Effect of cadmium on thyroid function in sheep

The objective of this experiment was to determine the effect of long-term low-dose administration of cadmium on thyroid function in sheep. In this experiment, ten healthy Iranian male sheep, aged about 1 year old, were randomly allocated into two equal groups of control (n = 5) and experiment (n = 5). Both groups were kept under the same conditions of food and environment. Treatment group received cadmium chloride (1 mg/kg/day) orally for 8 weeks. Blood sampling of two groups was done on days 0, 14, 28, 42, 56, and 70 every morning (8 to 9 a.m.). The function of the thyroid was evaluated by measuring the levels of serum thyroid hormones T3, T4, FT3, FT4, and TSH. The hepatic function in both groups was evaluated by measuring hepatic enzyme activities including alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ glutamyl transferase (GGT), and total bilirubin (TBIL). Serum levels of T3, T4, FT3, FT4, and TSH significantly decreased in cadmium-treated sheep when compared to control group (p < 0.05). Serum enzyme activities of ALT, AST, GGT, and TBIL in Cd-treated sheep were significantly increased in comparison with control group (p < 0.05). Our findings suggest that Cd-exposed sheep can be at a risk of low thyroid function.     

The integration of higher order form and motion by the human brain

Our experience with a dynamic environment has tuned our visual system to use form and motion as complementary sources of information for object recognition. To identify the neural systems involved in integrating form and motion information during dynamic object processing, we used an fMRI adaptation paradigm which factorially manipulated form and motion repetition. Observers were sequentially presented with pairs of rotating novel objects in which the form or rotation direction in depth could be repeated. They were required to discriminate either dimension of the second target object, while the first object served as a form and/or motion prime. At the behavioural level, observers were faster to recognize the target or discriminate its direction when primed by the same form. Importantly, this form priming effect was enhanced when prime and target objects rotated in the same direction. At the neural level, the two priming effects (i.e., the main effect of form repetition and the interaction between form and motion repetition) were associated with reduced activations in distinct brain regions. Bilateral lateral occipital regions exhibited reduced activation when form was repeated irrespective of rotation direction. In contrast, bilateral anterior fusiform and posterior middle temporal regions (overlapping with hMT+/V5) regions showed an adaptation effect that depended on both form and motion direction. Thus, the current results reveal a visual processing hierarchy with lateral occipito-temporal cortex representing an object's 3D structure, and anterior fusiform and posterior middle temporal regions being involved in spatio-temporal integration of form and motion during dynamic object processing.     

Clinically suspected myocarditis in COVID‐19 patients: Case series and review of the literature

This Study describes eleven patients positive for severe acute respiratory syndrome coronavirus 2. In our cases, females and younger patients developed more severe disease. In contrast, improvement in left ventricular ejection fraction and N‐terminal prohormone brain natriuretic peptide within the first week of treatment contributed to promising outcomes.     

Evaluation of drug‐drug interaction potential between omecamtiv mecarbil and rosuvastatin,a BCRP substrate,with a clinical study in healthy subjects and using a physiologically‐based pharmacokinetic model

