Biallelic somatic inactivation of the mismatch repair gene MLH1 in a primary skin melanoma

Inactivation of mismatch repair (MMR) genes has been linked to the hereditary nonpolyposis colon cancer syndrome and to a subset of sporadic cancers. A phenotypic characteristic of tumors with defective MMR is microsatellite instability (MSI). Although MSI has been reported in a proportion of cutaneous melanomas, inactivation of MMR genes in this tumor type has not been detected thus far. We recently described a human melanoma cell line, PR-Mel, and a cutaneous metastasis from the same patient, which displayed a MMR defect, and showed high MSI. Here we report that in the PR-Mel cell line both MLH1 alleles are somatically inactivated. One allele is lost through a chromosomal deletion of the region 3p21-24, whereas the remaining allele harbors a G --> A transition at position -1 of the acceptor splice site of intron 15, leading to the in-frame skipping of exon 16. The primary melanoma of the PR patient shows loss of heterozygosity at the BAT21 microsatellite marker, located in the MLH1 gene, and does not express the MLH1 and PMS2 proteins. Moreover, it harbors the same mutation detected in the PR-Mel cells. These results demonstrate that biallelic inactivation of MLH1 had occurred in the primary melanoma of the PR patient and suggest that disruption of MMR might have had a role in the development of the melanoma. This is the first report in which genetic defects leading to disruption of MMR function in a human melanoma have been identified.     

Pancreatic mucinous noncystic (colloid) carcinomas and intraductal papillary mucinous carcinomas are usually microsatellite stable.

Pancreatic mucinous noncystic (colloid) carcinomas (MNCC) differ from the usual ductal adenocarcinomas in their mucin expression profile and share with many extrapancreatic mucinous carcinomas the expression of MUC2. Because mucinous carcinomas are frequently associated with mutations of the DNA mismatch repair genes, causing them to exhibit the so-called mutator phenotype, we decided to investigate whether MNCCs of the pancreas are characterized by microsatellite instability (MSI). Twelve carcinomas with a mucinous phenotype (8 mucinous noncystic carcinomas, 3 intraductal papillary-mucinous carcinomas with an invasive muconodular component, and 1 ductal adenocarcinoma with an extensive mucinous noncystic component) and 11 ductal adenocarcinomas were immunostained with monoclonal antibodies to the mismatch repair gene products hMLH1, hMSH2, and hMSH6. For MSI analysis, DNA was isolated from microdissected tissue, and five primary microsatellites (BAT 25, BAT 26, D5S346, D17S250, and D2S123) were analyzed. MSI was diagnosed in case a novel allele was found, compared with the normal tissue. The criterion for LOH was a 75% signal reduction. All carcinomas tested exhibited nuclear expression of mismatch repair gene products, except for one MNCC that also showed MSI at the molecular level. The data suggest that pancreatic carcinomas with a mucinous phenotype (MUC2+/MUC1-) do not appear to normally exhibit mutations in the mismatch repair genes and therefore differ in their carcinogenesis from those in other organs.     

Electron microscopic studies on the attachment of Mycoplasma pneumoniae to guinea pig erythrocytes.

A mechanism of pathogenicity of Mycoplasma pneumoniae is its ability to attach to the surface of mammalian cells. It has previously been demonstrated by others that M. pneumoniae adheres with a specialized terminal structure, the "tip," to ciliated epithelial cells of the respiratory tract. In this report we show by electron microscopy that M. pneumoniae adsorbs with membrane sites other than the tip to guinea pig erythrocytes.     

Blood pressure reactions to acute psychological stress and future blood pressure status: a 10-year follow-up of men in the Whitehall II study

OBJECTIVE: The aim of this study was to examine whether blood pressure reactions to mental stress predicted future blood pressure and hypertension. METHODS: Blood pressure was recorded at an initial medical screening examination after which blood pressure reactions to a mental stress task were determined. A follow-up screening assessment of blood pressure and antihypertensive medication status was undertaken 10 years later. Data were available for 796 male public servants, between 35 and 55 years of age upon entry to the study. RESULTS: Systolic blood pressure reactions to mental stress were positively correlated with follow-up screening systolic blood pressure and to a lesser extent, follow-up diastolic pressure. In multivariate tests, by far the strongest predictors of follow-up blood pressures were initial screening blood pressures. In the case of follow-up systolic blood pressure, systolic reactions to stress emerged as an additional predictor of follow-up systolic blood pressure. With regard to follow-up diastolic blood pressure, reactivity did not enter the analogous equations. The same outcomes emerged when the analyses were adjusted for medication status. When hypertension at 10-year follow-up was the focus, both systolic and diastolic reactions to stress were predictive. However, with correction for age and initial screening blood pressure, these associations were no longer statistically significant. CONCLUSIONS: The results of this study provide modest support for the hypothesis that heightened blood pressure reactions to mental stress contribute to the development of high blood pressure. At the same time, they question the clinical utility of stress testing as a prognostic device.     

