Control of the mutagenicity of arylamines by protein kinases and phosphatases: II. Lack of response of rat liver N-acetyl transferases to phosphorylation modulators

OBJECTIVES: Endoscopic sphincterotomy has become a generally accepted method for extracting common bile duct stones in high risk or cholecystectomized patients. However, stone extraction is impossible by the usual methods in 5 to 10% of cases. The purpose of this study was to evaluate the effect of a recently developed solvent system in patients with large bile duct stones. METHODS: Forty four patients (15 men and 29 women, median age of years) underwent contact dissolution after unsuccessful Dormia extraction. Solvents were administered via a nasobiliary catheter in 41 patients following papillotomy and through a T-tube in 3 patients. Solvent mixtures (26 mM ethylene diamine tetraacetic acid, 40 mM sodium deoxycholate and 30% dimethyl sulfoxide in an alkaline aqueous solution; and a 70/30 dimethyl sulfoxide/methyl tert-butyl ether mixture) were infused continuously and alternatively for 2 hours. RESULTS: Bile duct stones disappeared in 13-24 hours of infusion in 11 patients. In 29 patients, a clear reduction in stone volume occurred, allowing complete endoscopic extraction of the fragments. In 4 patients, the size of the stone did not change. Only mild and transient side-effects including abdominal pain (68%), nausea (72%), vomiting (52%), diarrhea and sleepiness (50%) were observed. CONCLUSION: Direct dissolution therapy could be an effective method for the non-surgical management of large bile duct stones in selected patients when intra- or extracorporeal lithotripsy is unsuccessful.     

Signed rank statistics for coherent predictions

A generalization of Wilcoxon's signed rank test is proposed for testing a dose-response relationship with one or more outcomes. The test is useful in matched observational studies or in nonrandomized experiments that use dose-response relationships and predictions about multiple outcomes in an effort to distinguish actual treatment effects from hidden biases. A sensitivity analysis indicating whether a dose-response relationship or multiple predictions are confirmed with sufficient strength to reduce sensitivity to hidden bias is performed. Together, the test and the sensitivity analysis help to quantify the degree to which a coherent pattern of associations is present or absent, and the degree to which this strengthens or fails to strengthen evidence of cause and effect. Formal properties of tests of this kind are examined. The form of the optimal test is determined, though this test is not usable because it depends upon the values of the unknown parameters under study. Also examined are the conditions under which the proposed test resembles the optimal test, as well as the impact of various violations of those conditions on power. An example involving matched pairs exposed to varying doses of cadmium is considered in detail.     

Evaluation of the dizzy patient

This discussion has focused primarily on the history and physical examination of the patient with dizziness which, in fact, are the two most important elements in the evaluation process. To perform the examination expeditiously and completely, a broad differential diagnosis of dizziness must be kept in mind. The clinician should also keep in mind two basic objectives: first, to identify serious pathology (e.g., central nervous system lesion, brainstem ischemia, cardiac arrhythmia); and second, to recognize diseases that can be specifically treated, such as an endocrine abnormality, middle ear infection, Meniere's disease, or a drug reaction. Reassurance and/or vestibular rehabilitation are the mainstays of therapy for the patients not falling into the above two categories.     

Tumour seeding following percutaneous endoscopic gastrostomy placement in head and neck cancer

We report the case of a patient with advanced squamous carcinoma of the supraglottic larynx and hypopharynx who developed metastatic gastric deposits occurring at the site of a percutaneous endoscopic gastrostomy tube, inserted 10 months previously by the pull technique. We review seven previous reports of tumour deposits occurring at the site of placement of a percutaneous endoscopic gastrostomy in patients with head and neck cancer, and consider alternative methods of enteral feeding in such patients.     

Inhibition of double-stranded RNA-dependent protein kinase PKR by vaccinia virus E3: role of complex formation and the E3 N-terminal domain

The human double-stranded RNA (dsRNA)-dependent protein kinase PKR inhibits protein synthesis by phosphorylating translation initiation factor 2alpha (eIF2alpha). Vaccinia virus E3L encodes a dsRNA binding protein that inhibits PKR in virus-infected cells, presumably by sequestering dsRNA activators. Expression of PKR in Saccharomyces cerevisiae inhibits protein synthesis by phosphorylation of eIF2alpha, dependent on its two dsRNA binding motifs (DRBMs). We found that expression of E3 in yeast overcomes the lethal effect of PKR in a manner requiring key residues (Lys-167 and Arg-168) needed for dsRNA binding by E3 in vitro. Unexpectedly, the N-terminal half of E3, and residue Trp-66 in particular, also is required for anti-PKR function. Because the E3 N-terminal region does not contribute to dsRNA binding in vitro, it appears that sequestering dsRNA is not the sole function of E3 needed for inhibition of PKR. This conclusion was supported by the fact that E3 activity was antagonized, not augmented, by overexpressing the catalytically defective PKR-K296R protein containing functional DRBMs. Coimmunoprecipitation experiments showed that a majority of PKR in yeast extracts was in a complex with E3, whose formation was completely dependent on the dsRNA binding activity of E3 and enhanced by the N-terminal half of E3. In yeast two-hybrid assays and in vitro protein binding experiments, segments of E3 and PKR containing their respective DRBMs interacted in a manner requiring E3 residues Lys-167 and Arg-168. We also detected interactions between PKR and the N-terminal half of E3 in the yeast two-hybrid and lambda repressor dimerization assays. In the latter case, the N-terminal half of E3 interacted with the kinase domain of PKR, dependent on E3 residue Trp-66. We propose that effective inhibition of PKR in yeast requires formation of an E3-PKR-dsRNA complex, in which the N-terminal half of E3 physically interacts with the protein kinase domain of PKR.     

Updated estimates of condom effectiveness

This paper reports results of a study concerning the effectiveness of condoms in preventing HIV transmission. The study expands on a 1993 meta-analysis that pooled the results of a number of studies of HIV transmission in serodiscordant couples to arrive at an overall condom effectiveness estimate of 69%. A meta-analysis of studies that compared seroconversion rates among couples who regularly use condoms and those who used them inconsistently was conducted to determine the use and/or effectiveness of condoms in preventing HIV transmission. Results of the analysis indicated that condoms are 90-95% effective when used consistently. To illustrate the impact of differential assumptions regarding the effectiveness of condoms in preventing the transmission of HIV, a community of gay men is considered in which the prevalence rate of HIV infection is 20%, supposing each man has sex once a week with a monogamous partner from the same population. The expected annual incidence of HIV infection in this community is 13% if condoms are never used, while consistent use of 95% effective condoms would reduce the incidence to about 1%. In this example, the probability of transmission for 52 acts of condom-protected intercourse is less than for a single act of unprotected intercourse. Moreover, inconsistent condom use also offers some protection against HIV in which the reduction achieved by using condoms 50% of the time is equal to almost half the reduction associated with consistent use.     

Suprascapular neuropathy after distal clavicle excision

Two cases of suprascapular neuropathy after excision of the distal clavicle are reported. Both patients were treated successfully with neurolysis of the suprascapular nerve starting at the upper trunk of the brachial plexus. Anatomic dissections revealed that the suprascapular nerve is quite close (<1.4 cm) to the posterior aspect of the distal clavicle, within 2 to 3 cm of the acromioclavicular joint. To avoid the complication of suprascapular neuropathy that could be associated with this close relationship, it is recommended that no more than 1 cm of the distal clavicle be removed posteriorly. It is also recommended that minimal periosteal elevation should be performed on the posteroinferior border of the distal clavicle.