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure. In vitro, OM is an inhibitor of BCRP. Rosuvastatin, a BCRP substrate, is one of the most commonly prescribed medications in patients with heart failure. The potential for a pharmacokinetic (PK) drug‐drug interaction (DDI) was investigated, specifically to determine whether a single 50 mg dose of OM would impact the PKs of a single 10 mg dose of rosuvastatin in an open‐label study in 14 healthy subjects. The ratios of the geometric least‐square means (90% confidence intervals [CIs]) of rosuvastatin co‐administered with OM compared to rosuvastatin alone were 127.1% (90% CI 113.8–141.9), 132.8% (90% CI 120.7–146.1), and 154.2% (90% CI 132.8–179.1) for area under the plasma‐concentration time curve from time zero to infinity (AUC_inf), area under the plasma‐concentration time curve from time zero to time of last quantifiable concentration (AUC_last), and maximum observed plasma concentration (C_max), respectively. Whereas the DDI study with rosuvastatin was conducted with the co‐administration of a single dose of OM, in the clinical setting, patients receive OM at doses of 25, 37.5, or 50 mg twice daily (b.i.d.). Hence, to extrapolate the results of the DDI study to a clinically relevant scenario of continuous b.i.d. dosing with OM, physiologically‐based pharmacokinetic (PBPK) modeling was performed to explore the potential of BCRP inhibition following continuous b.i.d. dosing of OM at the highest 50 mg dose. Modeling results indicated that following 50 mg b.i.d. dosing of OM, the predicted ratios of the geometric means (90% CIs) for rosuvastatin AUC_inf and C_max were 1.18 (90% CI 1.16–1.20) and 2.04 (90% CI 1.99–2.10), respectively. Therefore, these results suggest that OM, following multiple dose administration, is a weak inhibitor of BCRP substrates and is in accordance with that observed in the single dose OM DDI clinical study.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Omecamtiv mecarbil (OM) is a cardiac myosin activator and is currently under investigation for the treatment of heart failure with reduced ejection fraction.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study investigated the drug‐drug interaction (DDI) potential of OM on the pharmacokinetics of rosuvastatin, a BCRP substrate, using a clinical study and a physiologically‐based pharmacokinetic (PBPK) modeling approach.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The clinical study and PBPK modeling analyses confirm that OM is expected to be a weak inhibitor of BCRP in the clinical setting.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study highlights the DDI potential of single doses of OM for BCRP substrates from a clinical study and demonstrates the importance of the PBPK modeling approach to investigate DDI effects following multiple doses of OM at therapeutic concentrations.     

Current complications and challenges in nonalcoholic steatohepatitis screening and diagnosis

Nonalcoholic steatohepatitis (NASH) can lead to complications such as liver failure, cirrhosis and hepatocellular carcinoma. The diagnostic gold standard for NASH is liver biopsy; however, other noninvasive methods have been developed. In this article, the authors evaluate current methods in NASH screening and diagnosis. Routine radiologic modalities were found to detect hepatic steatosis accurately, but were unable to establish the diagnosis of NASH or stage of fibrosis. Newly developed elastography based techniques seem promising to estimate liver fibrosis. Other noninvasive tests such as FibroTest, ELF, Hepascore, FIB-4, NFS, FLI and ION (biochemical panels) have AUROCs ranging between 0.80–0.98 for detecting advanced fibrosis but lack specificity for detecting mild fibrosis. Noninvasive tools, especially elastography, identify NASH associated advanced fibrosis potentially reducing liver biopsies. More research is needed to validate the clinical utility of these tests.     

Reconstitution of dendritic and natural killer-cell subsets after allogeneic stem cell transplantation: effects of endogenous flt3 ligand

Recovery of dendritic cells (DCs) and natural killer (NK) cells after allogeneic stem cell transplantation (SCT) is important for allograft responses and antitumor immunity and thus for treatment outcome. Regulation of this regenerative process is not well understood. We investigated the influence of endogenous cytokines on the recovery and diversification of DC and NK cell subsets up to 6 months after SCT. Reconstitution of circulating DCs and NK cells was rapid but accompanied by prolonged skewing of cell subsets. The speed of recovery of CD11c(+)CD123(low) DC1 exceeded that of CD11c(-) CD123(+) DC2, and correlated with plasma levels of flt3 ligand (FL), but not with granulocyte or granulocyte-macrophage colony-stimulating factors and stem cell factor. There was a 5-fold increase in interferon-gamma-producing CD56(high)CD16(-)/low NK cells and a corresponding reduction in the CD56(low)CD16(high) subset, accompanied by strongly reduced NK cell cytotoxicity. In vitro data implicate an inhibitory effect of cyclosporin A on NK cell differentiation and cytotoxicity. NK cell numbers did not correlate with plasma levels of FL or interleukin 15. Our results demonstrate that endogenous FL has distinct effects on the kinetics of reconstitution of DCs and NK cells and have potential implications for the modulation of immune responses after allogeneic SCT.     

Correlation between incidental fat deposition in the liver and pancreas in asymptomatic individuals

Abdominal Radiology - To explore the utility of two different fat quantification methods in the liver and pancreas and to test the accuracy of multi-echo Dixon as a single sequence in detecting...