The enhancing effects of Biobran/MGN-3, an arabinoxylan rice bran,on healthy old adults’ health-related quality of life: a randomized,double-blind,placebo-controlled clinical trial

Quality of Life Research - The world’s older population is growing rapidly and the need to find measures to combat age-associated decline of physical, mental, and cognitive functions and...     

Neuroprotective effects of hesperetin in mouse primary neurones are independent of CREB activation

Dietary flavonoids, including the citrus flavanone hesperetin, may have stimulatory effects on cytoprotective intracellular signalling pathways. In primary mouse cortical neurone cultures, but not SH-SY5Y human neuroblastoma cells or human primary dermal fibroblasts (Promocells), hesperetin (100–300 nM, 15 min) caused significant increases in the level of ERK1/2 phosphorylation, but did not increase CREB phosphorylation. Administration of hesperetin for 18 h did not alter gene expression driven by the cyclic AMP response element (CRE), assessed using a luciferase reporter system, but 300 nM hesperetin partially reversed staurosporine-induced cell death in primary neurones. Our data show that hesperetin is a neuroprotective compound at concentrations where antioxidant effects are unlikely to predominate. The effects of hesperetin are cell-type dependent and, unlike the flavanol (−)epicatechin, neuroprotection in vitro is not associated with enhanced CREB phosphorylation or CRE-mediated gene expression.     

3D segmentation of dental crown for volumetric age estimation with CBCT imaging

International Journal of Legal Medicine - In adult dental age estimation, segmentation of dental volumetric information from different tooth parts using cone-beam computed tomography (CBCT) has...     

Application of CYP3A4 in vitro data to predict clinical drug-drug interactions; predictions of compounds as objects of interaction

AIMS

The aim of this study was to explore and optimize the in vitro and in silico approaches used for predicting clinical DDIs. A data set containing clinical information on the interaction of 20 Pfizer compounds with ketoconazole was used to assess the success of the techniques.

METHODS

The study calculated the fraction and the rate of metabolism of 20 Pfizer compounds via each cytochrome P450. Two approaches were used to determine fraction metabolized (f_m); 1) by measuring substrate loss in human liver microsomes (HLM) in the presence and absence of specific chemical inhibitors and 2) by measuring substrate loss in individual cDNA expressed P450s (also referred to as recombinant P450s (rhCYP)) The fractions metabolized via each CYP were used to predict the drug–drug interaction due to CYP3A4 inhibition by ketoconazole using the modelling and simulation software SIMCYP®.

RESULTS

When in vitro data were generated using Gentest supersomes, 85% of predictions were within two-fold of the observed clinical interaction. Using PanVera baculosomes, 70% of predictions were predicted within two-fold. In contrast using chemical inhibitors the accuracy was lower, predicting only 37% of compounds within two-fold of the clinical value. Poorly predicted compounds were found to either be metabolically stable and/or have high microsomal protein binding. The use of equilibrium dialysis to generate accurate protein binding measurements was especially important for highly bound drugs.

CONCLUSIONS

The current study demonstrated that the use of rhCYPs with SIMCYP® provides a robust in vitro system for predicting the likelihood and magnitude of changes in clinical exposure of compounds as a consequence of CYP3A4 inhibition by a concomitantly administered drug.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Numerous retrospective analyses have shown the utility of in vitro systems for predicting potential drug–drug interactions (DDIs).
• Prediction of DDIs from in vitro data is commonly obtained using estimates of enzyme K_i, inhibitor and substrate concentrations and absorption rate for substrate and inhibitor.

WHAT THIS STUDY ADDS

• Using a generic approach for all test compounds, the findings from the current study showed the use of recombinant P450s provide a more robust in vitro measure of P450 contribution (fraction metabolized, f_m) than that achieved when using chemical inhibitors in combination with human liver microsomes, for the prediction of potential CYP3A4 drug–drug interactions prior to clinical investigation.
• The current study supported the use of SIMCYP®, a modelling and simulation software in utilizing the in vitro measures in the prediction of potential drug–drug interactions.

     

Functional characterization of genetic variants in NPC1L1 supports the sequencing extremes strategy to identify complex trait genes

Resequencing genes in individuals at extremes of the population distribution constitutes a powerful and efficient strategy to identify sequence variants associated with complex traits. An excess of sequence variants at one extreme relative to the other that is not due to chance or to population stratification constitutes evidence for genetic association and implies the presence of functionally significant sequence variants. Recently, we reported that non-synonymous sequence variants in Niemann-Pick type C1-like 1 (NPC1L1), an intestinal cholesterol transporter, were significantly more common among individuals with low cholesterol absorption than in those with high cholesterol absorption. To determine whether sequence variations identified in individuals with low cholesterol absorption affect protein function, we performed studies in cultured cells and in families. Expression of the mutant proteins in Chinese hamster ovarian-K1 cells revealed that a majority (14 of 20) of the variants identified in low absorbers were associated with very low levels of NPC1L1 protein. In two extended families, mean cholesterol absorption levels, as measured using stable isotopes, were significantly lower in family members with the sequence variants than in those without the variant. These data indicate that the excess of sequence variations in individuals with extreme phenotypes reflects an enrichment of functionally significant variants. These findings are consistent with in silico predictions that some sequence variations found in healthy individuals are as deleterious to protein function as mutations that, in other genes, cause monogenic diseases. Such sequence variations may explain a significant fraction of quantitative phenotypic variation in humans.     

