Secretion of human hepatitis B virus is inhibited by the imino sugar N-butyldeoxynojirimycin.

The imino sugar N-butyldeoxynojirimycin (NBDNJ) is a potent inhibitor of the oligosaccharide-trimming enzyme alpha-glucosidase I. Hepatitis B virus (HBV) contains three surface proteins (HBs proteins) of different sizes that are singly or doubly N-glycosylated and are essential for the formation of infectious virus. Therefore, the replication and secretion of HBV in the human hepatoma cell line HepG2 were studied in the presence of NBDNJ. In the stably HBV-transfected HepG 2.2.15 cells and in HBV-infected HepG2 cells, NBDNJ suppressed secretion of HBV particles and caused intracellular retention of HBV DNA. The secretion of subviral particles was less affected. These data suggest that inhibitors of oligosaccharide trimming may be useful for antiviral therapy of hepatitis B and for the study of the intracellular transport of the viral glycoproteins.     

Quantitative DNA measurement by flow cytometry and image analysis of human nonseminomatous germ cell testicular tumors

Current clinical staging, which includes the use of serum tumor markers and imaging techniques, fails to identify the 30–40% of clinical stage I (CS I) nonseminomatous germ cell testicular tumor (NSGCT) patients who have occult metastatic disease. Therefore, there is a real clinical need to evaluate new biological parameters of the primary tumor that might be useful as predictors of occult metastatic disease. This study was undertaken to compare quantitative DNA measurements by flow cytometry and image analysis in CS I NSGCT, and to analyze the relevance of these parameters for predicting occult lymph node involvement. Different blocks of formalin-fixed, paraffin-embedded NSGCTs of 62 CS I patients who underwent retroperitoneal lymph node dissection between 1985 and 1989 were prepared according to the Hedley technique, and analyzed by quantitative cytometry. Thirty-six (58.1%) patients had histologically proven lymph node involvement (pathological stage II), whereas 26 (41.9%) patients (pathological stage I) had neither lymph node metastases according to retroperitoneal lymph node dissection (RPLND) specimens nor tumor recurrence during follow-up. Concordant results were found in 76.5% of the samples by both cytometric techniques. For flow cytometry, the percentages of aneuploid cells in the S- and the G2M+S-phase were the most robust predictive parameters for lymph node involvement, whereas for image analysis the 5c exceeding rate (5cER) had the most predictive significance. Based on the experience obtained in this study, both cytometric techniques provide additional information on tumor aggressiveness that might be useful in therapeutic selection of early stage NSGCT patients for either RPLND or surveillance only.     

Testicular ultrasonography after chemotherapy for germ cell neoplasm: significance of highly hyperechoic lesions.

The sonographic appearance of the testis after administration of chemotherapy for metastatic germ cell neoplasm is not well known. Fifty-six patients (60 testes) who were previously treated with chemotherapy for metastatic germ cell neoplasm (originally diagnosed by removal of the contralateral testis or by biopsy of metastatic disease) underwent sonography followed by orchiectomy. The sonographic characteristics found to predict viable intratesticular tumor were: lesion size larger than 5 mm, fewer echoes than adjacent parenchyma (hypoechoic), inhomogeneous echo texture, poor margin definition, cystic areas, or highly hyperechoic foci within a hypoechoic lesion. Fibrosis was predicted by finding single or multiple small, highly hyperechoic lesions. These results suggest the potential for predicting the pathologic diagnosis in some patients after receiving chemotherapy for germ cell neoplasm.     

Effect of training frequency and specificity on isometric lumbar extension strength

To investigate the effects of training frequency and specificity of training on isolated lumbar extension strength, 72 men (age = 31 +/- 9 years) and 42 women (age = 28 +/- 9 years) were tested before and after 12 weeks of training. Each test involved the measurement of maximum voluntary isometric torque at 72 degrees, 60 degrees, 48 degrees, 36 degrees, 24 degrees, 12 degrees, and 0 degrees of lumbar flexion. After the pretraining tests, subjects were randomly stratified to groups that trained with variable resistance dynamic exercise every other week (1X/2 weeks, n = 19), once per week (1X/week, n = 22), twice per week (2X/week, n = 23) or three times per week (3X/week, n = 21); a group that trained isometrically once per week (n = 14); or a control group that did not train (n = 15). Analysis of covariance showed that all training groups improved their ability to generate isometric torque at each angle measured when compared with controls (P less than 0.05). There was no statistical difference in adjusted posttraining isometric torques among the groups that trained (P greater than 0.05), but dynamic training weight increased to a lesser extent (P less than 0.08) for the 1X/2 weeks group (26.6%) than for the groups that trained 1X/week, 2X/week, and 3X/week (37.2 to 41.4%). These data indicate that a training frequency as low as 1X/week provides an effective training stimulus for the development of lumbar extension strength. Improvements in strength noted after isometric training suggest that isometric exercise provides an effective alternative for developing lumbar strength.     

Pharmacogenetics of antipsychotic adverse effects: Case studies and a literature review for clinicians

There is a growing body of literature supporting the contribution of genetic variability to the mechanisms responsible for the adverse effects of antipsychotic medications particularly movement disorders and weight gain. Despite the current gap between research studies and the practical tools available to the clinician to identify such risks, it is hoped that in the foreseeable future, pharmacogenetics will become a critical aid to guide the development of personalized therapeutic regimes with fewer adverse effects. We provide a summary of two cases that are examples of using cytochrome P450 pharmacogenetics in an attempt to guide treatment in the context of recent literature concerning the role of pharmacogenetics in the manifestation of adverse effects of antipsychotic therapies. These examples and the review of recent literature on pharmacogenetics of antipsychotic adverse effects illustrate the potential for applying the principles of predictive, preventive, and personalized medicine to the therapy of psychotic disorders.     

Scale-up of Adhesive Transdermal Drug Delivery Systems

Pharmaceutical Research -     

Parastomal hernia.

Parastomal herniation is a common complication after stoma formation. The incidence can be reduced by using an extraperitoneal technique, limiting the size of the trephine to 1.5-2.0 cm or by strengthening with a mesh. If an intraperitoneal technique is used the intestine should be brought out through the rectus muscle. Generally, the symptoms are easily controlled with a support belt. Various techniques have been advocated for surgical repair. Fascial repair alone should no longer be performed owing to an unacceptably high recurrence rate, but should be combined with a prosthetic mesh. Relocation of the stoma should be performed for primary repairs.