Inhibition of adenovirus DNA polymerase by modified nucleoside triphosphate analogs correlate with their antiviral effects on cellular level

Adenovirus (Ad) infection results in significant morbidity and mortality in both immunocompetent and immunosuppressed hosts. There is currently no licensed chemotherapy effective in dealing with this virus infection. In this study the anti-adenoviral activity of a group of modified nucleoside analogs was investigated. The most efficient 3-fluorosubstituted nucleoside triphosphate inhibitors of Ad DNA polymerase were 3′-fluorothymidine triphosphate (IC₅₀ 0.63 μM), 2′,3′-dideoxy-3′-fluoroguanosine triphosphate (IC₅₀ 0.71 μM) and 2′,3′-dideoxy-3′-fluorouridine triphosphate (IC₅₀ 2.96 μM). The most efficient 2′,3′-dideoxynucleoside triphosphates were 2′,3′-dideoxycytidine triphosphate (ddCTP; IC₅₀ 1.0 μM), 2′,3′-dideoxyadenosine triphosphate (IC₅₀ 1.6 μM) and 2′,3′-dideoxythymidine triphosphate (IC₅₀ 1.82 μM). Kinetic studies indicate competitive inhibition of adenovirus DNA polymerase by ddCTP. These data confirm results previously obtained at the cellular level using a focus reduction assay involving Ad2-infected FL cells. Whereas the D-enantiomers 3′-fluorothymidine and 2′,3′-dideoxycytidine are potent inhibitors of adenoviral replication, the corresponding L-enantiomers exhibited no inhibitory activity. Received: 5 April 2000     

Clozapine-associated elevation of plasma cholinesterase

Objective The goal of this study was to identify adverse effects of the atypical neuroleptic clozapine on liver function and lipid metabolism. Methods Data which included serum levels of clozapine and its hepatic metabolite N-desmethyl clozapine were collected from medical records of patients treated with clozapine and controls. Results We identified a clozapine-associated marked elevation of plasma cholinesterase (ChE) with unchanged levels of AST, ALT or g-GT. ChE was correlated to the serum level of clozapine and even closer to N-desmethyl clozapine. For the total patient group we observed significant correlations of ChE with the body-mass index and body weight. However, clozapine-treated patients and controls did not differ with regard to body-mass index, triglycerides, and cholesterol. Conclusion We report for the first time a clozapine-associated and dose-dependent elevation of plasma ChE, which may be related to clozapine-associated effects on hepatic lipid metabolism or ChE enzyme induction. Received: 14 Mai 2001 / Accepted: 24 September 2001     

Ventricular fibrillation refractory to automatic internal cardiac defibrillator in Fabry's disease. Review of cardiovascular manifestations

Fabry's disease is a disorder of glycosphingolipid metabolism leading to alpha-galactosidase deficiency with systemic sequelae. Clinical cardiac manifestations include dysrhythmias, structural abnormalities apparent on echocardiography, and histologic changes secondary to glycosphingolipid deposition. The introduction of automated internal cardiac defibrillators (AICD) has been shown to decrease the incidence of circulatory collapse in individuals with known terminal arrhythmias. We present a patient with Fabry's disease, who underwent coronary angiography without finding of obstructive disease. He returned after aborted sudden cardiac death necessitating the placement of an AICD. He again presented after an episode of ventricular fibrillation refractory to internal defibrillation necessitating advanced life support, and subsequently expired. We review the electrocardiographic, cardiovascular structural, and histologic manifestations of Fabry's disease.     

