Altered enzyme activities of xenobiotic biotransformation in kidneys after subchronic administration of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) to rats

Activities of the xenobiotic metabolizing enzymes were measured in the liver, kidney, duodenum and lung microsomes and cytosol fractions of Wistar rats after subchronic administration of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), a potent bacterial mutagen in chlorinated drinking water. MX was administered by gavage at the dose level of 30 mg/kg for 18 weeks (low dose), or at the dose level which was raised gradually from 45 mg/kg for 7 weeks via 60 mg/kg for 2 weeks to a clearly toxic dose of 75 mg/kg for 5 weeks (high dose). Microsomal and cytosolic preparations were made and the activities of 7-ethoxyresorufin-O-deethylase (EROD), pentoxyresorufin-O-dealkylase (PROD), NADPH-cytochrome-c-reductase, UDP-glucuronosyltransferase (UDPGT) and glutathione-S-transferase (GST) were measured. Kidneys were affected most. A dose-dependent decrease was observed in EROD (90% in males, 80% in females at the high dose) and in PROD (58% in females, at the high dose) in kidneys. An increase was, however, detected in kidney NADPH-cytochrome-c-reductase (66% in females at high dose), UDPGT (89% in males and 97% in females at high dose) and GST activities (56% in males and 50% in females at high dose). MX caused only a few changes in the enzyme activities of the liver. The EROD activity was decreased 25% to 37%, both in the livers of males and females, but the total content of P450s was not altered. Hepatic GST activity was elevated in females in a dose-dependent manner (31% and 44%). GST activity was elevated in duodenum in females (59%) at the high dose. There were no marked changes in the enzyme activities in the lungs. MX was a weak inhibitor of EROD activity both in the liver and kidney microsomes in vitro, decreasing the EROD activity by 53% and 43%, respectively at the concentration of 0.9 mM. The results indicate that MX decreases the activity of phase I metabolism enzymes, but induces phase II conjugation enzyme activities, particularly in kidneys in vivo. It is possible that these changes contribute to metabolism of MX in kidneys and renders them susceptible to MX in the course of repeated exposure.     

Electrocardiographic changes during and after isoflurane-induced hypotension for neurovascular surgery

We evaluated the effects of isoflurane anaesthesia and induced hypotension in 33 neurosurgical patients by electrocardiographic monitoring and serial cardiac enzyme measurements. An electrocardiogram (ECG) and serum enzymes were obtained preoperatively, intraoperatively and postoperatively in the recovery room and for three consecutive days. ECG leads II, V1 and V5 were monitored continuously during anaesthesia. Patients who had had a subarachnoid haemorrhage and a high incidence of abnormal preoperative ECG (42 per cent). Ten patients developed ECG changes intraoperatively, but these changes were unrelated to isoflurane-induced hypotension. Fifty-three per cent of patients developed an abnormal postoperative ECG. These abnormalities consisted mostly of nonspecific ST segment or T wave changes. At no time was there an elevation in cardiac enzyme activity. We found that nonspecific ECG changes are relatively common in patients undergoing vascular neurosurgical procedures. There was no enzymatic evidence of myocardial infarction and we can only speculate that these ECG changes are related to intracranial surgical manipulation.     

Pneumococcal Vaccination in the Elderly

Pneumococcal infections, especially pneumococcal pneumonia and pneumococcal bacteraemia are leading causes of morbidity and mortality among the elderly. The emergence of penicillin-resistant pneumococcal strains together with the growing number of old people have emphasised the need for prevention of pneumococcal infections. Prospective cohort studies with pneumonia as the endpoint have so far left open the question of the rationale of vaccinating the risk groups with pneumococcal vaccine. Pneumococcal vaccine has been proven effective against pneumococcal bacteraemia, but the incidence of that disease and thus its importance to the individuals themselves and to the healthcare system is small. Adverse events associated with pneumococcal vaccine are quite frequent but, especially in the elderly, mild and do not limit its use. Clinicians should keep the pneumococcal vaccine in mind and discuss its use with their patients at increased risk for pneumococcal infection. However, before pneumococcal vaccine can be included in national vaccination programmes, its cost-effectiveness in preventing invasive infections must be assured or definitive evidence obtained of its effectiveness against non-invasive pneumococcal infection.     

