Experimental analysis of antimicrobial action of dicyclomine hydrochloride

Dicyclomine hydrochloride is an antispasmodic agent. The MIC of dicyclomine against standard strains of Gram positive and Gram negative bacteria were performed by NCCLS broth dilution technique. These drugs showed a rapid killing action on Gram positive bacteria, Staphylococcus aureus NCTC 6571, 8530 and several other reference strains. The killing effect against Gram negative bacteria, Shigella boydii 8 NCTC 254/66 and Salmonella typhimurium NCTC 74 showed that the drug was bacteriostatic with respect to these strains. High rate of killing was achieved for most strains of Gram positive bacteria within 2 h. When administered to Swiss strain of white mice at doses of 30 and 60 microg/g of mouse, the drug could significantly protect the animals challenged with 50 MLD of Salmonella typhimurium NCTC 74. According to chi2 test, the in vivo data were highly significant (p<0.001). Since dicyclomine showed a remarkable inhibitory action against several pathogenic bacteria, in the course of time, it may be developed as a potent antimicrobial agent for many bacterial infections.     

Urinary incontinence among mothers of multiples: the protective effect of cesarean delivery

OBJECTIVE: The purpose of this study was to assess the impact of delivery mode on the risk of urinary incontinence among women with previous multiple childbirth. STUDY DESIGN: A 77-item questionnaire was administered to 733 mothers of multiples. Multivariate regression was used to control for potentially confounding variables. RESULTS: The mean rate of stress urinary incontinence among women who were delivered by cesarean-only delivery was 39.6%, which was significantly lower than the 60.4% among women who reported previous vaginal births (P =.005). Cesarean-only delivery was associated with a markedly reduced risk (odds ratio, 0.52; P =.002) after controlling for age, parity, and body mass index by multivariate regression. Weaker associations were found for age (odds ratio, 1.08), body mass index (odds ratio, 1.06), and parity (odds ratio, 1.46). Urge incontinence was associated with parity, body mass index, and age, but not delivery mode (P =.76). CONCLUSION: Vaginal delivery represents a major risk factor for stress incontinence among mothers of multiples. Delivery by cesarean delivery only confers an independent protective effect.     

Evaluation of anti-inflammatory activity of chloroform extract of Bryonia laciniosa in experimental animal models

The anti-inflammatory effect of the leaves of Bryonia laciniosa was evaluated using carrageenan, dextran, histamine, serotonin induced rat paw oedema and cotton pellet induced granuloma (chronic) models in rats. In mice, carrageenan peritonitis test was performed for the extract by oral administration. The chloroform extract of Bryonia laciniosa (CEBL) exhibited significant anti-inflammatory effect at the dose 50, 100 and 200 mg/kg. Maximum inhibition (52.4%) was noted at the dose of 200 mg/kg after 3 h of drug treatment in carrageenan induced paw oedema, whereas the indomethacin (standard drug) produced 62.1% of inhibition. The extract exhibited significant anti-inflammatory activity in dextran induced paw oedema in a dose dependent manner. The extract also exhibited significant inhibition on the hind paw oedema in rats caused by histamine and serotonin respectively. In the chronic model (cotton pellet induced granuloma) the CEBL (200 mg/kg) and standard drug showed decreased formation of granuloma tissue by 50.1 and 57.3% (p<0.001) respectively. The extract also inhibited peritoneal leukocyte migration in mice. Thus, the present study revealed that the chloroform extract of Bryonia laciniosa exhibited significant anti-inflammatory activity in the tested models.     

Identification of tamoxifen-DNA adducts in monkeys treated with tamoxifen

The risk of developing endometrial cancer is increased in breast cancer patients treated with tamoxifen (TAM) and in healthy women undergoing TAM chemoprevention. We have detected previously TAM-DNA adducts in the endometrium of women receiving TAM (Shibutani et al., Carcinogenesis, 21: 1461-1467, 2000). To investigate the genotoxic damage induced by TAM in the uterus and other tissues of primates, we gave adult female cynomolgus monkeys six times the human-equivalent dose of TAM (2 mg/kg body weight/day) for 30 days. DNA samples were prepared from the uterus, ovary, liver, kidney, and brain cortex of three TAM-exposed monkeys and one control monkey and were analyzed as coded specimens. To identify the TAM-DNA adducts, we established a new high-performance liquid chromatography gradient system for (32)P-postlabeling/high-performance liquid chromatography analysis, which can resolve the trans- and cis-diastereoisomers of alpha-(N(2)-deoxyguanosinyl)TAM (dG-N(2)-TAM), alpha-(N(2)-deoxyguanosinyl)-N-desmethylTAM, and alpha-(N(2)-deoxyguanosinyl)tamoxifen N-oxide. Trans-forms of dG-N(2)-TAM and dG-N(2)-N-desTAM adducts were detected in the livers of all three TAM-fed monkeys at levels of 2.7 adducts/10(8) nucleotides and 1.7 adducts/10(8) nucleotides, respectively. The levels of dG-N(2)-TAM adducts observed in the uterus of one monkey and in the ovaries of two monkeys were approximately 10-fold lower than those observed in the livers. TAM exposure also induced dG-N(2)-TAM adduct in the brain cortex of all three monkeys with a value of 1.5 adducts/10(8) nucleotides. No TAM-DNA adducts were detected in the kidneys or in any tissues obtained from the unexposed monkey. Our results suggest that women receiving TAM may form genotoxic damage in many organs, including the reproductive organs.     

