Species differences in blood-mediated nitrosocimetidine denitrosation

Nitrosocimetidine (NC) is the nitrosated derivative of cimetidine (Tagamet), a p.o. administered drug used widely in the treatment of stomach ulcers. NC is capable of methylating DNA in vitro and in cultured cells in a manner similar to that of the laboratory carcinogens 1-methyl-2-nitro-1-nitrosoguanidine and methylnitrosourea (MNU) and gives positive indications in short-term in vitro tests for genotoxicity, generally held to be prognostic of compound carcinogenic potential. Nevertheless NC has been found to be a weak or non-carcinogen in the rat and mouse model systems and to produce minimal levels of tissue DNA alkylation when dosed p.o. or i.v. to rats. The results from our earlier experiments (D. E. Jensen, Cancer Res., 43: 5258-5267, 1983) indicated that compound denitrosation is the primary fate of NC in the rat and suggested that denitrosation is the blood, mediated by hemoglobin sulfhydryl residues, is perhaps the major detoxification mechanism. We now report that whole blood and hemoglobin isolated from various mammalian species differ in their capacity for NC degradation rate enhancement and for compound denitrosation. The observed whole blood activity in the degradation reaction (rat greater than mouse/guinea pig greater than human/hamster) paralleled the hemoglobin activity. The NC half-life in isolated rat blood, 37 degrees C, was found to be about 2 min and in hamster or human blood 27 min. For reference, the MNU half-life in isolated blood is 8 min. Compound denitrosation accounted for at least 75% of the degradation in rat blood and 40 to 55% in human and hamster blood. Parallel NC denitrosation activity was found in the various hemoglobin preparations. The NC degradation rates in the presence of the several hemoglobin species were roughly proportional to the number of sulfhydryls on the hemoglobin tetramers available for reaction with p-chloromercuribenzoate and approximated the rates observed in solutions containing equivalent concentrations of L-cysteine. The percentage of total decomposition due to compound denitrosation in the presence of rat hemoglobin, 95%, was found to be unique relative to the L-cysteine-mediated reactions (about 35%) and the reactions studied over the pH range 6 through 10, the denitrosation process never accounted for more than 50% of the total degradation. Chemically blocking the sulfhydryls on human hemoglobin using iodoacetamide deleted the NC degradation rate enhancement. We found no evidence for nitrosylhemoglobin formation.(ABSTRACT TRUNCATED AT 400 WORDS)     

Gastroduodenal mucosal hemodynamics by endoscopic reflectance spectrophotometry

The reflectance spectrophotometric technique measures an index of mucosal hemoglobin concentration and an index of oxygen saturation by spectral analysis of light reflected from the mucosal surface. Using a commercially available unit, a technique for obtaining reproducible endoscopic measurements with acceptable intraobserver and interobserver variability was developed in the anesthetized dogs. The reflectance spectrophotometric finding that experimentally induced prehepatic portal hypertension did not affect gastric mucosal blood flow was confirmed by hydrogen gas clearance measurements. Endoscopic studies in patients with active duodenal ulcer disease revealed a higher index of mucosal hemoglobin concentration and a normal index of oxygen saturation (i.e., an increase in blood flow) at the margin of the ulcer compared with the adjacent normal appearing mucosa.     

Isolation of pathogenic bacteria from hospital staff apparel in Nigeria

A survey of bacteria contamination of hospital staff apparel in use in Anambra State, Nigeria, was carried out to determine the extent of contamination by clinically important bacteria. Of a total of 125 swab samples of hospital staff apparel, 72 (58%) showed bacterial contamination including 32 (70%) of 46 samples from hand gloves, 28 of 45 (62%) samples from protective gowns, and 12 of 34 (35%) samples from face-shields. The potentially pathogenic bacteria isolated were Salmonella spp, Proteus vulgaris, Shigella dysenteriae, Pseudomonas aeruginosa and Staphylococcus aureus. The isolation of clinically important bacteria from the apparel suggests the need for improved infection control measures.     

The effects of peripherald-amphetamine, 4-OH amphetamine, and epinephrine on maintained discharge in the locus coeruleus with reference to the modulation of learning and memory by these substances

d-Amphetamine, 4-OH amphetamine, and epinephrine have been shown in many behavioral studies to facilitate memory when given post-training. The effect of these drugs on the maintained discharge of cells in the locus coeruleus (LC) was investigated using a route of administration (intraperitoneal) and a log-dose range of these drugs comparable to those used in the behavioral experiments.d-Amphetamine profoundly suppressed maintained discharge: an inhibitory effect was observed at every dose (0.1, 1.0, 10.0 mg/kg). In contrast, only the highest dose of 4-OH amphetamine (8.2 mg/kg) inhibited activity in the LC, and this effect was a modest one. Unlike the amphetamines, epinephrine (500 μ/kg) elevated maintained discharge. These results are discussed in the contex of the hypothesized involvement of the LC in the enhancement of memory by these drugs.     

Effect of high hematocrit and high blood flow rates on transmembrane pressure and ultrafiltration rate in hemodialysis.

Removal of prescribed ultrafiltration volumes in hemodialysis requires knowledge of both the ultrafiltration coefficient of the dialyzer and the average transmembrane pressure (TMP) in the dialyzer. While it has been a fairly common practice to assume that the TMP is constant along the length of the dialyzer, it actually decreases linearly from a maximum value at the blood inlet to a minimum value at the blood outlet. In the past, ignoring the difference between arterial and venous TMPs when calculating the dialysate pressure setting did not result in significant errors in ultrafiltration volume. However, with the introduction of erythropoietin therapy and the trend toward high-efficiency dialysis, increases in hematocrit and blood flow rate have led to axial variations in TMP which, if ignored, can lead to inaccurate fluid removal. The goals of this paper are to provide an understanding of how high hematocrits and high blood flow rates affect TMP and ultrafiltration rate, and to provide simple guidelines for ensuring accurate fluid removal. Sample calculations are given on the last page for easy reference.     