Retrospective study of the associations between hepatitis C virus infection and metabolic factors

AIM To evaluate the bidirectional association between metabolic syndrome(MS) components and antiviral treatment response for chronic hepatitis C virus(HCV) infection. METHODS This retrospective cohort study included 119 HCV + patients treated with pegylated-interferon-α and ribavirin. Metabolic characteristics and laboratory data were collected from medical records. Differences in baseline clinical and demographic risk factors between responders and non-responders were assessed using independent samples t-tests or χ~2 tests. The effects of sustained viral response(SVR) to antiviral treatment on de novo impairments in MS components, including impaired fasting glucose(IFG) and type 2 diabetes mellitus(T2DM), were assessed using univariable and multivariable logistic regression analysis, while the effect of MS components on SVR was assessed using univariable logistic regression analysis. RESULTS Of the 119 patients, 80(67%) developed SVR over the average 54 ± 13 mo follow-up. The cumulative risks for de novo T2DM and IFG were 5.07-(95%CI: 1.261-20.4, P = 0.022) and 3.87-fold higher(95%CI: 1.484-10.15, P = 0.006), respectively for non-responders than responders, when adjusted for the baseline risk factors age, sex, HCV genotype, high viral load, and steatosis. Post-treatment triglyceride levels were significantly lower in non-responders than in responders(OR = 0.27; 95%CI: 0.069-0.962, P = 0.044). Age and HCV genotype 3 were significantly different between responders and non-responders, and MS components were not significantly associated with SVR. Steatosis tended to attenuate SVR(OR = 0.596; 95%CI: 0.331-1.073, P = 0.08).CONCLUSION SVR was associated with lower de novo T2DM and IFG incidence and higher triglyceride levels. Patients infected with HCV should undergo T2DM screening and antidiabetic treatment.     

Enhanced Sensing Capacity of Terahertz Triple-Band Metamaterials Absorber Based on Pythagorean Fractal Geometry

A new design of a triple band perfect metamaterial absorber based on Pythagorean fractal geometry is proposed and analyzed for terahertz sensing applications. The proposed design showed an enhanced sensing performance and achieved three intensive peaks at 33.93, 36.27, and 38.39 THz, corresponding to the absorptivity of 98.5%, 99.3%, and 99.6%, respectively. Due to the symmetrical nature of the recommended design, the structure exhibited the characteristics of independency on the incident wave angles. Furthermore, a parametric study was performed to show the effects of the change in substrate type, resonator material, and substrate thickness on the absorption spectrum. At a fixed analyte thickness (0.5 μm), the resonance frequency of the design was found to be sensitive to the refractive index of the surrounding medium. The proposed design presented three ultra-sensitive responses of 1730, 1590, and 2050 GHz/RIU with the figure of merit (FoM) of 3.20, 1.54, and 4.28, respectively, when the refractive index was changed from 1.0 to 1.4. Additionally, the metamaterial sensor showed a sensitivity of 1230, 2270, and 1580 GHz/μm at the three resonance frequencies, respectively, when it was utilized for the detection of thickness variation at a fixed analyte refractive index (RI) of 1.4. As long as the RI of the biomedical samples is between 1.3 and 1.4, the proposed sensor can be used for biomedical applications.     

Reduced Gyral Window and Corpus Callosum Size in Autism: Possible Macroscopic Correlates of a Minicolumnopathy

Minicolumnar changes that generalize throughout a significant portion of the cortex have macroscopic structural correlates that may be visualized with modern structural neuroimaging techniques. In magnetic resonance images (MRIs) of fourteen autistic patients and 28 controls, the present study found macroscopic morphological correlates to recent neuropathological findings suggesting a minicolumnopathy in autism. Autistic patients manifested a significant reduction in the aperture for afferent/efferent cortical connections, i.e., gyral window. Furthermore, the size of the gyral window directly correlated to the size of the corpus callosum. A reduced gyral window constrains the possible size of projection fibers and biases connectivity towards shorter corticocortical fibers at the expense of longer association/commisural fibers. The findings may help explain abnormalities in motor skill development, differences in postnatal brain growth, and the regression of acquired functions observed in some autistic patients. Dr. Mannheim is affiliated with the Food and Drug Administration; however, this article was written in his private capacity. No official support or endorsement by the Food and Drug Administration is intended or should be inferred. This work was written as part of Judith Rumsey’s and Jay Giedd’s official duties as Government employees. The views expressed in this article do not necessarily represent the views of the National Institute of Mental Health, the National Institutes of Health, the Department of Health and Human Services, or the United States Government.     

Fulminant hepatic failure caused by Salmonella paratyphi A infection

We report a case of fulminant hepatic failure associated with Salmonella paratyphi A infection, in a 29-yearold patient who was admitted to the intensive care unit (ICU) with fever of two days, headache and vomiting followed by behavioural changes and disorientation. On examination, the patient appeared acutely ill, agitated, confused, and deeply jaundiced. Temperature 38.5℃, pulse 92/min, blood pressure 130/89 mmHg. Both samples of blood grew S. paratyphi A, which was sensitive to ceftriaxone and ciprofloxacin. Ceftriaxon was administered with high-dose dexamethasone. Two weeks after treatment with ceftriaxon, the patient was discharged in satisfactory condition.