The significance of serum levels of insulin-like growth factor-1 in patients with prostate cancer

OBJECTIVES: To compare the serum levels of insulin-like growth factor-1 (IGF-1) in patients with prostate cancer and in control patients with no malignancy, and to evaluate any possible influence of testicular androgen withdrawal on the level of IGF-1 in patients with prostate cancer. PATIENTS AND METHODS: IGF-1 was measured in serum samples from 238 patients using both a chemiluminescence method and a radio-immunoassay. From a subgroup of 19 patients presenting with newly diagnosed carcinoma of the prostate, IGF-1 and testosterone values were measured before and during the course of testicular androgen withdrawal, achieved by the administration of luteinizing hormone-releasing hormone (LHRH) analogues combined with anti-androgens. RESULTS: There were no significant differences in the mean serum levels of IGF-1 patients with and without prostate cancer (158.6 and 159.1 ng/mL, respectively). There were no significant differences in mean IGF-1 levels before and after antiandrogen therapy; the mean (median, SD, range) levels of testosterone (microg/L) and IGF-1 (ng/mL) before androgen withdrawal were 4.81 (4.84, 1.26, 3.11-6.93) and 157.1 (152.5, 26.7, 122.8-195. 1). After androgen withdrawal the corresponding values were 0.303 (0. 218, 0.24, 0.13-0.81) and 169.7 (31.7, 168.6, 124.9-227.6). A linear regression analysis (P = 0.76) and Spearman rank order correlation test (correlation coefficient -0.0613, P = 0.64) showed no association between levels of testosterone and IGF-1. Freeze and thaw cycles applied to the samples had no effect on the IGF-1 values measured. CONCLUSIONS: There was no significant association between IGF-1 serum levels and prostate cancer. Short-term androgen withdrawal using LHRH analogues combined with anti-androgens had no effect on the levels of IGF-1.     

First clinical experience with beta-trace protein (prostaglandin D synthase) as a marker for perilymphatic fistula

A diagnosis of perilymphatic fistula is still controversial. Recently, a case report indicated that beta-trace protein (prostaglandin D synthase) might be a potential marker for perilymphatic fluid. In this multicentre clinical case series study beta-trace protein was used as a marker for perilymphatic fluid fistula. Fifteen fluid samples were collected during diagnostic tympanoscopy. In addition, five samples were collected from patients with tympanic membrane perforation for use as as negative controls. Samples were obtained using precision glass capillaries and were analysed for beta-trace protein using laser nephelometry. The diagnosis of perilymphatic fistula was defined by the patient's history, the audiological and vestibular investigation and the findings at tympanoscopy. The cut-off level of beta-trace protein for perilymph-positive samples was chosen at 1.11 mg/l. The sensitivity and specificity were calculated using a 2 x 2 contingency table. There was no false positive result, but in two cases a false negative result was found. The specificity was 1 and the sensitivity was 0.81. The material of this first clinical study is small owing to the rarity of patients undergoing diagnostic tympanoscopy for perilymphatic fluid fistula. However, according to these preliminary results beta-trace protein might be a promising marker in the diagnosis of perilymphatic fluid fistulas.     

Radiographic versus ultrasound evaluation of the Risser Grade in adolescent idiopathic scoliosis: a prospective study of 46 patients

The determination of skeletal age is essential in the management of patients with scoliosis. One of the most frequently used techniques to determine skeletal maturity is the method described by Risser. However, repeated X-ray exposure in the follow-up examinations of scoliosis patients may increase the risk of cancer. We compared conventional radiological evaluation of the Risser grade with ultrasound evaluation. For scoliosis patients routine application of ultrasound in the follow-up examinations may significantly reduce radiation exposure. 46 adolescent idiopathic scoliosis patients (median age, 14.5 years) were investigated. Sonographic and radiographic assessment of Risser sign was carried out by two independent senior staff skeletal radiologists. Agreement of Risser Grade between the two diagnostic methods was determined by Kappa statistics. Coefficients <0.21, 0.21–0.40, 0.41–0.60, 0.61–0.80, and >0.80 were rated as poor, fair, moderate, good, and very good agreement. For Risser Grades I–III 100% agreement was found between the two methods. Disagreement between radiographic and sonographic evaluation was found in Risser Grades IV and V. In five patients, X-ray evaluation yielded Risser Grade V while ultrasound showed Risser Grade IV. In one patient, radiographic examination resulted in Risser Grade IV while Grade V was detected in ultrasound. Overall, the Kappa value showed very good agreement between the two diagnostic methods. Our findings suggest that ultrasound can be applied as an alternative method to X-ray evaluation in Risser Grade determination. It should be routinely used in clinical practice to reduce the patients exposure to radiation.     

