Neurophysiological responses to face, facial regions and objects in adults with Asperger's syndrome: an ERP investigation.

Face processing differences have been observed between AS and control subjects at the behavioural and neurological levels. The purpose of the present study was to investigate the neurophysiological basis of processing faces and facial features (eyes and mouths) in adults with AS relative to age- and gender-matched typically-developing controls. These results were compared with ERPs generated to objects in both groups to determine if any differences were specific to facial stimuli. Although both groups elicited earlier N170 latencies to faces than to face parts and to eyes relative to mouths, adults with AS exhibited delayed N170 latencies to faces and face parts relative to controls. This difference was not observed to objects. Together these findings suggest that adults with AS may be slower to process facial information.     

Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation

The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.      

The effect of elevated intracranial pressure on the vibrational response of the ovine head

Although potentially fatal increases in intracranial pressure (ICP) can occur in a number of pathological conditions, there is no reliable and noninvasive procedure to detect ICP elevation and quantitatively monitor changes over time. In this experimental study, the relationships between ICP elevation and the vibrational response of the head were determined. An ovine animal model was employed in which incremental increases in ICP were elicited and directly measured through intraventricular cannulae. At each ICP increment, a vibration source elicited a flexural response of the animal's head that was measured at four locations on the skull using accelerometers. Spectral analysis of the responses showed changes in proportion to ICP change up to roughly 20 cm H₂O (15 mm Hg) above normal; a clinically significant range. Both magnitude and phase changes at frequencies between 4 and 7 kHz correlated well (γ>0.92) with ICP across the study group. These findings suggest that the vibrational response of the head can be used to monitor changes in ICP noninvasively.     

Organotypic culture of embryonic electromotor system tissues from Torpedo marmorata

An explant culture system has been used to study the electric organ and electric lobe tissues of Torpedo marmorata at different stages during the development of the electromotor system.The myotubes in tissue expiants, taken from the electric organ primordia of 33–38 mm body-length embryos prior to electrocyte differentiation, contract spontaneously on explantation and have electrogenic membranes. The myotubes subsequently lose these properties in vitro and can differentiate in the absence of neural tissue into immature electrocytes which have morphologically characteristic postsynaptic membranes.Isolated expiants of differentiated electric organ tissue from 60–100 mm body-length embryos can be maintained for 3 to 4 weeks in vitro but cellular outgrowth is minimal. In contrast, a rapid, dense outgrowth of cells and a subsequent regeneration of myotubes occurs when differentiated electric organ explants are co-cultured with electric lobe tissue from embryos of the same stage. Cellular outgrowth from differentiated electric-organ tissue expiants can be stimulated by spinal cord, medulla, cerebellum and heart tissues but a subsequent regeneration of myotubes has not been observed. Myotube regeneration in the presence of electric lobe tissue is maximal with tissue from 60–80 mm body-length embryos. The myotubes that regenerate from differentiated electric organ expiants have not been observed to differentiate into electrocytes.Neuritic outgrowth in vitro occurs with electric lobe tissue taken at two different embryonic stages. The first stage corresponds to a period when most of the neuroepithelial cells in the lobe anlagen are withdrawing from the mitotic cycle and projecting axons into the branchial arches. The second, later stage is when the electromotorneurones are normally generating axon collaterals that are invading the interelectrocyte space of electrocyte columns. Maximum neuritic outgrowth at this second, later stage is obtained with tissue from 60–80 mm body-length embryos. Although neuritic invasion of electrocyte column expiants can be obtained in electric organ—electric lobe co-cultures at this later stage, synapses similar to those observed during the early stages of synaptogenesis in the electric organs in vivo have not been observed in vitro.     

Changes in peritoneal myeloid populations and their proinflammatory cytokine expression during infection with Listeria monocytogenes are altered in the absence of gamma/delta T cells

Evidence that gamma/delta T cells play a broad, immunoregulatory role has been accumulating steadily. We show here that myeloid cells are disregulated after peritoneal infection with Listeria monocytogenes in mice lacking gamma/delta T cells. Inflammatory populations of neutrophils and monocytes recruited to the site of infection remained longer. Intracellular cytokine analysis showed that frequencies of myeloid cells producing interleukin-12 and tumor necrosis factor alpha were higher and remained elevated longer after infection in mice genetically deficient in gamma/delta T cells. In vivo dye-tracking studies indicated that the majority of inflammatory monocytes differentiated into resident tissue macrophages in situ. In vitro experiments confirmed that monocytes harvested from mice lacking gamma/delta T cells were defective in their maturation process. This evidence suggests that gamma/delta T cells promote differentiation in the monocyte/macrophage lineage. These cells are important for bactericidal activity, inflammatory cytokine production, clearance of inflammatory neutrophils, and ultimately, antigen presentation to T cells. Regulation of monocyte/macrophage differentiation may underlie a broad segment of the phenotypic alterations that have been reported in mice lacking gamma/delta T cells.     

