Low triiodothyronine and cardiomyopathy in patients with end-stage renal disease

OBJECTIVES AND METHODS: Low free plasma triiodothyronine (fT3) is associated with inflammation and cardiovascular damage in patients with end-stage renal disease (ESRD). We investigated the relationship between fT3, left ventricular systolic function and left ventricular mass in a group of 234 dialysis patients, and modelled the association between fT3 and cardiomyopathy in statistical analyses including both direct (interleukin-6 and C-reactive protein) and inverse (serum albumin) acute phase inflammation markers. RESULTS: Plasma fT3 concentration in dialysis patients was significantly (P < 0.001) reduced in comparison with healthy participants and clinically euthyroid patients with normal renal function. Left ventricular systolic function was depressed (P 相似文献   

Neuromelanin-Sensitive Magnetic Resonance Imaging Changes in the Locus Coeruleus/Subcoeruleus Complex in Patients with Typical and Atypical Parkinsonism

Background

The locus coeruleus/subcoeruleus complex (LC/LsC) is a structure comprising melanized noradrenergic neurons.

Objective

To study the LC/LsC damage across Parkinson's disease (PD) and atypical parkinsonism in a large group of subjects.

Methods

We studied 98 healthy control subjects, 47 patients with isolated rapid eye movement sleep behavior disorder (RBD), 75 patients with PD plus RBD, 142 patients with PD without RBD, 19 patients with progressive supranuclear palsy (PSP), and 19 patients with multiple system atrophy (MSA). Twelve patients with MSA had proven RBD. LC/LsC signal intensity was derived from neuromelanin magnetic resonance imaging using automated software.

Results

The signal intensity was reduced in all parkinsonian syndromes compared with healthy control subjects, except in PD without RBD. The signal intensity decreased as age increased. Moreover, the signal intensity was lower in MSA than in isolated RBD and PD without RBD groups. In PD, the signal intensity correlated negatively with the percentage of REM sleep without atonia. There were no differences in signal intensity between PD plus RBD, PSP, and MSA.

Conclusions

Neuromelanin signal intensity was reduced in all parkinsonian disorders, except in PD without RBD. The presence of RBD in parkinsonian disorders appears to be associated with lower neuromelanin signal intensity. Furthermore, lower LC/LsC signal changes in PSP could be partly caused by the effect of age. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

The beneficial effect of interleukin‐12 on arthritis induced by group B streptococci is mediated by interferon‐γ and interleukin‐10 production

Objective

To assess the effect of interleukin‐12 (IL‐12) administration on the evolution of systemic infection and septic arthritis induced by group B streptococci (GBS) in mice.

Methods

CD1 mice were inoculated intravenously with arthritogenic strain 1/82 of type IV GBS. Exogenous murine IL‐12 was administered intraperitoneally 18 hours or 5 days after infection with 1 × 10⁷ GBS, at doses ranging from 0.5 to 2.5 μg per mouse. Mice were monitored daily for survival and for signs of arthritis. In a subsequent set of experiments, mice were killed at selected times for examination of bacterial clearance, histopathologic changes in the joints, and cytokine production.

Results

IL‐12 administration before the onset of clinical signs had a beneficial effect on GBS‐induced arthritis and was clearly dose‐dependent. The 2.5‐μg dose per mouse totally prevented death from GBS‐induced arthritis. The decrease in pathology was associated with a reduction of the bacterial burden and a change in the cytokine profile. In particular, systemic and joint levels of interferon‐γ (IFNγ) and IL‐10 significantly increased in mice treated with IL‐12, whereas a decrease in IL‐6 and IL‐1β production was observed. The beneficial effects of IL‐12, in terms of the incidence and severity of articular lesions, were reversed by coadministration of anti‐IFNγ or anti–IL‐10–neutralizing antibodies.

Conclusion

The findings of this study demonstrate that IL‐12 is important in controlling the cytokine production that leads to the evolution of GBS‐induced experimental arthritis. The amelioration of articular lesions is mostly attributable to IL‐12–induced IFNγ, but with a relevant participation of IL‐12–induced IL‐10.

     

3-[3-(Phenalkylamino)cyclohexyl]phenols: Synthesis,biological activity,and in silico investigation of a naltrexone-derived novel class of MOR-antagonists

The development of novel μ-opioid receptor (MOR) antagonists is one of the main objectives of drug discovery and development. Based on a simplified version of the morphinan scaffold, 3-[3-(phenalkylamino)cyclohexyl]phenol analogs were designed, synthesized, and evaluated for their MOR antagonist activity in vitro and in silico. At the highest concentrations, the compounds decreased by 52% to 75% DAMGO-induced GTPγS stimulation, suggesting that they acted as antagonists. Moreover, Extra-Precision Glide and Generalized-Born Surface Area experiments provided useful information on the nature of the ligand–receptor interactions, indicating a peculiar combination of C-1 stereochemistry and N-substitutions as feasibly essential for MOR–ligand complex stability. Interestingly, compound 9 showed the best experimental binding affinity, the highest antagonist activity, and the finest MOR–ligand complex stability. In silico experiments also revealed that the most promising stereoisomer (1R, 3R, 5S) 9 retained 1,3-cis configuration with phenol ring equatorial oriented. Further studies are needed to better characterize the pharmacodynamics and pharmacokinetic properties of these compounds.     

Defining the Riddle in Order to Solve It: There Is More Than One “Parkinson's Disease”

Background

More than 200 years after James Parkinsondescribed a clinical syndrome based on his astute observations, Parkinson's disease (PD) has evolved into a complex entity, akin to the heterogeneity of other complex human syndromes of the central nervous system such as dementia, motor neuron disease, multiple sclerosis, and epilepsy. Clinicians, pathologists, and basic science researchers evolved arrange of concepts andcriteria for the clinical, genetic, mechanistic, and neuropathological characterization of what, in their best judgment, constitutes PD. However, these specialists have generated and used criteria that are not necessarily aligned between their different operational definitions, which may hinder progress in solving the riddle of the distinct forms of PD and ultimately how to treat them.

Objective

This task force has identified current in consistencies between the definitions of PD and its diverse variants in different domains: clinical criteria, neuropathological classification, genetic subtyping, biomarker signatures, and mechanisms of disease. This initial effort for “defining the riddle” will lay the foundation for future attempts to better define the range of PD and its variants, as has been done and implemented for other heterogeneous neurological syndromes, such as stroke and peripheral neuropathy. We strongly advocate for a more systematic and evidence-based integration of our diverse disciplines by looking at well-defined variants of the syndrome of PD.

Conclusion

Accuracy in defining endophenotypes of “typical PD” across these different but interrelated disciplines will enable better definition of variants and their stratification in therapeutic trials, a prerequisite for breakthroughs in the era of precision medicine. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.