Analysis of the SRY gene in gonadal tissue of subjects with 46,XY gonadal dysgenesis.
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DNA↗
Biomedical subjects
J McLaughlin
Publications and source records attributed to J McLaughlin.
Brain potentials reflect violations of gender stereotypes.
Event-related brain potentials (ERPs) were recorded while 14 males and 14 females read sentences containing a reflexive pronoun that referred to a definitionally or stereotypically male or female antecedent noun. Pronouns that disagreed with the gender definition or gender stereotype of the antecedent elicited a large-amplitude positive wave. Violations of gender definitions elicited a larger positive wave than did violations of gender stereotypes. Furthermore, the positive wave elicited by stereotype violations persisted even when subjects judged these sentences to be acceptable. Finally, female subjects exhibited larger positivities than did male subjects, regardless of whether the gender mismatch involved a definitional or stereotypical antecedent. These results are taken to indicate that ERPs are sensitive to violations of gender-based occupational stereotypes and that the ERP response to stereotype violations is similar to the P600 effect elicited by a variety of syntactic anomalies.
Adult↗
Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer's disease.
A placebo-controlled crossover design, with each treatment period lasting 6 weeks, was used to investigate effects of dronabinol in 15 patients with a diagnosis of probable Alzhemer's disease who were refusing food. Eleven patients completed both study periods; one patient who died of a heart attack 2 weeks before the end of the study was also included in the analysis. The study was terminated in 3 patients: one developed a grand mal seizure and 2 developed serious intercurrent infections. Body weight of study subjects increased more during the dronabinol treatment than during the placebo periods. Dronabinol treatment decreased severity of disturbed behavior and this effect persisted during the placebo period in patients who received dronabinol first. Adverse reactions observed more commonly during the dronabinol treatment than during placebo periods included euphoria, somnolence and tiredness, but did not require discontinuation of therapy. These results indicate that dronabinol is a promising novel therapeutic agent which may be useful not only for treatment of anorexia but also to improve disturbed behavior in patients with Alzheimer's disease.
Aged↗
Childhood medulloblastoma in Ontario, 1977-1987: population-based results.
A retrospective review was carried out to study children, not more than 16 years old, with a confirmed diagnosis of medulloblastoma, who were residents of the Province of Ontario at the time of diagnosis between 1977 and 1987 inclusive. The provincial tumour registry provided the population database. One hundred and eight children with medulloblastoma were identified of whom 72 (67%) were initially treated at University of Toronto Centres and 36 (33%) at other Health Science Centres, hospitals, and Regional Cancer Centres (RCC) in Ontario. The hospital/Cancer Centre records were reviewed. The 5-year relapse-free survival (RFS) for all patients treated in Ontario was 58% (SE = 5%). Those treated in Toronto had a 5-year RFS of 65% (SE = 6%) compared to 44% (SE = 8%) for those treated in other RCCs in the province (P = 0.02). Relapse-free survival for the RCCs ranged from 25 to 60%, with a trend for improved survival with increasing centre size. Univariate analysis of determinants of relapse-free survival for all 108 patients showed the following variables to be significant: T-stage (Tx + T1 + T2 vs. T3A + T3B) P = 0.0004, M-stage (M0 + Mx vs. M1-4) P = 0.0006, extent of resection (total vs. less than total) P = 0.002, radiotherapy (craniospinal irradiation and posterior fossa boost vs. other) P = 0.02, and treatment centre (Toronto centres vs. RCC) P = 0.02. Cases treated at centres outside metropolitan Toronto had a nearly two-fold (relative risk = 1.93; 95% confidence interval = 1.07, 3.47) greater risk of recurrence or death than those seen in Toronto. However, in multivariate analysis this difference was not quite significant (P = 0.07) after controlling for stage (T and M), extent of resection, meningitis, and gender. These data suggest that patients with medulloblastoma should be referred for treatment to large centres with major pediatric neurosurgical and oncology resources.
Cerebellar Neoplasms↗
Nuclear localization of beta-catenin by interaction with transcription factor LEF-1.