Anti-HIV effects of chloroquine: inhibition of viral particle glycosylation and synergism with protease inhibitors

OBJECTIVE: We tested the effects of chloroquine (CQ) on glycosylation of HIV particles and in combination with protease inhibitors (PIs) on HIV replication and on P-glycoprotein (P-gp)/multidrug resistance protein-1 (MRP1). DESIGN: CD4 cell lines were infected with laboratory strains and peripheral blood mononuclear cells were infected with primary isolates for evaluation of the anti-HIV effects. Peripheral blood lymphocytes were evaluated for of P-gp and MRP1 functions. METHODS: HIV replication was assessed by enzyme-linked immunosorbent assay. HIV glycosylation was measured by metabolic labeling of viral particles with [H] glucosamine. Synergism was tested using isobolograms. P-gp and MRP1 functions were assayed using rhodamine 123 (Rh123) and carboxyfluorescein (CF) efflux assays, respectively. RESULTS: CQ alone inhibited HIV replication and glycosylation in a dose-dependent manner. In combination with indinavir (IDV), ritonavir, or saquinavir (SQV), CQ had a synergistic effect at concentrations found in plasma of subjects receiving malaria prophylaxis. CQ decreased the 50% effective concentration of IDV in primary isolates from Africa and restored the response to IDV or SQV in 3 PI-resistant isolates. CQ increased the block of Rh123 and CF efflux activity exerted by PIs. CONCLUSION: The inhibitory effects of CQ on HIV glycosylation are associated with synergistic effects in combination with PIs. The CQ/PI combination exerts combined inhibitory effects on P-gp and MRP1 function.     

Extinction responding by septal and normal rats following acquisition under four schedules of reinforcement

Extinction responding of animals with septal lesions was compared to that of normal animals following acquisition training under either DRL, FI, VI or FR reinforcement schedules (Part 1). During both acquisition and extinction, septals bar pressed more than normals. However, regardless of response levels, a given schedule changed behavior in the same direction for both septals and normals. Thus, if a given schedule led to a decrease in bar pressing by normals, it also led to a decrease by septals, although the absolute level of responding at which this occurred might be different for the two groups. Similarly, if a schedule led to an increase in responding by normals, it also led to an increase by septals. In Part 2 of the experiment operant levels of septals were not found to be different from those of normals, and noncontingent food delivery generated no more nor less bar pressing in septals than in normals. It was proposed that the septal area may be of importance in the initiation of behavior which competes with the required or reinforced response.     

Immunoglobulin M antibody responses to Mycobacterium ulcerans allow discrimination between cases of active Buruli ulcer disease and matched family controls in areas where the disease is endemic

Buruli ulcer disease (BUD) is an emerging disease caused by Mycobacterium ulcerans. In the present study we have characterized the serological reactivities of sera from volunteer case patients with laboratory-confirmed BUD and controls living in three different regions of Ghana where the disease is endemic to determine if serology may be useful for disease confirmation. Our results showed highly reactive immunoglobulin G (IgG) responses among patients with laboratory-confirmed disease, healthy control family members of the case patients, and sera from patients with tuberculosis from areas where BUD is not endemic. These responses were represented by reactivities to multiple protein bands found in the M. ulcerans culture filtrate (CF). In contrast, patient IgM antibody responses to the M. ulcerans CF (MUCF) proteins were more distinct than those of healthy family members living in the same village. A total of 84.8% (56 of 66) of the BUD patients exhibited strong IgM antibody responses against MUCF proteins (30, 43 and 70 to 80 kDa), whereas only 4.5% (3 of 66) of the family controls exhibited such responses. The sensitivity of the total IgM response for the patients was 84.8% (95% confidence interval [CI], 74.3 to 91.6%), and the specificity determined with sera from family controls was 95.5% (95% CI, 87.5 to 98.4%). These studies suggest that the IgM responses of patients with BUD will be helpful in the identification and production of the M. ulcerans recombinant antigens required for the development of a sensitive and specific serological assay for the confirmation of active BUD.     

Blood and Marrow Transplant Clinical Trials Network State of the Science Symposium 2007.

Outcomes of hematopoietic cell transplantation are steadily improving. New techniques have reduced transplant toxicities, and there are new sources of hematopoietic stem cells from unrelated donors. In June 2007 the Blood and Marrow Transplant Clinical Trials Network convened a State of the Science Symposium of more than 200 participants in Ann Arbor to identify the most compelling clinical research opportunities in the field. This report summarizes the symposium's discussions and identifies eleven high priority clinical trials that the network plans to pursue over the course of the next several years.