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PubMed2006

The sarcolemmal calcium pump, alpha-1 syntrophin, and neuronal nitric-oxide synthase are parts of a macromolecular protein complex.

The main role of the plasma membrane Ca2+/calmodulin-dependent ATPase (PMCA) is in the removal of Ca2+ from the cytosol. Recently, we and others have suggested a new function for PMCA as a modulator of signal transduction pathways. This paper shows the physical interaction between PMCA (isoforms 1 and 4) and alpha-1 syntrophin and proposes a ternary complex of interaction between endogenous PMCA, alpha-1 syntrophin, and NOS-1 in cardiac cells. We have identified that the linker region between the pleckstrin homology 2 (PH2) and the syntrophin unique (SU) domains, corresponding to amino acids 399-447 of alpha-1 syntrophin, is crucial for interaction with PMCA1 and -4. The PH2 and the SU domains alone failed to interact with PMCA. The functionality of the interaction was demonstrated by investigating the inhibition of neuronal nitric-oxide synthase-1 (NOS-1); PMCA is a negative regulator of NOS-1-dependent NO production, and overexpression of alpha-1 syntrophin and PMCA4 resulted in strongly increased inhibition of NO production. Analysis of the expression levels of alpha-1 syntrophin protein in the heart, skeletal muscle, brain, uterus, kidney, or liver of PMCA4-/- mice, did not reveal any differences when compared with those found in the same tissues of wild-type mice. These results suggest that PMCA4 is tethered to the syntrophin complex as a regulator of NOS-1, but its absence does not cause collapse of the complex, contrary to what has been reported for other proteins within the complex, such as dystrophin. In conclusion, the present data demonstrate for the first time the localization of PMCA1b and -4b to the syntrophin.dystrophin complex in the heart and provide a specific molecular mechanism of interaction as well as functionality.

Animals↗
PubMed2005

The antitumor monoclonal antibody 806 recognizes a high-mannose form of the EGF receptor that reaches the cell surface when cells over-express the receptor.

Overexpression of the EGFR is commonly caused by EGFR gene amplification and is sometimes associated with expression of a variant EGFR (de2-7 EGFR or EGFRvIII) bearing an internal deletion in its extracellular domain. mAb 806 is a novel EGFR antibody with significant antitumor activity that recognizes both the de2-7 EGFR and a subset of the wild-type (wt) EGFR when overexpressed, but does not bind the EGFR expressed in normal tissues. Recently, we demonstrated that the mAb 806 epitope is restricted to a short cysteine loop of the EGFR (amino acids 287-302) that is only available for antibody binding in a transitional form of the receptor, which occurs as the receptor changes from its inactive tethered conformation to a dimeric untethered form. The truncation associated with the de2-7 EGFR mutation renders this receptor constitutively untethered, leading to increased binding of mAb 806. We now show that mAb 806 preferentially binds the immature high-mannose wt and de2-7 EGFR precursors normally located in the endoplasmic reticulum, indicating that this form of the wt EGFR is also constitutively untethered. Using the unique specificity of mAb 806, we clearly demonstrated the presence of these high-mannose EGFR precursors on the cell surface. Given that the high-mannose forms of the wt EGFR must be untethered they may contribute to the spontaneous EGFR signaling reported in cells overexpressing the receptor. These precursor forms of the EGFR thus represent novel tumor targets and contribute to the exceptional selectivity of mAb 806 for EGFR when overexpressed in cancer cells. As our observations are likely to apply to other receptors overexpressed in cancer, they suggest a strategy for developing antitumor antibodies even when the target receptor is expressed in normal tissue.

Antibodies, Monoclonal↗
PubMed1991

Peritoneal trophoblastic implants after surgical management of tubal pregnancy.

Persistent trophoblast after salpingostomy occurs in up to 7% of cases of tubal pregnancy. Usually the retained trophoblast is within the fallopian tube, but recent reports have described viable implants on the serosal and omental surfaces. A survey was mailed to 100 members of the American Association of Gynecologic Laparoscopists to determine the incidence of the complication. The 25 respondents reported 14 cases of persistent trophoblast implanted on the pelvic serosal or omental surface. This complication followed 1.9% of the cases managed with laparoscopy and 0.6% managed with laparotomy. Some surgical steps can decrease the likelihood of this complication. Also, the beta-human chorionic gonadotropin level should be monitored postoperatively, even if management was with salpingectomy, and especially if the specimen was fragmented laparoscopically to facilitate its removal.

Canada↗
PubMed1991

Perspective taking and theory of mind: do children predict interpretive diversity as a function of differences in observers' knowledge?

