Drug use and the risk of major depressive disorder,alcohol dependence,and substance use disorders

BACKGROUND: The Children in the Community Study is a prospective longitudinal study investigating the association between early drug use (childhood, adolescence, and early 20s) and later psychiatric disorders (in the late 20s). METHODS: Using data from a community-based sample of 736 adults (50% female) from upstate New York, the subjects were interviewed at the mean ages of 14, 16, 22, and 27 years. Psychiatric disorders, measured by age-appropriate versions of the University of Michigan Composite International Diagnostic Interview, and participant's drug use were assessed. RESULTS: Adolescent and young adult tobacco use was significantly associated with an increased risk of alcohol dependence and substance use disorders at a mean age of 27 years, but not with new episodes of major depressive disorder. Earlier alcohol use significantly predicted later major depressive disorder, alcohol dependence, and substance use disorders in the late 20s, as did early marijuana use and other illicit drug use. Except for the effect of tobacco use on major depressive disorder, early drug use was significantly related to later psychiatric disorders, even after statistically controlling for age, sex, parental educational level, family income, and prior episodes of major depressive disorder and substance use disorders. CONCLUSIONS: Our results suggest that early drug use is associated with and predicts later psychiatric disorders. Preventive implications stem from the importance of studying a range of psychiatric disorders in the context of substance use assessed over a wide age range.     

Reversible posterior encephalopathy syndrome: case report

The posterior reversible leukoencephalopathy syndrome (PRES) is a recently proposed cliniconeuroradiologic entity.The most common causes of PRES are hypertensive encephalopathy, eclampsia, cyclosporin A neurotoxicity and the uremic encephalopathies.Most patients are markedly hypertensive at presentation, although some have only mildly elevated or even normal blood pressure. Symptoms may include headache, nausea, vomiting, altered mental status, seizures,stupor, and visual disturbances. On CT and MR studies, edema has been reported in a relatively symmetrical pattern, typically in the subcortical white matter and occasionally in the cortex of the occipital and parietal lobes. These often striking imaging findings usually are resolved on follow-up studies obtained after appropriate therapy. Diffusion-weighted images would not show hyperintense signal because of the presence of interstitial rather than cytotoxic edema. We report a case of PRES due to hypertensive encephalopathy studied by CT and MRI.     

Dorsolateral columns of the spinal cord are necessary for both suckling-induced neuroendocrine reflexes and the kyphotic nursing posture in lactating rats

Maternal behavior in rats consists of active behaviors, such as retrieval and licking of pups, and quiescent nursing, including the suckling-induced kyphotic (upright, dorsally-arched) posture. Because lesions of the dorsolateral, but not of the dorsal, columns are known to prevent the suckling-induced milk-ejection reflex, we asked whether the same is true for kyphosis as well. Bilateral lesions of the dorsolateral funiculus (DLF) or dorsal columns (DC) at spinal segments C(4-6) were made on day 5-8 postpartum; controls (CON) were subjected to a sham procedure. All aspects of maternal behavior and lactation were present in CON and DC dams soon after treatment. Among DLF dams, two had poor postural, ambulatory, and ingestive recovery that was associated with large lesions extending to the ventrolateral columns, while one with very small lesions continued to lactate. Of the remaining eight DLF dams, milk ejection was lost while recovery of retrieval and licking of pups occurred in all (between 1 and 4 days after surgery). All eight were quiescent for long periods in response to suckling but they did not display sustained kyphosis; rather, they nursed while prone or hunched over the pups, with little or no leg support, or while supine. Ventral trunk cutaneous sensitivity was present in all subjects. These data suggest that the dorsolateral funiculus relays both suckling-induced neuroendocrine and postural nursing reflexes that are mediated by separate supraspinal regions, hypothalamus and the ventrolateral sectors of the caudal periaqueductal gray, respectively.     

