Protective adaptation of low serum triiodothyronine in patients with chronic renal failure

Protective adaptation of low serum triiodothyronine in patients with chronic renal failure. Low serum triiodothyronine (T3) concentration is frequently found in patients with chronic renal failure (CRF). To test the hypothesis that this may serve to minimize protein catabolism in these patients, we measured nitrogen balance (Nb) in seven CRF and four control subjects in the basal state and when serum T3 concentration was elevated by L-triiodothyronine (LT3) and suppressed by sodium ipodate administration. In the basal state, both the controls and the CRF patients were in positive Nb, 0.02 ± 0.51 and 0.58 ± 0.34 g/day, respectively. During LT3 administration, Nb decreased to -0.80 ± 0.39 g/day in the CRF patients (P < 0.01), but remained positive, 0.22 ± 0.67 g/day, in the controls. There was a significant negative correlation between serum T3 concentration and Nb in the CRF patients (r = -0.63, P < 0.005), but not in the controls. Furthermore, urea nitrogen generation rate, calculated from urea kinetics, increased from a baseline of 4.6 ± 0.55 to 6.0 ± 0.50 mg/min during LT3 administration in the CRF patients (P < 0.01). Sodium ipodate, which significantly lowered serum T3 concentrations, had little effect on nitrogen metabolism in the controls and the CRF patients. These data support the concept that low serum T3 concentrations may confer a protective effect on CRF patients regarding protein-nitrogen conservation and provide a rationale for not correcting such deficiency

Cycler adequacy and prescription data in a national cohort sample: The 1997 core indicators report

Cycler adequacy and prescription data in a national cohort sample: The 1997 core indicators report.BackgroundThe Health Care Financing Administration Peritoneal Dialysis Core Indicator Project obtains data yearly in four areas of patient care: dialysis adequacy, anemia, blood pressure, and nutrition.MethodsAdequacy and dialysis prescription data were obtained using a standardized data abstraction form from a random sample of adult U.S. peritoneal dialysis patients who were alive on December 31, 1996.ResultsFor the cohort receiving cycler dialysis, 22% were unable to meet the National Kidney Foundation Dialysis Outcome Quality Initiatives (NKF-DOQI) dialysis adequacy guidelines because they did not have at least one adequacy measure during the six-month period of observation. Thirty-six percent of patients met NKF-DOQI guidelines for weekly Kt/V urea, 33% met guidelines for weekly creatinine clearance (CCr), and 24% met guidelines for both urea and creatinine clearances. The mean weekly adequacy values were 2.24 ± 0.56 for Kt/V urea and 67.5 ± 24.4 liter/1.73m2 for CCr, and the median values were 2.20 and 62.25 liter/1.73m2, respectively. The mean prescribed 24-hour volume was 12,040 ± 3255 ml, and the median prescribed volume was 11,783ml. Only 60% of patients were prescribed at least one daytime dwell. By logistic regression analysis, risk factors for an inadequate dose of dialysis included being in the highest quartile of body surface area (odds ratio = 3.3 for CCr and 3.4 for Kt/V urea) and a duration of dialysis greater than two years (odds ratio = 4.2 for CCr and 2.1 for Kt/V urea).ConclusionThere is much room for improvement in providing an adequate dose of dialysis to cycler patients. Practitioners should be more aggressive in increasing dwell volumes, adding daytime dwells, and adjusting nighttime dwell times in order to compensate for the loss of residual renal function over time. These changes can only be accomplished if practitioners measure periodically the dose of dialysis as outlined in the NKF-DOQI guidelines

The TREAT-NMD advisory committee for therapeutics (TACT): an innovative de-risking model to foster orphan drug development

Despite multiple publications on potential therapies for neuromuscular diseases (NMD) in cell and animal models only a handful reach clinical trials. The ability to prioritise drug development according to objective criteria is particularly critical in rare diseases with large unmet needs and a limited numbers of patients who can be enrolled into clinical trials. TREAT-NMD Advisory Committee for Therapeutics (TACT) was established to provide independent and objective guidance on the preclinical and development pathway of potential therapies (whether novel or repurposed) for NMD. We present our experience in the establishment and operation of the TACT. TACT provides a unique resource of recognized experts from multiple disciplines. The goal of each TACT review is to help the sponsor to position the candidate compound along a realistic and well-informed plan to clinical trials, and eventual registration. The reviews and subsequent recommendations are focused on generating meaningful and rigorous data that can enable clear go/no-go decisions and facilitate longer term funding or partnering opportunities. The review process thereby acts to comment on viability, de-risking the process of proceeding on a development programme. To date TACT has held 10 review meeting and reviewed 29 program applications in several rare neuromuscular diseases: Of the 29 programs reviewed, 19 were from industry and 10 were from academia; 15 were for novel compounds and 14 were for repurposed drugs; 16 were small molecules and 13 were biologics; 14 were preclinical stage applications and 15 were clinical stage applications. 3 had received Orphan drug designation from European Medicines Agency and 3 from Food and Drug Administration. A number of recurrent themes emerged over the course of the reviews and we found that applicants frequently require advice and education on issues concerned with preclinical standard operating procedures, interactions with regulatory agencies, formulation, repurposing, clinical trial design, manufacturing and ethics. Over the 5 years since its establishment TACT has amassed a body of experience that can be extrapolated to other groups of rare diseases to improve the community's chances of successfully bringing new rare disease drugs to registration and ultimately to marke

