Sn atomic ratio 90:10), prepared by using electron beam irradiation, were tested for glycerol electro-oxidation in single alkaline direct glycerol fuel cell (ADGFC). EDX analysis showed that the Pd:Sn atomic ratio is very similar to the nominal one. X-ray diffractograms of PdSn/C electrocatalyst showed the presence of Pd (fcc) phase. Cyclic voltammetry (CV) indicated that Pd/C and PdSn/C electrocatalysts have good activity for glycerol electro-oxidation, at room temperature. Experiments with single ADGFC were carried out from 60 to 90 deg C, using Pd/C and PdSn/C electrocatalysts and glycerol 2.0 mol.L -1 , as fuel. The best performance was obtained at 85 deg C, for both electrocatalysts. The Pd/C and PdSn/C electrocatalysts showed similar performance (34 mW cm -2 ), at 85 deg C. (author)

Blocking Tim-3 or/and PD-1 reverses dysfunction of tumor-infiltrating lymphocytes in HBV-related hepatocellular carcinoma.

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Liu, Furong; Zeng, Gucheng; Zhou, Shaotang; He, Xiaoshun; Sun, Nianfeng; Zhu, Xiaofeng; Hu, Anbin

2018-03-22

The immunosuppression of tumor-infiltrating lymphocytes (TILs) is associated with rapid progression of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). T cell Ig- and mucin-domain-containing molecule-3 (Tim-3) and programmed cell death 1 (PD-1) are important inhibitory molecules expressed on the surface of T cells, but their roles in the function of TILs in HBV-HCC are poorly understood. We aimed to study the roles of these two markers in HBV-HCC. Ninety patients with pathologically confirmed HBV-associated HCC were enrolled in our study. Blood samples, paired fresh tumor tissues and adjacent tissues were collected, and isolating peripheral blood mononuclear cells, TILs and adjacent-infiltrating lymphocytes were isolated from these samples. The patients were followed-up to allow survival analysis. Tim-3 or/and PD-1 was up-regulated expressed on CD4 + and CD8 + TILs in HBV-HCC patients and a higher proportion of TILs expressed PD-1 alone. Tim-3 + and PD-1 + TILs greatly decreased secretion of IFN-γ and TNF-α. Expression of Tim-3 and PD-1 on TILs negatively correlated with disease-free survival of HCC patients. Direct blockade of Tim-3 and PD-1 in vitro significantly enhanced TILs proliferation and secretion of IFN-γ and TNF-α. Expression of Tim-3 and/or PD-1 on TILs impairs their function and correlates negatively with disease-free survival in HBV-HCC. Direct blockade of Tim-3 and PD-1 restores anti-tumor effects of TILs, which suggests a potential target for novel immunotherapy in HBV-HCC. Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Measured glomerular filtration rate at dialysis initiation and clinical outcomes of Indian peritoneal dialysis patients

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N Prasad

2017-01-01

Full Text Available The optimal time for dialysis initiation remains controversial. Studies have failed to show better outcomes with early initiation of hemodialysis; even a few had shown increased adverse outcomes including poorer survival. Few studies have examined the same in patients on peritoneal dialysis (PD. Measured glomerular filtration rate (mGFR not creatinine-based estimated GFR is recommended as the measure of kidney function in end-stage renal disease (ESRD patients. The objective of this observational study was to compare the outcomes of Indian patients initiated on PD with different residual renal function (RRF as measured by 24-h urinary clearance method. A total of 352 incident patients starting on chronic ambulatory PD as the first modality of renal replacement therapy were followed prospectively. Patients were categorized into three groups as per mGFR at the initiation of PD (≤5, >5–10, and> 10 ml/min/1.73 m2. Patient survival and technique survival were compared among the three groups. Patients with GFR of ≤5 ml/min/1.73 m2 (hazard ratio [HR] - 3.42, 95% confidence interval [CI] - 1.85–6.30, P = 0.000 and> 5–10 ml/min/1.73 m2 (HR - 2.16, 95% CI - 1.26–3.71, P = 0.005 had higher risk of mortality as compared to those with GFR of> 10 ml/min/1.73 m2. Each increment of 1 ml/min/1.73 m2 in baseline GFR was associated with 10% reduced risk of death (HR - 0.90, 95% CI - 0.85–0.96, P = 0.002. Technique survival was poor in those with an initial mGFR of ≤5 ml/min/1.73 m2 as compared to other categories. RRF at the initiation was also an important factor predicting nutritional status at 1 year of follow-up. To conclude, initiation of PD at a lower baseline mGFR is associated with poorer patient and technique survival in Indian ESRD patients.

PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer: updated survival data.

Science.gov (United States)

Aguiar, Pedro N; De Mello, Ramon Andrade; Hall, Peter; Tadokoro, Hakaru; Lima Lopes, Gilberto de

2017-05-01

The treatment of non-small-cell lung cancer has changed after the development of the immune checkpoint inhibitors. Although the most studied biomarker is PD-L1 expression, its clinical significance is still debatable. In this article, we show the updated survival analysis of all published data. We searched in network and conference data sources for relevant clinical studies of immunotherapy for non-small-cell lung cancer that assessed the PD-L1 expression even as an exploratory analysis. The updated survival hazard ratios (HR) were included in the analysis. 14 studies with 2857 patients were included (2019 treated with immunotherapy). The response rate was as higher among PD-L1-positive patients (RR: 2.19, 95% CI: 1.63-2.94). PD-L1 expression was also related to better progression-free survival (HR: 0.69, 95% CI: 0.57-0.85) and better overall survival (HR: 0.77, 95% CI: 0.67-0.89). PD-L1 overexpression predicts activity as well as better survival for patients treated with immune checkpoint inhibitors.

The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors

Energy Technology Data Exchange (ETDEWEB)

Lin, David Yin-wei; Tanaka, Yoshimasa; Iwasaki, Masashi; Gittis, Apostolos G.; Su, Hua-Poo; Mikami, Bunzo; Okazaki, Taku; Honjo, Tasuku; Minato, Nagahiro; Garboczi, David N. (NIH); (Kyoto)

2008-07-29

Signaling through the programmed death 1 (PD-1) inhibitory receptor upon binding its ligand, PD-L1, suppresses immune responses against autoantigens and tumors and plays an important role in the maintenance of peripheral immune tolerance. Release from PD-1 inhibitory signaling revives 'exhausted' virus-specific T cells in chronic viral infections. Here we present the crystal structure of murine PD-1 in complex with human PD-L1. PD-1 and PD-L1 interact through the conserved front and side of their Ig variable (IgV) domains, as do the IgV domains of antibodies and T cell receptors. This places the loops at the ends of the IgV domains on the same side of the PD-1/PD-L1 complex, forming a surface that is similar to the antigen-binding surface of antibodies and T cell receptors. Mapping conserved residues allowed the identification of residues that are important in forming the PD-1/PD-L1 interface. Based on the structure, we show that some reported loss-of-binding mutations involve the PD-1/PD-L1 interaction but that others compromise protein folding. The PD-1/PD-L1 interaction described here may be blocked by antibodies or by designed small-molecule drugs to lower inhibitory signaling that results in a stronger immune response. The immune receptor-like loops offer a new surface for further study and potentially the design of molecules that would affect PD-1/PD-L1 complex formation and thereby modulate the immune response.

RuPd, RuCo, PdCo and RuPdCo materials as candidates for cathode catalyzers in PEM fuel cells; Materiales RuPd, RuCo, PdCo y RuPdCo como candidatos a catalizadores catodicos en celdas de combustible tipo PEM

Energy Technology Data Exchange (ETDEWEB)

Leyva Noyola, Fatima; Solorza Feria, Omar [Centro de Investigacion y Estudios Superiores del IPN, Mexico, D.F. (Mexico)]. E-mail: fleyva@cinvestav.mx

2009-09-15

This work reports on the catalytic activity of RuPd, RuCo, PdCo and RuPdCo material for oxygen reduction reaction (ORR). These materials were synthesized using chemical reduction with NaBH{sub 4} as a reducing agent in THF, in ambient temperature and pressure conditions. The evaluation of the catalytic activity was done using cyclic voltamperometry (CV) and rotary disc electrode (RDE) in H{sub 2}SO{sub 4} 0.5 M. The kinetic results showed that the electrochemical reaction involves 4 electrons and the transfer of the first electron is the determinant stage. The values of {alpha}, i0 and the Tafel slope were very similar for the four materials studied, around 0.4, 5x10{sup -6} mA cm{sup -2} and 60 mV dec-1, respectively. Although these values are less than those reported for nanostructured platinum, they are better than those reported for other materials such as pure Pd, which enables them to be considered as cathode catalysts for a proton exchange membrane fuel cell. [Spanish] En este trabajo se reporta la actividad catalitica de los materiales RuPd, RuCo, PdCo y RuPdCo para la reaccion de reduccion de oxigeno (RRO). Estos materiales fueron sintetizados por el metodo de reduccion quimica, usando NaBH{sub 4} como agente reductor en THF, en condiciones de temperatura y presion ambiental. La evaluacion de la actividad catalitica fue realizada usando Voltamperometria Ciclica (VC) y Electrodo Disco Rotatorio (EDR) en H{sub 2}SO{sub 4} 0.5 M. Los resultados cineticos mostraron que la reaccion electroquimica procede por la via de 4 electrones y la etapa determinante es la transferencia del primer electron. Los valores de {alpha}, i0 y pendiente de Tafel fueron muy similares para los 4 materiales estudiados, siendo estos de alrededor de 0.4, 5x10{sup -6} mA cm{sup -2} y 60 mV dec{sup -1}, respectivamente. Sin embargo, aun cuando estos valores son menores que los reportados para platino nanoestructurado, son mejores que los reportados para otros materiales como el Pd puro

Experimental investigation of the nature of the magnetoresistance effects in Pd-YIG hybrid structures.

Science.gov (United States)

Lin, Tao; Tang, Chi; Alyahayaei, Hamad M; Shi, Jing

2014-07-18

In bilayers consisting of Pd and yttrium iron garnet (Y(3)Fe(5)O(12) or YIG), we observe vanishingly small room-temperature conventional anisotropic magnetoresistance but large new magnetoresistance that is similar to the spin Hall magnetoresistance previously reported in Pt-YIG bilayers. We report a temperature dependence study of the two magnetoresistance effects in Pt-YIG bilayers. As the temperature is decreased, the new magnetoresistance shows a peak, whereas the anisotropic magnetoresistance effect starts to appear and increases monotonically. We find that the magnetoresistance peak shifts to lower temperatures in thicker Pd samples, a feature characteristic of the spin current effect. The distinct temperature dependence reveals fundamentally different mechanisms responsible for the two effects in such hybrid structures.

Color Discrimination in Patients with Gaucher Disease and Parkinson Disease.

Science.gov (United States)

Simon-Tov, Shlomi; Dinur, Tama; Giladi, Nir; Bar-Shira, Anat; Zelis, Mayaan; Zimran, Ari; Elstein, Deborah

2015-01-01

Poor color discrimination among patients with Parkinson disease (PD) has long been recognized. It has been shown that carrying one or two mutations in the β-glucocerebrosidase gene (GBA) for the autosomal disease Gaucher disease (GD), as based initially on clinical evidence, is a genetic risk factor for early-onset PD. The purpose of this study was to assess color discrimination in patients with one or two GBA mutations relative to healthy controls to ascertain whether this function is affected when persons with GD or even one GBA mutation develop PD. The Farnsworth-Munsell 100 hue test (FMHT) was evaluated among patients with GD+PD compared to patients with GD only, obligate GBA carriers with and without PD, patients with PD only, and healthy controls. FMHT outcome include computer-generated TES (Total Error Score) and values recommended by Vingrys & King-Smith. Six groups of 10 persons were tested. Significant differences were seen for male GD+PD and for age in PD. The highest mean TES was in the PD only group, the lowest in the GD only group. There was a significant difference because of PD in groups with GD and GBA carriers. GD+PD means were between GD only and PD only mean scores. These findings confirm that PD impacts color discrimination, more in males with GD+PD but nonetheless, GD+PD patients (but not GBA carriers) had better scores than PD only patients.

Starting lithium prophylaxis early v. late in bipolar disorder

DEFF Research Database (Denmark)

Kessing, Lars Vedel; Vradi, Eleni; Andersen, Per Kragh

2014-01-01

BACKGROUND: No study has investigated when preventive treatment with lithium should be initiated in bipolar disorder. AIMS: To compare response rates among patients with bipolar disorder starting treatment with lithium early v. late. METHOD: Nationwide registers were used to identify all patients...... with a diagnosis of bipolar disorder in psychiatric hospital settings who were prescribed lithium during the period 1995-2012 in Denmark (n = 4714). Lithium responders were defined as patients who, following a stabilisation lithium start-up period of 6 months, continued lithium monotherapy without being admitted...... to hospital. Early v. late intervention was defined in two ways: (a) start of lithium following first contact; and (b) start of lithium following a diagnosis of a single manic/mixed episode. RESULTS: Regardless of the definition used, patients who started lithium early had significantly decreased rates of non...

Monoclonal Antibody L1Mab-13 Detected Human PD-L1 in Lung Cancers.

Science.gov (United States)

Yamada, Shinji; Itai, Shunsuke; Nakamura, Takuro; Yanaka, Miyuki; Chang, Yao-Wen; Suzuki, Hiroyoshi; Kaneko, Mika K; Kato, Yukinari

2018-04-01

Programmed cell death ligand-1 (PD-L1) is a type I transmembrane glycoprotein expressed on antigen-presenting cells. It is also expressed in several tumor cells such as melanoma and lung cancer cells. A strong correlation has been reported between human PD-L1 (hPD-L1) expression in tumor cells and negative prognosis in cancer patients. Here, a novel anti-hPD-L1 monoclonal antibody (mAb) L 1 Mab-13 (IgG 1 , kappa) was produced using a cell-based immunization and screening (CBIS) method. We investigated hPD-L1 expression in lung cancer using flow cytometry, Western blot, and immunohistochemical analyses. L 1 Mab-13 specifically reacted hPD-L1 of hPD-L1-overexpressed Chinese hamster ovary (CHO)-K1 cells and endogenous hPD-L1 of KMST-6 (human fibroblast) in flow cytometry and Western blot. Furthermore, L 1 Mab-13 reacted with lung cancer cell lines (EBC-1, Lu65, and Lu99) in flow cytometry and stained lung cancer tissues in a membrane-staining pattern in immunohistochemical analysis. These results indicate that a novel anti-hPD-L1 mAb, L 1 Mab-13, is very useful for detecting hPD-L1 of lung cancers in flow cytometry, Western blot, and immunohistochemical analyses.

CO tolerance of PdPt/C and PdPtRu/C anodes for PEMFC

International Nuclear Information System (INIS)

Garcia, Amanda C.; Paganin, Valdecir A.; Ticianelli, Edson A.

2008-01-01

The performance of H 2 /O 2 proton exchange membrane fuel cells (PEMFCs) fed with CO-contaminated hydrogen was investigated for anodes with PdPt/C and PdPtRu/C electrocatalysts. The physicochemical properties of the catalysts were characterized by energy dispersive X-ray (EDX) analyses, X-ray diffraction (XRD) and 'in situ' X-ray absorption near edge structure (XANES). Experiments were conducted in electrochemical half and single cells by cyclic voltammetry (CV) and I-V polarization measurements, while DEMS was employed to verify the formation of CO 2 at the PEMFC anode outlet. A quite high performance was achieved for the PEMFC fed with H 2 + 100 ppm CO with the PdPt/C and PdPtRu/C anodes containing 0.4 mg metal cm -2 , with the cell presenting potential losses below 200 mV at 1 A cm -2 , with respect to the system fed with pure H 2 . For the PdPt/C catalysts no CO 2 formation was seen at the PEMFC anode outlet, indicating that the CO tolerance is improved due to the existence of more free surface sites for H 2 electrooxidation, probably due to a lower Pd-CO interaction compared to pure Pd or Pt. For PdPtRu/C the CO tolerance may also have a contribution from the bifunctional mechanism, as shown by the presence of CO 2 in the PEMFC anode outlet

Strategies for the optimal timing to start renal replacement therapy in critically ill patients with acute kidney injury.

Science.gov (United States)

Bagshaw, Sean M; Wald, Ron

2017-05-01

Renal replacement therapy (RRT) is increasingly utilized to support critically ill patients with severe acute kidney injury (AKI). The question of whether and when to start RRT for a critically ill patient with AKI has long troubled clinicians. When severe complications of AKI develop, the need to commence RRT is unambiguous. In the absence of such complications but in the presence of severe AKI, the optimal time and thresholds for starting RRT are uncertain. The majority of existing data have largely been derived from observational studies. These have been limited due to confounding by indication, considerable heterogeneity in case mix and illness severity, and variably applied definitions for both AKI and for how "timing" was anchored relative to starting RRT. It is unclear whether a preemptive or earlier strategy of RRT initiation aimed largely at avoiding complications related to AKI or a more conservative strategy where RRT is started in response to developing complications leads to better patient-centered outcomes and health services use. This question has been the focus of 2 recently completed randomized trials. In this review, we provide an appraisal of available evidence, discuss existing knowledge gaps, and provide perspective on future research that will better inform the optimal timing of RRT initiation in AKI. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Ethanol electro-oxidation in alkaline medium using Pd/c and PdRh/C electrocatalysts prepared by electron beam irradiation

International Nuclear Information System (INIS)

Silva, Dionisio Furtunato da; Geraldes, Adriana Napoleao; Pino, Eddy Segura; Spinace, Estevam Vitorio; Oliveira Neto, Almir; Linardi, Marcelo

2013-01-01

In this study, carbon-supported Pd (Pd/C) and bimetallic PdRh (Pd:Rh 90:10 atomic ratio) (PdRh/C) electrocatalysts were prepared using electron beam irradiation. The morphology and composition of the obtained materials were characterized by Cyclic voltammetry (VC), Chronoamperometry (CA), Energy dispersive X-ray (EDX), X-ray Diffraction (XRD) and Thermo-gravimetric analysis (TGA). The catalytic activities of the electrocatalysts toward the ethanol electro-oxidation were evaluated in alkaline medium in a single alkaline direct ethanol fuel cell (ADEFC), in a range temperature of 50 to 85 deg C. The best performances were obtained at 85 deg C (25 mW.cm -2 ) and 75 deg C (38 mW.cm -2 ) for Pd/C and PdRh/C electrocatalysts, respectively. The XRD of the PdRh/C electrocatalyst showed the presence of Pd-rich (fcc) phase. CV and CA experiments showed that PdRh/C electrocatalyst demonstrated superior activity toward ethanol electro-oxidation at room temperature, compared to Pd/C electrocatalyst. (author)

Orthopedic Management of Patients with Pompe Disease: A Retrospective Case Series of 8 Patients

Directory of Open Access Journals (Sweden)

Gerrit Haaker

2014-01-01

Full Text Available Introduction. Pompe disease (PD, a lysosomal storage disease as well as a neuromuscular disorder, is a rare disease marked by progressive muscle weakness. Enzyme replacement therapy (ERT in recent years allowed longer survival but brought new problems to the treatment of PD with increasing affection of the musculoskeletal system, particularly with a significantly higher prevalence of scoliosis. The present paper deals with the orthopedic problems in patients with PD and is the first to describe surgical treatment of scoliosis in PD patients. Patients and Methods. The orthopedic problems and treatment of eight patients with PD from orthopedic consultation for neuromuscular disorders are retrospectively presented. We analyzed the problems of scoliosis, hip dysplasia, feet deformities, and contractures and presented the orthopedic treatment options. Results. Six of our eight PD patients had scoliosis and two young patients were treated by operative spine stabilization with benefits for posture and sitting ability. Hip joint surgery, operative contracture release, and feet deformity correction were performed with benefits for independent activity. Conclusion. Orthopedic management gains importance due to extended survival and musculoskeletal involvement under ERT. Surgical treatment is indicated in distinct cases. Further investigation is required to evidence the effect of surgical spine stabilization in PD.