Vertebrate beta-catenin and Drosophila Armadillo share structural similarities suggesting that beta-catenin, like Armadillo, has a developmental signaling function. Both proteins are present as components of cell adherens junctions, but accumulate in the cytoplasm upon Wingless/Wnt signaling. beta-Catenin has axis-inducing properties like Wnt when injected into Xenopus blastomeres, providing evidence for participation of beta-catenin in the Wnt-pathway, but until now no downstream targets for beta-catenin have been identified. Here we demonstrate that beta-catenin binds to the HMG-type transcription factor lymphoid enhancer factor-1 (LEF-1), resulting in a nuclear translocation of beta-catenin both in cultured mouse cells and after ectopic expression of LEF-1 in two-cell mouse embryos. LEF-1/beta-catenin complexes bind to the promoter region of the E-cadherin gene in vitro, suggesting that this interaction could regulate E-cadherin transcription. As shown for beta-catenin, ectopic expression of LEF-1 in Xenopus embryos caused duplication of the body axis, indicating a regulatory role for a LEF-1-like molecule in dorsal mesoderm formation.
Amino Acid Sequence↗
Combined thoracoscopic/laparoscopic staging of esophageal cancer.
Unlike mediastinoscopy in lung cancer, there exists no standard minimally invasive test to stage esophageal cancer. If it were possible to obtain exact preoperative staging in esophageal cancer, patients could be separated prospectively to receive neoadjuvant therapy appropriately. We studied the feasibility and efficacy of thoracoscopic and laparoscopic lymph node staging in esophageal cancer. Thoracoscopic staging was performed in 45 patients with biopsy-proven carcinoma of the esophagus. Laparoscopic staging was done in the last 19 patients. Thoracoscopic staging was aborted in three patients because of adhesions. Thoracic lymph node stage was N0 in 39 patients and N1 in three; celiac lymph nodes were normal in 13 and diseased in six. Esophageal resection was performed in 30 patients after thoracoscopic staging; 17 of these underwent laparoscopic staging. Thoracoscopic staging showed N0 lymph node status in 28 patients and N1 in two patients. Two of the 28 patients (7%) with N0 disease were found at resection to have paraesophageal lymph node involvement (N1); thus the disease was understaged by thoracoscopic staging. Thoracoscopic staging was accurate in detecting the presence of diseased thoracic lymph nodes in 28 of 30 cases (93%). Laparoscopic staging detected normal celiac nodes in 12 patients and diseased lymph nodes in five patients. After esophagectomy, the final pathology report in the 12 patients with N0 disease was N0 in 11 and diseased lymph nodes in one patient. Thus laparoscopic staging was accurate in detecting lymph node metastases in 16 of 17 patients (94%). Thoracoscopic and laparoscopic staging are more accurate than existing staging methods. Six of 19 patients in whom laparoscopic staging was used had unsuspected celiac axis lymph node involvement that had been missed by standard noninvasive techniques. One of three patients with thoracic lymph nodes and three of six with celiac lymph nodes were downstaged after preoperative chemotherapy/radiotherapy. The role of thoracoscopy and laparoscopy in staging esophageal cancer should be further evaluated in a multiinstitutional trial.
Adenocarcinoma↗
Susceptibility testing of Haemophilus influenzae--an international collaborative study in quality assessment.
In order to compare the prevalence of antibiotic resistance in different geographical areas, it is necessary to ensure that agreement is achieved between laboratories on the assignment of strains to 'susceptible' and 'resistant' categories. An international quality assessment study, involving 15 laboratories in eight countries, was performed to investigate the standard of performance of the susceptibility testing of Haemophilus influenzae. One hundred and fifty strains of H. influenzae were distributed from the London Hospital Medical College (LHMC) to all laboratories who were asked to test the susceptibility of the strains to ampicillin, chloramphenicol, tetracycline, trimethoprim, cephalosporins and ciprofloxacin. Laboratories were also asked to provide the details of methodology to test the susceptibility. Significant discrepancy between the LHMC and the participating laboratories appeared in the detection of resistance to ampicillin (especially beta-lactamase-negative strains resistant to ampicillin) as well as the assignment of susceptibility and resistance to chloramphenicol, tetracycline and trimethoprim. Often these reflected the use of inappropriate breakpoints which led to erroneous assignment of susceptibility. Other variations including disc content, medium and supplement, inoculum as well as failure to measure zone sizes properly also led to some repeating anomalies.
Ampicillin↗
Abnormal cervical cytology leading to the diagnosis of a primary serous adenocarcinoma of the peritoneum.
A case is presented where abnormal cervical cytology in an asymptomatic female led to the diagnosis of a primary serous adenocarcinoma of the peritoneum. We would like to highlight the importance to the physician of a tumour diathesis on malignant cervical cytology.
Aged↗
Oligomerization of the ABL tyrosine kinase by the Ets protein TEL in human leukemia.
