Differential associations of sex and D2 dopamine receptor (DRD2) genotype with negative affect and other substance abuse risk markers in children of alcoholics

Children of alcoholics have increased risk for substance abuse problems. Self-medication of negative affect may be one developmental path to future substance abuse. Because the 146 young (adolescent) children of alcoholics in the current sample had not used enough abused substances to study substance use directly, the relation of substance abuse risk markers to negative affect was assessed. Because the D₂ dopamine receptor (DRD2) A₁ allele has been associated with alcoholism and other substance use disorders, negative affect, measured by the Beck Depression Inventory (BDI), was determined in four groups of children: boys and girls with the A₁⁺ allele (A₁A₁ and A₁A₂ genotypes) and with the A₁⁻ allele (A₂A₂ genotype). The other risk markers were stress, low amplitude of the P300 evoked potential, poor visuospatial functioning, novelty seeking (NS), and harm avoidance (HA). Stress was correlated with BDI scores in all groups. In contrast, low P300 was associated with BDI scores only in boys with the A₁⁺ allele (P = .04), NS was associated with BDI scores only in girls with the A₁⁺ allele (P = .02), and HA was associated with BDI scores only in boys with the A₁⁻ allele (P = .01). In addition, boys with the A₁⁺ allele had lower BDI (P = .05) and HA (P = .005) scores than the respective scores for boys with the A₁⁻ allele. Girls with the A₁⁻ allele had lower HA scores compared with scores for boys with the A₁⁻ allele (P = .02). Girls with the A₁⁺ allele had lower visuospatial functioning than that of boys with the A₁⁺ allele (P<.001). Results indicate that both sex and DRD2 genotype modify associations between negative affect and other substance abuse risk markers.     

Identification of human cytochrome P450 enzymes involved in the metabolism of IN-1130, a novel activin receptor-like kinase-5 (ALK5) inhibitor

1.?The in vitro metabolism of 3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide (IN-1130), a selective activin receptor-like kinase-5 (ALK5) inhibitor and a candidate drug for fibrotic disease, was studied.

2.?The cytochrome P450s (CYPs) responsible for metabolism of IN-1130 in liver microsomes of rat, mouse, dog, monkey and human, and in human CYP supersomes?, were identified using specific CYP inhibitors. The order of disappearance of IN-1130 in various liver microsomal systems studied was as follows: monkey, mouse, rat, human, and dog.

3.?Five distinct metabolites (M1–M5) were identified in all the above microsomes and their production was substantially inhibited by CYP inhibitors such as SKF-525A and ketoconazole. Among nine human CYP supersomes? examined, CYP3A4, CYP2C8, CYP2D6*1, and CYP2C19 were involved in the metabolism of IN-1130, and the production of metabolites were significantly inhibited by specific CYP inhibitors. IN-1130 disappeared fastest in CYP2C8 supersomes. CYP3A4 produced four metabolites of IN-1130 (M1–M4), whereas supersomes expressing human FMO cDNAs, such as FMO1, FMO3, and FMO5, produced no metabolites.

4.?Hence, it is concluded that metabolism of IN-1130 is mediated by CYP3A4, CYP2C8, CYP2D6*1, and CYP2C19.     

T lymphocytes isolated from patients with advanced colorectal cancer are suitable for gene immunotherapy approaches

Despite improvements in treatment, the 5-year survival for metastatic colorectal cancer remains poor. Novel approaches such as gene immunotherapy are being investigated to improve treatment. Retroviral gene transfer methods have been shown to transduce primary human T lymphocytes effectively resulting in the expression of therapeutic genes. However, a number of defects have been identified in T lymphocytes isolated from patients bearing tumour, which may have critical implications for the development of gene-targeted T cells as an anticancer therapy. To address this issue, primary T lymphocytes were isolated from patients with advanced colorectal cancer and tested for their ability to be transduced and to express subsequently a chimeric immune receptor consisting of a single-chain antibody fragment antigen-binding moiety specific for carcinoembryonic antigen (CEA) fused to the T cell receptor (TCR) CD3zeta chain. In 10 out of 10 patients, T lymphocytes were transduced, expanded in the absence of selection and tested for functional activity against CEA-expressing tumour cells. In each case, functional-specific cytotoxic activity was observed. Negligible activity was found in control cultures. This study highlights the feasibility of patient-derived T lymphocytes as a source of immune cells for autologous gene immunotherapy approaches.     

Clinical experiences of removing foreign bodies in the airway and esophagus with a rigid endoscope: a series of 3217 cases from 1970 to 1996.