Magnetic characteristics of CoPd and FePd antidot arrays on nanoperforated Al{sub 2}O{sub 3} templates

Energy Technology Data Exchange (ETDEWEB)

Maximenko, A., E-mail: Alexey.Maximenko@ifj.edu.pl [The Henryk Niewodniczanski Institute of Nuclear Physics Polish Academy of Sciences, Radzikowskiego Str. 152, 31-342 Krakow (Poland); Research Institute for Nuclear Problems of Belarusian State University, Bobruiskaya Str. 11, 220030 Minsk (Belarus); Fedotova, J. [Research Institute for Nuclear Problems of Belarusian State University, Bobruiskaya Str. 11, 220030 Minsk (Belarus); Marszałek, M.; Zarzycki, A.; Zabila, Y. [The Henryk Niewodniczanski Institute of Nuclear Physics Polish Academy of Sciences, Radzikowskiego Str. 152, 31-342 Krakow (Poland)

2016-02-15

Hard magnetic antidot arrays show promising results in context of designing of percolated perpendicular media. In this work the technology of magnetic FePd and CoPd antidot arrays fabrication is presented and correlation between surface morphology, structure and magnetic properties is discussed. CoPd and FePd antidot arrays were fabricated by deposition of Co/Pd and Fe/Pd multilayers (MLs) on porous anodic aluminum oxide templates with bowl-shape cell structure with inclined intercellular regions. FePd ordered L1{sub 0} structure was obtained by successive vacuum annealing at elevated temperatures (530 °C) and confirmed by XRD analysis. Systematic analysis of magnetization curves evidenced perpendicular magnetic anisotropy of CoPd antidot arrays, while FePd antidot arrays revealed isotropic magnetic anisotropy with increased out-of-plane magnetic contribution. MFM images of antidots showed more complicated contrast, with alternating magnetic dots oriented parallel and antiparallel to tip magnetization moment. - Highlights: • CoPd and FePd antidots were fabricated on porous anodic aluminum oxide templates. • CoPd antidot arrays have perpendicular magnetic anisotropy. • FePd antidot arrays revealed isotropic magnetic behavior. • The complex morphology of nanoporous template resulted in a complex magnetic domains image.

Comparing PD results with visual inspection

International Nuclear Information System (INIS)

Rossi, A.; Stone, G.C.

2005-01-01

ENEL is the main generation utility in Italy, with more than 200 hydro units and 120 turbine generators, totaling 39,000 MW of capacity. To help identify the maintenance needs of the stator windings in these units, ENEL has been gradually equipping the generators with partial discharge (PD) sensors that facilitate an on-line measurement of the PD. The paper describes results from several machines that have PD. In all cases, the high PD was confirmed by visual inspections. Although PD usually found the units with severe insulation problems, it was not always possible to determine the causes of the deterioration from the PD pattern. (author)

Electron Bernstein wave current drive in the start-up phase of a tokamak discharge

International Nuclear Information System (INIS)

Montes, A.; Ludwig, G.O.

1986-04-01

Current drive by electron Bernstein waves in the start-up phase of tokamak discharges is studied. A general analytical expression is derived for the figure of merit J/Pd associated with these waves. This is coupled with a ray tracing code, allowing the calculation of the total current generated per unit of incident power in realistic tokamak conditions. The resuts show that the electron Bernstein waves can drive substantial currents even at very low electron temperatures. (Author) [pt

Performance of the PdNi and PdNiSe as cathodes in PEM fuel cells; Desempeno de PdNi y PdNiSe como catodos en celdas de combustible tipo PEM

Energy Technology Data Exchange (ETDEWEB)

Santana, A.; Ramos-Sanchez, G.; Vazquez, G.; Solorza-Feria, O. [Centro de Investigaciones y de Estudios Avanzados del IPN, Mexico D.F. (Mexico)]. E-mail: gramos@cinvestav.mx

2009-09-15

The search for new materials capable of catalyzing oxygen reactions in low temperature fuel cells continues to be one of the key issues in the development of a hydrogen economy. Electrochemical and physical characterization studies have demonstrated that the PdNi and PdNiSe catalysts have adequate properties for use as cathodes in fuel cells. Nevertheless, the performance of the materials in proton exchange membrane (PEM) fuel cells depends not only on the catalytic properties but also on the adequate preparation of the electrocatalyst membrane interface (EMI). This work presents the results of the search for optimal conditions to prepare the EMIs with PdNi and PdNiSe cathodes. There are many variables for handling the preparation of the interfaces, nevertheless our search focuses on two: catalyst ratio/Vulcan Carbon® and the catalyst amount. Interfaces were prepared with an active area of 5 cm{sup 2} with PdNi and PdNiSe cathodes and carbon fabric anode with Pt E-tek®. These interfaces were tested with an ElectroChem model under different gas pressure and temperature conditions. The optimization method was carried out using a simplex method with the variables mentioned above and power density per unit mass and catalyst area as response variables. [Spanish] La busqueda de nuevos materiales capaces de catalizar la Reaccion de Oxigeno (RRO) en celdas de combustible de baja temperatura, sigue siendo uno de los temas clave para el desarrollo de una Economia del Hidrogeno. Estudios electroquimicos y de caracterizacion fisica han demostrado que los catalizadores PdNi y PdNiSe, tienen las propiedades adecuadas para poder ser utilizados como catodos en celdas de combustible; sin embargo el desempeno de los materiales en celdas de combustible de membrana de intercambio protonico (PEM), no solo depende de las propiedades del catalizador, sino tambien de la preparacion adecuada del Ensamble Membrana Electrocatalizador (EME). En este trabajo se presentan los resultados de la

Low Triiodothyronine Syndrome and Long-Term Cardiovascular Outcome in Incident Peritoneal Dialysis Patients.

Science.gov (United States)

Chang, Tae Ik; Nam, Joo Young; Shin, Sug Kyun; Kang, Ea Wha

2015-06-05

A direct association between low triiodothyronine (T3) syndrome and cardiovascular (CV) mortality has been reported in hemodialysis patients. However, the implications of this syndrome in peritoneal dialysis (PD) patients have not been properly investigated. This study examined the association between low T3 syndrome and CV mortality including sudden death in a large cohort of incident PD patients. This prospective observational study included 447 euthyroid patients who started PD between January 2000 and December 2009. Measurement of thyroid hormones was performed at baseline. All-cause and cause-specific deaths were registered during the median 46 months of follow-up. The survival rate was compared among three groups based on tertile of T3 levels. In Kaplan-Meyer analysis, patients with the lowest tertile were significantly associated with higher risk of all-cause and CV mortality including sudden death (P<0.001 for trend). In Cox analyses, T3 level was a significant predictor of all-cause mortality (per 10-unit increase, adjusted hazard ratio [HR], 0.86; 95% confidence interval [95% CI], 0.78 to 0.94; P=0.002), CV death (per 10-unit increase, adjusted HR, 0.84; 95% CI, 0.75 to 0.98; P=0.01), and sudden death (per 10-unit increase, adjusted HR, 0.69; 95% CI, 0.56 to 0.86; P=0.001) after adjusting for well known risk factors including inflammation and malnutrition. The higher T3 level was also independently associated with lower risk for sudden death (per 10-unit increase, adjusted HR, 0.71; 95% CI, 0.56 to 0.90; P=0.01) even when accounting for competing risks of death from other causes. T3 level at the initiation of PD was a strong independent predictor of long-term CV mortality, particularly sudden death, even after adjusting well known risk factors. Low T3 syndrome might represent a factor directly implicated in cardiac complications in PD patients. Copyright © 2015 by the American Society of Nephrology.

PD Lab

Directory of Open Access Journals (Sweden)

Marcel Bilow

2015-08-01

Full Text Available PD Lab explores the applications of building sector related product development.  PD lab investigates and tests digital production technologies like CNC milled wood connections. It will also act as a platform in its wider meaning to investigate the effects and influences of file to factory production, to explore the potential in the field of sustainability, material use, logistics and the interaction of stakeholders within the chain of the building process.

On nuclear DD synthesis at the initial stage of nanosecond vacuum discharge with deuterium-loaded Pd anode

Science.gov (United States)

Kurilenkov, Yu K.; Gus'kov, S. Yu; Karpukhin, V. T.; Oginov, A. V.; Samoylov, I. S.

2018-01-01

Earlier, there was demonstrated generation of DD neutrons in an interelectrode medium of a low-energy (˜ 1 J) nanosecond vacuum discharge with a hollow cathode and a deuterium-loaded Pd anode. There was revealed essential role of formation of a virtual cathode and a potential well corresponding thereto in the processes of collisional DD synthesis in the interelectrode space. In this work, we have obtained as a result of an experiment and discussed the neutron yield at the very initial stage of the discharge, when the beam of auto-electrons just starts to irradiate the non-ideal surface of the deuterium-loaded Pd anode.

Ethanol electro-oxidation in alkaline medium using Pd/c and PdRh/C electrocatalysts prepared by electron beam irradiation

Energy Technology Data Exchange (ETDEWEB)

Silva, Dionisio Furtunato da; Geraldes, Adriana Napoleao; Pino, Eddy Segura; Spinace, Estevam Vitorio; Oliveira Neto, Almir; Linardi, Marcelo, E-mail: dfsilva@ipen.br, E-mail: drinager@ig.com.br [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

2013-07-01

In this study, carbon-supported Pd (Pd/C) and bimetallic PdRh (Pd:Rh 90:10 atomic ratio) (PdRh/C) electrocatalysts were prepared using electron beam irradiation. The morphology and composition of the obtained materials were characterized by Cyclic voltammetry (VC), Chronoamperometry (CA), Energy dispersive X-ray (EDX), X-ray Diffraction (XRD) and Thermo-gravimetric analysis (TGA). The catalytic activities of the electrocatalysts toward the ethanol electro-oxidation were evaluated in alkaline medium in a single alkaline direct ethanol fuel cell (ADEFC), in a range temperature of 50 to 85 deg C. The best performances were obtained at 85 deg C (25 mW.cm{sup -2}) and 75 deg C (38 mW.cm{sup -2}) for Pd/C and PdRh/C electrocatalysts, respectively. The XRD of the PdRh/C electrocatalyst showed the presence of Pd-rich (fcc) phase. CV and CA experiments showed that PdRh/C electrocatalyst demonstrated superior activity toward ethanol electro-oxidation at room temperature, compared to Pd/C electrocatalyst. (author)

Cerebral Activations Related to Ballistic, Stepwise Interrupted and Gradually Modulated Movements in Parkinson Patients

Science.gov (United States)

Toxopeus, Carolien M.; Maurits, Natasha M.; Valsan, Gopal; Conway, Bernard A.; Leenders, Klaus L.; de Jong, Bauke M.

2012-01-01

Patients with Parkinson’s disease (PD) experience impaired initiation and inhibition of movements such as difficulty to start/stop walking. At single-joint level this is accompanied by reduced inhibition of antagonist muscle activity. While normal basal ganglia (BG) contributions to motor control include selecting appropriate muscles by inhibiting others, it is unclear how PD-related changes in BG function cause impaired movement initiation and inhibition at single-joint level. To further elucidate these changes we studied 4 right-hand movement tasks with fMRI, by dissociating activations related to abrupt movement initiation, inhibition and gradual movement modulation. Initiation and inhibition were inferred from ballistic and stepwise interrupted movement, respectively, while smooth wrist circumduction enabled the assessment of gradually modulated movement. Task-related activations were compared between PD patients (N = 12) and healthy subjects (N = 18). In healthy subjects, movement initiation was characterized by antero-ventral striatum, substantia nigra (SN) and premotor activations while inhibition was dominated by subthalamic nucleus (STN) and pallidal activations, in line with the known role of these areas in simple movement. Gradual movement mainly involved antero-dorsal putamen and pallidum. Compared to healthy subjects, patients showed reduced striatal/SN and increased pallidal activation for initiation, whereas for inhibition STN activation was reduced and striatal-thalamo-cortical activation increased. For gradual movement patients showed reduced pallidal and increased thalamo-cortical activation. We conclude that PD-related changes during movement initiation fit the (rather static) model of alterations in direct and indirect BG pathways. Reduced STN activation and regional cortical increased activation in PD during inhibition and gradual movement modulation are better explained by a dynamic model that also takes into account enhanced

Cerebral activations related to ballistic, stepwise interrupted and gradually modulated movements in Parkinson patients.

Directory of Open Access Journals (Sweden)

Carolien M Toxopeus

Full Text Available Patients with Parkinson's disease (PD experience impaired initiation and inhibition of movements such as difficulty to start/stop walking. At single-joint level this is accompanied by reduced inhibition of antagonist muscle activity. While normal basal ganglia (BG contributions to motor control include selecting appropriate muscles by inhibiting others, it is unclear how PD-related changes in BG function cause impaired movement initiation and inhibition at single-joint level. To further elucidate these changes we studied 4 right-hand movement tasks with fMRI, by dissociating activations related to abrupt movement initiation, inhibition and gradual movement modulation. Initiation and inhibition were inferred from ballistic and stepwise interrupted movement, respectively, while smooth wrist circumduction enabled the assessment of gradually modulated movement. Task-related activations were compared between PD patients (N = 12 and healthy subjects (N = 18. In healthy subjects, movement initiation was characterized by antero-ventral striatum, substantia nigra (SN and premotor activations while inhibition was dominated by subthalamic nucleus (STN and pallidal activations, in line with the known role of these areas in simple movement. Gradual movement mainly involved antero-dorsal putamen and pallidum. Compared to healthy subjects, patients showed reduced striatal/SN and increased pallidal activation for initiation, whereas for inhibition STN activation was reduced and striatal-thalamo-cortical activation increased. For gradual movement patients showed reduced pallidal and increased thalamo-cortical activation. We conclude that PD-related changes during movement initiation fit the (rather static model of alterations in direct and indirect BG pathways. Reduced STN activation and regional cortical increased activation in PD during inhibition and gradual movement modulation are better explained by a dynamic model that also takes into account

Periocular dermatitis: a report of 401 patients.

Science.gov (United States)

Temesvári, E; Pónyai, G; Németh, I; Hidvégi, B; Sas, A; Kárpáti, S

2009-02-01

Periocular contact dermatitis may appear as contact conjunctivitis, contact allergic and/or irritative eyelid and periorbital dermatitis, or a combination of these symptoms. The clinical symptoms may be induced by several environmental and therapeutic contact allergens. The aim of the present study was to map the eliciting contact allergens in 401 patients with periocular dermatitis (PD) by patch testing with environmental and ophthalmic contact allergens. Following the methodics of international requirements, 401 patients were tested with contact allergens of the standard environmental series, 133 of 401 patients with the Brial ophthalmic basic and supplementary series as well. Contact hypersensitivity was detected in 34.4% of the patients. Highest prevalence was seen in cases of PD without other symptoms (51.18%), in patients of PD associated with ophthalmic complaints (OC; 30.4%), and PD associated with atopic dermatitis (AD; 27.9%). In the subgroup of PD associated with seborrhoea (S) and rosacea (R), contact hypersensitivity was confirmed in 17.6%. Most frequent sensitisers were nickel sulphate (in 8.9% of the tested 401 patients), fragrance mix I (4.5%), balsam of Peru (4.0%), paraphenylendiamine (PPD) (3.7%), and thiomersal (3.5%). By testing ophthalmic allergens, contact hypersensitivity was observed in nine patients (6.7% of the tested 133 patients). The most common confirmed ophthalmic allergens were cocamidopropyl betaine, idoxuridine, phenylephrine hydrochloride, Na chromoglycinate, and papaine. Patients with symptoms of PD were tested from 1996 to 2006. The occurence of contact hypersensitivity in PD patients was in present study 34.4%. A relatively high occurrence was seen in cases of PD without other symptoms, in PD + OC and in PD + AD patients. The predominance of environmental contact allergens was remarkable: most frequent sensitizers were nickel sulphate, fragrance mix I, balsam of Peru, thiomersal, and PPD. The prevalence of contact

Seroprevalence of Anti-HCV Antibody in Patients with Chronic Kidney Disease before Starting Dialysis Therapy

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Fareha Jesmin Rabbi

2017-01-01

Full Text Available Background: Hepatitis C virus (HCV infection and chronic kidney disease are common and potentially serious medical problems throughout the world. In recent years, it has become clear that these two conditions are linked in several important ways. Indeed, some forms of renal diseases are precipitated by HCV infection and patients with end-stage renal disease (ESRD are at increased risk for acquiring HCV infection. Patients with chronic kidney disease typically show an impaired immune response compared with healthy individuals and also other risk factors related with treatment and management. CKD patients ultimately undergo end stage renal therapy like dialysis for their treatment and survival. Risk factors for the infections are more in dialysis period than in predialytic stages. Like other developing countries CKD patients with HCV infection are very common in our country. For this reason the CKD patients should be properly diagnosed knowing the infection status before dialysis which would help both the patient and doctor to choose their proper treatment approach. Objective: This cross-sectional study was done to know the prevalence of HCV infection in the CKD patients before starting dialysis therapy. Materials and Methods: A total of 197 patients with chronic kidney disease stage five (CKD-V before starting dialysis therapy were included as subjects of this study. Among the CKD patients anti-HCV was detected to see prevalence of hepatitis C virus infection. The patients were also tested for HBsAg to assess co-infection. After collecting all the data of different test results analyses were done by SPSS version 15.0. Results: In this study 195 (99% patients were anti-HCV negative and only two patients (1% were found positive. Conclusion: HCV infection in CKD patients before dialysis should be taken into account so that HCV negative CKD patients would not get the infection during dialysis and standard screening procedures should be taken to

Targeting immune co-stimulatory effects of PD-L1 and PD-L2 might represent an effective therapeutic strategy in stroke

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Sheetal eBodhankar

2014-08-01

Full Text Available Stroke outcome is worsened by the infiltration of inflammatory immune cells into ischemic brains. Our recent study demonstrated that PD-L1- and to a lesser extent PD-L2-deficient mice had smaller brain infarcts and fewer brain-infiltrating cells vs. WT mice, suggesting a pathogenic role for PD-Ligands in experimental stroke. We sought to ascertain PD-L1 and PD-L2-expressing cell types that affect T-cell activation, post-stroke in the context of other known co-stimulatory molecules. Thus, cells from male WT and PD-L-deficient mice undergoing 60 min of middle cerebral artery occlusion (MCAO followed by 96h of reperfusion were treated with neutralizing antibodies to study co-stimulatory and co-inhibitory interactions between CD80, CTLA-4, PD-1 and PD-Ls that regulate CD8+ and CD4+ T-cell activation. We found that antibody neutralization of PD-1 and CTLA-4 signaling post-MCAO resulted in higher proliferation in WT CD8+ and CD4+ T-cells, confirming an inhibitory role of PD-1 and CTLA-4 on T-cell activation. Also, CD80/CD28 interactions played a prominent regulatory role for the CD8+ T-cells and the PD-1/PD-L2 interactions were dominant in controlling the CD4+ T-cell responses in WT mice after stroke. A suppressive phenotype in PD-L1-deficient mice was attributed to CD80/CTLA-4 and PD-1/PD-L2 interactions. PD-L2 was crucial in modulating CD4+ T-cell responses, whereas PD-L1 regulated both CD8+ and CD4+ T-cells. To establish the contribution of PD-L1 and PD-L2 on regulatory B-cells (Bregs, infarct volumes were evaluated in male PD-L1- and PD-L2-deficient mice receiving IL-10+ B-cells 4h post-MCAO. PD-L2- but not PD-L1-deficient recipients of IL-10+ B-cells had markedly reduced infarct volumes, indicating a regulatory role of PD-L2 on Bregs. These results imply that PD-L1 and PD-L2 differentially control induction of T- and Breg-cell responses after MCAO, thus suggesting that selective targeting of PD-L1 and PD-L2 might represent a valuable therapeutic

A Radiation Badge Survey for Family Members Living With Patients Treated With a 103Pd Permanent Breast Seed Implant

International Nuclear Information System (INIS)

Keller, Brian M.; Pignol, Jean-Philippe; Rakovitch, Eileen; Sankreacha, Raxa; O'Brien, Peter

2008-01-01

Purpose: Sixty-seven patients with early-stage breast cancer were treated in a Phase I/II clinical trial using a 103 Pd permanent breast seed implant as adjuvant radiotherapy after breast-conserving surgery. We report the dose received by family members living with these patients and compare measured doses with theoretical worst-case scenario estimates. Methods and Materials: Exposure-rate measurements were taken at 1 m from the patient by using a calibrated low-energy survey meter. Landauer (Landauer Inc., Glenwood, IL) Luxel badges, with sensitivity of 0.01 mSv, were given to family members to wear after the implantation. Badge readings for 33 spouses and 28 other family members were used to estimate effective doses, and these were compared with theory. Results: Average preimplantation planning target volume from computed tomography was 50.3 ml (range, 18.0-96.7 ml), and average preimplantation distance between the skin and the most anterior planning target volume margin was 0.57 cm. The average maximum exposure rate was measured to be 2.4 ± 1.1 mR/h, and average measured dose to a spouse was 0.99 ± 1.0 mSv. The calculated exposure rates and spousal doses using preimplantation computed tomography scan data overestimated those measured. Average measured family member dose (excluding spouses) was 0.20 ± 0.58 mSv. Conclusions: Based on measured and calculated spousal doses, a permanent breast seed implant using 103 Pd is safe for the public. However, it is recommended that extra precautions in the way of a breast patch be used when patients with an implant will be in the vicinity of toddlers or pregnant women

Predictive Factors of One-Year Mortality in a Cohort of Patients Undergoing Urgent-Start Hemodialysis.

