Persistence of herpes simplex virus types 1 and 2 in infected individuals.

During a 23-month period, 18 patients with facial or genital herpetic lesions were examined; culture specimens from each patient were obtained three times per week for virologic studies. The isolated viruses were identified, and the average duration of herpesvirus in lesions was determined. Herpes simplex virus type 1 (HSV-1) was isolated from facial lesions for a mean duration of 3 1/2 days. In contrast, herpes simplex virus type 2 (HSV-2) was isolated from genital lesions for a mean duration of 5 1/2 days. The duration of viral persistence in lesions of patients with mild primary infection did not seem to differ from that in patients with recurrent infection.     

In vitro autoradiography of serotonin 5-HT(2A/2C) receptor-activated G protein: guanosine-5'-(gamma-[(35)S]thio)triphosphate binding in rat brain

Agonist activation of G protein-coupled receptors induces an increase in the binding of guanosine 5'-(gamma-[(35)S]thio)triphosphate ([(35)S]GTPgammaS); this increase in binding has been used as a tool to investigate receptor interaction with the heterotrimer guanine nucleotide-binding regulatory protein (G protein). The present study uses agonist-stimulated [(35)S]GTPgammaS binding to characterize serotonin 5-HT(2A/2C) receptors in rat brain membrane fractions and demonstrate the anatomical localization of the receptors by in vitro autoradiography on slide-mounted sections. The stimulatory effect of the agonist [1-(2,5-dimethoxy-4-iodophenyl)]-2 aminopropane (DOI) is compared to that of serotonin (5-HT). Autoradiography revealed a similar localization of DOI- and 5-HT-stimulated binding of [(35)S]GTPgammaS in distinct areas of prefrontal and parietal cortex, consistent with previously reported 5-HT(2A) receptor distribution. Specific binding was demonstrated in the frontal and parietal cortex, medial prefrontal, and cingular and orbital-insular areas as well as in the hippocampal formation, septal areas, the nucleus accumbens, and the choroid plexus. MDL 100105, a specific 5-HT(2A) antagonist, and ketanserin, an antagonist of 5-HT(2A/2C) receptors, blocked DOI stimulation in all labeled areas, whereas 5-HT stimulation was only partially blocked (70-80%). A small but significant inhibition was observed with the specific antagonist of 5-HT(2C/2B), SB 206553. This autoradiographic technique provides a useful tool for measuring in situ changes in specific receptor-Gq protein coupling in anatomically discrete brain regions, under physiological and pathological conditions.     

CARDIOVASCULAR ACTIVITY OF 14-DEOXY-11, 12-DIDEHYDROANDROGRAPHOLIDE IN THE ANAESTHETISED RAT AND ISOLATED RIGHT ATRIA

The cardiovascular activity of 14-deoxy-11,12-didehydroandrographolide (DDA) fromAndrographis paniculata(Burm.f.) Nees (Acanthaceae) was elucidated in anaesthetised Sprague–Dawley (SD) rats and isolated rat right atria. In anaesthetised rats, DDA produced significant falls in mean arterial blood pressure (MAP) and heart rate in a dose-dependent manner with the maximum decrease of 37.6±2.6% and 18.1±4.8%, respectively. The ED₅₀value for MAP was 3.43 mmol kg⁻¹. Pharmacological antagonist studies were done using this dose. The hypotensive action of DDA was not mediated through effects on the α-adrenoceptor, muscarinic cholinergic and histaminergic receptors, for it was not affected by phentolamine, atropine as well as pyrilamine and cimetidine. However, it seems to work via adrenoceptors, autonomic ganglia receptor and angiotensin-converting enzyme, since the hypotensive effect of DDA was negated or attenuated in the presence of propranolol, hexamethonium and captopril. In the isolated right atria, DDA caused negative chronotropic action and antagonised isoproterenol-induced positive chronotropic actions in a non-competitive and dose-dependent manner. These results further supported the bradycardia-inducing and β-adrenoceptor antagonistic properties of DDAin vivo.     

Prognostic factors and therapeutic options of radiotherapy in pediatric brain stem gliomas

BACKGROUND: A retrospective analysis was made to clarify the relationship between prognosis, radiation dose and survival of brain stem gliomas. METHODS: From 1983 to 1995, 22 children with brain stem tumors were treated by radiotherapy in the Veterans General Hospital-Taipei. Twelve patients had pathology proof and the remainder were diagnosed by computerized tomography and/or magnetic resonance imaging. Seven patients had postoperative radiotherapy. Fifteen patients had radiotherapy as primary management, five of whom had adjuvant chemotherapy. All patients received 4000-7060 cGy, either in conventional daily or hyperfractionated twice daily radiotherapy. Survival from date of diagnosis was calculated by the Kaplan-Meier method. Univariate analyses and multivariate analyses were calculated by the log rank test and the Cox proportional hazard model, respectively. RESULTS: Most patients showed improvement following treatment. The overall 2-year survival rate was 55.5% with a median survival of 27.1 months. Two-year survival for patients with primary management of operation and radiotherapy (n = 7), radiotherapy alone (n = 10) and radiotherapy with adjuvant chemotherapy (n = 5) were 66.7, 50 and 53.3%, respectively. In univariate analysis, the study revealed that the growth pattern of tumors and the simultaneous presence of cranial neuropathy and long tract sign were significant prognostic factors (P = 0.017 and 0.036). A trend of better outcome with radiation dose > 6600 cGy and the hyperfractionation scheme was also noted in our study (P = 0.0573 and 0.0615). However, only the hyperfractionation scheme was also noted in our study (P = 0.0573 and 0.0615). However, only the hyperfractionation scheme showed significance in multivariate analyses (P = 0.0355). Survival was not significantly affected by age, gender or method of diagnosis. CONCLUSION: Radiotherapy appears to be an effective treatment modality of brain stem tumors. Patients with both cranial neuropathy and long tract signs had a poorer outcome. Hyperfractionated radiotherapy may give better local control and lead to better survival.      

