Defective pancreatic beta-cell glycolytic signaling in hepatocyte nuclear factor-1alpha-deficient mice

Mutations in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene cause maturity onset diabetes of the young type 3, a form of type 2 diabetes mellitus. In mice lacking the HNF-1alpha gene, insulin secretion and intracellular calcium ([Ca2+]i) responses were impaired following stimulation with nutrient secretagogues such as glucose and glyceraldehyde but normal with non-nutrient stimuli such as potassium chloride. Patch clamp recordings revealed ATP-sensitive K+ currents (KATP) in beta-cells that were insensitive to suppression by glucose but normally sensitive to ATP. Exposure to mitochondrial substrates suppressed KATP, elevated [Ca2+]i, and corrected the insulin secretion defect. NAD(P)H responses to glucose were substantially reduced, and inhibitors of glycolytic NADH generation reproduced the mutant phenotype in normal islets. Flux of glucose through glycolysis in islets from mutant mice was reduced, as a result of which ATP generation in response to glucose was impaired. We conclude that hepatocyte nuclear factor-1alpha diabetes results from defective beta-cell glycolytic signaling, which is potentially correctable using substrates that bypass the defect.     

Recipes for digital living [ubiquitous computing in consumer electronics]

As networked devices become increasingly ubiquitous, the potential benefits to users increase exponentially. However, this potential can't be fully realized if it is entirely up to developers and manufacturers to expose the combined functionality buried in the expanding network. Recipes for digital living - created and modified by users themselves - offer an easy-to-understand, logically consistent way to capture and share the various ensembles possible in the expanding world of networked components.     

Regulation of CD95 (Apo-1/Fas) ligand and receptor expression in squamous-cell carcinoma by interferon-gamma and cisplatin

CD95 (Apo-1/Fas) ligand (CD95L) expression has been observed in various malignancies. In human primary cell lines from a squamous cell carcinoma (SCC) of the vulva, the effect of cisplatin (CDDP) and IFNgamma on the expression of CD95L and its 2 receptor isoforms, CD95 transmembrane (CD95tm) and CD95 soluble receptor, was studied at the mRNA and protein levels. Addition of CDDP and IFNgamma increased CD95L mRNA levels in the primary cell line 6-fold and 1.7-fold, respectively. In comparison, CD95tm mRNA levels were diminished by CDDP but increased 8-fold upon IFNgamma challenge. CD95L expressed by SCC cells was functionally relevant since these cells were able to induce CD95-specific apoptosis in autologous lymphocytes from the SCC-bearing patient. Thus, CD95L expression in SCC may contribute to tumor-associated immunosuppression, which may be modulated by CDDP and IFNgamma. In tumor samples of the primary SCC, CD95L expression was enhanced in the area of the border between invasive tumor tissue and surrounding stroma cells. The locally restricted over-expression of CD95L was congruent with the arrangement of apoptotic stroma cells in the direct vicinity of invading tumor tongues, suggesting a role as invasion factor for CD95L.     

Determination of the chromosomal relationship between mecA and gyrA in methicillin-resistant coagulase-negative staphylococci

OBJECTIVES: We evaluated the accuracy and precision of computer-assisted semen analysis (CASAs) to determine whether variations in the CASA results were related to the type of analyzer or to the type of specimens analyzed. METHODS: Semen specimens were analyzed manually and by CASA before freezing and after thawing. Multiple ejaculates (220 semen specimens) from normal healthy donors (n = 8) and 131 semen specimens from 57 patients with cancer were assessed. RESULTS: The differences between CASA and manual sperm counts and percent motility were higher in prefreeze and post-thaw specimens at sperm concentrations of less than 20 x 10(6)/mL. The differences between CASA and manual results were significant for cancer patients, compared with normal donors (P <0.01). CONCLUSIONS: CASA results are unreliable at sperm counts of less than 20 x 10(6)/mL and post-thaw motility is generally underestimated by CASAs.     