TEL is a member of the Ets family of transcription factors which are frequently rearranged in human leukemia. The mechanism of TEL-mediated transformation, however, is unknown. We report the cloning and characterization of a chromosomal translocation associated with acute myeloid leukemia which fuses TEL to the ABL tyrosine kinase. The TEL-ABL fusion confers growth factor-independent growth to the marine hematopoietic cell line Ba/F3 and transforms Rat-1 fibroblasts and primary murine bone marrow cells. TEL-ABL is constitutively tyrosine phosphorylated and localizes to the cytoskeleton. A TEL-ABL mutant containing an ABL kinase-inactivating mutation is not constitutively phosphorylated and is nontransforming but retains cytoskeletal localization. However, constitutive phosphorylation, cytoskeletal localization, and transformation are all dependent upon a highly conserved region of TEL termed the helix-loop-helix (HLH) domain. TEL-ABL formed HLH-dependent homo-oligomers in vitro, a process critical for tyrosine kinase activation. These experiments suggest that oligomerization of TEL-ABL mediated by the TEL HLH domain is required for tyrosine kinase activation, cytoskeletal localization, and transformation. These data also suggest that oligomerization of Ets proteins through the highly conserved HLH domain may represent a previously unrecognized phenomenon.
Aged↗
Breast cancer mortality between 1950 and 1987 after exposure to fractionated moderate-dose-rate ionizing radiation in the Canadian fluoroscopy cohort study and a comparison with breast cancer mortality in the atomic bomb survivors study.
The relationship between exposure to low-linear energy transfer ionizing radiation and subsequent breast cancer mortality risk is reported based on a further 7 years of follow-up in the Canadian fluoroscopy study. Amongst 31,917 women first treated for tuberculosis in a Canadian institution between 1930 and 1952, a total of 688 breast cancer deaths were observed between 1950 and 1987. There is a strong linear trend of increasing risk with increasing dose (P < 0.0001), with the excess relative risk per sievert decreasing with age at exposure (P = 0.0003). The excess relative risk is approximately constant between 5 and 39 years after exposure, with a suggestion of a decrease between 40 and 57 years after exposure, though this could be a chance effect (P = 0.22). Combined analyses of the Canadian fluoroscopy data and the data for the atomic bomb survivors with respect to breast cancer mortality are also reported. In general the two studies are reasonably consistent, the only distinct difference being the much greater excess relative risk per sievert amongst women exposed to very high doses in the province of Nova Scotia (P, heterogeneity <0.0001). Based on the combined data sets a simple relative risk (RR) model for the effect of a dose of D sieverts at age A years is developed: RR(D) = 1.0 + 0.52D exp[-0.10(A-15)]. This model fits the combined data well, and is used to predict excess lifetime risks of breast cancer mortality after radiation exposure from routine annual mammography.
Adolescent↗
Signaling by ABL oncogenes through cyclin D1.
Oncogenic signals induce cellular proliferation by deregulating the cell division cycle. Cyclin D1, a regulator of G1-phase progression, acts synergistically with ABL oncogenes in transforming fibroblasts and hematopoietic cells in culture. Synergy with v-Abl depended on a motif in cyclin D1 that mediates its binding to the retinoblastoma protein, suggesting that ABL oncogenes in part mediate their mitogenic effects via a retinoblastoma protein-dependent pathway. Overexpression of cyclin D1, but not cyclin E, rescued a signaling-defective src-homology 2 (SH2) domain mutant of BCR-ABL for transformation of cells in culture and malignant tumor formation in vivo. These results demonstrate that cyclin D1 can provide essential signals for malignant transformation in concert with an activated tyrosine kinase.
Animals↗
Alternative signals to RAS for hematopoietic transformation by the BCR-ABL oncogene.
Biological function of the BCR-ABL oncogene is dependent on its activated tyrosine kinase. Mutations that inactivate the SRC homology 2 (SH2) domain, the GRB2-binding site in BCR, or the major autophosphorylation site of the kinase domain selectively disrupt downstream signaling but not tyrosine kinase activity. Despite a loss of fibroblast transformation activity, all three mutants retain the ability to render hematopoietic cell lines growth factor independent and transform primary bone marrow cells in vitro. In vivo tests of malignant potential reveal a most critical role for signals dependent on the BCR-ABL SH2 domain. The efficiency of both fibroblast and hematopoietic transformation by BCR-ABL is strongly affected by increased dosage of the SHC adapter protein, which can connect tyrosine kinase signals to RAS. The BCR-ABL oncogene activates multiple alternative pathways to RAS for hematopoietic transformation.
Animals↗
'Normal' blood copper levels in horses.
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Animals↗
Genetic requirement for Ras in the transformation of fibroblasts and hematopoietic cells by the Bcr-Abl oncogene.