Immunohistochemical localization of syndecan-1 in normal and pathological human uterine cervix

Expression of syndecan-1, a cell surface proteoglycan that binds growth factors and extracellular matrix components, was studied in normal and pathological human uterine cervix using immunohistochemical methods. Normal cervical squamous epithelium showed positive staining for syndecan-1 in all cell layers, except the basal cell layer, whereas endocervical columnar epithelium stained weakly. In non-neoplastic reactive lesions, metaplastic squamous cells were positive for syndecan-1, whereas columnar cells showed weak or negative staining. In cervical condylomas, cells showing koilocytotic atypia were positive for syndecan-1. The progression of cervical intraepithelial neoplasia (CIN) grade I to grade III was associated with reduced syndecan-1 expression and localization of syndecan-1 to more superficial cell layers. In squamous cell carcinomas (SCCs), syndecan-1 expression correlated with histological differentiation, being absent from most poorly differentiated tumours. The results suggest that loss of syndecan-1 from atypical cells is an early event during cervical carcinogenesis and show a close association of syndecan-1 expression with preserved epithelial morphology and differentiation.     

Estrogen receptor genotype modulates myocardial perfusion in young men

Most of the effects of estrogens are mediated by estrogen receptors. Vascular endothelial cells and smooth muscle cells express estrogen receptor (ESR1) in both genders. A long genotype group of a common thymine-adenine (TA) dinucleotide repeat polymorphism in the regulatory region of this gene has previously been related to coronary artery disease. The present study examined whether coronary blood flow is affected by this genotype. A total of 49 healthy men were genotyped by PCR and divided into three groups according to median number of the ESR1 promoter TA repeat (=19), i.e., in the short allele genotype group both alleles were of fewer than 19 repeats whereas in the long allele group both alleles were 19 repeats or more. The intermediate group comprised men who had one short and one long allele. Myocardial blood flow was measured by positron emission tomography using [¹⁵O]water, performed at rest and during adenosine stimulation. Men with long alleles had lower adenosine-stimulated coronary flow than those with short alleles and those with one short and one long allelle. Our results suggest that adenosine-stimulated myocardial perfusion is lower in subjects with ESR1 long alleles than the other TA repeat genotypes.     

A novel loss of function mutation in exon 10 of the FSH receptor gene causing hypergonadotrophic hypogonadism: clinical and molecular characteristics

BACKGROUND: Inactivating mutations of the FSH receptor (FSHR) are a rare cause of hypergonadotrophic hypogonadism in women. Only one patient with primary amenorrhoea due to an FSHR gene mutation has been reported outside of Finland, where the prevalence of Ala189Val mutations is particularly high. METHODS AND RESULTS: Here, we describe the clinical, molecular genetic and functional characteristics associated with a novel inactivating mutation in exon 10 of the FSHR gene identified in a patient who presented with primary amenorrhoea at 17 years of age. The C to G transversion found at nucleotide 1043 causes a Pro348Arg substitution in the extracellular region of the FSHR and results in a mutant FSHR that is completely inactive in functional studies and that does not bind FSH. The proband exhibits apparent homozygosity for this recessive mutation. Her father is heterozygous for the mutation while analysis of exon 10 of the FSHR gene from her mother revealed only wild-type sequence. Chromosome painting was used to exclude deletions or rearrangements of 2p, and microsatellite markers did not show paternal uniparental isodisomy for this region. These findings suggest that the proband is hemizygous, with an inherited or de-novo microdeletion, or alternatively a de-novo gene conversion, of the accompanying FSHR allele. CONCLUSIONS: This case confirms the importance of the FSHR in female pubertal development and reproduction, and supports a relationship between phenotype and function for FSHR mutations.     

