Myopathy associated with homozygous PYROXD1 pathogenic variants detected by genome sequencing

Biallelic pathogenic variants in the gene PYROXD1 have recently been described to cause early-onset autosomal recessive myopathy. Myopathy associated with PYROXD1 pathogenic variants is rare and reported in only 17 individuals. Known pathogenic variants in PYROXD1 include missense, insertion and essential splice-site variants. Here we describe a consanguineous family of individuals affected with late-onset myopathy and homozygous PYROXD1 missense variants (NM_024854.5:c.464A>G [p.Asn155Ser]) expanding our understanding of the possible disease phenotypes of PYROXD1-associated myopathy.     

Effect of CYP3A5*1 expression on tacrolimus required dose after liver transplantation: A systematic review and meta‐analysis

We systematically collected eligible data to measure the effect of CYP3A5*1 expression on personalized tacrolimus therapy. Six databases were searched for studies on adult liver transplant recipients and donors of liver graft which reported tacrolimus dose requirement, trough blood concentration, and/or concentration/dose (C/D) ratio in expressers and nonexpressers of CYP3A5*1. Eligible data were pooled by meta‐analysis. Sixteen observational studies (1309 recipients, 1044 donors of liver graft) were included in the analyses. Tacrolimus C/D ratio was lower, and the dose was higher in recipient expressers of CYP3A5*1 and/or carriers of expresser liver graft at 1‐4 weeks and 2‐4, 6, and 12 months post‐transplantation. Tacrolimus blood concentration was lower at the first two weeks. Pair expressers were affected by about twofold, and the effect was different between ethnic groups. CYP3A5*1 expression in recipients increased tacrolimus required dose by 0.023 at first, 0.022 at third, and 0.012 mg/kg/day at sixth month. Its expression in graft tissue increased tacrolimus required dose by 0.024 at first, 0.035 at third, and 0.032 mg/kg/day at sixth month. Considering CYP3A5*1 polymorphism can be helpful in individualization of tacrolimus efficient dose prior to administration, and it can remove initial high‐risk lag time (over/underdose period before reaching target blood level) at first few days post‐transplantation.     

Disrupted amygdala-prefrontal functional connectivity in civilian women with posttraumatic stress disorder

Many features of posttraumatic stress disorder (PTSD) can be linked to exaggerated and dysregulated emotional responses. Central to the neurocircuitry regulating emotion are functional interactions between the amygdala and the ventromedial prefrontal cortex (vmPFC). Findings from human and animal studies suggest that disruption of this circuit predicts individual differences in emotion regulation. However, only a few studies have examined amygdala-vmPFC connectivity in the context of emotional processing in PTSD. The aim of the present research was to investigate the hypothesis that PTSD is associated with disrupted functional connectivity of the amygdala and vmPFC in response to emotional stimuli, extending previous findings by demonstrating such links in an understudied, highly traumatized, civilian population. 40 African-American women with civilian trauma (20 with PTSD and 20 non-PTSD controls) were recruited from a large urban hospital. Participants viewed fearful and neutral face stimuli during functional magnetic resonance imaging (fMRI). Relative to controls, participants with PTSD showed an increased right amygdala response to fearful stimuli (p_corr < .05). Right amygdala activation correlated positively with the severity of hyperarousal symptoms in the PTSD group. Participants with PTSD showed decreased functional connectivity between the right amygdala and left vmPFC (p_corr < .05). The findings are consistent with previous findings showing PTSD is associated with an exaggerated response of amygdala-mediated emotional arousal systems. This is the first study to show that the amygdala response may be accompanied by disruption of an amygdala-vmPFC functional circuit that is hypothesized to be involved in prefrontal cortical regulation of amygdala responsivity.     