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Luciene P Magalhães

Full Text Available Chronic kidney disease (CKD affects 10-15% of adult population worldwide. Incident patients on hemodialysis, mainly those on urgent-start dialysis at the emergency room, have a high mortality risk, which may reflect the absence of nephrology care. A lack of data exists regarding the influence of baseline factors on the mortality of these patients. The aim of this study was to evaluate the clinical and laboratory characteristics of this population and identify risk factors that contribute to their mortality.We studied 424 patients who were admitted to our service between 01/2006 and 12/2012 and were followed for 1 year. We analyzed vascular access, risk factors linked to cardiovascular disease (CVD and mineral and bone disease associated with CKD (CKD-MBD, and clinical events that occurred during the follow-up period. Factors that influenced patient survival were evaluated by Cox regression analysis.The patient mean age was 50 ± 18 years, and 58.7% of them were male. Hypertension was the main cause of primary CKD (31.8%. Major risk factors were smoking (19.6%, dyslipidemia (48.8%, and CVD (41%. Upon admission, most patients had no vascular access for hemodialysis (89.4%. Biochemical results showed that most patients were anemic with high C-reactive protein levels, hypocalcemia, hyperphosphatemia, elevated parathyroid hormone and decreased 25-hydroxy vitamin D. At the end of one year, 60 patients died (14.1%. These patients were significantly older, had a lower percentage of arteriovenous fistula in one year, and low levels of 25-hydroxy vitamin D.The combined evaluation of clinical and biochemical parameters and risk factors revealed that the mortality in urgent-start dialysis is associated with older age and low levels of vitamin D deficiency. A lack of a permanent hemodialysis access after one year was also a risk factor for mortality in this population.

Facial Emotion Recognition Impairment in Patients with Parkinson's Disease and Isolated Apathy

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Mercè Martínez-Corral

2010-01-01

Full Text Available Apathy is a frequent feature of Parkinson's disease (PD, usually related with executive dysfunction. However, in a subgroup of PD patients apathy may represent the only or predominant neuropsychiatric feature. To understand the mechanisms underlying apathy in PD, we investigated emotional processing in PD patients with and without apathy and in healthy controls (HC, assessed by a facial emotion recognition task (FERT. We excluded PD patients with cognitive impairment, depression, other affective disturbances and previous surgery for PD. PD patients with apathy scored significantly worse in the FERT, performing worse in fear, anger, and sadness recognition. No differences, however, were found between nonapathetic PD patients and HC. These findings suggest the existence of a disruption of emotional-affective processing in cognitive preserved PD patients with apathy. To identify specific dysfunction of limbic structures in PD, patients with isolated apathy may have therapeutic and prognostic implications.

Plot Description (PD)

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Robert E. Keane

2006-01-01

The Plot Description (PD) form is used to describe general characteristics of the FIREMON macroplot to provide ecological context for data analyses. The PD data characterize the topographical setting, geographic reference point, general plant composition and cover, ground cover, fuels, and soils information. This method provides the general ecological data that can be...

Synthesis of bimetallic Pt-Pd core-shell nanocrystals and their high electrocatalytic activity modulated by Pd shell thickness

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Li, Yujing; Wang, Zhi Wei; Chiu, Chin-Yi; Ruan, Lingyan; Yang, Wenbing; Yang, Yang; Palmer, Richard E.; Huang, Yu

2012-01-01

Bimetallic Pt-Pd core-shell nanocrystals (NCs) are synthesized through a two-step process with controlled Pd thickness from sub-monolayer to multiple atomic layers. The oxygen reduction reaction (ORR) catalytic activity and methanol oxidation reactivity of the core-shell NCs for fuel cell applications in alkaline solution are systematically studied and compared based on different Pd thickness. It is found that the Pd shell helps to reduce the over-potential of ORR by up to 50mV when compared to commercial Pd black, while generating up to 3-fold higher kinetic current density. The carbon monoxide poisoning test shows that the bimetallic NCs are more resistant to the CO poisoning than Pt NCs and Pt black. It is also demonstrated that the bimetallic Pt-Pd core-shell NCs can enhance the current density of the methanol oxidation reaction, lowering the over-potential by 35 mV with respect to the Pt core NCs. Further investigation reveals that the Pd/Pt ratio of 1/3, which corresponds to nearly monolayer Pd deposition on Pt core NCs, gives the highest oxidation current density and lowest over-potential. This study shows for the first time the systematic investigation of effects of Pd atomic shells on Pt-Pd bimetallic nanocatalysts, providing valuable guidelines for designing high-performance catalysts for fuel cell applications.Bimetallic Pt-Pd core-shell nanocrystals (NCs) are synthesized through a two-step process with controlled Pd thickness from sub-monolayer to multiple atomic layers. The oxygen reduction reaction (ORR) catalytic activity and methanol oxidation reactivity of the core-shell NCs for fuel cell applications in alkaline solution are systematically studied and compared based on different Pd thickness. It is found that the Pd shell helps to reduce the over-potential of ORR by up to 50mV when compared to commercial Pd black, while generating up to 3-fold higher kinetic current density. The carbon monoxide poisoning test shows that the bimetallic NCs are more

Potentially inappropriate prescribing in institutionalised older patients in Spain: the STOPP-START criteria compared with the Beers criteria

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Bonet M

2012-06-01

Full Text Available Objective: The aims of this study were to identify potentially inappropriate prescribing using the Beers and STOPP criteria. The START criteria were applied to detect prescription omission in the geriatric population. We compared the utility of these criteria in institutionalised older people.Methods: Descriptive study reviewing the medication and clinical records of 81 residents (aged 65 years and more by pharmacists in a nursing home in the Lleida region (Spain.Results: The mean patients’ age was 84 (SD=8 years, with an average of 5 drugs per resident (total prescriptions: 416 medicines. The Beers criteria identified potentially inappropriate medication use in 25% of patients and 48% of patients used at least 1 inappropriate medication according to STOPP criteria. The most frequent potentially inappropriate medications for both criteria were long-acting benzodiazepines and NSAIDs. START detected 58 potential prescribing omissions in 44% of patients. Calcium-vitamin D supplementation in osteoporosis was the most frequent rule (15%, but omissions corresponding to the cardiovascular system implied 23% of patients.Conclusion: The STOPP-START criteria reveal that potentially inappropriate prescribing (PIP is a highly prevalent problem among Spanish nursing home residents, and a statistically significant positive correlation was found between the number of medicines prescribed and the number of PIP detected in this study. The STOPP criteria detect a larger number of PI medications in this geriatric population than the Beers criteria. The prescribing omissions detected by the START criteria are relevant and require intervention. Pharmacists’ review of medications may help identify potentially inappropriate prescribing and, through an interdisciplinary approach, working with physicians may improve prescribing practices among geriatric residents of nursing homes.

Inter-rater variability in motor function assessment in Parkinson's disease between experts in movement disorders and nurses specialising in PD management.

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de Deus Fonticoba, T; Santos García, D; Macías Arribí, M

2017-05-23

In clinical practice, assessing patients with Parkinson's disease (PD) is a complex, time-consuming task. Our purpose is to provide a rigorous and objective evaluation of how motor function in PD patients is assessed by neurologists specialising in movement disorders, on the one hand, and by nurses specialising in PD management, on the other. We conducted an observational, cross-sectional, single-centre study of 50 patients with PD (52% men; mean age: 64.7 ± 8.7 years) who were assessed between 5 January 2016 and 20 July 2016. A neurologist and a nurse evaluated motor function in the early morning hours using the Unified Parkinson's Disease Rating Scale (UPDRS) parts III and IV and Hoehn & Yahr (H&Y) scale. Tests were administered in the same PD periods (in 48 patients during the 'off' time and in 2 patients during the 'on' time). Inter-rater variability was estimated with the intraclass correlation coefficient (ICC). Forty-nine patients (98%) were classified in the same H&Y stage by both raters. Assessment times were similar for both raters. ICC for UPDRS-IV and UPDRS-III total scores were 0.955 (Pde Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Design of Pd/PANI/Pd sandwich-structured nanotube array catalysts with special shape effects and synergistic effects for ethanol electrooxidation.

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Wang, An-Liang; Xu, Han; Feng, Jin-Xian; Ding, Liang-Xin; Tong, Ye-Xiang; Li, Gao-Ren

2013-07-24

Low cost, high activity, and long-term durability are the main requirements for commercializing fuel cell electrocatalysts. Despite tremendous efforts, developing non-Pt anode electrocatalysts with high activity and long-term durability at low cost remains a significant technical challenge. Here we report a new type of hybrid Pd/PANI/Pd sandwich-structured nanotube array (SNTA) to exploit shape effects and synergistic effects of Pd-PANI composites for the oxidation of small organic molecules for direct alcohol fuel cells. These synthesized Pd/PANI/Pd SNTAs exhibit significantly improved electrocatalytic activity and durability compared with Pd NTAs and commercial Pd/C catalysts. The unique SNTAs provide fast transport and short diffusion paths for electroactive species and high utilization rate of catalysts. Besides the merits of nanotube arrays, the improved electrocatalytic activity and durability are especially attributed to the special Pd/PANI/Pd sandwich-like nanostructures, which results in electron delocalization between Pd d orbitals and PANI π-conjugated ligands and in electron transfer from Pd to PANI.

Characteristics of Brain Perfusion in Patients of Parkinson's Disease

International Nuclear Information System (INIS)

Jeong, Young Jin; Park, Min Jung; Kim, Jae Woo; Kang, Young Kang

2008-01-01

It was well known that cerebral blood perfusion is normal or diffusely decreased in the majority of patients with Parkinson's disease (PD). Actually we interpreted brain perfusion SPECT images of PD patients in the clinical situation, we observed various cerebral perfusion patterns in patients with PD. So we performed brain perfusion SPECT to know the brain perfusion patterns of PD patients and the difference of perfusion patterns according to the sex and the age. Also we classified PD patients into small groups based on the brain perfusion pattern. Two hundred nineteen patients (M: 70, F: 149, mean age: 62.9±6.9 y/o) who were diagnosed as PD without dementia clinically and 55 patients (M: 15, F: 40, mean age: 61.4±9.2 y/o) as normal controls who had no past illness history were performed 99m Tc-HMPAO brain perfusion SPECT and neuropsychological test. At first, we compared all patients with PD and normal controls. Brain perfusion in left inferior frontal gyrus, left insula, left transverse temporal gyrus, left inferior parietal lobule, left superior parietal lobule, right precuneus, right caudate tail were lower in patients with PD than normal controls. Secondly, we compared male and female patients with PD and normal controls, respectively. Brain perfusion SPECT showed more decreased cerebral perfusion in left hemisphere than right side in both male and female patients compared to normal controls. And there was larger hypoperfusion area in female patients compared with male. Thirdly, we classified patients with PD and normal controls into 4 groups according to the age and compared brain perfusion respectively. In patient below fifties, brain perfusion in both occipitoparietal and left temporal lobe were lower in PD group. As the patients with PD grew older, hypoperfusion area were shown in both frontal, temporal and limbic lobes. Fourthly, We were able to divide patients into small groups based on cerebral perfusion pattern. There was normal cerebral blood

Variability in Immunohistochemical Detection of Programmed Death Ligand 1 (PD-L1) in Cancer Tissue Types

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Scognamiglio, Giosuè; De Chiara, Anna; Di Bonito, Maurizio; Tatangelo, Fabiana; Losito, Nunzia Simona; Anniciello, Annamaria; De Cecio, Rossella; D’Alterio, Crescenzo; Scala, Stefania; Cantile, Monica; Botti, Gerardo

2016-01-01

In normal cell physiology, programmed death 1 (PD-1) and its ligand, PD-L1, play an immunoregulatory role in T-cell activation, tolerance, and immune-mediated tissue damage. The PD-1/PD-L1 pathway also plays a critical role in immune escape of tumor cells and has been demonstrated to correlate with a poor prognosis of patients with several types of cancer. However, recent reports have revealed that the immunohistochemical (IHC) expression of the PD-L1 in tumor cells is not uniform for the use of different antibodies clones, with variable specificity, often doubtful topographical localization, and with a score not uniquely defined. The purpose of this study was to analyze the IHC expression of PD-L1 on a large series of several human tumors to correctly define its staining in different tumor tissues. PMID:27213372

The effectiveness of istradefylline for the treatment of gait deficits and sleepiness in patients with Parkinson's disease.

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Matsuura, Keita; Kajikawa, Hiroyuki; Tabei, Ken-Ichi; Satoh, Masayuki; Kida, Hirotaka; Nakamura, Naoko; Tomimoto, Hidekazu

2018-01-01

Istradefylline is useful in treating the wearing-off state in Parkinson's disease (PD). We investigated the effectiveness of istradefylline (ISD) in improving arousal, sleep, and gait deficits in patients with PD. We examined 14 patients with PD treated with ISD. We assessed the patients using the Unified Parkinson's Disease Rating Scale, Parkinson's Disease Questionnaire, Timed Up-and-Go test (TUG), Freezing of Gait Questionnaire (FOG-Q), Epworth Sleepiness Scale (ESS), and Parkinson's Disease Sleep Scale (PDSS) before and 1 month after ISD use. ESS scores were significantly lower 1 month after the start of ISD treatment (6.79±6.50) than before the intervention (8.14±6.15, Wilcoxon signed-rank test, p=0.0033). PDSS scores were not significantly different 1 month after beginning the treatment (112±23mm) when compared to those before the intervention (110±27mm, Wilcoxon signed-rank test, p=0.40). TUG scores were not changed after 1 month of ISD use (14.9±8.3s) when compared to those before the intervention (21.3±30.0s, Wilcoxon signed-rank test, p=0.59). Although these measures were not significantly affected by ISD treatment, some patients remarkably improved after the treatment. FOG-Q scores were significantly lower 1 month after the beginning of treatment (9.79±7.16) than those before the intervention (12.14±5.82, Wilcoxon signed-rank test, p=0.030). ISD may improve daytime sleepiness and FOG in patients with PD. Copyright © 2017 Elsevier B.V. All rights reserved.

Preparation of 103Pd seed-molecular plating of 103Pd onto silver rod

International Nuclear Information System (INIS)

Zhang Chunfu; Wang Yongxian; Tian Haibin; Yin Duanzhi

2002-01-01

A method for 103 Pd 'molecular plating' onto the surface of a silver rod is reported. The optimal composition of the plating bath is as follows: palladium chloride 0.1 mol/l, formaldehyde 2 mol/l, nitric acid 1 mol/l, and formic acid 0.4 mol/l. The 103 Pd molecular plating procedure will last 25 min at 30 deg. C. This article provides a valuable experience for the preparation of 103 Pd brachytherapy seed

G6PD Deficiency and Antimalarial Efficacy for Uncomplicated Malaria in Bangladesh: A Prospective Observational Study.

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Benedikt Ley

Full Text Available The Bangladeshi national treatment guidelines for uncomplicated malaria follow WHO recommendations but without G6PD testing prior to primaquine administration. A prospective observational study was conducted to assess the efficacy of the current antimalarial policy.Patients with uncomplicated malaria, confirmed by microscopy, attending a health care facility in the Chittagong Hill Tracts, Bangladesh, were treated with artemether-lumefantrine (days 0-2 plus single dose primaquine (0.75mg/kg on day2 for P. falciparum infections, or with chloroquine (days 0-2 plus 14 days primaquine (3.5mg/kg total over 14 days for P. vivax infections. Hb was measured on days 0, 2 and 9 in all patients and also on days 16 and 30 in patients with P. vivax infection. Participants were followed for 30 days. The study was registered with the clinical trials website (NCT02389374.Between September 2014 and February 2015 a total of 181 patients were enrolled (64% P. falciparum, 30% P. vivax and 6% mixed infections. Median parasite clearance times were 22.0 (Interquartile Range, IQR: 15.2-27.3 hours for P. falciparum, 20.0 (IQR: 9.5-22.7 hours for P. vivax and 16.6 (IQR: 10.0-46.0 hours for mixed infections. All participants were afebrile within 48 hours, two patients with P. falciparum infection remained parasitemic at 48 hours. No patient had recurrent parasitaemia within 30 days. Adjusted male median G6PD activity was 7.82U/gHb. One male participant (1/174 had severe G6PD deficiency (<10% activity, five participants (5/174 had mild G6PD deficiency (10-60% activity. The Hb nadir occurred on day 2 prior to primaquine treatment in P. falciparum and P. vivax infected patients; mean fractional fall in Hb was -8.8% (95%CI -6.7% to -11.0% and -7.4% (95%CI: -4.5 to -10.4% respectively.The current antimalarial policy remains effective. The prevalence of G6PD deficiency was low. Main contribution to haemolysis in G6PD normal individuals was attributable to acute malaria rather

Domain structures and magnetization reversal in Co/Pd and CoFeB/Pd multilayers

Energy Technology Data Exchange (ETDEWEB)

Sbiaa, R., E-mail: rachid@squ.edu.om [Department of Physics, Sultan Qaboos University, P.O. Box 36, PC 123 (Oman); Ranjbar, M. [Physics Department, University of Gothenburg, 412 96 Gothenburg (Sweden); Åkerman, J. [Physics Department, University of Gothenburg, 412 96 Gothenburg (Sweden); Materials Physics, School of ICT, Royal Institute of Technology (KTH), 164 40 Kista (Sweden)

2015-05-07

Domain structures and magnetization reversal of (Co/Pd) and (CoFeB/Pd) multilayers with 7 and 14 repeats were investigated. The Co-based multilayers show much larger coercivities, a better squareness, and a sharper magnetization switching than CoFeB-based multilayers. From magnetic force microscopy observations, both structures show strong reduction in domains size as the number of repeats increases but the magnetic domains for Co-based multilayers are more than one order of magnitude larger than for CoFeB-based multilayers. By imaging domains at different times, breaks in the (CoFeB/Pd) multilayer stripes were observed within only few hours, while no change could be seen for (Co/Pd) multilayers. Although CoFeB single layers are suitable for magnetoresistive devices due to their large spin polarization and low damping constants, their lamination with Pd suffers mainly from thermal instability.