In 3 experiments, children's ability to vary their responses on perspective-taking tasks as a function of the other person's age was examined. In Experiment 1,4- and 5-year-olds were shown to be accurate in their judgments about the knowledge of a 6-month-old baby, a 4-year-old child, and an adult. In Experiment 2, 4-year-olds were asked to determine if a baby, child, and adult would be able to identify an object from a restricted view showing either an identifiable part, a small nondescript part, or no part of the object. Children tended to report that the observer would be able to identify the object from an identifiable or nondescript part. Their judgments were not affected by the age of the observer. Experiment 3 replicated the asymmetry in performance on the general knowledge task and the restricted view task and extended these results by testing 4-year-olds, 6-year-olds, and adults using a within-subjects design.

Adult↗
PubMed1997

Age and sex distributions of hematological malignancies in the U.K.

This paper reports on an analysis of nearly 27,000 hematological malignancies diagnosed in the U.K. in the 10-year period 1984 to 1993. The unique observations provided in this analysis are the similarity of the sex-specific curves by age for acute myeloid leukemia, myelodysplasia types, polycythemia rubra vera, and myelofibrosis (or myelosclerosis). The unusual age-sex-specific distribution of essential thrombocythemia, suggesting a unique epidemiology, has never been reported before. The unusual female excess of the nodular sclerosing adolescent peak in Hodgkin's disease and its rapid fall with time is potentially of great importance. An even younger childhood peak of acute lymphoblastic leukemia is presented. Overall these data represent the most reliable available in the U.K., being population based, specially collected and will form the basis of considerable further investigations.

Acute Disease↗
PubMed1991

Community lifestyle characteristics and incidence of Hodgkin's disease in young people.

Risk of Hodgkin's disease (HD) in young adults has frequently been associated with limited access to social contact in childhood and related correlates of childhood social class. In addition, case clustering has sometimes been associated with influxes of population into relatively isolated communities. To investigate this further, disease incidence rates for HD at ages 0 to 24 from a specialist tumour registry have been regressed against relevant electoral ward characteristics derived from routine census and Ordnance Survey data for England and Wales. Proximity to built-up areas and higher socio-economic status (SES) emerge as significant risk factors. The relative risks are 1.21 (95% Cl: 1.01-1.46) for high SES wards and 1.29 (1.05-1.58) for "inner zone" wards. No association of disease risk with distance travelled to work was apparent. Regions farther from built-up areas have a lower overall incidence and a shift, particularly for males, of the age distribution towards older ages. The distribution resembles the intermediate pattern for HD reported from European rural areas of low SES but never previously for high SES. Isolated areas also show an increased intensity of spatial clustering (29% of cases being classified as clustered). These findings have implications for the 'late host response' model which suggest a viral aetiology for Hodgkin's disease in young people and provide a basis for future analytical studies.

Adult↗
PubMed1998

Role of REM sleep and dream variables in the prediction of remission from depression.

To test the hypothesis that REM sleep and/or dreams contribute to overnight mood regulation, 61 subjects were tested on the Beck Depression Inventory (BDI), and for 3 nights of monitored sleep on two occasions, once close to, and 1 year after, a marital separation. Forty-nine percent of the variance in the follow-up BDI could be accounted for by the initial BDI score, and three sleep and dream variables associated with the mood regulatory hypothesis: eye movement density in the first REM, strength of the affect in the first dream and total number of negative dreams recalled from REM awakenings. Among the 39 who met BDI depression criteria initially, 71.8% could be classified correctly as remitted or not remitted at follow-up by discriminant function analysis based on the presence of negative dreams the first vs. second half of the night. Subjects reporting more negative dreams at the beginning and fewer at the night's end were more likely to be in remission 1 year later than were those with fewer negative dreams at the beginning and more at the end of the night. Early negative dreams may reflect a within-sleep mood regulation process taking place, while those that occur later may indicate a failure in the completion of this process.

Adult↗
PubMed1988

Acute myeloid leukemia in adults: a case-control study in Yorkshire.

This paper reports the results of a case-control analysis of 161 cases of acute myeloid leukemia and 310 matched hospital controls. The patients were interviewed between 1982 and 1986. The study shows a weak association for cases with previous malignant disease. Furnace workers show excess risks. Urticaria and vertigo are in excess, as well as some aspects of family medical histories, including multiple sclerosis and cases of leukemia/lymphoma in blood relations.

Adult↗
PubMed1986

Reported satisfaction, fluctuation of vision, and glare among patients one year after surgery in the Prospective Evaluation of Radial Keratotomy (PERK) Study.