In vitro effects of VD-99-11 onAngiostrongylus cantonensis and isolated frog rectus

In vitro effects of VD-99-11 were examined using adultAngiostrongylus cantonensis and isolated frog rectus. InA. cantonensis, paralysis was elicited by VD-99-11 at 10^–9–10^–6 g/ml. The paralysis caused by VD-99-11 (10^–8 g/ml) was antagonized by picrotoxin or bicuculline but not by phentolamine. A relationship between VD-99-11 and gabergic antagonists was observed in worm preparations contracted by eserine or pyrantel: VD-99-11 at higher concentrations (3×10^–6 g/ml) caused a marked contraction. In worm preparations contracted with eserine or pyrantel, the only additional contraction induced by VD-99-11 (5×10^–6 g/ml) was antagonized by strychnine. In experiments on the guanidine (2.5×10^–3 M)-induced twitch responses in isolated frog rectus, marked stimulation was caused by VD-99-11 (3–5×10^–6 g/ml). The stimulated responses induced by VD-99-11 were antagonized by tetrodotoxin,d-tubocurarine, strychnine, and hemicholinium-3, respectively. These results suggest that VD-99-11 seems superior to milbemycin D, milbemycin oxime, and ivermectin in some aspects, such as in vitro potency, though this new substance is similar to these drugs in having two different actions on the gabergic mechanism at lower concentrations and on the cholinergic mechanism at higher concentrations.     

A genome-wide association study identifies a breast cancer risk variant in ERBB4 at 2q34: results from the Seoul Breast Cancer Study

Introduction

Although approximately 25 common genetic susceptibility loci have been identified to be independently associated with breast cancer risk through genome-wide association studies (GWAS), the genetic risk variants reported to date only explain a small fraction of the heritability of breast cancer. Furthermore, GWAS-identified loci were primarily identified in women of European descent.

Methods

To evaluate previously identified loci in Korean women and to identify additional novel breast cancer susceptibility variants, we conducted a three-stage GWAS that included 6,322 cases and 5,897 controls.

Results

In the validation study using Stage I of the 2,273 cases and 2,052 controls, seven GWAS-identified loci [5q11.2/MAP3K1 (rs889312 and rs16886165), 5p15.2/ROPN1L (rs1092913), 5q12/MRPS30 (rs7716600), 6q25.1/ESR1 (rs2046210 and rs3734802), 8q24.21 (rs1562430), 10q26.13/FGFR2 (rs10736303), and 16q12.1/TOX3 (rs4784227 and rs3803662)] were significantly associated with breast cancer risk in Korean women (P _trend < 0.05). To identify additional genetic risk variants, we selected the most promising 17 SNPs in Stage I and replicated these SNPs in 2,052 cases and 2,169 controls (Stage II). Four SNPs were further evaluated in 1,997 cases and 1,676 controls (Stage III). SNP rs13393577 at chromosome 2q34, located in the Epidermal Growth Factor Receptor 4 (ERBB4) gene, showed a consistent association with breast cancer risk with combined odds ratios (95% CI) of 1.53 (1.37-1.70) (combined P for trend = 8.8 × 10^-14).

Conclusions

This study shows that seven breast cancer susceptibility loci, which were previously identified in European and/or Chinese populations, could be directly replicated in Korean women. Furthermore, this study provides strong evidence implicating rs13393577 at 2q34 as a new risk variant for breast cancer.     

EGFR exon 19 in‐frame deletion and polymorphisms of DNA repair genes in never‐smoking female lung adenocarcinoma patients

We explored potential associations between genetic polymorphisms in genes related to DNA repair and detoxification metabolism and epidermal growth factor receptor (EGFR) mutations in a cohort of 410 never‐smoking patients with lung adenocarcinoma. Multivariate‐adjusted odds ratios (aORs) and corresponding 95% confidence intervals (CI) of EGFR mutation status in association with the genotypes of DNA repair and detoxification metabolism genes were evaluated using logistic regression analysis. We found an association between in‐frame deletion in EGFR exon 19 and a single nucleotide polymorphism (SNP) rs1800566C/T located in NQO1 (aOR, 2.2 with 95% CI, 1.0–4.8) in female never‐smokers. The SNP rs744154C/G in ERCC4 was also associated with the EGFR exon 19 in‐frame deletion both in never‐smokers (aOR, 1.7 with 95% CI, 1.0–3.0) and female never‐smokers (aOR, 1.9 with 95% CI, 1.0–3.6). Although the association was marginally significant in multivariate logistic regression analysis, the A/A genotype of rs1047840 in EXO1 was associated with a 7.6‐fold increase in the occurrence of the EGFR exon 19 in‐frame deletion in female never‐smokers. Moreover, risk alleles in NQO1, ERCC4 and EXO1 were associated with an increasing aOR of the EGFR exon 19 in‐frame deletion both in never‐smokers (p = 0.007 for trend) and female never‐smokers (p = 0.002 for trend). Our findings suggest that the in‐frame deletion in EGFR exon 19 is associated with polymorphisms in DNA repair and detoxification metabolism genes in never‐smoking lung adenocarcinoma patients, especially in females.