Taking Up Offenses: Secondhand Forgiveness and Group Identification

When a person or group is mistreated, those not directly harmed by the transgression might still experience antipathy toward offenders, leading to secondhand forgiveness dynamics similar to those experienced by firsthand victims. Three studies examine the role of social identification in secondhand forgiveness. Study 1 shows that the effects of apologies on secondhand victims are moderated by level of identification with the wronged group. Study 2 shows that identification with the United States was associated with less forgiveness and greater blame and desire for retribution directed at the 9/11 terrorists, and these associations were primarily mediated by anger. Finally, Study 3 shows that participants whose assimilation needs were primed were less forgiving toward the perpetrators of an assault on ingroup members than participants whose differentiation needs were primed, an effect that was mediated by empathy for the victims.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Directed Evolution of a Selective and Sensitive Serotonin Sensor via Machine Learning

Serotonin plays a central role in cognition and is the target of most pharmaceuticals for psychiatric disorders. Existing drugs have limited efficacy; creation of improved versions will require better understanding of serotonergic circuitry, which has been hampered by our inability to monitor serotonin release and transport with high spatial and temporal resolution. We developed and applied a binding-pocket redesign strategy, guided by machine learning, to create a high-performance, soluble, fluorescent serotonin sensor (iSeroSnFR), enabling optical detection of millisecond-scale serotonin transients. We demonstrate that iSeroSnFR can be used to detect serotonin release in freely behaving mice during fear conditioning, social interaction, and sleep/wake transitions. We also developed a robust assay of serotonin transporter function and modulation by drugs. We expect that both machine-learning-guided binding-pocket redesign and iSeroSnFR will have broad utility for the development of other sensors and in vitro and in vivo serotonin detection, respectively

Eradication of Metastatic Renal Cell Carcinoma after Adenovirus-Encoded TNF-Related Apoptosis-Inducing Ligand (TRAIL)/CpG Immunotherapy

Despite evidence that antitumor immunity can be protective against renal cell carcinoma (RCC), few patients respond objectively to immunotherapy and the disease is fatal once metastases develop. We asked to what extent combinatorial immunotherapy with Adenovirus-encoded murine TNF-related apoptosis-inducing ligand (Ad5mTRAIL) plus CpG oligonucleotide, given at the primary tumor site, would prove efficacious against metastatic murine RCC. To quantitate primary renal and metastatic tumor growth in mice, we developed a luciferase-expressing Renca cell line, and monitored tumor burdens via bioluminescent imaging. Orthotopic tumor challenge gave rise to aggressive primary tumors and lung metastases that were detectable by day 7. Intra-renal administration of Ad5mTRAIL+CpG on day 7 led to an influx of effector phenotype CD4 and CD8 T cells into the kidney by day 12 and regression of established primary renal tumors. Intra-renal immunotherapy also led to systemic immune responses characterized by splenomegaly, elevated serum IgG levels, increased CD4 and CD8 T cell infiltration into the lungs, and elimination of metastatic lung tumors. Tumor regression was primarily dependent upon CD8 T cells and resulted in prolonged survival of treated mice. Thus, local administration of Ad5mTRAIL+CpG at the primary tumor site can initiate CD8-dependent systemic immunity that is sufficient to cause regression of metastatic lung tumors. A similar approach may prove beneficial for patients with metastatic RCC

EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0–49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease

Optically active histidin-2-ylidene stabilised gold nanoparticles

Drawing from the natural amino acid chiral pool, L and D histidines were utilized as chiral NHC ligands in the synthesis of NHC-stabilized chiroptical gold nanoparticles. Centrifugal size selection afforded monodisperse gold nanoparticles which display mirrored signals in CD spectroscopy