We studied satisfaction with the results of radial keratotomy one year after surgery on one eye as reported by 354 patients in the Prospective Evaluation of Radial Keratotomy (PERK) Study. We measured satisfaction using an index based on ten questions that were part of a longer psychometric questionnaire. Patients were generally satisfied with the results of radial keratotomy-48% were very satisfied, 42% were moderately satisfied, and 10% were dissatisfied. A lot of trouble with fluctuating vision was reported by 12% of patients before surgery and by 34% one year after surgery; 17% reported a lot of trouble with glare both before surgery and one year after surgery. The three major factors that influenced satisfaction were uncorrected visual acuity, residual refractive error, and subjective daily fluctuation in vision. A multiple regression equation that incorporated these three variables, glare, and patient sex was able to predict only 46% of the variance in patient satisfaction.

Adult↗
PubMed1999

Intragenic recombinants of Plasmodium falciparum identified by in situ polymerase chain reaction.

We report an in situ PCR technique for visualising amplified DNA of blood forms of Plasmodium falciparum on microscope slides by fluorescence microscopy. The method is used to assess the changes in frequency of different alleles of the MSP1 gene in cultures of the progeny of a cross. We show that parasites with a recombinant form of this protein possess an initial growth advantage before declining in numbers over the long-term.

Alleles↗
PubMed1985

Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC): childhood cancer and the consumption of debendox and related drugs in pregnancy.

Attention has recently focused on the possible teratogenic effects of the combination antiemetic doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride (Debendox/Bendectin) prescribed to pregnant women. The Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC), a case-control investigation has analysed data derived from interview reports and medical records of 555 mothers of children (under 15 years) with cancer and 1110 mothers of matched control children. Separate analyses of interview reports and medical records both suggested that antiemetic ingestion during the index pregnancy does not increase the risk of developing childhood malignant disease in the exposed foetus. No dose-response relationship was evident. The lack of any significant relative risks held good for diagnostic sub-groups and when the trimester of ingestion was considered. Our results suggest that antimetics of this type are unlikely to be transplacental carcinogens.

Adolescent↗
PubMed1994

Elevated c-Src tyrosine kinase activity in premalignant epithelia of ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with a high incidence of colon cancer. Dysplasia is a precursor to carcinoma and a predictor of malignant potential; epithelia containing high-grade or severe dysplasia is most likely to develop cancer. The cellular oncogene c-src and its viral homologue v-src (the transforming gene of Rous sarcoma virus) encode 60-kD cytoplasmic, membrane-associated protein tyrosine kinases. For the viral protein or transforming mutants of the cellular protein (Src), a close correlation exists between elevated tyrosine kinase activity and malignant transformation of cells. Previously, we and others observed elevated Src activity in sporadic colon carcinomas and benign adenomas at greatest risk for developing cancer (those with large size, villous architecture, and/or severe dysplasia). Here we report that Src activity and protein abundance are also elevated in neoplastic UC epithelia. Activity is highest in malignant and severely dysplastic epithelia, and 6-10-fold higher in mildly dysplastic than in nondysplastic epithelia. Thus, Src activity is elevated in premalignant UC epithelia, which is at greatest risk for developing cancer. The data suggest that activation of the src proto-oncogene is an early event in the genesis of UC colon cancer.

Adenoma↗
PubMed1992

An outbreak of hepatitis A in Gloucester, UK.

During an outbreak of hepatitis A that occurred in Gloucester, UK between September 1989 and January 1991, 162 clinical cases were identified through notifications and laboratory reports, a monthly attack rate of 1.05 per 10,000 residents. The highest attack rate was seen in 5-14-year-olds. There were significant correlations between hepatitis A attack rates in the electoral wards of Gloucester and with the Jarman UPA 8 scores for the wards and with overcrowding, unemployment, under 5-year-olds and ethnic minority. The use of human normal immune globulin prophylaxis (HNIG) for household contacts was unsuccessful in ending the outbreak, partly because only one third of cases reported a household contact with recent hepatitis A. Our experience does not support the use of HNIG in stopping community-wide outbreaks of hepatitis A. Two public health campaigns were mounted during the outbreak; both were followed by a fall in the number of cases. Greater priority should be given to the implementation and evaluation of public health campaigns in future community-wide outbreaks of hepatitis A.

Adolescent↗
PubMed1997

[Immunohematologic study and transfusion approach to patients with public antibodies].