On formation mechanism of Pd-Ir bimetallic nanoparticles through thermal decomposition of [Pd(NH3)4][IrCl6

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Asanova, Tatyana I.; Asanov, Igor P.; Kim, Min-Gyu; Gerasimov, Evgeny Yu.; Zadesenets, Andrey V.; Plyusnin, Pavel E.; Korenev, Sergey V.

2013-10-01

The formation mechanism of Pd-Ir nanoparticles during thermal decomposition of double complex salt [Pd(NH3)4][IrCl6] has been studied by in situ X-ray absorption (XAFS) and photoelectron (XPS) spectroscopies. The changes in the structure of the Pd and Ir closest to the surroundings and chemical states of Pd, Ir, Cl, and N atoms were traced in the range from room temperature to 420 °C in inert atmosphere. It was established that the thermal decomposition process is carried out in 5 steps. The Pd-Ir nanoparticles are formed in pyramidal/rounded Pd-rich (10-200 nm) and dendrite Ir-rich (10-50 nm) solid solutions. A d charge depletion at Ir site and a gain at Pd, as well as the intra-atomic charge redistribution between the outer d and s and p electrons of both Ir and Pd in Pd-Ir nanoparticles, were found to occur.

PD-L1-specific T cells

DEFF Research Database (Denmark)

Ahmad, Shamaila Munir; Borch, Troels Holz; Hansen, Morten

2016-01-01

-specific T cells that recognize both PD-L1-expressing immune cells and malignant cells. Thus, PD-L1-specific T cells have the ability to modulate adaptive immune reactions by reacting to regulatory cells. Thus, utilization of PD-L1-derived T cell epitopes may represent an attractive vaccination strategy...... for targeting the tumor microenvironment and for boosting the clinical effects of additional anticancer immunotherapy. This review summarizes present information about PD-L1 as a T cell antigen, depicts the initial findings about the function of PD-L1-specific T cells in the adjustment of immune responses...

Alternative splice variants of the human PD-1 gene

DEFF Research Database (Denmark)

Nielsen, Christian; Ohm-Laursen, Line; Barington, Torben

2005-01-01

PD-1 is an immunoregulatory receptor expressed on the surface of activated T cells, B cells, and monocytes. We describe four alternatively spliced PD-1 mRNA transcripts (PD-1Deltaex2, PD-1Deltaex3, PD-1Deltaex2,3, and PD-1Deltaex2,3,4) in addition to the full length isoform. PD-1Deltaex2 and PD-1...... and flPD-1 upon activation suggests an important interplay between the putative soluble PD-1 and flPD-1 possibly involved in maintenance of peripheral self-tolerance and prevention of autoimmunity....

The Significance of the PD-L1 Expression in Non-Small-Cell Lung Cancer: Trenchant Double Swords as Predictive and Prognostic Markers.

Science.gov (United States)

Takada, Kazuki; Toyokawa, Gouji; Shoji, Fumihiro; Okamoto, Tatsuro; Maehara, Yoshihiko

2018-03-01

Lung cancer is the leading cause of death due to cancer worldwide. Surgery, chemotherapy, and radiotherapy have been the standard treatment for lung cancer, and targeted molecular therapy has greatly improved the clinical course of patients with non-small-cell lung cancer (NSCLC) harboring driver mutations, such as in epidermal growth factor receptor and anaplastic lymphoma kinase genes. Despite advances in such therapies, the prognosis of patients with NSCLC without driver oncogene mutations remains poor. Immunotherapy targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) has recently been shown to improve the survival in advanced NSCLC. The PD-L1 expression on the surface of tumor cells has emerged as a potential biomarker for predicting responses to immunotherapy and prognosis after surgery in NSCLC. However, the utility of PD-L1 expression as a predictive and prognostic biomarker remains controversial because of the existence of various PD-L1 antibodies, scoring systems, and positivity cutoffs. In this review, we summarize the data from representative clinical trials of PD-1/PD-L1 immune checkpoint inhibitors in NSCLC and previous reports on the association between PD-L1 expression and clinical outcomes in patients with NSCLC. Furthermore, we discuss the future perspectives of immunotherapy and immune checkpoint factors. Copyright © 2017 Elsevier Inc. All rights reserved.

Characterization of PD-1 upregulation on tumor-infiltrating lymphocytes in human and murine gliomas and preclinical therapeutic blockade.

Science.gov (United States)

Dejaegher, Joost; Verschuere, Tina; Vercalsteren, Ellen; Boon, Louis; Cremer, Jonathan; Sciot, Raf; Van Gool, Stefaan W; De Vleeschouwer, Steven

2017-11-01

Blockade of the immune checkpoint molecule programmed-cell-death-protein-1 (PD-1) yielded promising results in several cancers. To understand the therapeutic potential in human gliomas, quantitative data describing the expression of PD-1 are essential. Moreover, due the immune-specialized region of the brain in which gliomas arise, differences between tumor-infiltrating and circulating lymphocytes should be acknowledged. In this study we have used flow cytometry to quantify PD-1 expression on tumor-infiltrating T cells of 25 freshly resected glioma cell suspensions (10 newly and 5 relapsed glioblastoma, 10 lower grade gliomas) and simultaneously isolated circulating T cells. A strong upregulation of PD-1 expression in the tumor microenvironment compared to the blood circulation was seen in all glioma patients. Additionally, circulating T cells were isolated from 15 age-matched healthy volunteers, but no differences in PD-1 expression were found compared to glioma patients. In the murine GL261 malignant glioma model, there was a similar upregulation of PD-1 on brain-infiltrating lymphocytes. Using a monoclonal PD-1 blocking antibody, we found a marked prolonged survival with 55% of mice reaching long-term survival. Analysis of brain-infiltrating cells 21 days after GL261 tumor implantation showed a shift in infiltrating lymphocyte subgroups with increased CD8+ T cells and decreased regulatory T cells. Together, our results suggest an important role of PD-1 in glioma-induced immune escape, and provide translational evidence for the use of PD-1 blocking antibodies in human malignant gliomas. © 2017 UICC.

PD-L1 protein expression assessed by immunohistochemistry is neither prognostic nor predictive of benefit from adjuvant chemotherapy in resected non-small cell lung cancer.

Science.gov (United States)

Tsao, M-S; Le Teuff, G; Shepherd, F A; Landais, C; Hainaut, P; Filipits, M; Pirker, R; Le Chevalier, T; Graziano, S; Kratze, R; Soria, J-C; Pignon, J-P; Seymour, L; Brambilla, E

2017-04-01

The expression of programmed death (PD) ligand 1 (PD-L1) protein expression assessed by immunohistochemistry (IHC) has been correlated with response and survival benefit from anti-PD-1/PD-L1 immune checkpoint inhibitor therapies in advanced non-small cell lung carcinoma (NSCLC). The efficacy of several agents appears correlated with PD-L1 expression. It remains controversial whether PD-L1 is prognostic in NSCLC. We assessed the prognostic value of PD-L1 IHC and its predictive role for adjuvant chemotherapy in early stage NSCLC. Tumor sections from three pivotal adjuvant chemotherapy trials (IALT, JBR.10, CALGB 9633) using the E1L3N antibody were studied in this pooled analysis. PD-L1 staining intensity and percentage in both tumor cells (TCs) and immune cells (ICs) were scored by two pathologists. The average or consensus PD-L1 expression levels across intensities and/or percent cells stained were correlated with clinicopathological and molecular features, patient survivals and potential benefit of adjuvant chemotherapy. Results from 982 patients were available for analysis. Considering staining at any intensities for overall PD-L1 expression, 314 (32.0%), 204 (20.8%) and 141 (14.3%) tumor samples were positive for PD-L1 staining on TCs using cut-offs at ≥1%, ≥10% and ≥25%, respectively. For PD-L1 expressing ICs, 380 (38.7%), 308 (31.4%) and 148 (15.1%) were positive at ≥ 1%, ≥10% and 25% cut-offs, respectively. Positive PD-L1 was correlated with squamous histology, intense lymphocytic infiltrate, and KRAS but not with TP53 mutation. EGFR mutated tumors showed statistically non-significant lower PD-L1 expression. PD-L1 expression was neither prognostic with these cut-offs nor other exploratory cut-offs, nor were predictive for survival benefit from adjuvant chemotherapy. PD-L1 IHC is not a prognostic factor in early stage NSCLC patients. It is also not predictive for adjuvant chemotherapy benefit in these patients. © The Author 2017. Published by

The Pd distribution and Cu flow pattern of the Pd-plated Cu wire bond and their effect on the nanoindentation

International Nuclear Information System (INIS)

Lin, Yu-Wei; Wang, Ren-You; Ke, Wun-Bin; Wang, I-Sheng; Chiu, Ying-Ta; Lu, Kuo-Chang; Lin, Kwang-Lung; Lai, Yi-Shao

2012-01-01

Highlights: ► Pd distribution in Pd-plated Cu wires reveals the whirlpool flow pattern of Cu. ► The mechanisms of the Cu flow behavior and Pd distribution are proposed. ► At Pd-rich phases, small voids formed and followed the direction of Cu flow. ► Nanoindentation studies show the Cu ball bond is harder in regions with Pd. - Abstract: The Pd plating on the 20 μm Cu wire dissolves in the free air ball (FAB) and the Cu ball bond during the wire bonding process without forming intermetallic compounds. The limiting supply of Pd and the short bonding process, 15 ms of thermosonic bonding, result in uneven distribution of Pd in the as produced Cu ball bond. Also, the Pd-rich phase may accompany small voids formed within the FAB and the wire bond, and following the direction of semi-solid Cu flow. The Pd distribution, as evidenced by the focused ion beam (FIB) and wavelength dispersive X-ray spectroscopy (WDS) mapping, reveals the whirlpool flow pattern of Cu within the FAB and the ball bond. Pd distributes within the copper ball through convective transport by the copper flow. Additionally, hardness measurements by nanoindentation testing show that the Cu ball bond is harder in the regions where Pd exists.

Methanol steam reforming over Pd/ZnO and Pd/CeO{sub 2} catalysts

Energy Technology Data Exchange (ETDEWEB)

Ranganathan, Easwar S.; Bej, Shyamal K.; Thompson, Levi T. [University of Michigan, Department of Chemical Engineering, 3026 H.H. Dow Building, 2300 Hayward Avenue, Ann Arbor, MI 48109-2136 (United States)

2005-08-10

The goal of work described in this paper was to better understand the methanol steam reforming (MSR) activity and selectivity patterns of ZnO and CeO{sub 2} supported Pd catalysts. This reaction is being used to produce H{sub 2}-rich gas for a number of applications including hydrogen fuel cells. The Pd/ZnO catalysts had lower MSR rates but were more selective for the production of CO{sub 2} than the Pd/CeO{sub 2} catalysts. The CH{sub 3}OH conversion rates were proportional to the H{sub 2} chemisorption uptake suggesting that the rate determining step was catalyzed by Pd. The corresponding turnover frequencies averaged 0.8+/-0.3s{sup -1} and 0.4+/-0.2s{sup -1} at 230{sup o}C for the Pd/ZnO and Pd/CeO{sub 2} catalysts, respectively. The selectivities are explained based on the reaction pathways, and characteristics of the support. The key surface intermediate appeared to be a formate. The ZnO supported catalysts had a higher density of acidic sites and favored pathways where the intermediate was converted to CO{sub 2} while the CeO{sub 2} supported catalysts had a higher density of basic sites and favored the production of CO.

Paired Comparison of PD-L1 Expression on Cytologic and Histologic Specimens from Malignancies in the Lung Assessed with PD-L1 IHC 28-8pharmDx and PD-L1 IHC 22C3pharmDx

DEFF Research Database (Denmark)

Skov, Birgit G.; Skov, Torsten

2017-01-01

of the patients are diagnosed on cytology alone. We hypothesized that cytologic cell block material is suitable for PD-L1 analysis. Materials and Methods: Eighty-six paired samples of malignancies from the lung where cytologic cell block and histologic material were available from the same lesion were stained...... with PD-L1 IHC 28-8pharmDx and PD-L1 IHC 22C3pharmDx. Scorings of like material (cytology or histology) stained with different assays were analyzed in order to evaluate the analytical agreement between assays. Scoring of different materials stained with like assays were analyzed in order to evaluate...... the agreement between cytology and histology. Results: A high degree of agreement was found between 28- 8pharmDx and 22C3pharmDx, whether applied to histologic or cytologic cell blocks, with Pearson R2 of 0.95. The Pearson R2 between 2 rounds of assessment of the same assay on the same type of material was also...

Supported Pd nanoclusters for the hydrogen mitigation application in severe accidents

Energy Technology Data Exchange (ETDEWEB)

Shao, Zhengfeng; Zhu, Hongzhi; Zhang, Zhi; Zheng, Zhenghua [China Academy of Engineering Physics, P. O. Box 919-71, Mianyang 621700 (China); Ma, Guohua [University of Science and Technology of Southwest, Mianyang 621010 (China); Lai, Xinchun; Li, Rong; Tang, Tao; Fu, Jun [China Academy of Engineering Physics, P. O. Box 919-71, Mianyang 621700 (China); Gao, Bo, E-mail: gaobo@caep.cn [China Academy of Engineering Physics, P. O. Box 919-71, Mianyang 621700 (China)

2017-05-15

Highlights: • Pd catalysts were prepared by electroless deposition path with no extra reduction agents. • The Pd catalysts not only have good hydrogen-oxygen recombination efficiency, but also have good stability. • The catalysts were proved to have good resistance to poisoning. • Pd catalysts could be supposed to be used for PARs in severe accidents. - Abstract: Accidents at TMI, USA and Fukushima, Japan have emphasized the need for hydrogen mitigation during nuclear plant accidental conditions, especially during severe accidents which will be no power, massive hydrogen, high temperature, long-term operation, and poisoning environment. Passive autocatalytic recombiners with catalyst sheets are the promising way to deal with the situation in severe accidents. Here we report a new kind of catalyst sheets based on stainless steel supported Pd nanoclusters prepared by electroless deposition route. The catalyst sheets were characterised for morphology and composition of surface by SEM and EDS. The catalytic activity of the catalyst sheets has been evaluated under the conditions of higher temperature, long-term operation and poisoning environments. The catalyst sheets showed high activity and good stability either operating above 500 °C for 24 h or continuous operating for 25 days. For the obtained catalyst sheets after exposed to methanal, iodine vapor and BaSO{sub 4} aerosol respectively with corresponding concentrations higher than SA conditions, the start-up time for H{sub 2}-O{sub 2} recombination reaction was less than 1 min and the catalytic efficiency was more than 90%. These results indicate the potential application of this type of catalyst sheets for hydrogen mitigation in severe accidents.

Evaluation of colloidal Pd and Pd-alloys as anode electrocatalysts for direct borohydride fuel cells applications

Energy Technology Data Exchange (ETDEWEB)

Atwan, M.H. [General Motors R and D Technical Center, Warren, MI (United States); Gyenge, E.L. [British Columbia Univ., Vancouver, BC (Canada). Dept. of Chemical and Biological Engineering; Northwood, D.O. [Windsor Univ., ON (Canada). Dept. of Mechanical, Automotive and Materials Engineering

2010-07-01

An evaluation was conducted to assess the use of colloidal palladium (Pd) and Pd alloys as anode electrocatalysts for direct borohydride fuel cell applications. A modified Bonneman method was used to investigate borohydride oxidation on supported Pd and Pd-alloy nano-electrocatalysts. Cyclic voltammetry (CV), rotating disk electrode (RDE) voltammetry, and single fuel cell test stations were used to determine Tafel slopes, exchange current densities, oxidation peak potentials, and fuel cell performance. The study also investigated the influence of temperature and oxidant flow and fuel flow rates on fuel cell performance. The study showed that the current density of the fuel cell increased with increases in temperature for all the investigated Pd electrocatalysts. However, the increase in current density was not as high as expected when fuel flow rates were increased. A current density of 50 mA cm{sup -2} was observed at 298 K with a Pd-Ir anode catalyst operating at a cell voltage of 0.5 V. 28 refs., 1 tab., 15 figs.

Anti PD-L1 DUrvalumab combined with Cetuximab and RadiOtherapy in locally advanced squamous cell carcinoma of the head and neck: A phase I/II study (DUCRO).

Science.gov (United States)

Bonomo, Pierluigi; Desideri, Isacco; Loi, Mauro; Mangoni, Monica; Sottili, Mariangela; Marrazzo, Livia; Talamonti, Cinzia; Greto, Daniela; Pallotta, Stefania; Livi, Lorenzo

2018-02-01

Head and neck squamous cell carcinoma (HNSCC) has been increasingly recognized as an immune suppressive malignancy. The efficacy of immune checkpoint inhibitors (ICI's) in the context of recurrent/metastatic (R/M) setting anticipates the possible integration of immunotherapy into the therapeutic armamentarium of locally advanced disease. Durvalumab (DUR) is a humanized monoclonal IgG1, anti-PD-L1 antibody with promising data in R/M HNSCC. The aim of our study is to test the antitumor activity of a combined regimen incorporating an immune checkpoint inhibitor into a conventional bio-radiation strategy for the cure of unfavorable locally advanced HNSCC. In this open label, multi-center, single-arm, phase I/II study, enrolled patients will receive Radiotherapy (RT) (69.9 Gy/2.12 Gy in 33 fractions) with concurrent Cetuximab (CTX) (400 mg/m 2 1 week before RT start followed by 250 mg/m 2 weekly) and DUR (fixed dose of 1500 mg every 4 weeks starting from RT-CTX week 1) followed by adjuvant DUR (to a maximum of 6 months after completion of RT-CTX). Primary endpoint of the study is 2-year progression-free survival (PFS). A safety run-in is planned after the enrollment of first 12, 24 and 36 patients. Patients affected by high-risk (≥N2a or ≥T3, any N) larynx, hypopharynx and HPV negative oropharynx or HPV-positive oropharynx (≥T2, ≥N2b, ≥10 pack/years) will be eligible. Conventional intensification strategies failed to provide any benefit for the cure of locally advanced HNSCC. For the still prevalent HPV-negative population and the high risk-HPV positive disease, there is an unmet need for alternative treatment paradigms. Potentially, the inhibition of the PD-1/PD-L1 checkpoint may synergize with both CTX and RT through immunologic interplay, ultimately aiming to reverse the HNSCC-induced immune suppression. The DUCRO study will seek to demonstrate if such a strategy may be safe and active. NCT number: NCT03051906Eudract number: 2016-004668-20.

Sleep stability and transitions in patients with idiopathic REM sleep behavior disorder and patients with Parkinson's disease.

Science.gov (United States)

Christensen, Julie Anja Engelhard; Jennum, Poul; Koch, Henriette; Frandsen, Rune; Zoetmulder, Marielle; Arvastson, Lars; Christensen, Søren Rahn; Sorensen, Helge Bjarrup Dissing

2016-01-01

Patients with idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) are at high risk of developing Parkinson's disease (PD). As wake/sleep-regulation is thought to involve neurons located in the brainstem and hypothalamic areas, we hypothesize that the neurodegeneration in iRBD/PD is likely to affect wake/sleep and REM/non-REM (NREM) sleep transitions. We determined the frequency of wake/sleep and REM/NREM sleep transitions and the stability of wake (W), REM and NREM sleep as measured by polysomnography (PSG) in 27 patients with PD, 23 patients with iRBD, 25 patients with periodic leg movement disorder (PLMD) and 23 controls. Measures were computed based on manual scorings and data-driven labeled sleep staging. Patients with PD showed significantly lower REM stability than controls and patients with PLMD. Patients with iRBD had significantly lower REM stability compared with controls. Patients with PD and RBD showed significantly lower NREM stability and significantly more REM/NREM transitions than controls. We conclude that W, NREM and REM stability and transitions are progressively affected in iRBD and PD, probably reflecting the successive involvement of brain stem areas from early on in the disease. Sleep stability and transitions determined by a data-driven approach could support the evaluation of iRBD and PD patients. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation.