Perihematoma cerebral blood flow is unaffected by statin use in acute intracerebral hemorrhage patients

Statin therapy has been associated with improved cerebral blood flow (CBF) and decreased perihematoma edema in animal models of intracerebral hemorrhage (ICH). We aimed to assess the relationship between statin use and cerebral hemodynamics in ICH patients. A post hoc analysis of 73 ICH patients enrolled in the Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial (ICH ADAPT). Patients presenting <24 hours from ICH onset were randomized to a systolic blood pressure target <150 or <180 mm Hg with computed tomography perfusion imaging 2 hours after randomization. Cerebral blood flow maps were calculated. Hematoma and edema volumes were measured planimetrically. Regression models were used to assess the relationship between statin use, perihematoma edema and cerebral hemodynamics. Fourteen patients (19%) were taking statins at the time of ICH. Statin-treated patients had similar median (IQR Q25 to 75) hematoma volumes (21.1 (9.5 to 38.3) mL versus 14.5 (5.6 to 27.7) mL, P=0.25), but larger median (IQR Q25 to 75) perihematoma edema volumes (2.9 (1.7 to 9.0) mL versus 2.2 (0.8 to 3.5) mL, P=0.02) compared with nontreated patients. Perihematoma and ipsilateral hemispheric CBF were similar in both groups. A multivariate linear regression model revealed that statin use and hematoma volumes were independent predictors of acute edema volumes. Statin use does not affect CBF in ICH patients. Statin use, along with hematoma volume, are independently associated with increased perihematoma edema volume.     

Deposition of calcium salts in a case of pulmonary zygomycosis: histopathologic and chemical findings

We report a case of pulmonary zygomycosis associated with unusual deposition of calcium salt crystals. The patient was a 75-year-old female who had onset of cough and shortness of breath. She was treated for community-acquired pneumonia but died despite intensive therapy. Postmortem examination revealed diffuse alveolar damage and multifocal necrotizing pneumonia associated with herpes simplex infection and invasive zygomycosis. Birefringent particles were seen associated with fungal elements in the lung parenchyma, within bronchial cartilage, and in blood vessel walls. By infrared spectroscopy, the birefringent particles in the pulmonary parenchyma and within bronchial cartilage had spectral characteristics of calcium oxalate dihydrate and calcium oxalate monohydrate, respectively. The birefringent crystals within vascular walls were identified as calcium carbonate. This case documents the chemical composition and location of 3 different calcium salt crystals in pulmonary zygomycosis. It also shows that among pulmonary fungal infections, calcium oxalate deposition is not restricted to aspergillosis.     

Genome expression analysis by suppression subtractive hybridization identified overexpression of Humanin, a target gene in gastric cancer chemoresistance

Background

In cancer cells, apoptosis is an important mechanism that influences the outcome of chemotherapy and the development of chemoresistance. To find the genes involved in chemoresistance and the development of gastric cancer, we used the suppression subtractive hybridization method to identify the genes that are overexpressed in gastric cancer tissues compared to normal gastric tissues.

Results

In the suppression subtractive hybridization library we constructed, the most highly overexpressed genes were humanin isoforms. Humanin is a recently identified endogenous peptide that has anti-apoptotic activity and has been selected for further study due to its potential role in the chemoresistance of gastric cancer. Upregulation of humanin isoforms was also observed in clinical samples by using quantitative real-time PCR. Among the studied isoforms, humanin isoform 3, with an expression level of 4.166 ± 1.44 fold, was the most overexpressed isoform in GC.

Conclusions

The overexpression of humanin in gastric cancer suggests a role for chemoresistance and provides new insight into the biology of gastric cancer. We propose that humanin isoforms are novel targets for combating chemoresistance in gastric cancer.     

