Beneficial effects of S-adenosyl-L-methionine on blood-brain barrier breakdown and neuronal survival after transient cerebral ischemia in gerbils

In the present study, the effect of bradykinin on basal and precontracted mouse-isolated trachea was investigated. In basal conditions mouse-isolated tracheal rings do not respond to bradykinin. However, when the tracheal rings were precontracted with carbachol (10(-7) M) a relaxation with bradykinin (3 x 10(-9)-3 x 10(-7)) was found. The maximal response amounted 69.7+/-4.1% (n=15) with a pD2 value of 7.2+/-0.21. The selective bradykinin B2 receptor antagonist HOE 140 (10(-10)-10(-8) M) antagonized the bradykinin-induced relaxation, while the bradykinin B1 receptor antagonist des-Arg9-Leu8-bradykinin (10(-6) M) had no influence. The selective bradykinin B1 receptor agonist des-Arg9-bradykinin (10(-6) M) caused a small relaxation (8.4+/-2.5%, n=6), which could be antagonized completely by the selective bradykinin B1 receptor antagonist des-Arg9-Leu8-bradykinin (10(-6) M) while addition of the selective bradykinin B2 receptor antagonist HOE 140 (10(-8) M) was without effect. In the presence of indomethacin (10(-6) M) the relaxation of bradykinin was completely abolished. Pretreatment of the tracheal rings with capsaicin, or the presence of the selective NK1 receptor antagonist RP 67851 (10(-6) M) or the presence of the nitric oxide synthase inhibitor L-NAME (3 x 10(-4) M) had no effect on the bradykinin-induced relaxation. In conclusion, these results demonstrate that the mouse-isolated tracheal is a preparation in which bradykinin exerts a relaxant response via stimulation of bradykinin B2 receptors. This response is probably mediated by prostaglandins.     

Recurrent DNA copy number changes in 1q, 4q, 6q, 9p, 13q, 14q and 22q detected by comparative genomic hybridization in malignant mesothelioma

Comparative genomic hybridization (CGH) analyses were performed on 27 human pleural mesothelioma tumour specimens, consisting of 18 frozen tumours and nine paraffin-embedded tumours, to screen for gains and losses of DNA sequences. Copy number changes were detected in 15 of the 27 specimens with a range from one to eight per specimen. On average, more losses than gains of genetic material were observed. The loss of DNA sequences occurred most commonly in the short arm of chromosome 9 (p21-pter), in 60% of the abnormal specimens. Other losses among the abnormal specimens were frequently detected in the long arms of chromosomes 4 (q31.1-qter, 20%), 6 (q22-q24, 33%), 13 (33%),14 (q24-qter, 33%) and 22 (q13, 20%). A gain in DNA sequences was found in the long arm of chromosome 1 (cen-qter) in 33% of the abnormal specimens. Our analysis is the first genome-wide screening for gains and losses of DNA sequences using comparative genomic hybridization in malignant pleural mesothelioma tumours. The recurrent DNA sequence changes detected in this study suggest that the corresponding chromosomal areas most probably contain genes important for the initiation and progression of mesothelioma.     

Evaluation of the echinocandin antifungal MK-0991 (L-743,872): efficacies in mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis

The in vivo activity of the Merck antifungal echinocandin drug candidate MK-0991 (L-743,872) was evaluated in mouse models of disseminated candidiasis, aspergillosis, and cryptococcosis. The echinocandins are potent inhibitors of 1,3-beta-D-glucan synthase. Two models of disseminated candidiasis were used. In a Candida albicans mouse survival model with both DBA/2N and CD-1 mice, estimates of the 50% effective doses (ED50s) of MK-0991 were 0.04 and 0.10 mg/kg of body weight/dose at 21 days after challenge, respectively. In a C. albicans target organ assay (TOA) with DBA/2N mice, MK-0991 at levels of > or =0.09 mg/kg/dose significantly reduced the numbers of C. albicans CFU/g of kidneys compared to the numbers in the kidneys of control mice from 1 to 28 days after challenge. Even when given as a single intraperitoneal dose either 30 min or 24 h after challenge, MK-0991 was effective and significantly reduced the numbers of C. albicans CFU/g of kidney compared to those in the controls. MK-0991 was >300-fold less active when it was administered orally than when it was administered parenterally. MK-0991 was efficacious in mouse TOAs against other C. albicans strains and Candida species including Candida tropicalis, Candida (Torulopsis) glabrata, Candida lusitaniae, Candida parapsilosis, and Candida krusei. MK-0991 was ineffective against disseminated Cryptococcus neoformans infections. In the model of disseminated aspergillosis in mice, MK-0991 at doses of > or =0.02 mg/kg/dose significantly prolonged the survival of DBA/2N mice, with estimates of the ED50 and ED90 of MK-0991 being 0.03 and 0.12 mg/kg/dose, respectively, at 28 days after challenge. MK-0991 is a potent, parenterally administered therapeutic agent against disseminated candidiasis and aspergillosis that warrants further investigation in human clinical trials.     

Intramural post-traumatic haematomas of the duodenum: are there any late sequelae of operative intervention?