Science.gov (United States)

Bardhan, Kankana; Anagnostou, Theodora; Boussiotis, Vassiliki A

2016-01-01

The immune system maintains a critically organized network to defend against foreign particles, while evading self-reactivity simultaneously. T lymphocytes function as effectors and play an important regulatory role to orchestrate the immune signals. Although central tolerance mechanism results in the removal of the most of the autoreactive T cells during thymic selection, a fraction of self-reactive lymphocytes escapes to the periphery and pose a threat to cause autoimmunity. The immune system evolved various mechanisms to constrain such autoreactive T cells and maintain peripheral tolerance, including T cell anergy, deletion, and suppression by regulatory T cells (T Regs ). These effects are regulated by a complex network of stimulatory and inhibitory receptors expressed on T cells and their ligands, which deliver cell-to-cell signals that dictate the outcome of T cell encountering with cognate antigens. Among the inhibitory immune mediators, the pathway consisting of the programed cell death 1 (PD-1) receptor (CD279) and its ligands PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273) plays an important role in the induction and maintenance of peripheral tolerance and for the maintenance of the stability and the integrity of T cells. However, the PD-1:PD-L1/L2 pathway also mediates potent inhibitory signals to hinder the proliferation and function of T effector cells and have inimical effects on antiviral and antitumor immunity. Therapeutic targeting of this pathway has resulted in successful enhancement of T cell immunity against viral pathogens and tumors. Here, we will provide a brief overview on the properties of the components of the PD-1 pathway, the signaling events regulated by PD-1 engagement, and their consequences on the function of T effector cells.

The PD1: PD-L1/2 pathway from discovery to clinical implementation

Directory of Open Access Journals (Sweden)

Kankana Bardhan

2016-12-01

Full Text Available The immune system has the difficult challenge of discerning and defending against a diversity of microbial pathogens, while simultaneously avoiding self-reactivity. T lymphocytes function as effectors and regulators of the immune system. While central tolerance mechanism results in deletion of the majority of self-reactive T lymphocytes during thymic selection, a fraction of self reactive lymphocytes escapes to the periphery and retains the potential to inflict destructive autoimmune pathology. The immune system evolved various mechanisms to restrain such auto-reactive T cells and maintain peripheral tolerance, including T cell anergy, deletion, and suppression by regulatory T cells (TRegs. These effects are regulated by a complex network of stimulatory and inhibitory receptors expressed on T cells and their ligands, which deliver cell-to-cell signals that dictate the outcome of T cell encountering with cognate antigens. Among the inhibitory immune mediators, the pathway consisting of the programmed cell death 1 (PD-1 receptor (CD279 and its ligands PD-L1 (B7-H1, CD274 and PD-L2 (B7-DC; CD273 plays a vital role in the induction and maintenance of peripheral tolerance and for the maintenance of T cell homeostasis. In contrast to its beneficial role in self-tolerance, the PD-1: PD-L1/L2 pathway mediates potent inhibitory signals that prevent the expansion and function of T effector cells and have detrimental effects on antiviral and antitumor immunity. Therapeutic targeting of this pathway has resulted in successful enhancement of T cell immunity against viral pathogens and tumors. Here, we will provide a brief overview on the properties of the components of the PD-1 pathway, the signaling events that are regulated by PD-1 triggering, and their consequences on the function of T effector cells.

Body Weight and Body Mass Index in Patients with End-Stage Cystic Fibrosis Stabilize After the Start of Enteral Tube Feeding.

Science.gov (United States)

Hollander, Francis M; de Roos, Nicole M; Belle van Meerkerk, Gerdien; Teding van Berkhout, Ferdinand; Heijerman, Harry G M; van de Graaf, Ed A

2017-11-01

Enteral tube feeding (ETF) is widely used in patients with cystic fibrosis (CF) and end-stage lung disease, but previous studies have been limited to investigating whether ETF improves outcomes in patients with moderately or mildly impaired pulmonary function. This study investigated body weight, body mass index (BMI; calculated as kg/m 2 ), pulmonary function, and the presence of CF-related diabetes before and after the start of ETF. This was a retrospective observational study. Data from 26 adult patients in an outpatient setting who had end-stage CF (19 women) and had been using ETF for at least 6 months between 2000 and 2014 were analyzed. Body weight, BMI, pulmonary function (forced expiratory volume in 1 second as percent of predicted) and incidence of CF-related diabetes from 6 months before to 6 months after starting ETF. Time effects were tested with one-way analysis of variance for data that were normally distributed and the Friedman test for non-parametric data. Correlations were tested with Pearson's r or Spearman's ρ, depending on the distribution of the data. Mean body weight increased by 3.5 kg (95% CI 2.2 to 4.8 kg) after patients started ETF. In women, mean BMI decreased by 0.7 in the 6 months before the start of ETF (PETF to 25% after 6 months (P=0.0013), with similar trends in women and men. There was no correlation between changes in weight and lung function. CF-related diabetes was already present in 12 patients and developed in 1 more patient after the start of ETF. ETF improved body weight and BMI but not pulmonary function in 26 patients with end-stage CF. Clinical outcomes were similar in women and men, but the sample size of men was too small to determine statistical significance. Copyright © 2017 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.

Whole-brain diffusion-tensor changes in parkinsonian patients with impulse control disorders.

Science.gov (United States)

Yoo, Hye Bin; Lee, Jee-Young; Lee, Jae Sung; Kang, Hyejin; Kim, Yu Kyeong; Song, In Chan; Lee, Dong Soo; Jeon, Beom Seok

2015-01-01

The aim of this study was to determine the changes in diffusion-tensor images associated with medication-related impulse control disorder (ICD) in Parkinson's disease (PD) patients undergoing chronic dopamine-replacement therapy. Nineteen PD patients, comprising 10 with ICD (PD-ICD) and 9 without ICD (PD-nonICD), and 18 age-matched healthy controls (HCs) with no cognitive or other psychiatric disorders were analyzed. All subjects underwent 3-T magnetic resonance diffusion-tensor imaging. For all PD patients, clinical data on PD duration, antiparkinsonian medication dosages, Unified Parkinson's Disease Rating Scale and Mini-Mental State Examination were collected. Whole-brain voxel-based measures of fractional anisotropy (FA) and mean diffusivity (MD) were analyzed. In comparison with HCs, the PD-nonICD subjects had low FA at the bilateral orbitofrontal areas. While the PD-ICD subjects exhibited no such difference, their FA was significantly elevated at the anterior corpus callosum. Analysis of FA between the two PD groups revealed that FA in the anterior corpus callosum, right internal capsule posterior limbs, right posterior cingulum, and right thalamic radiations were significantly higher (corrected p<0.05) in the PD-ICD than in the PD-nonICD patients. MD did not differ between the PD-ICD and PD-nonICD groups in any brain regions. The PD-ICD patients appear to have relatively preserved white-matter integrity in the regions involved in reward-related behaviors compared to PD-nonICD patients. Further investigation is required to determine whether the difference in FA between PD-ICD and PD-nonICD patients reflects microstructural differences in the pathological progression of PD or is secondary to ICD.

Caffeine as symptomatic treatment for Parkinson disease (Café-PD): A randomized trial.

Science.gov (United States)

Postuma, Ronald B; Anang, Julius; Pelletier, Amelie; Joseph, Lawrence; Moscovich, Mariana; Grimes, David; Furtado, Sarah; Munhoz, Renato P; Appel-Cresswell, Silke; Moro, Adriana; Borys, Andrew; Hobson, Douglas; Lang, Anthony E

2017-10-24

To assess effects of caffeine on Parkinson disease (PD). In this multicenter parallel-group controlled trial, patients with PD with 1-8 years disease duration, Hoehn & Yahr stages I-III, on stable symptomatic therapy were randomized to caffeine 200 mg BID vs matching placebo capsules for 6-18 months. The primary research question was whether objective motor scores would differ at 6 months (Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale [MDS-UPDRS]-III, Class I evidence). Secondary outcomes included safety and tolerability, motor symptoms (MDS-UPDRS-II), motor fluctuations, sleep, nonmotor symptoms (MDS-UPDRS-I), cognition (Montreal Cognitive Assessment), and quality of life. Sixty patients received caffeine and 61 placebo. Caffeine was well-tolerated with similar prevalence of side effects as placebo. There was no improvement in motor parkinsonism (the primary outcome) with caffeine treatment compared to placebo (difference between groups -0.48 [95% confidence interval -3.21 to 2.25] points on MDS-UPDRS-III). Similarly, on secondary outcomes, there was no change in motor signs or motor symptoms (MDS-UPDRS-II) at any time point, and no difference on quality of life. There was a slight improvement in somnolence over the first 6 months, which attenuated over time. There was a slight increase in dyskinesia with caffeine (MDS-UPDRS-4.1+4.2 = 0.25 points higher), and caffeine was associated with worse cognitive testing scores (average Montreal Cognitive Assessment = 0.66 [0.01, 1.32] worse than placebo). Caffeine did not provide clinically important improvement of motor manifestations of PD (Class I evidence). Epidemiologic links between caffeine and lower PD risk do not appear to be explained by symptomatic effects. NCT01738178. This study provides Class I evidence that for patients with PD, caffeine does not significantly improve motor manifestations. © 2017 American Academy of Neurology.

Work disability in non-radiographic axial spondyloarthritis patients before and after start of anti-TNF therapy

DEFF Research Database (Denmark)

Wallman, Johan K; Jöud, Anna; Olofsson, Tor

2017-01-01

Society criteria for axial spondyloarthritis and starting anti-TNF treatment during 2004-11, were retrieved from the observational South Swedish Arthritis Treatment Group study. Patient information was linked to Swedish Social Insurance Agency data on sick leave and disability pension from 1 year before...

Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti-PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells.

Science.gov (United States)

Boyerinas, Benjamin; Jochems, Caroline; Fantini, Massimo; Heery, Christopher R; Gulley, James L; Tsang, Kwong Yok; Schlom, Jeffrey

2015-10-01

Several anti-PD-1/PD-L1 monoclonal antibodies (mAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these mAbs is to inhibit PD-1 on immune cells interacting with PD-L1 on tumor cells. These mAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective mAb-mediated cancer therapies. A fully human anti-PD-L1 mAb would potentially be able to block PD-1/PD-L1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti-PD-L1 mAb. The studies reported here demonstrate (i) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (ii) IFNγ can enhance tumor cell PD-L1 expression and, in some cases, enhance ADCC tumor cell lysis; (iii) purified NK cells are potent effectors for avelumab; (iv) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (v) very low levels of avelumab-mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (vi) the addition of IL12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti-PD-L1 mAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity. ©2015 American Association for Cancer Research.

Colloidal lithography nanostructured Pd/PdO x core–shell sensor for ppb level H2S detection

Science.gov (United States)

Benedict, Samatha; Lumdee, Chatdanai; Dmitriev, Alexandre; Anand, Srinivasan; Bhat, Navakanta

2018-06-01

In this work we report on plasma oxidation of palladium (Pd) to form reliable palladium/palladium oxide (Pd/PdO x ) core–shell sensor for ppb level H2S detection and its performance improvement through nanostructuring using hole-mask colloidal lithography (HCL). The plasma oxidation parameters and the sensor operating conditions are optimized to arrive at a sensor device with high sensitivity and repeatable response for H2S. The plasma oxidized palladium/palladium oxide sensor shows a response of 43.1% at 3 ppm H2S at the optimum operating temperature of 200 °C with response and recovery times of 24 s and 155 s, respectively. The limit of detection (LoD) of the plasma oxidised beam is 10 ppb. We further integrate HCL, a bottom-up and cost-effective process, to create nanodiscs of fixed diameter of 100 nm and varying heights (10, 15 and 20 nm) on 10 nm thin Pd beam which is subsequently plasma oxidized to improve the H2S sensing characteristics. The nanostructured Pd/PdO x sensor with nanodiscs of 100 nm diameter and 10 nm height shows an enhancement in sensing performance by 11.8% at same operating temperature and gas concentration. This nanostructured sensor also shows faster response and recovery times (15 s and 100 s, respectively) compared to the unstructured Pd/PdO x counterpart together with an experimental LoD of 10 ppb and the estimated limit going all the way down to 2 ppb. Material characterization of the fabricated Pd/PdO x sensors is done using UV–vis spectroscopy and x-ray photoemission spectroscopy.

Antibody-dependent cellular cytotoxicity (ADCC) activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells

Science.gov (United States)

Fantini, Massimo; Heery, Christopher R.; Gulley, James L.; Tsang, Kwong Yok; Schlom, Jeffrey

2015-01-01

Several anti-PD1/PD-L1 monoclonal antibodies (MAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these MAbs is to inhibit PD1 on immune cells interacting with PD-L1 on tumor cells. These MAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective MAb-mediated cancer therapies. A fully human anti-PD-L1 MAb would potentially be able to block PD-L1/PD1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti-PD-L1 MAb. The studies reported here demonstrate (a) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (b) IFNγ can enhance tumor cell PD-L1 expression and in some cases enhance ADCC tumor cell lysis; (c) purified NK cells are potent effectors for avelumab; (d) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (e) very low levels of avelumab-mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (f) the addition of IL12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti-PD-L1 MAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity. PMID:26014098

Factors influencing access to education, decision making, and receipt of preferred dialysis modality in unplanned dialysis start patients.

Science.gov (United States)

Machowska, Anna; Alscher, Mark Dominik; Reddy Vanga, Satyanarayana; Koch, Michael; Aarup, Michael; Qureshi, Abdul Rashid; Lindholm, Bengt; Rutherford, Peter A

2016-01-01

Unplanned dialysis start (UPS) leads to worse clinical outcomes than planned start, and only a minority of patients ever receive education on this topic and are able to make a modality choice, particularly for home dialysis. This study aimed to determine the predictive factors for patients receiving education, making a decision, and receiving their preferred modality choice in UPS patients following a UPS educational program (UPS-EP). The Offering Patients Therapy Options in Unplanned Start (OPTiONS) study examined the impact of the implementation of a specific UPS-EP, including decision support tools and pathway improvement on dialysis modality choice. Linear regression models were used to examine the factors predicting three key steps: referral and receipt of UPS-EP, modality decision making, and actual delivery of preferred modality choice. A simple economic assessment was performed to examine the potential benefit of implementing UPS-EP in terms of dialysis costs. The majority of UPS patients could receive UPS-EP (214/270 patients) and were able to make a decision (177/214), although not all patients received their preferred choice (159/177). Regression analysis demonstrated that the initial dialysis modality was a predictive factor for referral and receipt of UPS-EP and modality decision making. In contrast, age was a predictor for referral and receipt of UPS-EP only, and comorbidity was not a predictor for any step, except for myocardial infarction, which was a weak predictor for lower likelihood of receiving preferred modality. Country practices predicted UPS-EP receipt and decision making. Economic analysis demonstrated the potential benefit of UPS-EP implementation because dialysis modality costs were associated with modality distribution driven by patient preference. Education and decision support can allow UPS patients to understand their options and choose dialysis modality, and attention needs to be focused on ensuring equity of access to educational

Decreased sleep spindle density in patients with idiopathic REM sleep behavior disorder and patients with Parkinson's disease.

Science.gov (United States)

Christensen, Julie A E; Kempfner, Jacob; Zoetmulder, Marielle; Leonthin, Helle L; Arvastson, Lars; Christensen, Søren R; Sorensen, Helge B D; Jennum, Poul

2014-03-01

To determine whether sleep spindles (SS) are potentially a biomarker for Parkinson's disease (PD). Fifteen PD patients with REM sleep behavior disorder (PD+RBD), 15 PD patients without RBD (PD-RBD), 15 idiopathic RBD (iRBD) patients and 15 age-matched controls underwent polysomnography (PSG). SS were scored in an extract of data from control subjects. An automatic SS detector using a Matching Pursuit (MP) algorithm and a Support Vector Machine (SVM) was developed and applied to the PSG recordings. The SS densities in N1, N2, N3, all NREM combined and REM sleep were obtained and evaluated across the groups. The SS detector achieved a sensitivity of 84.7% and a specificity of 84.5%. At a significance level of α=1%, the iRBD and PD+RBD patients had a significantly lower SS density than the control group in N2, N3 and all NREM stages combined. At a significance level of α=5%, PD-RBD had a significantly lower SS density in N2 and all NREM stages combined. The lower SS density suggests involvement in pre-thalamic fibers involved in SS generation. SS density is a potential early PD biomarker. It is likely that an automatic SS detector could be a supportive diagnostic tool in the evaluation of iRBD and PD patients. Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Motor and Non-motor Features: Differences between Patients with Isolated Essential Tremor and Patients with Both Essential Tremor and Parkinson's Disease

Directory of Open Access Journals (Sweden)

Apostolia Ghika

2015-08-01

Full Text Available Background: Patients with essential tremor (ET who develop Parkinson’s disease (ET->PD may differ with respect to motor features (MFs and non-motor features (NMFs from patients with isolated ET. Few studies have assessed this issue. Methods: In this retrospective chart review, we analyzed data on MFs and NMFs of 175 patients, including 54 ET->PD and 121 ET, actively followed in the Athens University 1st Neurology Department. Results: Significantly more ET->PD than ET patients reported asymmetric tremor at ET onset (68.5% vs. 14.9%, p<0.001.  Significantly more ET than ET->PD patients had head tremor (43.5% vs. 13.2%, p<0.001 and cerebellar signs (41.3% vs. 9.3%, p<0.001. More ET than ET->PD patients reported hearing impairment (65.3% vs. 28.3%, p<0.001 and restless legs syndrome (34.8% vs. 3.7%, p<0.001. Conversely, a larger proportion of ET->PD than ET patients reported rapid eye movement behavior disorder (51.9% vs. 10.0%, p<0.001, constipation (67.9% vs. 36.4%, p<0.001, and olfactory dysfunction (83.3% vs. 36.4%, p<0.001. Discussion: The subset of ET->PD patients may have distinct MFs and NMFs that should be assessed further for the possible predictive value for the emergence of PD.  

Peritoneal dialysis technique success during the initial 90 days of therapy.

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Guest, Steven; Hayes, Andrew C; Story, Kenneth; Davis, Ira D

2012-01-01

Comparisons of technique success by peritoneal dialysis (PD) modality have typically excluded the initial 90 days of therapy. We analyzed a database of 51,469 new PD starts from 2004 to 2008 in the United States. The analysis concentrated on the initial 90 days of therapy to determine technique success and the impact of the continuous ambulatory PD (CAPD) and automated PD (APD) modalities. Overall, 13.3% of patients stopped PD within 90 days. Of patients starting directly on APD, 14.3% stopped PD within 90 days. Of patients starting on CAPD, 12.6% stopped PD within 90 days, and 63.4% changed to APD within 90 days. Only 3.3% of the latter patients failed to reach 90 days of therapy. By comparison, technique failure occurred in 28.8% of those initiating with and remaining on CAPD. We conclude that initial training to perform CAPD, with timely transfer to APD within the first 3 months, was associated with the greatest technique success at 90 days. The reasons for that success are unclear, and further research should be directed to determining factors responsible. It is possible that patients trained initially to CAPD but converted to APD have a greater understanding of the total therapy, which improves confidence. Those converted to APD may be more appreciative of the lifestyle benefits of APD, which translates into improved compliance; alternatively, technical factors associated with APD may be responsible. Those technical factors may include improved catheter function in the recumbent position during APD or the reduced infection risk associated with just 2 connect/disconnect procedures in APD compared with 8 in CAPD.