Mitigation of Methimazole-Induced Hepatic Injury by Taurine in Mice

Methimazole is the most widely prescribed antithyroid medication in humans. However, hepatotoxicity is a deleterious adverse effect associated with methimazole administration. No specific protective agent has been developed against this complication yet. This study was designed to investigate the role of taurine as a hepatoprotective agent against methimazole-induced liver injury in mice. Different reactive metabolites were proposed to be responsible for methimazole hepatotoxicity. Hence, methimazole-induced liver injury was investigated in intact and/or enzyme-induced animals in the current investigation. Animals were treated with methimazole (200 mg/kg, by gavage), and hepatic injury induced by this drug was investigated in intact and/or enzyme-induced groups. Markers such as lipid peroxidation, hepatic glutathione content, alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in plasma, and histopathological changes in the liver of animals were monitored after drug administration. Methimazole caused liver injury as revealed by increased plasma ALT. Furthermore, a significant amount of lipid peroxidation was detected in the drug-treated animals, and hepatic glutathione reservoirs were depleted. Methimazole-induced hepatotoxicity was more severe in enzyme-induced mice. The above-mentioned alterations in hepatotoxicity markers were endorsed by significant histopathological changes in the liver. Taurine administration (1 g/kg, i.p.) effectively alleviated methimazole-induced liver injury in both intact and/or enzyme-induced animals.     

Cyproterone acetate-loaded nanostructured lipid carriers: effect of particle size on skin penetration and follicular targeting

Cyproterone acetate (CPA) is used to treat various skin disorders such as acne, hirsutism, and alopecia. Due to the limited skin penetration of CPA, nanostructured lipid carriers (NLCs) with different size ranges were considered in this study in order to enhance skin penetration and to target hair follicles. Drug loading, drug release and morphological assessment were evaluated for each targeted size (100, 300, and 600?nm). Ex vivo skin penetration was also investigated using Franz diffusion cells. Finally, in vivo follicular targeting was evaluated using rhodamine B-loaded micro and nanoparticles. Results revealed that 60–85% of drug was slowly released from lipid nanoparticles within 72?h. CPA-NLC with average diameter of 600?nm had better penetration and deposition in dermis-epidermis layer, also CPA-NLC 100 and 300?nm significantly increased drug penetration in dermis-epidermis in comparison to free CPA. Follicular targeting results revealed that NLC 300?nm had the best accumulation capacity in hair follicles. CPA-NLC with average diameter of 300?nm could be a promising topical novel drug delivery system for specific targeting of hair follicles and sebaceous glands to treat androgenic skin disorders such as acne, hirsutism, and alopecia.     

Inhibition of lipolysis improves insulin sensitivity in protease inhibitor-treated HIV-infected men with fat redistribution

BACKGROUND: Fatty acid concentrations are increased in patients with HIV and fat redistribution and may contribute to insulin resistance in this population. OBJECTIVE: We determined the effects of acute inhibition of lipolysis on insulin sensitivity in HIV-infected patients with fat redistribution who were receiving a protease inhibitor. DESIGN: Seven HIV-infected men [age: 45 +/- 2 y; body mass index (in kg/m(2)): 28.8 +/- 1.9] with a fasting insulin concentration > or= 104 pmol/L (15 micro IU/mL), combined visceral adiposity and peripheral lipoatrophy, and receiving a protease inhibitor were studied. Tolbutamide-modified frequently sampled intravenous-glucose-tolerance tests (FSIGTTs) were performed after randomized double-blind administration of acipimox (500 mg at -90 and 0 min), a potent inhibitor of lipolysis, and placebo. The subjects completed 2 FSIGTTs separated by 3-7 d. RESULTS: At baseline, fasting insulin and fatty acid concentrations were 27.6 +/- 5.0 micro IU/mL and 0.83 +/- 0.08 mmol/L (normal range: 0.1-0.6 mmol/L), respectively. Fatty acid concentrations were significantly reduced after acipimox compared with placebo (fatty acid area under the curve: acipimox = 73 +/- 8 compared with placebo = 122 +/- 12 mmol x 270 min/L, P = 0.002). Acipimox treatment resulted in a significant increase in the insulin sensitivity index (acipimox = 1.63 +/- 0.5 compared with placebo = 0.88 +/- 0.3 x 10(-4) x min(-1) x micro IU/mL, P = 0.015). CONCLUSIONS: Acute inhibition of lipolysis and reduction in fatty acid concentrations are associated with improved insulin sensitivity in patients with HIV lipodystrophy and hyperinsulinemia. Further studies are needed to determine whether long-term antilipolytic strategies to reduce fatty acid concentrations may be useful in treating the metabolic disturbances associated with HIV lipodystrophy.