Assessment of the Effect of High or Low Protein Diet on the Human Urine Metabolome as Measured by NMR

The objective of this study was to identify urinary metabolite profiles that discriminate between high and low intake of dietary protein during a dietary intervention. Seventy-seven overweight, non-diabetic subjects followed an 8-week low-calorie diet (LCD) and were then randomly assigned to a high (HP) or low (LP) protein diet for 6 months. Twenty-four hours urine samples were collected at baseline (prior to the 8-week LCD) and after dietary intervention; at months 1, 3 and 6, respectively. Metabolite profiling was performed by 1H NMR and chemometrics. Using partial least squares regression (PLS), it was possible to develop excellent prediction models for urinary nitrogen (root mean square error of cross validation (RMSECV) = 1.63 mmol/L; r = 0.89) and urinary creatinine (RMSECV = 0.66 mmol/L; r = 0.98). The obtained high correlations firmly establish the validity of the metabolomic approach since urinary nitrogen is a well established biomarker for daily protein consumption. The models showed that trimethylamine-N-oxide (TMAO) is correlated to urinary nitrogen. Furthermore, urinary creatine was found to be increased by the HP diet whereas citric acid was increased by the LP diet. Despite large variations in individual dietary intake, differentiated metabolite profiles were observed at the dietary group-level

CyPPA, a Positive SK3/SK2 Modulator, Reduces Activity of Dopaminergic Neurons, Inhibits Dopamine Release, and Counteracts Hyperdopaminergic Behaviors Induced by Methylphenidate1

Dopamine (DA) containing midbrain neurons play critical roles in several psychiatric and neurological diseases, including schizophrenia and attention deficit hyperactivity disorder, and the substantia nigra pars compacta neurons selectively degenerate in Parkinson’s disease. Pharmacological modulation of DA receptors and transporters are well established approaches for treatment of DA-related disorders. Direct modulation of the DA system by influencing the discharge pattern of these autonomously firing neurons has yet to be exploited as a potential therapeutic strategy. Small conductance Ca2+-activated K+ channels (SK channels), in particular the SK3 subtype, are important in the physiology of DA neurons, and agents modifying SK channel activity could potentially affect DA signaling and DA-related behaviors. Here we show that cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA), a subtype-selective positive modulator of SK channels (SK3 > SK2 > > > SK1, IK), decreased spontaneous firing rate, increased the duration of the apamin-sensitive afterhyperpolarization, and caused an activity-dependent inhibition of current-evoked action potentials in DA neurons from both mouse and rat midbrain slices. Using an immunocytochemically and pharmacologically validated DA release assay employing cultured DA neurons from rats, we show that CyPPA repressed DA release in a concentration-dependent manner with a maximal effect equal to the D2 receptor agonist quinpirole. In vivo studies revealed that systemic administration of CyPPA attenuated methylphenidate-induced hyperactivity and stereotypic behaviors in mice. Taken together, the data accentuate the important role played by SK3 channels in the physiology of DA neurons, and indicate that their facilitation by CyPPA profoundly influences physiological as well as pharmacologically induced hyperdopaminergic behavior

In a secondary care setting, differences between neck pain subgroups classified using the Quebec task force classification system were typically small - A longitudinal study

Background: The component of the Quebec Task Force Classification System that subgroups patients based on the extent of their radiating pain and neurological signs has been demonstrated to have prognostic implications for patients with low back pain but has not been tested on patients with neck pain (NP). The main aim of this study was to examine the association between these subgroups, their baseline characteristics and outcome in chronic NP patients referred to an outpatient hospital department. Methods: This was an observational study of longitudinal data extracted from systematically collected, routine clinical data. Patients were classified into Local NP only, NP + arm pain above the elbow, NP + arm pain below the elbow, and NP with signs of nerve root involvement (NP + NRI). Outcome was pain intensity and activity limitation. Associations were tested in longitudinal linear mixed models. Results: A total of 1,852 people were classified into subgroups (64 % females, mean age 49 years). Follow ups after 3, 6 and 12 months were available for 45 %, 32 % and 40 % of those invited to participate at each time point. A small improvement in pain was observed over time in all subgroups. There was a significant interaction between subgroups and time, but effect sizes were small. The local NP subgroup improved slightly less after 3 months as compared with all other groups, but continued to have the lowest level of pain. After 6 and 12 months, those with NP + pain above the elbow had improved the least and patients with NP + NRI had experienced the largest improvements in pain intensity. Similar results were obtained for activity limitation. Conclusions: This study found baseline and outcome differences between neck pain subgroups classified using the Quebec Task Force Classification System. However, differences in outcome were typically small in size and mostly differentiated the local NP subgroup from the other subgroups. A caveat to these results is that they were obtained in a cohort of chronic neck pain patients who only displayed small improvements over time and the results may not apply to other cohorts, such as people at earlier stages of their clinical course and in other clinical settings

Animal models for COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiological agent of coronavirus disease 2019 (COVID-19), an emerging respiratory infection caused by the introduction of a novel coronavirus into humans late in 2019 (frst detected in Hubei province, China). As of 18 September 2020, SARS-CoV-2 has spread to 215 countries, has infected more than 30 million people and has caused more than 950,000 deaths. As humans do not have pre-existing immunity to SARS-CoV-2, there is an urgent need to develop therapeutic agents and vaccines to mitigate the current pandemic and to prevent the re-emergence of COVID-19. In February 2020, the World Health Organization (WHO) assembled an international panel to develop animal models for COVID-19 to accelerate the testing of vaccines and therapeutic agents. Here we summarize the fndings to date and provides relevant information for preclinical testing of vaccine candidates and therapeutic agents for COVID-19.info:eu-repo/semantics/acceptedVersio