To determine the functional importance of Ras in transformation by Abl oncogenes, we used a genetic approach to measure the effect of impaired Ras activity on the ability of Bcr-Abl or v-Abl to transform cells. Expression of the catalytic domain of the GTPase activating protein for Ras (Gap C terminus) impaired soft agar colony formation by fibroblasts expressing v-Abl or Bcr-Abl by 70-80%. To test Ras function in a model that more closely resembles clinical diseases involving Bcr-Abl, double gene retroviruses expressing Bcr-Abl paired with the Gap C terminus or dominant negative Ras were introduced into naive mouse bone marrow cells. Transformation by Bcr-Abl was completely blocked in both situations. Coexpression of normal c-H-Ras accelerated the transforming activity of Bcr-Abl. These findings show that Ras activation is essential for the leukemogenic activity of Abl oncogenes in two distinct model systems. The results genetically define a connection between the Bcr-Abl cytoplasmic tyrosine kinase and Ras and add to the accumulating evidence that deregulation of Ras is a central event in the genesis of a number of molecularly distinct forms of human myeloid leukemia.
Animals↗
Quantitative measures of human immunodeficiency virus-specific antibodies predict progression to AIDS.
Studies examining specific antibodies directed against antigenic components of human immunodeficiency virus (HIV), as potential markers of progression to AIDS, have reported inconsistent results. We used reflectance densitometry and survival analysis to determine whether single quantitative measures of HIV-specific antibodies predicted progression to AIDS in a prospective cohort of 159 HIV-infected homosexual men. Lowered baseline levels of p24 antibody and p24/gp41 antibody ratio were independent predictors of progression to AIDS and retained statistical significance after simultaneously controlling for CD4:CD8 ratio, age, use of zidovudine, and clinical symptoms. Quantitative measures of p24 antibody and p24/gp41 antibody ratio warrant further study with regards to their clinical application as markers of HIV disease progression.
Acquired Immunodeficiency Syndrome↗
The molecular chaperone function of alpha-crystallin is impaired by UV photolysis.
Buffer solutions of the lens protein gamma-crystallin and the enzymes aldolase and liver alcohol dehydrogenase became turbid and formed solid precipitate upon exposure to an elevated temperature of 63 degrees C or to UV radiation at 308 nm. When alpha-crystallin was added to the protein solutions in stoichiometric amounts, heat or UV irradiation did not cause turbidity, or turbidity developed much less rapidly than in the absence of alpha-crystallin. Hence, normal alpha-crystallin functioned as a "molecular chaperone," providing protection against both UV and heat-induced protein aggregation. When alpha-crystallin was preirradiated with UV at 308 nm, its ability to function as a chaperone vis-a-vis both UV and heat-induced aggregation was significantly impaired, but only at relatively high UV doses. A major effect of preirradiation of alpha-crystallin was to cause interpeptide crosslinking among the alpha A2 and alpha B2 subunits of the alpha-crystallin macromolecule. In our experiments alpha-crystallin was exposed to UV doses, which resulted in 0.50 and 90% crosslinking as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. alpha-Crystallin samples that were 50% and 90% crosslinked gave chaperone protection, which was increasingly impaired relative to unirradiated alpha-crystallin. The results are consistent with the notion that UV irradiation of alpha-crystallin results in loss of chaperone binding sites.
Animals↗
Comparative antimicrobial activities of the penem WY-49605 (SUN5555) against recent clinical isolates from five U.S. medical centers.
The in vitro activity of WY-49605 (SUN5555) (WY) was compared with those of cefaclor, cefixime, and amoxicillin-clavulanic acid against 2,958 consecutive clinical isolates from five medical centers and 402 respiratory pathogens from 18 other facilities. Most members of the family Enterobacteriaceae were inhibited by WY (MIC at which 50% of the isolates are inhibited [MIC50], < or = 2.0 micrograms/ml). MIC90s of > or = 8.0 micrograms/ml were observed for Enterobacter cloacae, Serratia spp., and Proteus mirabilis. WY was the most active drug against methicillin-susceptible Staphylococcus aureus (MIC90, 0.12 microgram/ml) and other coagulase-negative staphylococci (MIC90, 4.0 micrograms/ml). The four drugs were not active against nonenteric gram-negative bacilli, methicillin-resistant Staphylococcus aureus, and Staphylococcus haemolyticus. At 2.0 micrograms/ml, WY inhibited 82% of Enterococcus faecalis strains and was equal to or superior to the other drugs against streptococci, Haemophilus influenzae, and Moraxella catarrhalis.
Amoxicillin↗