Carbon-Supported Pd and PdFe Alloy Catalysts for Direct Methanol Fuel Cell Cathodes

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Luis M. Rivera Gavidia

2017-05-01

Full Text Available Direct methanol fuel cells (DMFCs are electrochemical devices that efficiently produce electricity and are characterized by a large flexibility for portable applications and high energy density. Methanol crossover is one of the main obstacles for DMFC commercialization, forcing the search for highly electro-active and methanol tolerant cathodes. In the present work, carbon-supported Pd and PdFe catalysts were synthesized using a sodium borohydride reduction method and physico-chemically characterized using transmission electron microscopy (TEM and X-ray techniques such as photoelectron spectroscopy (XPS, diffraction (XRD and energy dispersive spectroscopy (EDX. The catalysts were investigated as DMFC cathodes operating at different methanol concentrations (up to 10 M and temperatures (60 °C and 90 °C. The cell based on PdFe/C cathode presented the best performance, achieving a maximum power density of 37.5 mW·cm−2 at 90 °C with 10 M methanol, higher than supported Pd and Pt commercial catalysts, demonstrating that Fe addition yields structural changes to Pd crystal lattice that reduce the crossover effects in DMFC operation.

Validation of the Risk Prediction Models STATE-Score and START-Strategy to Guide TACE Treatment in Patients with Hepatocellular Carcinoma.

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Mähringer-Kunz, Aline; Kloeckner, Roman; Pitton, Michael B; Düber, Christoph; Schmidtmann, Irene; Galle, Peter R; Koch, Sandra; Weinmann, Arndt

2017-07-01

Several scoring systems that guide patients' treatment regimen for transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) have been introduced, but none have gained widespread acceptance in clinical practice. The purpose of this study is to externally validate the Selection for TrAnsarterial chemoembolization TrEatment (STATE)-score and START-strategy [i.e., sequential use of the STATE-score and Assessment for Retreatment with TACE (ART)-score]. From January 2000 to September 2015, 933 patients with HCC underwent TACE at our institution. All variables needed to calculate the STATE-score and implement the START-strategy were determined. STATE comprised serum albumin, up-to-seven criteria, and C-reactive protein (CRP). ART comprised an increase in aspartate aminotransferase, the Child-Pugh score, and a radiological tumor response. Overall survival was calculated, and multivariate analysis performed. In addition, the STATE-score and START-strategy were validated using the Harrell's C-index and integrated Brier score (IBS). The STATE-score was calculated in 228 patients. Low and high STATE-scores corresponded to median survival of 14.3 and 20.2 months, respectively. Harrell's C was 0.558 and IBS 0.133. For the STATE-score, significant predictors of survival were up-to-seven criteria (p = 0.006) and albumin (p = 0.022). CRP values were not predictive (p = 0.367). The ART-score was calculated in 207 patients. Combining the STATE-score and ART-score led to a Harrell's C of 0.580 and IBS of 0.132. The STATE-score was unable to reliably determine the suitability for initial TACE. The START-strategy only slightly improved the predictive ability compared to the ART-score alone. Therefore, neither the STATE-score nor START-strategy alone provides sufficient certainty for clear-cut clinical decisions.

Comparison of weight changes following unilateral and staged bilateral STN DBS for advanced PD.

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Lee, Eric M; Kurundkar, Ashish; Cutter, Gary R; Huang, He; Guthrie, Barton L; Watts, Ray L; Walker, Harrison C

2011-09-01

Unilateral and bilateral subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson's disease (PD) result in weight gain in the initial postoperative months, but little is known about the changes in weight following unilateral and staged bilateral STN DBS over longer time intervals. A case-control comparison evaluated weight changes over 2 years in 43 consecutive unilateral STN DBS patients, among whom 25 elected to undergo staged bilateral STN DBS, and 21 age-matched and disease severity matched PD controls without DBS. Regression analyses incorporating age, gender, and baseline weight in case or control were conducted to assess weight changes 2 years after the initial unilateral surgery. Unilateral STN DBS and staged bilateral STN DBS patients gained 3.9 ± 2.0 kg and 5.6 ± 2.1 kg versus their preoperative baseline weight (P < 0.001, respectively) while PD controls without DBS lost 0.8 ± 1.1 kg. Although bilateral STN DBS patients gained 1.7 kg more than unilateral STN DBS patients at 2 years, this difference was not statistically significant (P = 0.885). Although there was a trend toward greater weight gain in staged bilateral STN DBS patients versus unilateral patients, we found no evidence for an equivalent or synergistic increase in body weight following placement of the second DBS electrode.

Study of hyperfine interactions in intermetallic compounds Gd(Ni,Pd,Cu)In, Tb(Ni,Pd)In, Dy(Ni,Pd)In and Ho(Ni,Pd)In; Estudo de interacoes hiperfinas em compostos intermetalicos Gd(Ni,Pd,Cu)In, Tb(Ni,Pd)In, Dy(Ni,Pd)In e Ho(Ni,Pd)In

Energy Technology Data Exchange (ETDEWEB)

Lapolli, Andre Luis

2006-07-01

Systematic behavior of magnetic hyperfine field (B{sub hf}) in the intermetallic compounds Gd(Ni,Pd,Cu)In Tb(Ni,Pd)In, Dy(Ni,Pd)In and Ho(Ni,Pd)In was studied by Perturbed Gamma-Gamma Angular Correlation spectroscopy. The measurements of B{sub hf} were carried out at the rare earth atom and in sites using the nuclear probes {sup 140}Ce and {sup 11}'1Cd respectively. The variation of hyperfine field with temperature, in most cases, follows the Brillouin function predicted from the molecular field theory. The hyperfine field values at rare earth atom sites obtained from {sup 140}Ce probe as well as at in sites obtained from {sup 111}Cd probe for each series of compounds were extrapolated to zero Kelvin B{sub hf}(T=0) from these curves. These values were compared with the values of the literature for other compounds containing the same rare earth element and all of them show a linear relationship with the ordering temperature. This indicates that the main contribution to B{sub hf} comes from the conduction electron polarization (CEP) through Fermi contact interaction and the principal mechanism of magnetic interaction in these compounds can be described by the RKKY type interaction. The values of B{sub hf}(T=0) for each family of intermetallic compounds RNiIn and RPdIn when plotted as a function of 4f spin projection of rare earth element also shows a linear relationship. Exceptions are the results for the compounds RNiIn obtained with {sup 111}Cd probe where a small deviation from linearity is observed. The results of the measurements carried out with the {sup 111}Cd probe were also analyzed to obtain the hyperfine parameters of the quadrupole interaction as a function of temperature for RPdln and GdNiIn compounds. The results show that for the compound GdPdIn there might be some Gd-In disorder at high temperature. (author)

Study of hyperfine interactions in intermetallic compounds Gd(Ni,Pd,Cu)In, Tb(Ni,Pd)In, Dy(Ni,Pd)In and Ho(Ni,Pd)In; Estudo de interacoes hiperfinas em compostos intermetalicos Gd(Ni,Pd,Cu)In, Tb(Ni,Pd)In, Dy(Ni,Pd)In e Ho(Ni,Pd)In

Energy Technology Data Exchange (ETDEWEB)

Lapolli, Andre Luis

2006-07-01

Systematic behavior of magnetic hyperfine field (B{sub hf}) in the intermetallic compounds Gd(Ni,Pd,Cu)In Tb(Ni,Pd)In, Dy(Ni,Pd)In and Ho(Ni,Pd)In was studied by Perturbed Gamma-Gamma Angular Correlation spectroscopy. The measurements of B{sub hf} were carried out at the rare earth atom and in sites using the nuclear probes {sup 140}Ce and {sup 11}'1Cd respectively. The variation of hyperfine field with temperature, in most cases, follows the Brillouin function predicted from the molecular field theory. The hyperfine field values at rare earth atom sites obtained from {sup 140}Ce probe as well as at in sites obtained from {sup 111}Cd probe for each series of compounds were extrapolated to zero Kelvin B{sub hf}(T=0) from these curves. These values were compared with the values of the literature for other compounds containing the same rare earth element and all of them show a linear relationship with the ordering temperature. This indicates that the main contribution to B{sub hf} comes from the conduction electron polarization (CEP) through Fermi contact interaction and the principal mechanism of magnetic interaction in these compounds can be described by the RKKY type interaction. The values of B{sub hf}(T=0) for each family of intermetallic compounds RNiIn and RPdIn when plotted as a function of 4f spin projection of rare earth element also shows a linear relationship. Exceptions are the results for the compounds RNiIn obtained with {sup 111}Cd probe where a small deviation from linearity is observed. The results of the measurements carried out with the {sup 111}Cd probe were also analyzed to obtain the hyperfine parameters of the quadrupole interaction as a function of temperature for RPdln and GdNiIn compounds. The results show that for the compound GdPdIn there might be some Gd-In disorder at high temperature. (author)

Gut microbiota in patients with Parkinson's disease in southern China.

Science.gov (United States)

Lin, Aiqun; Zheng, Wenxia; He, Yan; Tang, Wenli; Wei, Xiaobo; He, Rongni; Huang, Wei; Su, Yuying; Huang, Yaowei; Zhou, Hongwei; Xie, Huifang

2018-05-16

Accumulating evidence has revealed alterations in the communication between the gut and brain in patients with Parkinson's disease (PD), and previous studies have confirmed that alterations in the gut microbiome play an important role in the pathogenesis of numerous diseases, including PD. The aim of this study was to determine whether the faecal microbiome of PD patients in southern China differs from that of control subjects and whether the gut microbiome composition alters among different PD motor phenotypes. We compared the gut microbiota composition of 75 patients with PD and 45 age-matched controls using 16S rRNA next-generation-sequencing. We observed significant increases in the abundance of four bacterial families and significant decreases in the abundance of seventeen bacterial families in patients with PD compared to those of the controls. In particular, the abundance of Lachnospiraceae was reduced by 42.9% in patients with PD, whereas Bifidobacteriaceae was enriched in patients with PD. We did not identify a significant difference in the overall microbial composition among different PD motor phenotypes, but we identified the association between specific taxas and different PD motor phenotypes. PD is accompanied by alterations in the abundance of specific gut microbes. The abundance of certain gut microbes was altered depending on clinical motor phenotypes. Based on our findings, the gut microbiome may be a potential PD biomarker. Copyright © 2018 Elsevier Ltd. All rights reserved.

Targeting PD-1/PD-L1 in lung cancer: current perspectives

Directory of Open Access Journals (Sweden)

González-Cao M

2015-07-01

Full Text Available María González-Cao,1 Niki Karachaliou,1 Santiago Viteri,1 Daniela Morales-Espinosa,1 Cristina Teixidó,2 Jesús Sánchez Ruiz,3 Miquel Ángel Molina-Vila,2 Mariacarmela Santarpia,4 Rafael Rosell1,2,5,61Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain; 2Pangaea Biotech SL, Barcelona, Spain; 3Centro Nacional de Investigación Oncología (CNIO, Madrid, Spain; 4Medical Oncology Unit, Human Pathology Department, University of Messina, Messina, Italy; 5Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Badalona, Barcelona, Spain; 6Fundación Molecular Oncology Research, Barcelona, SpainAbstract: Increased understanding of tumor immunology has led to the development of effective immunotherapy treatments. One of the most important advances in this field has been due to pharmacological design of antibodies against immune checkpoint inhibitors. Anti-PD-1/PD-L1 antibodies are currently in advanced phases of clinical development for several tumors, including lung cancer. Results from Phase I–III trials with anti-PD-1/PD-L1 antibodies in non-small-cell lung cancer have demonstrated response rates of around 20% (range, 16%–50%. More importantly, responses are long-lasting (median duration of response, 18 months and fast (50% of responses are detected at time of first tumor evaluation with very low grade 3–4 toxicity (less than 5%. Recently, the anti-PD-1 antibody pembrolizumab received US Food and Drug Administration (FDA breakthrough therapy designation for treatment of non-small-cell lung cancer, supported by data from a Phase Ib trial. Another anti-PD-1 antibody, nivolumab, has also been approved for lung cancer based on survival advantage demonstrated in recently released data from a Phase III trial in squamous cell lung cancer.Keywords: immunotherapy, immunoncology

Antibody-dependent cellular cytotoxicity (ADCC) activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells

OpenAIRE

Boyerinas, Benjamin; Jochems, Caroline; Fantini, Massimo; Heery, Christopher R.; Gulley, James L.; Tsang, Kwong Yok; Schlom, Jeffrey

2015-01-01

Several anti-PD1/PD-L1 monoclonal antibodies (MAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these MAbs is to inhibit PD1 on immune cells interacting with PD-L1 on tumor cells. These MAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective MAb-mediated cancer therapies. A fully human anti-PD-L...

White matter microstructure damage in tremor-dominant Parkinson's disease patients

International Nuclear Information System (INIS)

Luo, ChunYan; Song, Wei; Chen, Qin; Yang, Jing; Shang, Hui-Fang; Gong, QiYong

2017-01-01

Resting tremor is one of the cardinal motor features of Parkinson's disease (PD). Several lines of evidence suggest resting tremor may have different underlying pathophysiological processes from those of bradykinesia and rigidity. The current study aims to identify white matter microstructural abnormalities associated with resting tremor in PD. We recruited 60 patients with PD (30 with tremor-dominant PD and 30 with nontremor-dominant PD) and 26 normal controls. All participants underwent clinical assessment and diffusion tensor MRI. We used tract-based spatial statistics to investigate white matter integrity across the entire white matter tract skeleton. Compared with both healthy controls and the nontremor-dominant PD patients, the tremor-dominant PD patients were characterized by increased mean diffusivity (MD) and axial diffusivity (AD) along multiple white matter tracts, mainly involving the cerebello-thalamo-cortical (CTC) pathway. The mean AD value in clusters with significant difference was correlated with resting tremor score in the tremor-dominant PD patients. There was no significant difference between the nontremor-dominant PD patients and controls. Our results support the notion that resting tremor in PD is a distinct condition in which significant microstructural white matter changes exist and provide evidence for the involvement of the CTC in tremor genesis of PD. (orig.)

Characteristics of Brain Perfusion in Patients of Parkinson's Disease

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Jeong, Young Jin; Park, Min Jung; Kim, Jae Woo; Kang, Young Kang [Dong-A University College of Medicine, Busan (Korea, Republic of)

2008-02-15

It was well known that cerebral blood perfusion is normal or diffusely decreased in the majority of patients with Parkinson's disease (PD). Actually we interpreted brain perfusion SPECT images of PD patients in the clinical situation, we observed various cerebral perfusion patterns in patients with PD. So we performed brain perfusion SPECT to know the brain perfusion patterns of PD patients and the difference of perfusion patterns according to the sex and the age. Also we classified PD patients into small groups based on the brain perfusion pattern. Two hundred nineteen patients (M: 70, F: 149, mean age: 62.9{+-}6.9 y/o) who were diagnosed as PD without dementia clinically and 55 patients (M: 15, F: 40, mean age: 61.4{+-}9.2 y/o) as normal controls who had no past illness history were performed {sup 99m}Tc-HMPAO brain perfusion SPECT and neuropsychological test. At first, we compared all patients with PD and normal controls. Brain perfusion in left inferior frontal gyrus, left insula, left transverse temporal gyrus, left inferior parietal lobule, left superior parietal lobule, right precuneus, right caudate tail were lower in patients with PD than normal controls. Secondly, we compared male and female patients with PD and normal controls, respectively. Brain perfusion SPECT showed more decreased cerebral perfusion in left hemisphere than right side in both male and female patients compared to normal controls. And there was larger hypoperfusion area in female patients compared with male. Thirdly, we classified patients with PD and normal controls into 4 groups according to the age and compared brain perfusion respectively. In patient below fifties, brain perfusion in both occipitoparietal and left temporal lobe were lower in PD group. As the patients with PD grew older, hypoperfusion area were shown in both frontal, temporal and limbic lobes. Fourthly, We were able to divide patients into small groups based on cerebral perfusion pattern. There was normal

Fulminant Diabetes in a Patient with Advanced Melanoma on Nivolumab

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Nora Chokr

2018-01-01

Full Text Available Background. Anti-PD-1 agents were approved for advanced melanoma after the landmark trial Checkmate-037. Anti-PD-1 agents can breach immunologic tolerance. Fulminant diabetes is an immune endocrinopathy that results from a violent immune attack leading to complete destruction of pancreatic beta cells in genetically predisposed people. We present a rare case of fulminant diabetes precipitated by anti-PD-1 immunotherapy. Case. A 61-year-old male with advanced melanoma presented with a three-day history of nausea, vomiting, and malaise. He was started on nivolumab and ipilimumab. After the third dose, he developed a generalized rash and was prescribed high-dose prednisone. Labs revealed potassium 9.5 mmol/L, sodium 127 mmol/L, bicarbonate 31 mmol, arterial blood pH 7.14, and beta-hydroxybutyrate 13.7 mmol/L. He was diagnosed with diabetic ketoacidosis. Hemoglobin A1C was 6.9%. C-peptide was undetectable (<0.1 ng/ml. Glutamic acid decarboxylase autoantibodies, zinc transporter 8 autoantibodies, insulin autoantibodies, islet antigen 2 autoantibodies, and islet cell antibodies were all negative. Conclusion. Anti-PD-1 immunotherapy is effective in cancers refractory to standard chemotherapy. These agents can precipitate autoimmune disorders. As the use of anti-PD-1 agents is expected to rise, physicians should be educated about the potential side effects. We recommend conducting routine blood glucose checks in patients on these agents.

Monoamine transporter availability in Parkinson's disease patients with or without depression

International Nuclear Information System (INIS)

Hesse, Swen; Meyer, Philipp M.; Barthel, Henryk; Sabri, Osama; Strecker, Karl; Wegner, Florian; Isaias, Ioannis Ugo; Schwarz, Johannes; Oehlwein, Christian

2009-01-01

Depression is a common symptom in patients suffering from Parkinson's disease (PD) and markedly reduces their quality of life. As post-mortem studies have shown, its presence may reflect extensive cell loss in the midbrain and brainstem with imbalances in monoaminergic neurotransmitters. However, in vivo evidence of specific monoaminergic deficits in depressed PD patients is still sparse. Therefore, we studied PD patients with depression (PD+D) and without depression (PD-D) using high-resolution single-photon emission computed tomography (SPECT) and the monoamine transporter marker [ 123 I]FP-CIT. A magnetic resonance imaging-based region-of-interest analysis was applied to quantify the specific-to-nondisplaceable [ 123 I]FP-CIT binding coefficient V 3 '' in the striatum, thalamus and midbrain/brainstem regions. PD+D patients had significantly lower V 3 '' compared with PD-D patients in the striatum (p 3 '' than controls (p 3 '' nor midbrain/brainstem V 3 '' differed from those in PD-D patients (p=0.168, p=0.201) or controls (p=0.384, p=0.318). Our data indicate that depression in PD is associated with a more pronounced loss of striatal dopamine transporter availability that is most likely secondary to increased dopaminergic degeneration. In addition, depressed PD patients have a lower availability of midbrain/brainstem monoamine transporters than nondepressed PD patients. These findings provide in vivo evidence in support of the known post-mortem data demonstrating more extensive nerve cell loss in PD with depression and indicate that SPECT imaging can help to identify pathophysiological changes underlying nonmotor symptoms in this common movement disorder. (orig.)

PD-L1 expression and the immune microenvironment in primary invasive lobular carcinomas of the breast.

