Identification of sex hormone-binding globulin in the human hypothalamus

Gonadal steroids are known to influence hypothalamic functions through both genomic and non-genomic pathways. Sex hormone-binding globulin (SHBG) may act by a non-genomic mechanism independent of classical steroid receptors. Here we describe the immunocytochemical mapping of SHBG-containing neurons and nerve fibers in the human hypothalamus and infundibulum. Mass spectrometry and Western blot analysis were also used to characterize the biochemical characteristics of SHBG in the hypothalamus and cerebrospinal fluid (CSF) of humans. SHBG-immunoreactive neurons were observed in the supraoptic nucleus, the suprachiasmatic nucleus, the bed nucleus of the stria terminalis, paraventricular nucleus, arcuate nucleus, the perifornical region and the medial preoptic area in human brains. There were SHBG-immunoreactive axons in the median eminence and the infundibulum. A partial colocalization with oxytocin could be observed in the posterior pituitary lobe in consecutive semithin sections. We also found strong immunoreactivity for SHBG in epithelial cells of the choroid plexus and in a portion of the ependymal cells lining the third ventricle. Mass spectrometry showed that affinity-purified SHBG from the hypothalamus and choroid plexus is structurally similar to the SHBG identified in the CSF. The multiple localizations of SHBG suggest neurohypophyseal and neuroendocrine functions. The biochemical data suggest that CSF SHBG is of brain rather than blood origin.     

Reduced number of CRF-containing neurons in the central amygdala correlated with enhanced locomotor activity following early postnatal corticosterone treatment in the Wistar rat

In the present study, newborn rats were implanted with corticosterone (CORT) containing polymers at postnatal day 0 (releasing rate 320-80 microg CORT/kg body weight and day). Controls received a CORT-free implant. All implants were removed at postnatal day 12. At the age of 16-20 weeks, these animals were tested for emotional behavior using an elevated plus-maze and fear-sensitized acoustic startle response. On the elevated plus-maze significant differences were found between hormone treated and control animals. The CORT-group demonstrated higher numbers of entries into closed arms and all arms, and the time spent in the center of the maze was significantly enhanced. Hormone-treated and control rats showed a significant fear sensitization of the acoustic startle response. However, no significant differences were observed between the two groups. The number of CRF-immunopositive neurons in the central nucleus of the amygdala was decreased after CORT treatment, whereas the number of NPY-immunopositive neurons and total number of neurons in the amygdala did not differ significantly between both groups. In conclusion, early postnatal stress induced by CORT administration in neonatal rats led to a higher locomotor activity correlated with changes in the number of CRF containing neurons in the central nucleus of the amygdala.     

Video and CD-ROM as a training tool for performing neurologic examinations of 1-year-old children in a multicenter epidemiologic study

In lieu of traditional training of examiners to identify cerebral palsy on a neurologic examination at age 1 year, we proposed an alternative approach using a multimedia training video and CD-ROM we developed after a two-step validation process. We hypothesized that use of CD-ROM interactive training will lead to reliable and valid performance of the neurologic examination by both pediatric neurologists and nonpediatric neurologists. All examiners were asked to take one of six interobserver variability tests found on the CD-ROM on two occasions. In the first interobserver variability evaluation, 89% (531 of 594) of the responses agreed with the gold standard responses. Following annotated feedback to the examiners about the two items that had a 60% correct rate, the correct response rate rose to 93% (114 of 123). In the second interobserver variability evaluation, 88% (493 of 560) of the responses agreed with the gold standard responses. Following annotated feedback to the examiners about the four items that had a 70% correct rate, the correct response rate rose to 96% (104 of 108). Interactive CD-ROM examination training is an efficient and cost-effective means of training both neurologists and non-neurologists to perform structured neurologic examinations in 1-year-old children. It provides an effective means to evaluate interobserver variability, offers a route for feedback, and creates an opportunity to reevaluate variability, both immediately and at periodic intervals.     