Application of fluorescence in situ hybridization techniques in clinical genetics: use of two alphoid repeat probes detecting the centromeres of chromosomes 13 and 21 or chromosomes 14 and 22, respectively

Two cloned DNA fragments, one derived from an alpha satellite subfamily common to chromosomes 13 and 21, and the other derived from a similar subfamily common to chromosomes 14 and 22, have been used as biotinylated probes in in situ hybridization studies. Under high stringency conditions, chromosome specific centromeric labelling can be obtained. The applications of this technique in clinical situations are illustrated on metaphases from a fetus with trisomy 21, a fetus with trisomy 13, and a child with clinical features of cat-eye syndrome.     

Single-dose and steady-state pharmacokinetics of diltiazem administered in two different tablet formulations.

Single-dose and steady state pharmacokinetics of diltiazem administered in two different oral formulations were assessed with particular reference to rate and extent of absorption. Following single dose administration a significant difference in tmax was observed (2.9 +/- 1.9 and 6.8 +/- 2.6 hr respectively) whereas differences in AUC, t1/2 and Cmax were not significant. The AUC (mean +/- S.D.) values following single dose administration of Cardil and Cardizem were 678.4 +/- 321.5 and 948.6 +/- 580.6 ng.ml-1.hr respectively. The mean and the 95% confidence limits for the observed ratio AUCCardil/AUCCardizem are 0.89 and 0.44-1.34 respectively. At steady-state a significant difference between Cmax/Cmin and tmax was seen Cmax/Cmin being 4.9 and 3.2 respectively and Tmax being 2.7 +/- 2.0 and 6.0 +/- 2.8 hr respectively, whereas Cmax and AUC did not differ significantly. The AUC (mean +/- S.D.) values in steady state of Cardil and Cardizem were 880.1 +/- 399.8 and 1056.8 +/- 509.8 ng.ml-1.hr respectively. The mean and the 95% confidence limits for the observed ratio AUCCardil/AUCCardizem are 0.96 and 0.66-1.26 respectively. Although the observed ratios AUCCardil/AUCCardizem in both the single-dose and the steady-state study do not differ significantly from 1.0, the confidence limits exceed the acceptable values given by Poulsen & Juul (personal communication 1990) (a 20% decrease or increase of the ratio to 0.8 or 1.2).     

Does the shunt opening pressure influence the effect of shunt surgery in normal pressure hydrocephalus?

Summary Thirteen patients with normal pressure hydrocephalus were operated upon with an externally manoeuvrable shunt system (Sophy SU8) in order to investigate its influence on clinical outcome, intracranial pressure and cranial CT parameters. The opening pressure was set at high at surgery and lowered stepwise at intervals of three months to medium and low. The clinical condition, intracranial pressure and cranial CT parameters were examined at the end of the 3 months interval on each pressure level.The patients improved within the first 3 months inspite of an unchanged mean intracranial pressure and remained in a stable clinical condition during the rest of the study period. The intracranial pressure was significantly reduced at 9 months. The ventricular index, Evans index, temporal horn and third ventricle width were reduced 3 months post-operatively and did not change significantly during the rest of the study. The pre-operative third ventricle width was correlated to high psychometric test results after shunt surgery. Reduction in ventricular index, Evans index and third ventricle width after surgery correlated to improvement in psychometric scoring.The clinical improvement after shunt surgery for normal pressure hydrocephalus is seen within 3 months and is independent of the adjusted valve pressure.     

Arteriovenous malformations that rupture during pregnancy: a management dilemma

Summary Intracranial haemorrhage due to rupture of an arteriovenous malformation (AVM) during pregnancy is a rare but serious condition that warrants prompt recognition. Once the diagnosis is made, the management is primarily based on neurosurgical rather than obstetric considerations. Due to its rarity, no definitive guidelines exist, and the best time to perform elective surgery (i.e., at presentation or at completion of the pregnancy) is ill-defined. This report describes three patients recently treated at our institution who had AVMs that ruptured during pregnancy. These cases well summarize the difficulties encountered in treating such patients. The diagnostic as well as the therapeutic implications of this condition are discussed.     

Comparison studies of HPV detection in areas at different risk for cervical cancer.

The hypothesis of a geographical correlation between HPV detection rates and incidence of cervical cancer has been investigated in studies of various types. However, results from these studies are equivocal, in contrast to findings concerning other suspected risk factors which seem to correlate well with the cervical cancer incidence. Possible explanations include (1) greater sensitivity of ecological studies to cumulative exposures such as lifetime number of sexual partners, lifetime smoking and seroprevalence of herpes simplex virus type 2, than to HPV DNA prevalence which does not reflect cumulative exposure to HPV and (2) misclassification in the HPV diagnosis leading to wrong prevalence estimates. In future research, it will be important to establish the sensitivity and specificity of the different methods and conduct intra- and interlaboratory validation studies in order to standardize methods. In spite of the limitations of cross-sectional studies, the measurement of HPV prevalence and its correlation with, for example, sexual behaviour is still valuable for our understanding and interpretation of the role of HPV infections.