Reduced levels of dystrophin associated proteins in the brains of mice deficient for Dp71

Duchenne muscular dystrophy (DMD) is a progressive degenerative lethal muscle disease. A significant proportion of DMD affected children suffer also from mental retardation. The rod shaped protein, dystrophin, which is absent from or defective in the muscle of DMD patients, binds to a number of membrane associated proteins (known collectively as dystrophin associated proteins [DAPs]). The levels of DAPs is greatly reduced in the muscle of DMD patients and mdx mice, which lack dystrophin. In addition to dystrophin isoforms, the DMD gene codes also for several smaller proteins. One of the small proteins, Dp71, is expressed in most or all non-muscle tissues and is the major DMD gene product in the brain. The function of the small DMD gene products is unknown. Here we show that mutant mice which do not express the smaller non-muscle products of the DMD gene have a reduced level of DAPs in their brain. This suggests that Dp71 is important for the formation and/or stabilization of a DAPs complex in brain.      

Effect of altered intestinal water transport on rabbit ileal blood flow.

A method is described for measuring ileal blood flow in the anesthetized (pentobarbital sodium) rabbit by the intraventricular injection of microspheres (15 micrometer) labeled with cerium-141 or chromium-51; with this method the amount of labeled microspheres lodging in the tissue is proportional to the blood flow. Blood flow to the ileal mucosa plus submucosa could be separated from flow to the ileal muscularis propria plus serosa by this technique. Simultaneous and sequential injections of radiolabeled microspheres gave similar measurements of ileal blood flow and did not affect ileal water absorption. Increasing ileal water absorption by treatment with the glucocorticoid methylprednisolone (3 mg/100 g per day for 3 days) increased blood flow to both compartments of the ileum and also to the colon, liver, and kidneys; methylprednisolone treatment did not alter blood flow when studies were performed before the methylprednisolone-induced increase in ileal water absorption had occurred. In contrast, intestinal secretagogues that induced both active ileal secretion (purified cholera toxin and serotonin) and passive ileal secretion (hypertonic mannitol) did not affect ileal blood flow. These studies indicate that increased ileal water absorption is associated with increased ileal blood flow, whereas intestinal secretion is not necessarily associated with an alteration in ileal blood flow.     

Evidence for continuing neuropsychological impairments in depression

BACKGROUND: Neuropsychological deficits have been reported in patients with major depressive disorder (MDD) during an acute episode of MDD. Little is known whether these abnormalities persist when patients are remitted. The purpose of the present study was to describe the neuropsychological functioning of fully remitted, unmedicated patients with a history of MDD by focusing on tasks related to prefrontal cortex functioning. METHODS: Twenty-eight young to middle-aged, unmedicated, fully remitted patients with MDD were compared to 23 healthy control subjects on tasks from the Cambridge Automated Neuropsychological Test Battery (CANTAB) and the California Verbal Learning Test (CVLT). RESULTS: Patients with remitted MDD relative to controls were impaired on tasks of rapid visual information processing (RVIP), psychomotor performance and spatial working memory (SWM). After correction for residual depressive symptoms, deficits in sustained attention remained significant. LIMITATIONS: CANTAB tasks are not equated for difficulty, and difficulty differences between the CANTAB tasks and the CVLT are not known. CONCLUSIONS: These findings suggest deficits in sustained attention as vulnerability marker for MDD. The functional importance of this finding and the neuronal networks involved remain to be elucidated.     

Immunolocalization of the apoptosis regulating proteins Bcl-2 and Bax in human endometrium and isolated peritoneal fluid macrophages in endometriosis