This study examined 11,333 rigid endoscopy procedures performed in the Department of Otolaryngology, National Taiwan University Hospital, during a 27-year period from 1970 to 1996. Among these cases, 3217 were performed to remove foreign bodies from the airway (459 cases, 14.3%) and esophagus (2758 cases, 85.7%). Retrospective analysis of these data revealed that peanuts (217 cases) and animal bones (1184 cases) were the most frequent foreign bodies encountered in the airway and esophagus, respectively. The successful rate of removal of these foreign bodies was 99.9% (3213/3217). The complication rate was only 0.2% (8/3217), and the mortality rate was less than 0.1% (2/3217). On the basis of these results, we conclude that foreign bodies in the airway and esophagus can be removed safely under direct visualization through rigid endoscopy with relatively few complications. A significant finding in this study is the declining trend in the number of cases in recent years. Despite the decline in the number of procedures, endoscopic removal of foreign bodies remains as a vital skill of the aerodigestive tract surgeon.     

Prevalence of antibodies to hepatitis C virus in the hemodialysis unit.

An enzyme immunoassay was used to detect antibodies to hepatitis C virus (anti-HCV) in 261 patients and 69 staff members of a hemodialysis unit. The prevalence of anti-HCV was 46.7% in patients and 2.9% in staff members (p less than 0.001). The prevalence of anti-HCV increased significantly with increasing duration of hemodialysis (p less than 0.001), but was not related to age, sex, history of blood transfusion, status of hepatitis B or hepatitis A virus infection, or serum ALT. Patients with hepatitis episode increased with increasing duration of hemodialysis and showed a significantly higher prevalence of anti-HCV than those without (63.1 vs. 34.7%, p less than 0.001). The prevalence of anti-HCV in patients with hepatitis also increased with increasing duration of hemodialysis (p = 0.05). Thus, HCV appears to be the major cause of hepatitis in hemodialysis patients. Besides strict infection control measures, further studies are needed to determine the mode of HCV infection and its prevention in the hemodialysis unit.     

Most patients are eligible for an alternative to conventional whole breast irradiation for early‐stage breast cancer: A National Cancer Database Analysis

We evaluated the proportion of patients eligible for alternatives to standard whole breast irradiation (WBI) following breast‐conserving surgery using the National Cancer Database (NCDB). Using the 2016 dataset, Stage I‐III patients were identified. Eligibility for hypofractionated WBI (HFRT), accelerated partial breast irradiation (APBI) and endocrine therapy (ET‐alone) was defined using eligibility from large clinical trials as well as consensus guidelines. For patients with pN0 breast cancer, 20.6% and 37.0% were eligible for ET‐alone based on the CALGB 9343/PRIME‐II trials, respectively. In terms of HFRT, 72.5% and 50.4% were eligible based on IMPORT LOW/ASTRO HFRT guidelines, respectively. Based on IMPORT LOW/GEC‐ESTRO trial/ASTRO guidelines/ABS guidelines/GEC‐ESTRO guidelines, 72.5%, 86.1%, 39.0%, 72.5%, 45.7%, respectively, were eligible for APBI. Of those who qualify for HFRT per ASTRO guidelines, approximately 90% were eligible for APBI and 50% for ET‐alone. This analysis shows that a large proportion of patients with node‐negative breast cancer are eligible for HFRT, APBI and/or ET‐alone after breast‐conserving surgery.     

The real-time ultrasonography of pancreatic pseudocyst: comparison of infected and noninfected pseudocysts

The real-time ultrasonograms of 15 patients with pancreatic pseudocysts (10 infected and 5 noninfected) were analyzed to evaluate difference in ultrasound characteristics between the infected and noninfected pseudocysts. Only those who underwent ultrasound-guided aspiration or operation within one week after sonography were reviewed according to the size, multiplicity, air content, internal echoes, and wall characteristics (such as thickness, regularity, and calcification) of pseudocysts. Among these ultrasonographic features of pseudocysts, there was no statistically significant difference between the infected and noninfected pseudocysts in cyst size, wall characteristics (thickness, regularity, and calcification), multiplicity, and air content. The most important and unique feature was the internal echoes within the pseudocyst. The internal echoes were classified into three grades. All the infected pseudocysts and one noninfected pseudocysts had internal echoes of grade 1. The difference is statistically significant (p = 0.0037). These results indicate that grading internal echogenicity of the pseudocysts with real-time ultrasonographies can add additional information important in differentiating infected from noninfected pseudocysts.