The data of nine children with post-traumatic intramural haematoma of the duodenum treated in Aghia Sophia Children's Hospital of Athens from 1967 to 1980 were retrospectively analysed. Diagnosis was preoperative in all but two children, in whom diagnosis was made during laparotomy. All but one were managed by operative intervention which consisted of simple evacuation of the haematoma and closure of the serosal incision in two out of eight children. Six out of eight children operated on were followed up for 15 years, during which they were free of symptoms. Hypotonic duodenography performed in the above patients was negative for deformity or stricture of the duodenum.     

Treatment of chronic cardiac insufficiency with coenzyme Q10, results of meta-analysis in controlled clinical trials

Meta-analysis applied to eight controlled clinical trials of coenzyme Q10 (CoQ10)-treatment of congestive heart failure revealed a significant improvement a several important cardiac parameters such as ejection fraction (EF), stroke volume (SV), cardiac output (CO), cardiac index (CI) and end diastolic volume index (EDVI). Concerning the improvement in SV and CO the average patient in the CoQ10 group had a higher score than respectively 76% and 73% of the patients in the placebo group. The improvement in CO and SV was also significant when considering of homogeneity. Additional controlled clinical trials seem justified which may strengthen the power of the meta-analyses. However, based on available results, it can not be excluded that CoQ10 may have a future role a adjunctive therapy in a dosage of 100-200 mg/day in the treatment of chronic congestive heart failure.     

Detection of p53 protein overexpression and DNA ploidy analysis in colon cancer

BACKGROUND/AIMS: This study was designed to demonstrate the accumulation of the mutant p53 protein in human neoplasms. The correlation of flow cytometric DNA ploidy pattern with p53 expression using the immunoblotting technique was also investigated. METHODOLOGY: In this study, the occurrence of p53 overexpression was analyzed in 34 cases of adenocarcinoma of the colon by western immunoblotting technique, using an anti-human p53 monoclonal antibody (Do-7). The nuclear protein extract from human colon tumor specimens was immunoblotted relative to protein standards of known molecular weight. Flow cytometric analysis was used to study the DNA ploidy pattern of the tumor cells. RESULTS: Monoclonal antibody p53-Do 7 detected a single band of 53 KDa in 70.5% (24 of 34) of the tumor specimens examined. Whereas, no bands were detected in the normal colon mucosa. The relation between p53 overexpression and the clinicopathological variable (Dukes' staging) was studied and no significant difference in p53 overexpression between Dukes' stages B and C was found. Flow cytometric analysis revealed a higher incidence of DNA aneuploidy in 75% (15 of 20) of p53 positive cases compared with 64.3% (9 of 14) in the diploid tumors. CONCLUSION: The immunoblotting technique can successfully detect the mutant p53 and is therefore expected to provide valuable information on the role of p53 in the process of carcinogenesis.     

Second cancers after medulloblastoma: population-based results from the United States and Sweden

Medulloblastoma, one of the most common central nervous system (CNS) tumors in children, requires aggressive multimodality therapy including surgery, radiation therapy, and occasionally chemotherapy. Given its intensive treatment regimen and improved survival during the past 20 years, it is likely that a cohort of survivors will result who may incur consequences of therapy, including a second cancer. We used population-based data from the United States and Sweden to estimate risks of second neoplasms in patients with histologically confirmed medulloblastoma (n = 1,262). Overall, there was a 5.4-fold excess of second neoplasms (95 percent confidence interval = 3.3-8.4) based on 20 observed and 3.7 expected cancers. The second cancers occurred eight to 432 months after initial diagnosis (median, 73 months) with significantly elevated ratios for all intervals examined except for less than one year after initial diagnosis. Significantly elevated risks were seen for cancers of the salivary glands, cervix uteri, brain and CNS, thyroid gland, and acute lymphoblastic leukemia. Of the 15 second cancers with treatment data, seven occurred in the radiation field or within areas of scatter while two others may have been radiation-related. Although based on small numbers of second cancers, the results suggest that as survival increases, some patients with medulloblastoma will have an increased risk of a second cancer, particularly a radiation-related cancer. Thus, as survival improves, late-occurring consequences of diagnosis and treatment will need to be carefully assessed. Identification of patients hypersensitive to radiation therapy, such as those with Gorlin Syndrome, should also be attempted in order to reduce the sequelae from intensive radiation exposure.     

Assessment of the influence of the compliant aortic root on aortic valve mechanics by means of a geometrical model

In recent years several researchers have suggested that the changes in the geometry and angular dimensions of the aortic root which occur during the cardiac cycle are functional to the optimisation of aortic valve function, both in terms of diminishing leaflet stresses and of fluid-dynamic behaviour. The paper presents an analytical parametric model of the aortic valve which includes the aortic root movement. The indexes used to evaluate the valve behaviour are the circumferential membrane stress and the stress at the free edge of the leaflet, the index of bending strain, the bending of the leaflet at the line attachment in the radial and circumferential directions and the shape of the conduit formed by the leaflets during systole. In order to evaluate the role of geometric changes in valve performance, two control cases were considered, with different reference geometric configuration, where the movement of the aortic root was ignored. The results obtained appear consistent with physiological data, especially with regard to the late diastolic phase and the early ejection phase, and put in evidence the role of the aortic root movement in the improvement of valve behaviour.