Endometriosis, a debilitating disease associated with infertility, is characterized by the prolonged presence of ectopic endometrial tissue and the involvement of activated peritoneal fluid macrophages. Apoptosis, which occurs in both endometrium and peritoneal fluid macrophages, is controlled in part by members of the Bcl-2/Bax family of proteins. Here, through immunohistochemical staining, we investigated the Bcl-2/Bax status in endometrium and peritoneal fluid macrophages in endometriosis. Bcl-2/Bax immunoreactivity was found predominantly in the glandular epithelial cells, mainly during the proliferative phase of the menstrual cycle for Bcl-2 but throughout the entire menstrual cycle for Bax. Ectopic endometrium contained a population of Bcl-2 positive. Bax negative tissue macrophages. Fluorescence-activated cell sorting of isolated peritoneal fluid macrophages showed that women with endometriosis had a significantly higher proportion of Bcl-2 positive macrophages than the non- endometriotic group. The proportion of Bax positive peritoneal fluid macrophages was significantly elevated in women without endometriosis. The increased proportion of Bcl-2 positive macrophages found in women with endometriosis may predispose these cells to resist apoptosis. The continued survival of these active cells could have important consequences for the survival and proliferation of the ectopic endometrial tissue.      

Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders

Methionine synthase catalyzes the remethylation of homocysteine to methionine in a methylcobalamin-dependent reaction. We used specific regions of homology within the methionine synthase sequences of several lower organisms to clone a human methionine synthase cDNA by a combination of RT-PCR and inverse PCR. The enzyme is 1265 amino acids in length and contains the seven residue structure-based sequence fingerprint identified for cobalamin-containing enzymes. The gene was localized to chromosome 1q43 by the FISH technique. We have identified one missense mutation and a 3 bp deletion in patients of the cblG complementation group of inherited homocysteine/folate disorders by SSCP and sequence analysis, as well as an amino acid substitution present in high frequency in the general population. We discuss the possibility that a mild deficiency of methionine synthase activity could be associated with mild hyperhomocysteinemia, a risk factor for cardiovascular disease and possibly neural tube defects.      

Family history in delusional depression

Family psychiatric history was compared in the 472 first-degree relatives of 31 delusional and 35 nondelusional inpatients who met DSM III criteria for major depression with melancholia. Morbid risks for psychiatric illness or for psychiatric treatment variables did not differ between the two groups. Specifically, rates of affective and psychotic illnesses in families did not distinguish delusional from nondelusional probands. The findings do not support the hypothesis of a genetic relationship of nonaffective psychosis to delusional depression.     

Childhood antecedents of adult obesity. Do chubby infants become obese adults?

We investigated whether obese infants tend to become obese adults. Records of subjects born between 1945 and 1955 were reviewed to select three cohorts based on weight in the first six months of age, which exceeded the 90th percentile at least once, ranged between 25th and 75th percentiles or was below 10th percentile at least once. Three hundred and sixty-six subjects, now between 20 and 30 years of age, were located and their present height and weight determined. Thirty-six per cent of those exceeding the 90th percentile as infants were overweight adults, as compared to 14 per cent of the average age and light-weight infants. A significant increase (chi square = 17.2, p less than 0.001) in adult obesity was evident when the infant exceeded the 75th percentile that was independent of his height. Social class, educational level, and parental weight all correlated with adult weight (p less than 0.001). Sex and ordinal position of birth did not. The data suggest that infant weight correlates strongly with adult weight independently of other factors considered.     

Receptor sensitivity and the mechanism of action of antidepressant treatment. Implications for the etiology and therapy of depression

Considerable evidence suggests that the acute effects of antidepressant treatments on brain norepinephrine (NE) and serotonin (5-HT) systems cannot account fully for their delayed therapeutic action. This review evaluates the effects of long-term antidepressant treatment on biogenic amine metabolism and on various indexes of presynaptic and postsynaptic receptor function. In contrast to variable effects on NE and 5-HT turnover and on presynaptic receptor sensitivity almost all long-term antidepressant treatments produce consistent alterations in a number of measures of postsynaptic amine receptor sensitivity. Long-term treatment has been found to reduce beta-adrenergic sensitivity while enhancing responses to serotonergic and alpha-adrenergic stimulation, suggesting that modulation of receptor sensitivity may be a mechanism of action common to tricyclic antidepressants, "atypical" antidepressants, monoamine oxidase inhibitors, and electroconvulsive therapy. These findings provide support for hypotheses of amine receptor abnormalities in depression and indicate the need for expanded studies of amine receptor function in patients.