Brachytelephalangic chondrodysplasia punctata in an extremely premature infant

We report on 3 sibs (2 males and one female) with sensorineural deafness. The presence of ovarian dysgenesis in the girl suggested a diagnosis of Perrault syndrome. In addition our patients have a sensory polyneuropathy and amelogenesis imperfecta. Two of the patients have mild mental retardation, fine choreatic movements, and dyspraxia. It is discussed whether these findings are part of a separate clinical entity or should be included within the spectrum of the Perrault syndrome. © 1994 Wiley-Liss, Inc.     

Enzymatic removal of H-2 alloantigens from the surface of P815-(X2) mouse tumor cells

After treatment with papain (6 mg/ml) for 1 h, P815 tumor cells became resistant to complement-mediated lysis by mouse alloantibodies of different specificities. Immunofluorescence and absorption studies indicated that this resistance was associated with removel of the corresponding antigenic determinants from the cell surface. In contrast, papain-treated tumor cells were fully susceptible to lysis by rabbit antiserum against P815 cells, indicating a) no alteration of the membrane sensitivity to complement damage, and b) a dissociation between structure and/or localization of allo- and xenoantigens. Papain-treated cells were also completely resistant to lysis by cytolytic T lymphocytes (CTL) during the first 60 min after completion of the enzyme treatment. Susceptibility to lysis by either CTL or alloantibody and complement reappeared within a few hours after incubation in culture medium and was virtually normal by 6 h. Treatment of P815 cells with trypsin (2 mg/ml) had no effect on either humoral or cellular lytic activities.     

ECS produced disruption or facilitation of discriminated active avoidance performance in rats

Two experiments investigated the effect of electroconvulsive shock on the performance of a one-way active avoidance response. In the first experiment it was found that if the response was learned under scopolamine, ECS given prior to relearning failed to produce a deficit. The second experiment demonstrated that ECS facilitated relearning of a response trained to a low criterion level while it disrupted performance of a response trained to a strict criterion. These results support other indications that Deutsch's memory model has predictive value for proactive effects of ECS on relearning (retrieval).     

Effect of methoxime combined with anticholinergic, anticonvulsant or anti-HCN drugs in tabun-poisoned mice

The effect of methoxime combined with a) atropine, b) benactyzine, c) atropine and natrium thiosulphate, d) atropine and diazepam on antidotal treatment effectiveness was studied in tabun-poisoned mice. In addition, the influence of pretreatment consisiting of pyridostigmine, benactyzine and trihexyphenidyle (PANPAL) administered 2 hours before tabun intoxication on the treatment effectivity of methoxime combined with e) atropine or f) benactyzine was tested. The most efficacious therapeutic mixture in non-pretreated mice was methoxime, atropine and diazepam. Natrium thiosulphate did not significantly increase neither decrease the antidotal treatment efficacy in comparison with methoxime and atropine alone. Pretreatment with PANPAL significantly decreased tabun toxicity (nearly 4 times in methoxime and benactyzine combination and more than 4 times in atropine and methoxime mixture). The present study demonstrates that the tabun toxicity in mice is more effectively reduced when PANPAL prophylactically is administered than in case of treatment with methoxime and cholinergic drug alone. We established that anticholinergic drug option in the therapeutic mixture of methoxime and anticholinergic drug did not cause the difference in the antidotal treatment effectivities.     

Translocation (6;9)(p23;q34) in acute nonlymphocytic leukemia: Three new cases

Several recent reports have described cases of acute nonlymphocytic leukemia with a unique chromosome translocation, t(6;9)(p23;q34). We have studied three additional patients who have acute nonlymphocytic leukemia and t(6;9)(p23;q34). Our findings provide additional support for the suggestion that this translocation is yet another distinct cytogenetic abnormality associated with myeloproliferative disorders.     

Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein.

In this study the authors have developed a model with which can be studied directly the influence of circulating anti-myelin antibody on the clinical and pathologic course of inflammatory T-cell-mediated experimental allergic encephalomyelitis (EAE) in the rat. EAE was induced by passive transfer of either myelin basic protein (MBP)-activated spleen cells derived from sensitized donors or long-term-cultured MBP-specific T-cell lines. At the onset of the disease, monoclonal antibodies against a myelin/oligodendrocyte glycoprotein (MOG) were injected intravenously. This antigen is exposed on the surface of central nervous system myelin and oligodendrocytes. Intravenous injection of the antibody in the course of T-cell-mediated transfer EAE augmented the severity and duration of clinical signs and resulted in the formation of large, confluent demyelinated plaques.