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Thompson, Elizabeth D; Taube, Janis M; Asch-Kendrick, Rebecca J; Ogurtsova, Aleksandra; Xu, Haiying; Sharma, Rajni; Meeker, Alan; Argani, Pedram; Emens, Leisha A; Cimino-Mathews, Ashley

2017-11-01

Tumor-infiltrating lymphocytes and immune checkpoint proteins such as PD-L1 are potential prognostic factors and therapeutic targets in breast cancer. Most studies characterizing the breast tumor immune microenvironment have focused on ductal carcinomas. Here we investigate the tumor microenvironment of primary invasive lobular carcinomas. Previously constructed tissue microarrays of 47 lobular carcinomas were labeled by immunohistochemistry for PD-L1, CD8, CD20, and FoxP3. The stromal immune infiltrate density was qualitatively scored as a percentage of tumor area: 1+ (50%). The average immune cell subtype per high-power field was quantitatively scored. The percentage PD-L1 labeling on tumor-infiltrating lymphocytes was scored as none, focal (lobular carcinomas contained PD-L1 + tumor-infiltrating lymphocytes with the majority showing 1+ immune infiltrates with focal-moderate PD-L1 labeling. PD-L1 was expressed by tumor cells in 17% of lobular carcinomas. In contrast to ductal carcinomas, there was no correlation between the immune infiltrate density, the PD-L1 expression by lobular carcinoma cells, tumor grade, or the expression of estrogen receptor or human epidermal growth factor receptor-2. However, both the tumor-infiltrating lymphocyte density and the average CD8 + T-cell counts correlated with immune cell PD-L1 status (P=0.004 and 0.03, respectively). Similar to breast ductal carcinomas, PD-L1 + lobular breast carcinomas had higher numbers of PD-L1 + tumor-infiltrating lymphocytes (63%) than PD-L1 - lobular carcinomas (23%; P=0.04). These data show that a subset of primary breast lobular carcinomas both express PD-L1 on tumor cells and contain PD-L1 + tumor-infiltrating lymphocytes, suggesting the possibility of both constitutive and adaptive PD-L1 expression. Together, these results support immunotherapy as a potential treatment for a subset of patients with primary invasive lobular breast carcinomas.

Surgical treatment in patients with double elevator palsy.

Science.gov (United States)

Yurdakul, Nazife Sefi; Ugurlu, Seyda; Maden, Ahmet

2009-01-01

To evaluate the effectiveness of surgical treatment performed in patients with double elevator palsy (DEP). Patients diagnosed with congenital DEP between April 2003 and March 2007 were included in the study. The cases with positive traction test had inferior rectus (IR) recession followed by full tendon width muscle transposition Knapp surgery or partial tendon width transposition operation, while those without positive traction test underwent transposition procedure alone. Transposition surgery was combined with recession and resection of horizontal rectus muscles in patients with exotropia according to the amount of horizontal deviation. Eyelid surgery was applied in patients with ptosis following strabismus surgery. The average age of 13 patients was 14+/-32.5 years (range, 3-60 years). Five patients (38%) were female and 8 patients (62%) were male. The mean preoperative hypotropia was decreased from 29.2+/-3.5 prism diopters (PD) (range, 16-45 PD) to 2.6+/-2.8 PD (range, 0-6 PD) postoperatively. The median amount of horizontal deviation in patients with exotropia (n=4) was 30 PD (range, 25-45 PD) preoperatively; it was reduced to 2 PD (range, 0-8 PD) postoperatively. Mean follow-up period was 14.1+/-2.8 months (range, 6-31 months). Five patients (38%) underwent eyelid surgery, and all achieved cosmetically satisfactory results. Transposition surgery alone or combined with IR recession is an effective procedure in treatment of double elevator palsy. In patients with moderate horizontal deviations, recession and resection of horizontal rectus muscles combined with transposition provide correction of the horizontal deviation at the same time.

Fatigue in Patients with Parkinson’s Disease

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Kazuo Abe

2000-01-01

Full Text Available Purpose: Fatigue is a complaint frequently encountered among patients with Parkinson’s disease (PD, however, the pathophysiological mechanism remains unclear. Methods: We evaluated fatigue in 26 patients clinically diagnosed to have PD (16 men, 10 women and age- and sex- matched 26 controls (16 men, 10 women without neurological deficits by using a fatigue scale. In addition to neurological and neuropsychological examinations, all patients underwent MRI and SPECT using 99mTc-HMPAO. Results: Patients with PD had normal cognitive function as judged by the MMSE, but showed significantly high scores with the fatigue and depression scales in comparison to controls (p. There was no significant correlation between the depression scale and the fatigue scale, or between the degree of disability and the fatigue scale in patients with PD, although a significant correlation existed between the depression scale and the fatigue scale in controls. With SPECT, a significant correlation was found between the fatigue scale and the reduction of perfusion in the frontal lobe (p in patients with PD. Conclusions: The present study suggested that sense of fatigue in patients with PD might be associated with frontal lobe dysfunction.

Size and alloying induced shift in core and valence bands of Pd-Ag and Pd-Cu nanoparticles

International Nuclear Information System (INIS)

Sengar, Saurabh K.; Mehta, B. R.; Govind

2014-01-01

In this report, X-ray photoelectron spectroscopy studies have been carried out on Pd, Ag, Cu, Pd-Ag, and Pd-Cu nanoparticles having identical sizes corresponding to mobility equivalent diameters of 60, 40, and 20 nm. The nanoparticles were prepared by the gas phase synthesis method. The effect of size on valence and core levels in metal and alloy nanoparticles has been studied by comparing the values to those with the 60 nm nanoparticles. The effect of alloying has been investigated by comparing the valence and core level binding energies of Pd-Cu and Pd-Ag alloy nanoparticles with the corresponding values for Pd, Ag, and Cu nanoparticles of identical sizes. These effects have been explained in terms of size induced lattice contractions, alloying induced charge transfer, and hybridization effects. The observation of alloying and size induced binding energy shifts in bimetallic nanoparticles is important from the point of view of hydrogen reactivity

A Comparison of Treatment-Seeking Behavioral Addiction Patients with and without Parkinson’s Disease

Science.gov (United States)

Sauvaget, Anne; Jiménez-Murcia, Susana; Fernández-Aranda, Fernando; Granero, Roser; Grall-Bronnec, Marie; Victorri-Vigneau, Caroline; Bulteau, Samuel; Derkinderen, Pascal; Vanelle, Jean M.; Hakansson, Anders; Mestre-Bach, Gemma; Steward, Trevor; Menchón, José M.

2017-01-01

The administration of dopaminergic medication to treat the symptoms of Parkinson’s disease (PD) is associated with addictive behaviors and impulse control disorders. Little is known, however, on how PD patients differ from other patients seeking treatments for behavioral addictions. The aim of this study was to compare the characteristics of behavioral addiction patients with and without PD. N = 2,460 treatment-seeking men diagnosed with a behavioral addiction were recruited from a university hospital. Sociodemographic, impulsivity [Barratt Impulsiveness Scale (BIS-11)], and personality [Temperament and Character Inventory-Revised (TCI-R)] measures were taken upon admission to outpatient treatment. Patients in the PD group were older and had a higher prevalence of mood disorders than patients without PD. In terms of personality characteristics and impulsivity traits, PD patients appeared to present a more functional profile than PD-free patients with a behavioral addiction. Our results suggest that PD patients with a behavioral addiction could be more difficult to detect than their PD-free counterparts in behavioral addiction clinical setting due to their reduced levels of impulsivity and more standard personality traits. As a whole, this suggests that PD patients with a behavioral addiction may have different needs from PD-free behavioral addiction patients and that they could potentially benefit from targeted interventions. PMID:29163234

Preparation of supported Au–Pd and Cu–Pd by the combined strong ...

Indian Academy of Sciences (India)

BOONTIDA PONGTHAWORNSAKUN

2017-10-25

Oct 25, 2017 ... Bimetallic catalyst; Au–Pd/TiO2; Cu–Pd/TiO2; strong electrostatic adsorption; electroless deposition .... The liquid samples .... composition and gas mixture product at the outlet of reactor ... the TiO2 support (no change in the deposition curve of. TiO2). ..... TrimmDL1980In Design of Industrial Catalysts (Ams-.

Immunohistochemical Analysis of PD-L1 Expression in Canine Malignant Cancers and PD-1 Expression on Lymphocytes in Canine Oral Melanoma.

Science.gov (United States)

Maekawa, Naoya; Konnai, Satoru; Okagawa, Tomohiro; Nishimori, Asami; Ikebuchi, Ryoyo; Izumi, Yusuke; Takagi, Satoshi; Kagawa, Yumiko; Nakajima, Chie; Suzuki, Yasuhiko; Kato, Yukinari; Murata, Shiro; Ohashi, Kazuhiko

2016-01-01

Spontaneous cancers are common diseases in dogs. Among these, some malignant cancers such as oral melanoma, osteosarcoma, hemangiosarcoma, and mast cell tumor are often recognized as clinical problems because, despite their high frequencies, current treatments for these cancers may not always achieve satisfying outcomes. The absence of effective systemic therapies against these cancers leads researchers to investigate novel therapeutic modalities, including immunotherapy. Programmed death 1 (PD-1) is a costimulatory receptor with immunosuppressive function. When it binds its ligands, PD-ligand 1 (PD-L1) or PD-L2, PD-1 on T cells negatively regulates activating signals from the T cell receptor, resulting in the inhibition of the effector function of cytotoxic T lymphocytes. Aberrant PD-L1 expression has been reported in many human cancers and is considered an immune escape mechanism for cancers. In clinical trials, anti-PD-1 or anti-PD-L1 antibodies induced tumor regression for several malignancies, including advanced melanoma, non-small cell lung carcinoma, and renal cell carcinoma. In this study, to assess the potential of the PD-1/PD-L1 axis as a novel therapeutic target for canine cancer immunotherapy, immunohistochemical analysis of PD-L1 expression in various malignant cancers of dogs was performed. Here, we show that dog oral melanoma, osteosarcoma, hemangiosarcoma, mast cell tumor, mammary adenocarcinoma, and prostate adenocarcinoma expressed PD-L1, whereas some other types of cancer did not. In addition, PD-1 was highly expressed on tumor-infiltrating lymphocytes obtained from oral melanoma, showing that lymphocytes in this cancer type might have been functionally exhausted. These results strongly encourage the clinical application of PD-1/PD-L1 inhibitors as novel therapeutic agents against these cancers in dogs.

Immunohistochemical Analysis of PD-L1 Expression in Canine Malignant Cancers and PD-1 Expression on Lymphocytes in Canine Oral Melanoma.

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Naoya Maekawa

Full Text Available Spontaneous cancers are common diseases in dogs. Among these, some malignant cancers such as oral melanoma, osteosarcoma, hemangiosarcoma, and mast cell tumor are often recognized as clinical problems because, despite their high frequencies, current treatments for these cancers may not always achieve satisfying outcomes. The absence of effective systemic therapies against these cancers leads researchers to investigate novel therapeutic modalities, including immunotherapy. Programmed death 1 (PD-1 is a costimulatory receptor with immunosuppressive function. When it binds its ligands, PD-ligand 1 (PD-L1 or PD-L2, PD-1 on T cells negatively regulates activating signals from the T cell receptor, resulting in the inhibition of the effector function of cytotoxic T lymphocytes. Aberrant PD-L1 expression has been reported in many human cancers and is considered an immune escape mechanism for cancers. In clinical trials, anti-PD-1 or anti-PD-L1 antibodies induced tumor regression for several malignancies, including advanced melanoma, non-small cell lung carcinoma, and renal cell carcinoma. In this study, to assess the potential of the PD-1/PD-L1 axis as a novel therapeutic target for canine cancer immunotherapy, immunohistochemical analysis of PD-L1 expression in various malignant cancers of dogs was performed. Here, we show that dog oral melanoma, osteosarcoma, hemangiosarcoma, mast cell tumor, mammary adenocarcinoma, and prostate adenocarcinoma expressed PD-L1, whereas some other types of cancer did not. In addition, PD-1 was highly expressed on tumor-infiltrating lymphocytes obtained from oral melanoma, showing that lymphocytes in this cancer type might have been functionally exhausted. These results strongly encourage the clinical application of PD-1/PD-L1 inhibitors as novel therapeutic agents against these cancers in dogs.

Preparation of 103Pd seeds. Part 2. 'Molecular Plating' of 103Pd onto copper rod

International Nuclear Information System (INIS)

Chunfu Zhang; Yongxian Wang; Haibin Tian; Duanzhi Yin

2002-01-01

A method for 103 Pd 'molecular plating' onto the surface of the copper rod is reported. The optimal composition of the plating bath was: palladium chloride 2 g/l, ammonium hydroxide (28%) 150 ml/l, sodium hypophosphite 12 g/l, and ammonium chloride 37 g/l. The whole procedure of 103 Pd 'molecular plating' will last 50 minutes at 40 deg C. Valuable experience for the preparation of 103 Pd seeds is provided. (author)

The immune checkpoint regulator PD-L1 is a specific target for naturally occurring CD4(+) T cells

DEFF Research Database (Denmark)

Munir, Shamaila; Andersen, Gitte Holmen; Svane, Inge Marie

2013-01-01

Programmed cell death 1 ligand 1 (PD-L1) is an important regulator of T-cell responses and may consequently limit anticancer immunity. We have recently identified PD-L1-specific, cytotoxic CD8(+) T cells. In the present study, we develop these findings and report that CD4(+) helper T cells...... spontaneously recognize PD-L1. We examined the locality of a previously identified HLA-A*0201-restricted PD-L1-epitope for the presence of possible CD4(+) T-cell epitopes. Thus, we identified naturally occurring PD-L1-specific CD4(+) T cells among the peripheral blood lymphocytes of cancer patients...... and - to lesser extents - healthy donors, by means of ELISPOT assays. PD-L1-specific CD4(+) T cells appeared to be TH17 cells exhibiting an effector T-cell cytokine profile. Hence, PD-L1-specific CD4(+) T cells released interferon γ (IFNγ), tumor necrosis factor α (TNFα) and interleukin-17 (IL-17) in response...

Unraveling the reaction mechanism on nitrile hydration catalyzed by [Pd(OH2)4]2+: insights from theory.

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Tílvez, Elkin; Menéndez, María I; López, Ramón

2013-07-01

Density functional theory methodologies combined with continuum and discrete-continuum descriptions of solvent effects were used to investigate the [Pd(OH2)4](2+)-catalyzed acrylonitrile hydration to yield acrylamide. According to our results, the intramolecular hydroxide attack mechanism and the external addition mechanism of a water molecule with rate-determining Gibbs energy barriers in water solution of 27.6 and 28.3 kcal/mol, respectively, are the most favored. The experimental kinetic constants of the hydration started by hydroxide, k(OH), and water, k(H2O), attacks for the cis-[Pd(en)(OH2)2](2+)-catalyzed dichloroacetonitrile hydration rendered Gibbs energy barriers whose energy difference, 0.7 kcal/mol, is the same as that obtained in the present study. Our investigation reveals the nonexistence of the internal attack of a water ligand for Pd-catalyzed nitrile hydration. At the low pHs used experimentally, the equilibrium between [Pd(OH2)3(nitrile)](2+) and [Pd(OH2)2(OH)(nitrile)](+) is completely displaced to [Pd(OH2)3(nitrile)](2+). Experimental studies in these conditions stated that water acts as a nucleophile, but they could not distinguish whether it was a water ligand, an external water molecule, or a combination of both possibilities. Our theoretical explorations clearly indicate that the external water mechanism becomes the only operative one at low pHs. On the basis of this mechanistic proposal it is also possible to ascribe an (1)H NMR signal experimentally detected to the presence of a unidentate iminol intermediate and to explain the influence of nitrile concentration reported experimentally for nitriles other than acrylonitrile in the presence of aqua-Pd(II) complexes. Therefore, our theoretical point of view on the mechanism of nitrile hydration catalyzed by aqua-Pd(II) complexes can shed light on these relevant processes at a molecular level as well as afford valuable information that can help in designing new catalysts in milder and more

Mitochondrial Calcium Dysregulation Contributes to Dendrite Degeneration Mediated by PD/LBD-Associated LRRK2 Mutants.

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Verma, Manish; Callio, Jason; Otero, P Anthony; Sekler, Israel; Wills, Zachary P; Chu, Charleen T

2017-11-15

Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to development of late-onset familial Parkinson's disease (PD), with clinical features of motor and cognitive dysfunction indistinguishable from sporadic PD. Calcium dysregulation plays an important role in PD pathogenesis, but the mechanisms of neurodegeneration remain unclear. Recent reports indicate enhanced excitatory neurotransmission in cortical neurons expressing mutant LRRK2, which occurs before the well-characterized phenotype of dendritic shortening. As mitochondria play a major role in the rapid buffering of cytosolic calcium, we hypothesized that altered mitochondrial calcium handling contributes to dendritic retraction elicited by the LRRK2-G2019S and -R1441C mutations. In primary mouse cortical neurons, we observed increased depolarization-induced mitochondrial calcium uptake. We found that expression of mutant LRRK2 elicited transcriptional upregulation of the mitochondrial calcium uniporter (MCU) and the mitochondrial calcium uptake 1 protein (MICU1) with no change in levels of the mitochondrial calcium antiporter NCLX. Elevated MCU and MICU1 were also observed in LRRK2-mutated patient fibroblasts, along with increased mitochondrial calcium uptake, and in postmortem brains of sporadic PD/PDD patients of both sexes. Transcriptional upregulation of MCU and MICU1 was caused by activation of the ERK1/2 (MAPK3/1) pathway. Inhibiting ERK1/2 conferred protection against mutant LRRK2-induced neurite shortening. Pharmacological inhibitors or RNAi knockdown of MCU attenuated mitochondrial calcium uptake and dendritic/neuritic shortening elicited by mutant LRRK2, whereas expression of a constitutively active mutant of NCLX that enhances calcium export from mitochondria was neuroprotective. These data suggest that an increased susceptibility to mitochondrial calcium dysregulation contributes to dendritic injury in mutant LRRK2 pathogenesis. SIGNIFICANCE STATEMENT Cognitive dysfunction and dementia are

Delusional Jealousy (Othello Syndrome) in 67 Patients with Parkinson’s Disease

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Kataoka, Hiroshi; Sugie, Kazuma

2018-01-01

Othello syndrome (OS) is a type of paranoid delusional jealousy, characterized by the false absolute certainty of the infidelity of a partner. Because OS has infrequently occurred in patients with Parkinson’s disease (PD), the characteristics of OS in PD remain unclear. We reviewed the clinical characteristics of this syndrome in PD. We reviewed 67 patients who had PD with OS. OS was more common in men (45 patients) than in women (22 patients), and it frequently occurred in middle-aged patients. Until the onset of OS, the duration of PD (range, 2–19.8 years) and the duration of treatment with PD medications (range, 2 months to 18.5 years) varied. At the onset of OS, cognition was preserved in most patients. 42 of 47 patients had other psychiatric disorders in addition to OS, and 5 patients had isolated OS. Persecutory or other paranoid delusions developed in 34 patients with OS. OS was associated with PD medication in 25 of 26 patients, especially in patients, used the dopamine agonists. The dose of the PD medication associated with OS was decreased or these drugs were withdrawn to facilitate the treatment of OS. In most patients, OS disappeared or the severity of OS was reduced. OS is infrequent in patients with PD, but is likely to be easily detected because OS is commonly accompanied by persistent paranoid and sexual delusions. When clinicians encounter such patients, the withdrawal or reduction of dopamine agonists should be attempted, and if necessary, additional treatment with clozapine is recommended. PMID:29563893

Delusional Jealousy (Othello Syndrome in 67 Patients with Parkinson’s Disease

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Hiroshi Kataoka

2018-03-01

Full Text Available Othello syndrome (OS is a type of paranoid delusional jealousy, characterized by the false absolute certainty of the infidelity of a partner. Because OS has infrequently occurred in patients with Parkinson’s disease (PD, the characteristics of OS in PD remain unclear. We reviewed the clinical characteristics of this syndrome in PD. We reviewed 67 patients who had PD with OS. OS was more common in men (45 patients than in women (22 patients, and it frequently occurred in middle-aged patients. Until the onset of OS, the duration of PD (range, 2–19.8 years and the duration of treatment with PD medications (range, 2 months to 18.5 years varied. At the onset of OS, cognition was preserved in most patients. 42 of 47 patients had other psychiatric disorders in addition to OS, and 5 patients had isolated OS. Persecutory or other paranoid delusions developed in 34 patients with OS. OS was associated with PD medication in 25 of 26 patients, especially in patients, used the dopamine agonists. The dose of the PD medication associated with OS was decreased or these drugs were withdrawn to facilitate the treatment of OS. In most patients, OS disappeared or the severity of OS was reduced. OS is infrequent in patients with PD, but is likely to be easily detected because OS is commonly accompanied by persistent paranoid and sexual delusions. When clinicians encounter such patients, the withdrawal or reduction of dopamine agonists should be attempted, and if necessary, additional treatment with clozapine is recommended.