Diagnosis of hypertension and high blood pressure levels negatively affect cognitive function in older adults

bdBackground: Hypertension is associated with diminished performance on tests of cognitive function. The degree to which those diagnosed with hypertension have controlled blood pressure (BP) levels may be a critical determinant of cognitive outcomes. Persons with hypertension and poorly controlled BP are likely to display the worst performance on cognitive tests.Purpose: The purpose is to examine potential interactive relations of hypertension diagnostic status and current BP levels to cognitive function.Methods: Participants were 101 healthy older adults (ages 53–84, 62% male, 90% White, 29% diagnosed with hypertension) who engaged in biomedical and neuropsychological assessment.Results: After statistical adjustment for age and education, persons with high BP performed more poorly than those with normal BP on the Visual Reproductions—Immediate and Delayed Recall and the Grooved Pegboard tests. Diagnosed hypertension was related to poorer performance on the Grooved Pegboard tests. An interaction of diagnosed hypertension and BP level revealed that those diagnosed with hypertension and also having poorly controlled BP levels performed least well on the Grooved Pegboard tests and the Trail Making Test-Part A.Conclusion: Irrespective of prior diagnostic status, individuals with high BP displayed compromised performance on tests of nonverbal memory, motor speed, and manual dexterity. However, as compared to the other groups, those diagnosed with hypertension and also having poorly controlled BP elevation were most vulnerable to difficulties on tests of perceptuo-motor speed, motor speed, and manual dexterity. These findings suggest the need for increased attention to preventative efforts with respect to BP assessment and control in older adults to help preserve cognitive function. Karl J. Maier is now in the Department of Psychology at Salisbury University. This work was supported by National Institutes of Health Grant R29 AG15112, and K24 AG00930; a VA Merit Grant, Bristol Myers Squibb Medical Imaging, Inc., the Department of Veterans Affairs Baltimore Geriatric Research Education and Clinical Center; and the Geriatrics and Gerontology Education and Research Program of the University of Maryland, Baltimore. We thank Denise Cooper, Karen Gibbs, Layne Goble, Joseph Snow, and Carol Tankard for their assistance with data collection.     

Pathogenesis of prion diseases

Prion diseases are rare neurological disorders that may be of genetic or infectious origin, but most frequently occur sporadically in humans. Their outcome is invariably fatal. As the responsible pathogen, prions have been implicated. Prions are considered to be infectious particles that represent mainly, if not solely, an abnormal, protease-resistant isoform of a cellular protein, the prion protein or PrP^C. As in other neurodegenerative diseases, aggregates of misfolded protein conformers are deposited in the CNS of affected individuals. Pathogenesis of prion diseases comprises mainly two equally important, albeit essentially distinct, topics: first, the mode, spread, and amplification of infectivity in acquired disease, designated as peripheral pathogenesis. In this field, significant advances have implicated an essential role of lymphoid tissues for peripheral prion replication, before a likely neural spread to the CNS. The second is the central pathogenesis, dealing, in addition to spread and replication of prions within the CNS, with the mechanisms of nerve cell damage and death. Although important roles for microglial neurotoxicity, oxidative stress, and complement activation have been identified, we are far from complete understanding, and therapeutic applications in prion diseases still need to be developed.     

Rifaximin--a novel antimicrobial for enteric infections

Rifaximin is a poorly absorbed rifamycin antimicrobial drug with in vitro activity against Gram-positive, Gram-negative and anaerobic bacteria. The minimal concentration that inhibits 90% of strains of bacterial pathogens (MIC90) ranges between 32 and 64 microg/ml. Less than 1% of the drug is absorbed after oral administration. After three days of therapy, the average fecal level of this drug is 8000 microg/g of stool. Selection of resistant mutants, a problem with the related rifampin, appears to be unusual with rifaximin. Rifaximin shortens the duration of travelers' diarrhea and non-dysenteric diarrheal illness due to enterotoxigenic, enteroaggregative E. coli and Shigella sonnei without major alteration of aerobic fecal flora and without important side effects. The drug has been successfully used in preliminary studies of small bowel bacterial overgrowth syndrome and hepatic encephalopathy. To explain the beneficial effect of the drug on bacterial diarrhea without change in colonic flora or high rates of pathogen eradication, rifaximin may be more active against pathogens in the small bowel rather than the colon and/or the drug may alter the virulence of enteric pathogens in addition to organism inhibition.     

Analyses of minimal residual disease based on Flt3 mutations in allogeneic peripheral blood stem cell transplantation

Purpose Activating Flt3 mutations are observed in about 30% of patients with acute myeloid leukaemia (AML) and individual Flt3 mutations are applicable for minimal residual disease (MRD) analyses.Methods We investigated the MRD status in four AML patients carrying different Flt3 mutations (three patients with Flt3 length mutations of the juxtamembrane domain, one patient carrying a mutation of the Flt3 tyrosine kinase domain, i.e. Flt3-TKD mutation) who underwent allogeneic peripheral blood stem cell transplantation (PBSCT). Residual leukaemia cells were retrospectively determined by real-time PCR at different time points.Results We can demonstrate a good correlation between the course of MRD status and clinical events in all four investigated patients.Conclusion These examples demonstrate the potential impact of Flt3 based MRD status not only after but also prior to allogeneic PBSCT.