OBJECTIVES: To analyze the different immunohematologic studies required to identify anti-red cell antibodies directed against high incidence antigens and comment the best tranfusion management. PATIENTS AND METHODS: Five patients with suspected anti-red cell alloantibodies directed against high frequency antigens are reported. After a positive antibody screening test (AST), an agglutination test with a commercial panel of 24 red cells was performed. Red cells were treated with proteolytic enzymes and AET to try to identify the circulating antibody. However, it was necessary to send the samples to reference laboratories for definitive identification. In order to evaluate the haemolytic potential of the antibody serum samples were treated with DTT and immunoglobulin subtype was studied with the capillary agglutination test. Finally, we analyze the half life of Cr51 labelled red cells. To obtain compatible blood for transfusion, autologous transfusion and cross-match with blood from direct relatives were performed. RESULTS: AST was positive in every case. A decrease in the agglutination test was observed after ficin treatment in two patients, and an increase in the remaining. The treatment of red cells with ZZAP and AET resulted in a decrease of agglutination in three cases and an increase in the remaining two. Specificity of the antibodies was as follows: anti-Cellano (two cases), anti-Ku (one case) and anti-Yta (two cases). Anti-Kell antibodies were IgG1 and anti-Cartwright antibodies were IgG4. One patient was transfused with autologous blood alone, another patient received compatible blood from direct relatives. A third patient was transfused both with autologous and allogeneic compatible blood. The fourth patient did not need red cell transfusion and, finally the last patient had to be transfused with incompatible blood but no postransfusion haemolysis was observed. CONCLUSIONS: In patients with anti-red cell antibodies against high-frequency antigens, red blood cells treatment with proteolytic enzymes (ZZAP, ficin) and AET are useful techniques to approach to their identification. Beside this, the study of type and subtype of Ig are necessary to know the haemolytic activity of the antibody. Regarding the transfusional management, autologous transfusion, crossmatch with blood from direct relatives and cryopreservation of compatible blood are the most adequate attitudes to cover future needs.

Adult↗
PubMed1978

The esterase D polymorphism in patients with diabetes or carcinoma of the bladder and a matched sample of non-donor controls.

Results are reported for the Esterase D polymorphism in a sample of the general population from the Durham area. Gene frequencies agree well with those previously reported from the north of England. No differences are revealed when the sample is subdivided on the basis of age. No significant differences are observed between this sample and two disease series from the same region, one with diabetes, the other with carcinoma of the bladder. This holds true when the disease groups are considered with regard to current age, age at diagnosis, and in the case of the diabetic, current treatment.

Adolescent↗
PubMedDate not supplied

The role of sleep in changing our minds: a psychologist's discussion of papers on memory reactivation and consolidation in sleep.

The group of papers on memory reactivation and consolidation during sleep included in this volume represents cutting edge work in both animals and humans. They support that the two types of sleep serve different necessary functions. The role of slow wave sleep (SWS) is reactivation of the hippocampal-neocortical circuits activated during a waking learning period, while REM sleep is responsible for the consolidation of this new learning into long-term memory. These studies provide further insights into mechanisms involved in brain plasticity. Robeiro has demonstrated the upregulation of an immediate-early gene (IEG zif 268) to waking levels, which occurs only in REM and only in connection with new learning. McNaughton and his group have identified electrical indicators that the hippocampus and neocortex are talking to each other by testing the coactivation of hippocampal sharp wave bursts in SWS and shifts from down to up states of activation in the neocortex. In human studies Smith's group reports work on individual differences such as intelligence and presleep alcohol that affect postsleep performance, and Stickgold and collaborators report that a short nap will improve performance if it contains REM sleep. Payne and Nadel suggest that the recall benefit associated with REM sleep may be due to its association with increased cortisol levels. These papers are important not only in their individual contributions but also in revitalizing the work coordinating waking and sleep. This promises to further the understanding of how our unique capacity to learn from experience and modify our behavior takes place.

Animals↗
PubMed1999

Colony integration and the expression of the Hox gene, Cnox-2, in Hydractinia symbiolongicarpus (Cnidaria: Hydrozoa).

The stolonal mat is an anatomical feature correlated with increased colonial integration in several lineages of the cnidarian class Hydrozoa. Cnox-2 is a Hox gene known to be expressed in the body column of the cnidarian polyp. We report the pattern of Cnox-2 expression in both the stolonal mat and free stolons of the hydroid Hydractinia symbiolongicarpus. The gene is found to have high levels of expression in the mat similar to that found in the basal portion of the polyp, but it is not detectably expressed in those regions of free stolons where polyps are budded. These findings suggest that the stolonal mat arose via an expansion of the basal ectoderm of the polyp.

Animals↗