Mutagenic events induced by 4-hydroxyequilin in supF shuttle vector plasmid propagated in human cells

Increased incidence of breast, ovarian and endometrial cancers are observed in women receiving estrogen replacement therapy (ERT). Equilin and equilenin are the major components of the widely prescribed drug used for ERT. These equine estrogens are metabolized primarily to 4-hydroxyequilin (4-OHEQ) and 4-hydroxyequilenin, respectively, which are autoxidized to react with DNA, resulting in the various DNA damages. To explore the mutagenic potential of equine estrogen metabolites, a double-stranded pMY189 shuttle vector carrying a bacteria suppressor tRNA gene, supF, was exposed to 4-OHEQ and transfected into human fibroblast. Plasmids containing mutations in the supF gene were detected with indicator bacteria and mutated colonies obtained were analyzed by automatic DNA sequencing. The proportion of plasmids with the mutated supF gene was increased dose-dependently. The majority of the 4-OHEQ-induced mutations were base substitutions (78%); another 22% were deletions and insertions. Among the base substitutions, 56% were single base substitutions and 19% were multiple base substitutions. The majority (86%) of the 4-OHEQ-induced single base substitutions occurred at the C:G site. C:G --> G:C and C:G --> A:T mutations were detected preferentially with lesser numbers of C:G --> T:A transitions. Sixty-two percent of base substitutions were observed particularly at C:G pairs in (5')-TC/AG-(5') sequences. Using (32)P-post-labeling/gel electrophoresis analysis, 4-OHEN-dC was a major adduct, followed by lesser amounts of 4-OHEN-dA adduct. Mutations observed at C:G pairs may result from 4-OHEN-dC adduct. These results indicated that 4-OHEQ is mutagenic, generating mutations primarily at C:G pairs in (5')-TC/AG-(5') sequences.     

Serum nitrate levels as an index of endothelial function in pre-eclamsia and normal pregnancy

The study was conducted in St. John's Medical College Hospital and Department of Physiology, with the aim of studying the serum nitrate levels in pre-eclampsia and normal pregnancy. The total number of subjects studied in various groups were 159, control (n = 55), first trimester (n = 13), second trimester normal (n = 42), second trimester pre-eclampsia/PET (n = 5), third trimester normal (n = 32), third trimester pre-eclampsia/PET (n = 12). The serum nitrate was measured by one step enzymatic assay using Nitrate reductase from Aspergillus species. The nitrate levels in the third trimester pre-eclamptic group was found to be significant lower (P = 0.02), as compared to normal subjects, however the renal functions were normal in all the subjects.     

Generalisation of conditioned fear and its behavioural expression in mice

Mice are favourite subjects in molecular and genetic memory research and frequently studied with classical fear conditioning paradigms that use an auditory cue (conditioned stimulus, CS(+)) to predict an aversive, unconditioned stimulus (US). Yet the conditions that control fear memory specificity and generalisation and their behavioural expression in such conditioned mice have not been analysed systematically. In the current study we addressed these issues in the most widely used mouse strain of behavioural genetics, C57Bl/6. In keeping with findings in other species we demonstrate the dependence of fear memory generalisation on training intensity (i.e. both US intensity and the number of CS(+) and US applied) after both excitatory (explicitly paired presentation of CS(+) and US) and inhibitory training (explicitly unpaired presentation of CS(+) and US). Furthermore, inhibitory overtraining was associated with changes of uncued anxiety-like behaviour in a light/dark exploration test, indicative of an emotional sensitisation reaction as consequence of a lack of US predictability. Together our results describe the qualitatively and quantitatively different increases of defensive behaviour in response to conditioned stimuli of different salience and identify training conditions that lead to fear memory generalisation and emotional sensitisation in C57Bl/6 inbred mice.     

Sinocranial aspergillosis: a form of central nervous system aspergillosis in south India

Of the 21 patients with aspergillosis of central nervous system seen during the years 1990-1997, 16 (76%) had aspergillosis of sino-cranial origin. The occupation in patients with sino-cranial aspergillosis was either agricultural or manual work and predisposing risk factors were present in only two (12.5%) patients. Skull-base syndromes were the presenting features in 13 patients and three patients presented with features of intracranial space-occupying lesion. Paranasal sinus mass lesions were seen in all the 16 patients. Computerized tomography showed intracranial extradural-enhancing mass lesions in the anterior, middle or posterior cranial fossa in nine (68%) patients, intracranial and orbital lesions in four and orbital lesions in three. Well-formed granuloma with dense fibrosis was the histological feature. Survival rates were not good even after surgical and antifungal chemotherapy. Surgical treatment was subradical in our series. The majority of cases of sinocranial aspergillosis are reported from countries with temperate climates and the high incidence in these regions is probably related to constant exposure to the high spore content of pathogenic Aspergillus species in the 'mouldy' work environment.