Aerobic capacity in adults with tetralogy of Fallot

BACKGROUND: We investigated the aerobic capacity of 168 adult patients who had undergone successful surgical repair of retralogy of Fallot at the University of Toronto Congenital Cardiac Centre for Adults. METHODS: We compared values of peak uptake of oxygen, peak heart rate, forced vital capacity, and forced expiratory volume in 1 second to predicted values for their age groups. RESULTS: The patients who had undergone surgical repair of tetralogy of Fallot demonstrated an overall diminished peak uptake of oxygen, at 51%,and peak heart rate, at 79%, compared to predicted values. No difference in peak aerobic capacity was found according to the initial surgical strategy of palliation or repair. CONCLUSIONS: Adult patients who have undergone surgical repair of tetralogy of Fallot have lower peak uptake of oxygen, and peak heart rate, compared to predicted values. The reduction in the peak heart rate may affect their exercise capacity. The peak uptake of oxygen also decreased with increasing age at the time of testing, and the age at surgical repair.     

Soluble transforming growth factor-beta type III receptor gene transfection inhibits fibrous airway obliteration in a rat model of Bronchiolitis obliterans

Post-transplant bronchiolitis obliterans (BO) is characterized by fibroproliferation and fibrous obliteration of distal airways in chronically rejected lungs. In this study, using a rat heterotopic allogeneic tracheal transplant model of BO, we evaluated the expression of transforming growth factor-beta (TGFbeta) during the development of airway fibrous obliteration. Immunohistochemical analysis revealed TGFbeta staining in infiltrating mononuclear cells at Days 2 and 7, and in the fibrous tissues until Day 21. Soluble TGFbeta receptor type III (TGFBIIIR), by blocking TGFbeta binding to its membrane receptors, functions as a TGFbeta antagonist. To study the role of TGFbeta in the development of BO, adenoviral-mediated soluble TGFBIIIR gene transfection (5 x 10(9) particles) was performed topically at the site of transplant on Day 5 after transplantation, which leads to inhibition of fibrous airway obliteration. In contrast, empty vector gene delivered through intramuscular injection, or given locally at Days 0 or 10 after tracheal transplantation had no significant effect. These results suggest that TGFbeta expressed in the allografts plays a pivotal role in the pathogenesis of BO. Soluble TGFBIIIR may competitively inhibit TGFbeta activity locally. Adenoviral-mediated soluble TGFBIIIR gene transfection should be further explored as a potential therapeutic modality for BO and other conditions involving chronic fibrosis.     

Management of metabolic complications of therapy

Considerable efforts are underway to define effective strategies for the treatment of metabolic complications of HIV therapy. Clearly these problems dominate the overall approach to treatment of HIV infection in the settings where antiretroviral agents are accessible. While progress has been made it has been slow, and accompanied by disappointments. There are currently no effective treatments for lipoatrophy, and while treatments for dyslipidemia have been described, in most cases the improvement is incomplete. While these efforts must continue it is hoped that a new focus on prevention of metabolic complications will begin to emerge in the year ahead.     

The effect of proteasome inhibitors on mammalian erythroid terminal differentiation

OBJECTIVES: Murine erythroblasts infected with the anemia-inducing strain of Friend virus (FVA cells) terminally differentiate to the reticulocyte stage after 48 hours of culture in vitro in response to erythropoietin (EPO). The objective of this study was to determine the possible role of proteasome-mediated proteolysis during the terminal differentiation of FVA cells. MATERIALS AND METHODS: The proteasome inhibitors MG132 and lactacystin were used to perturb the normal function of proteasomes during terminal differentiation. Effects of proteasome inhibitors on terminal differentiation were quantitated by evaluation of cellular morphology after benzidine staining and by Western blot analyses. RESULTS: Treatment of EPO-stimulated FVA cells with lactacystin or MG132 at later periods of culture increased accumulations of nuclear and cytosolic ubiquitinated proteins and decreased nuclear extrusion to less than 40% of controls. CONCLUSIONS: Our results suggest that the proteasomal degradation of ubiquitinated proteins plays an important role in the enucleation of mammalian erythroblasts.