Redox functionality mediated by adsorbed oxygen on a Pd oxide film over a Pd(100) thin structure: a first-principles study

International Nuclear Information System (INIS)

Kusakabe, K; Ikuno, Y k; Nagara, H; Harada, K

2009-01-01

Stable oxygen sites on a PdO film over a Pd(100) thin structure with a (√5x√5)R27 o surface unit cell are determined using the first-principles electronic structure calculations with the generalized gradient approximation. The adsorbed monatomic oxygen goes to a site bridging two twofold-coordinated Pd atoms or to a site bridging a twofold-coordinated Pd atom and a fourfold-coordinated Pd atom. Estimated reaction energies of CO oxidation by reduction of the oxidized PdO film and N 2 O reduction mediated by oxidation of the PdO film are both exothermic. Motion of the adsorbed oxygen atom between the two stable sites is evaluated using the nudged elastic band method, where an energy barrier for a translational motion of the adsorbed oxygen may become ∼0.45 eV, which is low enough to allow fluxionality of the surface oxygen at high temperatures. The oxygen fluxionality is allowed by the existence of twofold-coordinated Pd atoms on the PdO film, whose local structure has a similarity to that of Pd catalysts for the Suzuki-Miyaura cross-coupling. Although NO x (including NO 2 and NO) reduction is not always catalyzed by the PdO film only, we conclude that continual redox reactions may happen mediated by oxygen-adsorbed PdO films over a Pd surface structure, when the influx of NO x and CO continues, and when the reaction cycle is kept on a well-designed oxygen surface.

Olfactory training in patients with Parkinson's disease.

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Antje Haehner

Full Text Available OBJECTIVE: Decrease of olfactory function in Parkinson's disease (PD is a well-investigated fact. Studies indicate that pharmacological treatment of PD fails to restore olfactory function in PD patients. The aim of this investigation was whether patients with PD would benefit from "training" with odors in terms of an improvement of their general olfactory function. It has been hypothesized that olfactory training should produce both an improved sensitivity towards the odors used in the training process and an overall increase of olfactory function. METHODS: We recruited 70 subjects with PD and olfactory loss into this single-center, prospective, controlled non-blinded study. Thirty-five patients were assigned to the olfactory training group and 35 subjects to the control group (no training. Olfactory training was performed over a period of 12 weeks while patients exposed themselves twice daily to four odors (phenyl ethyl alcohol: rose, eucalyptol: eucalyptus, citronellal: lemon, and eugenol: cloves. Olfactory testing was performed before and after training using the "Sniffin' Sticks" (thresholds for phenyl ethyl alcohol, tests for odor discrimination, and odor identification in addition to threshold tests for the odors used in the training process. RESULTS: Compared to baseline, trained PD patients experienced a significant increase in their olfactory function, which was observed for the Sniffin' Sticks test score and for thresholds for the odors used in the training process. Olfactory function was unchanged in PD patients who did not perform olfactory training. CONCLUSION: The present results indicate that olfactory training may increase olfactory sensitivity in PD patients.

Transfer of allogeneic CD4+ T cells rescues CD8+ T cells in anti-PD-L1–resistant tumors leading to tumor eradication

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Arina, Ainhoa; Karrison, Theodore; Galka, Eva; Schreiber, Karin; Weichselbaum, Ralph R.; Schreiber, Hans

2017-01-01

Adoptively transferred CD8+ T cells can stabilize the size of solid tumors over long periods of time by exclusively recognizing antigen cross-presented on tumor stroma. However, these tumors eventually escape T cell–mediated growth control. The aim of this study was to eradicate such persistent cancers. In our model, the SIYRYYGL antigen is expressed by cancer cells that lack the MHC-I molecule Kb needed for direct presentation, but the antigen is picked up and cross-presented by tumor stroma. A single injection of antigen-specific 2C CD8+ T cells caused long-term inhibition of tumor growth, but without further intervention, tumors started to progress after approximately 3 months. Escape was associated with reduced numbers of circulating 2C cells. Tumor-infiltrating 2C cells produced significantly less TNFα and expressed more of the “exhaustion” markers PD-1 and Tim-3 than T cells from lymphoid organs. High-dose local ionizing radiation, depletion of myeloid-derived suppressor cells, infusions of additional 2C cells, and antibodies blocking PD-L1 did not prevent tumor escape. In contrast, adoptive transfer of allogeneic CD4+ T cells restored the numbers of circulating Ag-specific CD8+ T cells and their intratumoral function, resulting in tumor eradication. These CD4+ T cells had no antitumor effects in the absence of CD8+ T cells and recognized the alloantigen cross-presented on tumor stroma. CD4+ T cells might also be effective in cancer patients when PD1/PD-L1 blockade does not rescue intratumoral CD8+ T-cell function and tumors persist. PMID:28077434

Nanostructure analysis of friction welded Pd-Ni-P/Pd-Cu-Ni-P metallic glass interface

International Nuclear Information System (INIS)

Ohkubo, T.; Shoji, S.; Kawamura, Y.; Hono, K.

2005-01-01

Friction welded Pd 40 Ni 40 P 20 /Pd 40 Cu 30 Ni 10 P 20 metallic glass interface has been characterized by energy filtering transmission electron microscopy. The interface is fully amorphous with a gradual compositional change of Cu and Ni in the range of 30 nm. By annealing above T g , the interdiffusion of Cu and Ni progressed in the supercooled liquid region, and the crystallization occurred from the Pd 40 Ni 40 P 20 glass

Qualitative Characteristics of Depression in Parkinson's Patients and Controls.

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Kritzinger, Cleo; Vollstedt, Eva-Juliane; Hückelheim, Katja; Lorwin, Anne; Graf, Julia; Tunc, Sinem; Klein, Christine; Kasten, Meike

2015-01-01

Depression is common in Parkinson's disease (PD); in light of typical PD pathology it may differ phenomenologically from depression in the general population. To assess depressive symptoms in PD patients and control groups and compare symptom profiles. After postal screening of 10,000 citizens of Lübeck, 642 participants were examined and the Beck Depression Inventory (BDI) was sufficiently answered by 477 subjects. Based on motor examinations, we distinguished PD patients, Healthy Controls (HC, no motor impairment), and Disease Controls (DC, motor impairment other than PD). The sample comprised 331 men and 311 women, aged 65 ± 8 years. Out of the overall sample, 198 (41.5%) had a BDI score ≥9. BDI results above 9 points occurred in 34.5% of HC, 50.3% of DC, and 42.4% of PD patients. Compared to the control groups (HC, DC) the PD patients endorsed more "dissatisfaction" and "loss of appetite" but less "feelings of guilt," "self-hate," and "loss of libido." Depressive symptoms are more frequent in PD patients compared to HC but not DC. Interestingly, the distribution of individual symptoms of the BDI differs between groups with an emphasis on loss of pleasure/enjoyment in the PD group, a symptom typically considered to be dopaminergically transmitted.

Potential of Diffusion Tensor Imaging and Relaxometry for the Detection of Specific Pathological Alterations in Parkinson's Disease (PD.

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Regina Esterhammer

Full Text Available The purpose of the present study was to evaluate the potential of multimodal MR imaging including mean diffusivity (MD, fractional anisotropy (FA, relaxation rates R2 and R2* to detect disease specific alterations in Parkinson's Disease (PD. We enrolled 82 PD patients (PD-all with varying disease durations (≤5 years: PD≤5, n = 43; >5 years: PD>5, n = 39 and 38 matched healthy controls (HC, receiving diffusion tensor imaging as well as R2 and R2* relaxometry calculated from multi-echo T2*-weighted and dual-echo TSE imaging, respectively. ROIs were drawn to delineate caudate nucleus (CN, putamen (PU, globus pallidus (GP and substantia nigra (SN on the co-registered maps. The SN was divided in 3 descending levels (SL 1-3. The most significant parameters were used for a flexible discrimination analysis (FDA in a training collective consisting of 25 randomized subjects from each group in order to predict the classification of remaining subjects. PD-all showed significant increases in MD, R2 and R2* within SN and its subregions as well as in MD and R2* within different basal ganglia regions. Compared to the HC group, the PD≤5 and the PD>5 group showed significant MD increases within the SN and its lower two subregions, while the PD≤5 group exhibited significant increases in R2 and R2* within SN and its subregions, and tended to elevation within the basal ganglia. The PD>5 group had significantly increased MD in PU and GP, whereas the PD≤5 group presented normal MD within the basal ganglia. FDA achieved right classification in 84% of study participants. Micro-structural damage affects primarily the SN of PD patients and in later disease stages the basal ganglia. Iron contents of PU, GP and SN are increased at early disease stages of PD.

PD-L1 Expression Induced by the 2009 Pandemic Influenza A(H1N1 Virus Impairs the Human T Cell Response

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Nuriban Valero-Pacheco

2013-01-01

Full Text Available PD-L1 expression plays a critical role in the impairment of T cell responses during chronic infections; however, the expression of PD-L1 on T cells during acute viral infections, particularly during the pandemic influenza virus (A(H1N1pdm09, and its effects on the T cell response have not been widely explored. We found that A(H1N1pdm09 virus induced PD-L1 expression on human dendritic cells (DCs and T cells, as well as PD-1 expression on T cells. PD-L1 expression impaired the T cell response against A(H1N1pdm09 by promoting CD8+ T cell death and reducing cytokine production. Furthermore, we found increased PD-L1 expression on DCs and T cells from influenza-infected patients from the first and second 2009 pandemic waves in Mexico City. PD-L1 expression on CD8+ T cells correlated inversely with T cell proportions in patients infected with A(H1N1pdm09. Therefore, PD-L1 expression on DCs and T cells could be associated with an impaired T cell response during acute infection with A(H1N1pdm09 virus.

Outcomes of intradetrusor onabotulinum toxin A injection in patients with Parkinson's disease.

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Vurture, Gregory; Peyronnet, Benoit; Feigin, Andrew; Biagioni, Milton C; Gilbert, Rebecca; Rosenblum, Nirit; Frucht, Steven; Di Rocco, Alessandro; Nitti, Victor W; Brucker, Benjamin M

2018-05-16

To assess the safety and efficacy of intradetrusor onabotulinum toxin A injections for the treatment of overactive bladder (OAB) in patients with Parkinson's disease (PD). All PD patients who underwent intradetrusor injections of onabotulinum toxin A (BoNT-A) for storage symptoms between 2010 and 2017 were included in a retrospective study. A 100 U dose of BoNT-A (Botox®, Allergan Irvine, CA) was used for the first injection in all patients. The primary endpoint was clinical success defined as any subjective improvement in OAB symptoms self-assessed by the patients 4 weeks after the injections. Out of 24 patients analyzed, 19 reported improvement of their OAB symptoms 4 weeks after the first injection (79.2%) with complete resolution of urgency urinary incontinence in seven patients (29.1%; P < 0.001). The average post-void residual (PVR) increased significantly after the first injection from 17.6 to 125.3 mL (P < 0.001). Three of the patients had to start clean intermittent catheterization (CIC) after the first injection (12.5%). Out of 49 injections in total, only five caused incomplete bladder emptying requiring the use of CIC (10.2%). Higher pre-injection PVR was significantly associated with both a lower chance of symptomatic improvement (P = 0.04) and a higher risk of incomplete bladder emptying with institution of CIC (P = 0.047). Intradetrusor injections of BoNT-A 100 U appeared as a safe and effective option in PD patients with OAB symptoms and a low PVR before the injection. Higher preoperative PVR was the strongest predictor of both treatment failure and postoperative urinary retention requiring CIC. © 2018 Wiley Periodicals, Inc.

A Comparison of Treatment-Seeking Behavioral Addiction Patients with and without Parkinson’s Disease

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Anne Sauvaget

2017-11-01

Full Text Available The administration of dopaminergic medication to treat the symptoms of Parkinson’s disease (PD is associated with addictive behaviors and impulse control disorders. Little is known, however, on how PD patients differ from other patients seeking treatments for behavioral addictions. The aim of this study was to compare the characteristics of behavioral addiction patients with and without PD. N = 2,460 treatment-seeking men diagnosed with a behavioral addiction were recruited from a university hospital. Sociodemographic, impulsivity [Barratt Impulsiveness Scale (BIS-11], and personality [Temperament and Character Inventory-Revised (TCI-R] measures were taken upon admission to outpatient treatment. Patients in the PD group were older and had a higher prevalence of mood disorders than patients without PD. In terms of personality characteristics and impulsivity traits, PD patients appeared to present a more functional profile than PD-free patients with a behavioral addiction. Our results suggest that PD patients with a behavioral addiction could be more difficult to detect than their PD-free counterparts in behavioral addiction clinical setting due to their reduced levels of impulsivity and more standard personality traits. As a whole, this suggests that PD patients with a behavioral addiction may have different needs from PD-free behavioral addiction patients and that they could potentially benefit from targeted interventions.

Dynamics diffusion behaviors of Pd small clusters on a Pd(1 1 1) surface

International Nuclear Information System (INIS)

Liu, Fusheng; Hu, Wangyu; Deng, Huiqiu; He, Rensheng; Yang, Xiyuan; Lu, Kuilin; Deng, Lei; Luo, Wenhua

2010-01-01

Using molecular dynamics, nudged elastic band and modified analytic embedded atom methods, the self-diffusion dynamics properties of palladium atomic clusters up to seven atoms on the Pd (1 1 1) surface have been studied at temperatures ranging from 300 to 1000 K. The simulation time varies from 20 to 75 ns according to the cluster sizes and the temperature ranges. The heptamer and trimer are more stable than the other neighboring clusters. The diffusion coefficients of the clusters are derived from the mean square displacement of the cluster's mass-center, and the diffusion prefactors D 0 and activation energies E a are derived from the Arrhenius relation. The activation energy of the clusters increases with the increasing atom number in the clusters, especially for Pd 6 to Pd 7 . The analysis of trajectories shows the noncompact clusters diffuse by the local diffusion mechanism but the compact clusters diffuse mainly by the whole gliding mechanism, and some static energy barriers of the diffusion modes are calculated. From Pd 2 to Pd 6 , the prefactors are in the range of the standard value 10 −3  cm 2  s −1 , and the prefactor of Pd 7 cluster is 2 orders of magnitude greater than that of the single Pd adatom because of a large number of nonequivalent diffusion processes. The heptamer can be the nucleus in the room temperature range according to nucleation theory

Clinical characteristics of sleep disorders in patients with Parkinson's disease.

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Mao, Zhi-Juan; Liu, Chan-Chan; Ji, Su-Qiong; Yang, Qing-Mei; Ye, Hong-Xiang; Han, Hai-Yan; Xue, Zheng

2017-02-01

In order to investigate the sleep quality and influencing factors in patients with Parkinson's disease (PD), 201 PD patients were enrolled and underwent extensive clinical evaluations. Subjective sleep evaluation was assessed using the Pittsburgh Sleep Quality Index (PSQI), and the Epworth Sleepiness Scale (ESS). It was found that poor sleep quality (77.11%) and excessive daytime sleepiness (32.34%) were commonly seen in PD patients and positively correlated with disease severity. Then 70 out of the 201 PD patients and 70 age- and sex-matched controls underwent a polysomnographic recording. The parameters were compared between PD group and control group and the influencing factors of sleep in PD patients were analyzed. The results showed that sleep efficiency (SE) was significantly decreased (Psleep latency (SL) and the arousal index (AI) were increased (Psleep time (TST) were positively correlated with the Hoehn and Yahr (H&Y) stage. There was significant difference in the extent of hypopnea and hypoxemia between the PD group and the control group (Psleep quality and a high prevalence of sleep disorder, which may be correlated with the disease severity. Respiratory function and oxygen supply are also affected to a certain degree in PD patients.

Enhancement in anomalous Hall resistivity of Co/Pd multilayer and CoPd alloy by Ga+ ion irradiation

KAUST Repository

Guo, Zaibing

2014-02-01

In this paper, we report the effect of Ga+ ion irradiation on anomalous Hall effect (AHE) and longitudinal resistivity (ρxx) in [Co(3 Å)/Pd(5 Å)]80 multilayer and Co 42Pd58 alloy. 4- and 2-fold increases in anomalous Hall resistivity (ρAH) in the Co/Pd multilayer and CoPd alloy have been observed after irradiations at doses of 2.4 × 1015 and 3.3×10 15 ions/cm2, respectively. Skew scattering and side jump contributions to AHE have been analyzed based on the scaling relationship ρAH = aρxx + bρ2xx. For the Co/Pd multilayer, AHE is mainly affected by ion irradiation-induced interface diffusion and defects. For the CoPd alloy, the increase in doses above 1.5 × 1015 ions/cm2 induces a sign change in skew scattering, followed by the skew scattering contribution to AHE overwhelming the side jump contribution, this phenomenon should be attributed to irradiation-induced defects and modifications in chemical ordering. © Copyright EPLA, 2014.

Attachment styles in patients with avoidant personality disorder compared with social phobia.

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Eikenaes, Ingeborg; Pedersen, Geir; Wilberg, Theresa

2016-09-01

Avoidant personality disorder (AvPD) and social phobia (SP) are common, closely related conditions. Little is known about the underlying processes related to the social discomfort of subjects with AvPD and SP. Both disorders are associated with interpersonal problems. An attachment perspective may shed light on similarities and differences in close relationships between the disorders. The aim of the study was to compare self-reported attachment styles in patients with AvPD and SP. We expected that patients with AvPD would have more attachment anxiety and avoidance and more often a Fearful attachment style, compared with SP. This is a cross-sectional multisite study of 90 adult patients with AvPD and SP. Patients with AvPD with and without SP (AvPD group) were compared with patients with SP without AvPD (SP group). Patients were assessed using structured diagnostic interviews and self-reporting questionnaires, including Experiences in Close Relationships (ECR). The ECR dimensions, Anxiety and Avoidance, and the new described five factors of the ECR were used. The AvPD group had higher levels of attachment anxiety than the SP group, especially for the sub-factors Anxiety for abandonment and Separation frustration. The diagnostic groups did not differ in levels of avoidance. Anxiety for abandonment was still associated with AvPD after controlling for symptom disorders and the criteria of other personality disorders. A Fearful attachment style was more frequent among patients with AvPD. The results indicate AvPD is associated with more attachment anxiety than SP. Fear of abandonment may play a significant role in the AvPD pathology. This is the first study to compare attachment styles in patients with avoidant personality disorder (AvPD) and social phobia (SP). The AvPD group had higher attachment-related anxiety than the SP group, and anxiety was most pronounced for the fear of abandonment. Fear of abandonment may play an important role in the AvPD pathology. �