Mortality among tuberculosis patients in The Netherlands in the period 1993-1995

This study aimed to estimate excess mortality among tuberculosis patients in The Netherlands and identify risk factors for tuberculosis-associated mortality. The national tuberculosis register provided data on patients diagnosed in the period 1993-1995. Excess mortality in tuberculosis cases, according to age and sex, was determined by comparison with national mortality rates. Risk factors were identified and adjustment for confounders was carried out using Cox's proportional hazard analysis. Of 4,340 patients alive at diagnosis, 258 died within 1 yr while on treatment. The Kaplan-Meier survival probability after 1 yr was 93%. Tuberculosis patients had a standardized mortality ratio of 8.3. Independent risk factors for mortality were: gender; age; presence of a malignancy or human immunodeficiency virus (HIV) infection; addiction to alcohol or drugs; localization of tuberculosis; and the type of medical officer having made the diagnosis. Of all deaths, 83% occurred in two risk groups comprising 21% of tuberculosis patients: those aged > or =65 yrs and those having HIV infection or a malignancy. Tuberculosis patients in The Netherlands are at a considerably increased risk of death. However, the prognosis is very good for those aged less than 65 yrs and without human immunodeficiency virus infection or a malignancy.     

A test of the hypothesis that diagnostic ultrasound disrupts myelination in neonatal rats

Neonatal rats were exposed or sham exposed for 30 min to pulsed ultrasound [2.25 MHz carrier frequency, 1 microsecond pulse length, 50 Hz pulse repetition frequency (PRF), 50 W/cm2 Imax, 2 mW/cm2 ITA], euthanised and prepared for electron microscopic analysis of the nodes of Ranvier of the dorsal and ventral roots of the spinal cord. There was also a cage control. All materials were processed and scored blindly, evaluating whether perinodal myelin was normal. Rats from all regimens had areas of disrupted myelination. There was no statistically significant difference among the regimens for absence of myelination. The results did not confirm an earlier report that diagnostic ultrasound disrupts myelination in neonatal rats.     

Childhood history of anxiety in adults with panic disorder: association with anxiety sensitivity and comorbidity

Converging lines of evidence indicate a nonspecific link between childhood anxiety disorders and adult panic disorder. Anxiety sensitivity, defined as the fear of anxiety symptoms, was hypothesized to be a potential mediating variable in this link. This study examined the association among childhood history of anxiety disorders, current anxiety symptoms, and anxiety sensitivity in a sample of 100 patients with panic disorder undergoing treatment. Fifty-five percent of the patients had histories of one or more childhood anxiety disorders. Despite the heterogeneity of symptoms and treatment interventions among these patients, a childhood history of anxiety was associated with comorbid anxiety conditions, agoraphobic avoidance, and anxiety sensitivity scores. Anxiety sensitivity was itself a significant predictor of current severity of illness, but a childhood history of anxiety was not. These findings are consistent with the hypothesis that having an anxiety disorder during childhood is linked with patterns of anxiety and phobic avoidance in adulthood, including the level of anxiety sensitivity in patients with panic disorder.     

Language disorders and learning disabilities in school-refusing adolescents

OBJECTIVE: We undertook this study to test the hypothesis that school-refusing adolescents hospitalized on an inpatient psychiatric unit have more language and learning disabilities than diagnosis-, age-, and sex-matched psychiatric controls. METHOD: The Woodcock-Johnson Tests of Achievement-Revised (WJTA-R), the WISC-R, the Adolescent Language Screening Test, the Clinical Evaluation of Language Fundamentals-Revised, and the Test of Language Competence (TLC) were given to a group of well-characterized, primarily depressed school refusers and matched psychiatric controls. RESULTS: We found that school-refusing adolescents had significantly lower WISC-R verbal intelligence scores, lower Math and Written Language subscale scores on the WJTA-R, and lower scores on the TLC than nonrefusers. School refusers were found to have a significantly higher incidence of both language impairments and learning disabilities than controls. CONCLUSIONS: We infer that academic and communicative frustration and the adolescent's resulting inability to meet the academic and social demands in the school environment may play a role in the etiology of school refusal.     

Speech-driven facial animation using a hierarchical model

A system capable of producing near video-realistic animation of a speaker given only speech inputs is presented. The audio input is a continuous speech signal, requires no phonetic labelling and is speaker-independent. The system requires only a short video training corpus of a subject speaking a list of viseme-targeted words in order to achieve convincing realistic facial synthesis. The system learns the natural mouth and face dynamics of a speaker to allow new facial poses, unseen in the training video, to be synthesised. To achieve this the authors have developed a novel approach which utilises a hierarchical and nonlinear principal components analysis (PCA) model which couples speech and appearance. Animation of different facial areas, defined by the hierarchy, is performed separately and merged in post-processing using an algorithm which combines texture and shape PCA data. It is shown that the model is capable of synthesising videos of a speaker using new audio segments from both previously heard and unheard speakers.