1alpha,25-Dihydroxyvitamin D3 down-regulates expression of prostate specific membrane antigen in prostate cancer cells

BACKGROUND: Prostate specific membrane antigen (PSMA) expression correlates with prostate cancer grade and is increased in hormone-refractory prostate cancer. The increased expression of PSMA following androgen deprivation therapy may be a consequence of the down-regulation of PSMA expression by androgen. Moreover, 1alpha,25-dihydroxyvitamin D3 (1,25-VD) has been shown to suppress prostate cancer progression as well as cell motility and invasion. Since PSMA is positively correlated with both of these characteristics, we hypothesized that 1,25-VD would regulate PSMA expression. METHODS: LNCaP prostate cancer cells were treated with 1,25-VD, followed by analysis of cell surface PSMA expression. The PSMA enhancer, located within the third intron of the PSMA gene, was cloned into a reporter vector and regulation by 1,25-VD was investigated. The role of the androgen receptor (AR) in 1,25-VD mediated suppression of PSMA expression was examined using Casodex and AR specific siRNA. RESULTS: Surface expression of PSMA was significantly decreased in a dose-dependent manner by 10 nM 1,25-VD or greater. Regulation by 1,25-VD occurred at the level of the PSMA enhancer. Over-expression of the vitamin D receptor (VDR) also decreased expression of PSMA. Additionally, suppression of AR translation using siRNA technology blocked the suppressive effect of 1,25-VD on PSMA expression, however inhibition of PSMA expression by 1,25-VD occurred in the absence of androgens. CONCLUSIONS: Suppression of PSMA by 1,25-VD occurs at the level of the PSMA enhancer and is elevated by over-expression of the VDR. This regulation involves the AR, but is not dependent on the presence of androgens.     

Obesity Diagnosis and Care Practices in the Veterans Health Administration

BACKGROUND  

In response to dramatic increases in obesity prevalence, clinical guidelines urge health care providers to prevent and treat obesity more aggressively.     

Are psychiatric disorders independent risk factors for new-onset epilepsy in older individuals?

This retrospective study examined whether psychiatric conditions are directly related to epilepsy or, rather, are associated with underlying central nervous system (CNS) disorders linked to subsequent epilepsy. We examined data from a sample of older veterans (>65 years) receiving care from the Veterans Health Administration during fiscal year 2000. We compared individuals with new-onset epilepsy and individuals without epilepsy to examine the extent to which psychiatric disorders were associated with new-onset epilepsy; this analysis controlled for demographic and premorbid neurological risk factors previously associated with new-onset epilepsy. Premorbid psychiatric conditions occurred at higher rates in the epilepsy versus nonepilepsy groups, foremost including depression (17% vs 12%), anxiety (12% vs 8%), psychosis (12% vs 5%), and substance abuse (8% vs 4%). However, in the final model, only psychosis (OR = 1.4, CI 1.2–1.6) was significantly associated with epilepsy when controlling for neurological disorders and psychiatric conditions (e.g., stroke, dementia, brain tumor, head injury).     

Special Education Services for Children Involved with Child Welfare/Child Protective Services

This paper examines educational and behavioral characteristics and special education service use for a subsample of 2477 children enrolled in the National Survey of Child and Adolescent Wellbeing (NSCAW), the first national, longitudinal study of youth following investigation for alleged maltreatment through the child welfare system (CW). Almost one-fifth of children were characterized as severe on educational indices and 47% as severe on behavioral indices. Nineteen percent were currently receiving special education services, 17% had previously received these services, and the remainder had never received them. Over half (51%) of children characterized as severe on educational or behavioral indices were not receiving special education services. Caregivers indicated that youth were being served primarily under categories of Emotional Disturbance (35%) and Speech and Language Impairment (30%). Further exploration of the role of schools, particularly school psychologists, in providing supports for children involved with CW is discussed.     

Pelvic fractures in a pediatric level I trauma center

OBJECTIVES: Assess the characteristics associated with the risk of complications and mortality in children sustaining pelvic fractures. SETTING: Urban university pediatric Level I trauma center in a large metropolitan community. PATIENTS/PARTICIPANTS: Retrospective analysis of 57 consecutive children with 66 pelvic fractures seen between 1993 and 1999. INTERVENTION: Fifty-two patients were treated nonoperatively, and five patients required operative stabilization (four acetabular fractures and one partial sacroiliac joint disruption). MAIN OUTCOME MEASURE: Type and cause of pelvic fracture, type of management used, incidence of associated injuries, hemorrhage requiring transfusion, and mortality. RESULTS: Hemorrhage directly related to the pelvic fracture occurred in only one patient (2%), whereas 11 other patients required transfusions associated with other body-area injuries. Three patients with pelvic fractures died (5%), but deaths were due to other body-area injuries. CONCLUSIONS: Children with pediatric pelvic fractures require careful evaluation for other body-area injuries, as these are most likely to be related to hemorrhage or mortality.     

SecA2-dependent secretion of autolytic enzymes promotes Listeria monocytogenes pathogenesis

Pathogenic bacteria secrete proteins that promote invasion of host tissues and resistance to immune responses. However, secretion mechanisms that contribute to the enormous morbidity and mortality of Gram-positive bacteria are largely undefined. An auxiliary protein secretion system (SecA2) has recently emerged in Listeria monocytogenes and eight other Gram-positive pathogens. Here, a proteomics approach identified seventeen SecA2-dependent secreted and surface proteins of L. monocytogenes, the two most abundant of which [the p60 and N-acetylmuramidase (NamA) autolysins] hydrolyze bacterial peptidoglycan (PGN) and contribute to host colonization. SecA2-deficient (DeltaSecA2) bacteria were rapidly cleared after systemic infection of murine hosts, and in cultured cells showed reduced cell-cell spread. p60 or NamA deficiencies (Deltap60 and DeltaNamA) caused intermediate reductions in bacterial virulence in vivo, yet showed no defect for infection of cultured cells. Restoration of virulence in Deltap60 bacteria required full-length p60 with an intact catalytic domain, suggesting that PGN hydrolysis by p60 is crucial for L. monocytogenes virulence. Coordinated PGN hydrolysis by p60 and NamA activities is predicted to generate a muramyl glycopeptide, glucosaminylmuramyl dipeptide (GMDP), which is known to modify host inflammatory responses. Thus, SecA2-dependent secretion may promote release of muramyl peptides that subvert host pattern recognition.