Succession of mutations in the Sabin strain of type 3 poliovirus replicating in the central nervous system of monkeys

Pentachlorophenol (PCP), which has been used as a wood preservative, was reported to be a liver carcinogen in mice. To investigate the initial effects of PCP administration under the same conditions of exposure as in the carcinogenic study, we examined oxidative stress and cell proliferation, along with other hepatotoxicological parameters, in the livers of B6C3F1 mice fed PCP in their diet at doses of 0.03, 0.06, and 0.12% for up to 4 weeks. We observed significant increases of 8-OHdG levels in hepatic nuclear DNA at doses of 0.03% and above at 2 and 4 weeks. Likewise, dose-dependent increases in the labeling index of cells were detected by counting those that had incorporated 5-bromo-2'-deoxyuridine throughout the experimental period. Also, we found significant elevations of the liver weights, concurrent with increases in hepatic DNA content in the treated mice, which again were dose-related. Serum aspartic transferase activity at doses of 0.06% and above were significantly increased despite these changes being slight. Also, histopathological examination provided no evidence of necrotic changes, but severe hepatocyte swelling in the treated mouse livers. These data indicate that PCP might be able to induce cell proliferation in the mouse liver, as well as induce oxidative DNA damage, suggesting both changes may play an important role in hepatocarcinogenesis.     

Clear cell differentiation in choroidal melanoma. COMS report no. 8. Collaborative Ocular Melanoma Study Group

OBJECTIVE: To describe 2 enucleated eyes of patients enrolled in the Collaborative Ocular Melanoma Study that contained primary choroidal melanoma with clear cell features. METHODS: During a 9-year period, 1493 eyes enucleated as part of the Collaborative Ocular Melanoma Study routinely processed for histologic examination were evaluated by the pathology review committee (H.E.G, D.M.A, and W.R.G). Two eyes with unusual variants of choroidal melanoma were identified and immunostained for S100 protein and HMB 45. Portions of the tumors were processed for electron microscopic examination. RESULTS: Results of electron microscopic examination of both tumors displayed malignant melanoma (mixed cell type with many malignant cells with clear cytoplasm). The cytoplasm of the clear cells stained with periodic acid-Schiff and failed to stain when pretreated with diastase. Results of immunohistochemical stains in both tumors were positive for S100 protein and HMB 45 in the tumor cells. Results of electron microscopic examination showed that the cytoplasm of the clear cells contained scattered glycogen granules, premelanosomes, and melanosomes. CONCLUSION: These cases represent a clear cell variant of malignant melanoma of the choroid. This tumor should not be confused with metastatic clear cell carcinoma to the choroid.     

Usefulness of sotalol for life-threatening ventricular arrhythmias

Two trial designs have been used in evaluating sotalol in patients with sustained tachyarrhythmias: open-label dose escalation and randomized comparison with reference agents. At least 7 open-label studies (n = 16-65) have been reported from single centers in patients in whom trials of numerous other antiarrhythmic agents were unsuccessful. At the doses used, usually 320-640 mg/day, plasma concentrations were in the range associated with both beta blockade and class III antiarrhythmic activity (2-3 micrograms/mL). These concentrations produced electrophysiologic changes that were consistent across studies: 10-16% increase in right ventricular effective refractory period (ERP), 4-8% increase in corrected QT interval (QTc), and 17-30% increase in sinus cycle length (corresponding to a 15-23% decrease in heart rate). In these open-label trials, sotalol suppressed inducible ventricular tachyarrhythmias in 20-72% of patients; the higher degrees of efficacy were reported when induction protocols were confined to double extrastimuli. Side effects leading to discontinuation of sotalol in patients with sustained ventricular tachycardia or fibrillation include fatigue (4.0%), marked bradycardia (3.0%), torsades de pointes (3.0%), and heart failure or pulmonary edema (1.0%). A multicenter randomized trial compared intravenous sotalol with intravenous procainamide in a double-blind prospective fashion. Sotalol suppressed ventricular tachyarrhythmias inducible with triple extrastimuli in 15 (30%) of 50 patients, whereas procainamide was effective in 10 (20%) of 50. In this and other series, responsiveness to sotalol was prospectively identified by a particularly fast tachycardia at baseline (e.g., cycle length of < 270 msec), but not by the extent of changes in global indices of repolarization (QTc, ERP).(ABSTRACT TRUNCATED AT 250 WORDS)     

Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients

PURPOSE: To examine the mechanism of the decreased frequency of severe hypoglycemia with implantable pump therapy compared with subcutaneous intensive therapy. PATIENTS AND METHODS: Eight subjects with insulin-dependent diabetes mellitus (IDDM), enrolled in an implantable insulin pump study, were admitted to the General Clinical Research Center and on 2 separate days were given either a dose of preprandial insulin chosen to maintain normoglycemia for a standard (450 kcal, 50% carbohydrate) breakfast or 1.75 times the dose. The two doses were administered subcutaneously (by syringe or with an external pump) during one inpatient admission and by implantable pump (intraperitoneally, n=6; or intravenously, n=2) during a separate admission. Blood glucose, plasma-free insulin, and neurocognitive function were measured for 4 hours after the meal. RESULTS: Subcutaneous administration resulted in 7 episodes of hypoglycemia (2 with the usual dose and 5 with the 1.75-fold dose), defined as blood glucose less than 50 mg/dL; implantable pump treatment resulted in only 2 episodes, both with the 1.75-fold dose (P <0.05, Fisher's two-tailed test for implantable versus subcutaneous). Compared with subcutaneous delivery, implantable pump therapy provided significantly lower insulin levels during the final 2 hours after administration of the usual dose and the 1.75-fold dose (P <0.005). In addition to the decreased frequency of hypoglycemia, implantable pump therapy resulted in significantly lower area under the glycemia curve during the first 120 minutes with the 1.75-fold dose compared with subcutaneous administration. CONCLUSIONS: The lower frequency of severe hypoglycemia with intensive therapy administered by implantable pump therapy is explained by the more rapid clearance of insulin delivered intraperitoneally or intravenously compared with intensive subcutaneous injection regimens. The lower frequency of severe hypoglycemia with implantable pump therapy compared with subcutaneous therapy demonstrated in clinical trials is confirmed by this study, in which we attempted to induce hypoglycemia.     

Effect of ambient solar ultraviolet radiation on incidence of squamous-cell carcinoma of the eye

BACKGROUND: We have investigated the geographic distribution of squamous-cell carcinoma of the eye to assess whether solar ultraviolet light is a risk factor for this disease. METHODS: We used routinely collected population-based cancer incidence data and published measurements of ambient solar ultraviolet light in our analysis. FINDINGS: The incidence of squamous-cell carcinoma of the eye declined by 49% of each 10 degrees increase in latitude (p < 0.0001), falling from more than 12 cases per million per year in Uganda (latitude 0.3(0)) to less than O.2 per million per year in the UK (latitude > 50(0)). Solar ultraviolet radiation decreases with increasing latitude, and the incidence of squamous-cell carcinoma of the eye decreased by 29% per unit reduction in ultraviolet exposure (p < 0.0001). INTERPRETATION: Our results are compatible with the hypothesis that exposure to solar ultraviolet light is an important cause of squamous-cell carcinoma of the eye.     

Binocular processes in vernier acuity

The contribution of synthesis and dietary sequestration to the high arachidonate content of the lone star tick, Amblyomma americanum, salivary glands was investigated by assessing the salivary metabolites of various radiolabeled fatty acid substrates administered to partially fed females. A portion of each of the fatty acids studied was incorporated into the fatty acid moiety of the phospholipid fraction. [14C]acetate was metabolized only into myristic, palmitic, palmitoleic, steric, and oleic acids. [3H]oleic acid, [14C]linoleic acid, [14C]gamma-linolenic acid and [14C]eicosatrienoic acids were incorporated into salivary gland phospholipids but underwent little change including elongation and/or desaturation to arachidonate. Ingested [3H]arachidonic acid was readily taken up by the salivary gland and distributed among the lipid classes in a pattern markedly different from that of the other fatty acids tested. We conclude that ticks are unable to synthesize arachidonic acid for incorporation into the salivary glands, but rather sequester it from the host bloodmeal.     

A comparative analysis of subchondral replacement with polymethylmethacrylate or autogenous bone grafts in dogs

A comparative analysis was made of subchondral replacement with polymethylmethacrylate and autogeneic bone grafts in defects in the medial femoral condyles of dogs. The defect produced a 50% reduction in subchondral stiffness. An in vitro preparation helped establish that subchondral stiffness returned to normal after reconstruction with polymethylmethacrylate. The in vivo model demonstrated a reduction in subchondral stiffness in both groups at three weeks, but the bone grafted side returned to normal and the methylmethacrylate side recovered to 79% of the control at 12 weeks. There were no deleterious effects on the articular cartilage in either group when analyzed histologically and biochemically. A marked increase in new bone formation and subchondral porosity was found in the polymethylmethacrylate groups. This study supports the clinical use of subchondral polymethylmethacrylate after the exteriorization and curettage of benign bone tumors such as giant cell tumors.