Potentiation of central effects of L-dopa by an inhibitor of catechol-O-methyltransferase

Summary The effects of a COMT-inhibitor, U-0521, and a MAO-B-inhibitor, l-deprenyl, on L-dopa-induced circling behaviour were compared in 6-OHDA-lesioned rats. The actions of U-0521 and l-deprenyl on the anticataleptic effect of L-dopa were also studied. Both U-0521 and l-deprenyl were found to potentiate L-dopa-induced circling behaviour and anticataleptic effect of L-dopa. In both test systems the L-dopa potentiation of l-deprenyl was longer-lasting than that caused by U-0521. Thus inhibition of COMT, like inhibition of MAO, is able to enhance the central effects of L-dopa. This principle might be beneficial in the treatment of Parkinson's disease especially if COMT-inhibitors with greater performance can be developed.     

High expression of nitric oxide synthases is a favorable prognostic sign in non-small cell lung carcinoma

Immunohistochemical expression of neuronal (n), endothelial (e), and inducible (i) NOS and their association with the type, grade, apoptotic index, proliferation of tumors and the survival of patients were investigated in 89 biopsies of non-small cell lung carcinoma (NSCLC). In tumor cells, expression of iNOS was detected in 35/89 (40%) cases, while 79/89 (89%) and 72/89 (81%) cases showed weak to intense positivity for eNOS and nNOS, respectively. Strong eNOS staining was seen significantly more often in adenocarcinomas than in squamous cells carcinomas (p=0.016), and iNOS immunoreactivity was seen more often in grade I-II tumors than in grade III tumors (p=0.024). There was no significant difference between the low and high apoptotic indexes or between the low and high proliferation rates of tumors in any instance of NOS staining. The patients with tumors showing high nNOS expression tended to have better survival than the others (p=0.06, log-rank; p=0.04, Bresow; p=0.048, Tarone-Ware). Similarly, the patients with tumors showing high expression of iNOS, eNOS and nNOS, as determined by a combined sum index, had a better survival than those with a low sum index for these enzymes (p<0.05). The results show intense expression of eNOS and nNOS, and moderate expression of iNOS in tumor cells of non-small cell carcinoma. Intense NOSs expression seems to be a favorable prognostic sign in non-small cell lung carcinoma.     

Serum levels of vitamin D metabolites and the subsequent risk of colon and rectal cancer in Finnish men

Experimental and human epidemiologic data suggest a protective rolefor vitamin D in large bowel cancer. To investigate this association, weconducted a nested case-control study within a Finnish clinical trial cohort.Cases (n = 146) were participants diagnosed with primary adenocarcinoma ofthe large bowel. Controls were matched (2:1) to cases on age, date ofbaseline blood draw, and study clinic. Prediagnostic serum levels of thevitamin D metabolites, 25-hydroxyvitamin D (25-OH D), and1,25-dihydroxyvitamin D (1,25-DIOHD) were used as primary exposure measures.The baseline geometric-mean serum level of 25-OH D was 11.6 percent lower incases than in controls (12.2 cf 13.8 ug/l, P = 0.01) while serum levels of1,25-DIOH D did not differ by case-control status. No association was seenbetween serum levels of 1,25-DIOH D and large bowel cancer risk. However, theestimated relative risk (RR) of large bowel cancer decreased with increasinglevel of serum 25-OH D and the associa tion was more pronounced for rectalcancer (55 cases; RR by quartile = 1.00, 0.93, 0.77, 0.37; trend P = 0.06).Neither exclusion of early cases nor multivariate adjustment for potentialconfounders materially altered these estimates. There was no evidence ofeffect modification by level of 1,25-dihydroxyvitamin D or with other knownrisk-factors for large bowel cancer.