Regional right ventricular function and timing of contraction in healthy volunteers evaluated by strain‐encoded MRI

Purpose

To prospectively determine the feasibility and accuracy of strain‐encoded (SENC) magnetic resonance imaging (MRI) for the characterization of the right ventricular free wall (RVFW) strain and timing of contraction at 3.0 Tesla (3T) MRI.

Materials and Methods

In 12 healthy volunteers the RVFW was divided into three segments (anterior, lateral, and inferior) in each of three short‐axis (SA) slices (apical, mid, and basal) and into three segments (apical, mid, and basal) in a four‐chamber view. The study was repeated on a different day and interobserver and interstudy agreements were evaluated.

Results

Maximal systolic longitudinal strain values were highest at the apex and base, with a pronounced decrease in the medial segments (apex: –19.1% ± 1.4; mid: –17.4% ± 2; base: –19.4% ± 2.4, P < 0.001), and maximal systolic circumferential strain showed the highest values at the apex (apex: –18.1% ± 1.7; mid: –17.6% ± 1.2; base: –16.6% ± 0.9, P < 0.001). Peak systolic longitudinal and circumferential shortening occurred earliest at the apex compared to the mid‐ventricle and base. Excellent interobserver and interstudy correlation and agreement were observed.

Conclusion

The use of SENC MRI for the assessment of normal RV contraction pattern is feasible and accurate in 3T MRI. J. Magn. Reson. Imaging 2008;28:1379–1385. © 2008 Wiley‐Liss, Inc.     

Non‐infectious inflammatory disorders of the nail apparatus

Inflammatory non‐infectious diseases of the nails are not uncommon. The nail changes may look different in the same diseases, but also very much alike in various different nail disorders depending on which particular structure of the nail apparatus is involved. Of all skin diseases, psoriasis is the one with the most frequent nail involvement. The presence of many pits allows the diagnosis to be made, but salmon spots and onycholysis are also characteristic features. Lichen planus may occur isolated on the nails or in association with lesions of the skin and adjacent mucosal membranes. Longitudinal striations and loss of the nail plate shine are the most frequent features of nail lichen planus. The more severe the alopecia areata is and the younger the patient is, the more often it affects the nail, usually with a rough surface and loss of shine. Eczemas and various autoimmune dermatoses may also affect the nails but the changes are not clinically specific.     

Oligohydramnios-induced lung hypoplasia: the influence of timing and duration in gestation

We drained amniotic fluid for periods of 5 and 10 days at various times in gestation between days 40 and 55 in the guinea pig (term is 67 days). We analyzed the impact of this procedure on fetal lung growth and used untouched littermate fetuses as controls. During the canalicular stage of lung development, total lung DNA per gram of fetal weight was significantly reduced after only 5 days of oligohydramnios and the percent change did not vary between the two consecutive 5-day periods studied (period A, days 40 to 45, delta of -0.047 mg, p = 0.004; period B, days 45 to 50, delta of -0.042 mg, p = 0.002). The impact of the same duration of oligohydramnios on lung growth later in gestation, during the terminal sac stage of lung development, was less (period C, days 50 to 55, delta of -0.027 mg, p = 0.097). This reduction in effect between period A or B and C was significant at the 0.05 level using a one-way analysis of variance. Two overlapping 10-day periods were also studied. In both experiments, the percent changes in lung DNA per gram of fetal weight between experimental and littermate controls were significant (period D, days 40 to 50, delta of -0.072 mg, p = 0.001; period E, days 45 to 55, delta of -0.047 mg, p = 0.001). The inhibitory effect of oligohydramnios on lung growth was more marked in period D than E (significant at the 0.05 level).(ABSTRACT TRUNCATED AT 250 WORDS)     

Sp?tmetastase eines Granulosazelltumors bei einer 74-j?hrigen Patientin

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