Interventions associated with brown adipose tissue activation and the impact on energy expenditure and weight loss: A systematic review.

Background: Brown adipose tissue (BAT) plays a role in modulating energy expenditure. People with obesity have been shown to have reduced activation of BAT. Agents such as ß-agonists, capsinoids, thyroid hormone, sildenafil, caffeine, or cold exposure may lead to activation of BAT in humans, potentially modulating metabolism to promote weight loss. Methods: We systematically searched electronic databases for clinical trials testing the effect of these agents and cold exposure on energy expenditure/thermogenesis and the extent to which they may impact weight loss in adults. Results: A total of 695 studies from PubMed, Web of Science, and Medline electronic databases were identified. After the removal of duplicates and further evaluation, 47 clinical trials were analyzed. We observed significant heterogeneity in the duration of interventions and the metrics utilized to estimate thermogenesis/energy expenditure. Changes observed in energy expenditure do not correlate with major weight changes with different interventions commonly known to stimulate thermogenesis. Even though cold exposure appears to consistently activate BAT and induce thermogenesis, studies are small, and it appears to be an unlikely sustainable therapy to combat obesity. Most studies were small and potential risks associated with known side effects of some agents such as ß-agonists (tachycardia), sibutramine (hypertension, tachycardia), thyroid hormone (arrhythmias) cannot be fully evaluated from these small trials. Conclusion: Though the impact of BAT activation and associated increases in energy expenditure on clinically meaningful weight loss is a topic of great interest, further data is needed to determine long-term feasibility and efficacy.

Spinocerebellar Ataxia Type 2: Clinicogenetic Aspects, Mechanistic Insights, and Management Approaches.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant cerebellar ataxia that occurs as a consequence of abnormal CAG expansions in the ATXN2 gene. Progressive clinical features result from the neurodegeneration of cerebellum and extra-cerebellar structures including the pons, the basal ganglia, and the cerebral cortex. Clinical, electrophysiological, and imaging approaches have been used to characterize the natural history of the disease, allowing its classification into four distinct stages, with special emphasis on the prodromal stage, which is characterized by a plethora of motor and non-motor features. Neuropathological investigations of brain tissue from SCA2 patients reveal a widespread involvement of multiple brain systems, mainly cerebellar and brainstem systems. Recent findings linking ataxin-2 intermediate expansions to other neurodegenerative diseases such as amyotrophic lateral sclerosis have provided insights into the ataxin-2-related toxicity mechanism in neurodegenerative diseases and have raised new ethical challenges to molecular predictive diagnosis of SCA2. No effective neuroprotective therapies are currently available for SCA2 patients, but some therapeutic options such as neurorehabilitation and some emerging neuroprotective drugs have shown palliative benefits.

Spinocerebellar Ataxia Type 2 Is Associated with the Extracellular Loss of Superoxide Dismutase but Not Catalase Activity.

BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is an inherited and still incurable neurodegenerative disorder. Evidence suggests that pro-oxidant agents as well as factors involved in antioxidant cellular defenses are part of SCA2 physiopathology. AIM: To assess the influence of superoxide dismutase (SOD3) and catalase (CAT) enzymatic activities on the SCA2 syndrome. METHOD: Clinical, molecular, and electrophysiological variables, as well as SOD3 and CAT enzymatic activities were evaluated in 97 SCA2 patients and in 64 age- and sex-matched control individuals. RESULTS: Spinocerebellar ataxia type 2 patients had significantly lower SOD3 enzymatic activity than the control group. However, there were no differences between patients and controls for CAT enzymatic activity. The effect size for the loss of patients' SOD3 enzymatic activity was 0.342, corresponding to a moderate effect. SOD3 and CAT enzymatic activities were not associated with the CAG repeat number at the ATXN2 gene. SOD3 and CAT enzymatic activities did not show significant associations with the age at onset, severity score, or the studied electrophysiological markers. CONCLUSION: There is a reduced SOD3 enzymatic activity in SCA2 patients with no repercussion on the clinical phenotype.

LC-MS/MS quantification of next-generation biotherapeutics: a case study for an IgE binding Nanobody in cynomolgus monkey plasma.

BACKGROUND: Nanobodies(®) are therapeutic proteins derived from the smallest functional fragments of heavy chain-only antibodies. The development and validation of an LC-MS/MS-based method for the quantification of an IgE binding Nanobody in cynomolgus monkey plasma is presented. RESULTS: Nanobody quantification was performed making use of a proteotypic tryptic peptide chromatographically enriched prior to LC-MS/MS analysis. The validated LLOQ at 36 ng/ml was measured with an intra- and inter-assay precision and accuracy <20%. The required sensitivity could be obtained based on the selectivity of 2D LC combined with MS/MS. No analyte specific tools for affinity purification were used. Plasma samples originating from a PK/PD study were analyzed and compared with the results obtained with a traditional ligand-binding assay. Excellent correlations between the two techniques were obtained, and similar PK parameters were estimated. CONCLUSION: A 2D LC-MS/MS method was successfully developed and validated for the quantification of a next generation biotherapeutic.

Unexpanded and intermediate CAG polymorphisms at the SCA2 locus (ATXN2) in the Cuban population: evidence about the origin of expanded SCA2 alleles.

The role of short, large or intermediate normal alleles (ANs) of the ataxin-2 gene in generating expanded alleles (EAs) causing spinocerebellar ataxia type 2 (SCA2) is poorly understood. It has been postulated that SCA2 prevalence is related to the frequency of large ANs. SCA2 shows the highest worldwide prevalence in Cuban population, which is therefore a unique source for studying the relationship between the frequency of large and intermediate alleles and the frequency of SCA2 mutation. Through genetic polymorphism analyses in a comprehensive sample (~3000 chromosomes), we show that the frequency of large ANs in the ataxin-2 gene is the highest worldwide, although short ANs are also frequent. This highly polymorphic population displayed also high variability in the CAG sequence, featured by loss of the anchor CAA interruption(s). In addition, large ANs showed germinal and somatic instability. Our study also includes related genotypic, genealogical and haplotypic data and provides substantial evidence with regard to the role of large and intermediate alleles in the generation of pathological EAs.