Beta interferon regulation of glucose metabolism is PI3K/Akt dependent and important for antiviral activity against coxsackievirus B3.

UNLABELLED: An effective type I interferon (IFN)-mediated immune response requires the rapid expression of antiviral proteins that are necessary to inhibit viral replication and virus spread. We provide evidence that IFN-ß regulates metabolic events important for the induction of a rapid antiviral response: IFN-ß decreases the phosphorylation of AMP-activated protein kinase (AMPK), coincident with an increase in intracellular ATP. Our studies reveal a biphasic IFN-ß-inducible uptake of glucose by cells, mediated by phosphatidylinositol 3-kinase (PI3K)/Akt, and IFN-ß-inducible regulation of GLUT4 translocation to the cell surface. Additionally, we provide evidence that IFN-ß-regulated glycolytic metabolism is important for the acute induction of an antiviral response during infection with coxsackievirus B3 (CVB3). Last, we demonstrate that the antidiabetic drug metformin enhances the antiviral potency of IFN-ß against CVB3 both in vitro and in vivo. Taken together, these findings highlight an important role for IFN-ß in modulating glucose metabolism during a virus infection and suggest that the use of metformin in combination with IFN-ß during acute virus infection may result in enhanced antiviral responses. IMPORTANCE: Type I interferons (IFN) are critical effectors of an antiviral response. These studies describe for the first time a role for IFN-ß in regulating metabolism--glucose uptake and ATP production--to meet the energy requirements of a robust cellular antiviral response. Our data suggest that IFN-ß regulates glucose metabolism mediated by signaling effectors similarly to activation by insulin. Interference with IFN-ß-inducible glucose metabolism diminishes the antiviral response, whereas treatment with metformin, a drug that increases insulin sensitivity, enhances the antiviral potency of IFN-ß.

Antiviral strategies: the present and beyond.

Historically, vaccine strategies have proven to be most effective at eradicating the targeted virus infections. With the advent of new or re-emerging altered viruses, some of which jump species to infect humans, the threat of viral pandemics exists. The protracted time to develop a vaccine during a pandemic necessitates using antiviral drugs in the intervening months prior to vaccine availability. Antiviral drugs that are pathogen specific, for example Amantidine, Tamiflu and Relenza, targeted against influenza viruses, are associated with the emergence of virus strains that are drug resistant. The use of ribavirin, a more broad spectrum antiviral, in combination therapies directed against influenza and hepatitis C virus, has proven effective, albeit to a modest extent. Attention is focused on the potential use of interferons (IFN)-alpha/beta as broad spectrum antivirals in acute infections, to invoke both direct antiviral effects against viruses and activation of specific immune effector cells.

Obesity and weight gain in relation to depression: findings from the Stirling County Study.

OBJECTIVE: This study concerns the question of whether obese subjects in a community sample experience depression in a different way from the nonobese, especially whether they overeat to the point of gaining weight during periods of depression. DESIGN: A representative sample of adults was interviewed regarding depression and obesity. SUBJECTS: The sample consisted of 1396 subjects whose interviews were studied regarding relationships between obesity and depression and among whom 114 had experienced a major depressive episode at some point in their lives and provided information about the symptoms experienced during the worst or only episode of major depression. MEASUREMENTS: The Diagnostic Interview Schedule (DIS) was used to identify major depressive episodes. Information was also derived from the section on Depression and Anxiety (DPAX) of the Stirling Study Schedule. Obesity was calculated as a body mass index >30. Logistic regressions were employed to assess relationships, controlling for age and gender, by means of odds ratios and 95% confidence intervals. RESULTS: In the sample as a whole, obesity was not related to depression although it was associated with the symptom of hopelessness. Among those who had ever experienced a major depressive episode, obese persons were 5 times more likely than the nonobese to overeat leading to weight gain during a period of depression (P<0.002). These obese subjects, compared to the nonobese, also experienced longer episodes of depression, a larger number of episodes, and were more preoccupied with death during such episodes. CONCLUSIONS: Depression among obese subjects in a community sample tends to be more severe than among the nonobese. Gaining weight while depressed is an important marker of that severity. Further research is needed to understand and possibly prevent the associations, sequences and outcomes among depression, obesity, weight gain and other adversities.

Continuous passive motion applied to whole joints stimulates chondrocyte biosynthesis of PRG4.

UNLABELLED: Continuous passive motion (CPM) is currently a part of patient rehabilitation regimens after a variety of orthopedic surgical procedures. While CPM can enhance the joint healing process, the direct effects of CPM on cartilage metabolism remain unknown. Recent in vivo and in vitro observations suggest that mechanical stimuli can regulate articular cartilage metabolism of proteoglycan 4 (PRG4), a putative lubricating and chondroprotective molecule found in synovial fluid and at the articular cartilage surface. OBJECTIVES: (1) Determine the topographical variation in intrinsic cartilage PRG4 secretion. (2) Apply a CPM device to whole joints in bioreactors and assess effects of CPM on PRG4 biosynthesis. METHODS: A bioreactor was developed to apply CPM to bovine stifle joints in vitro. Effects of 24h of CPM on PRG4 biosynthesis were determined. RESULTS: PRG4 secretion rate varied markedly over the joint surface. Rehabilitative joint motion applied in the form of CPM regulated PRG4 biosynthesis, in a manner dependent on the duty cycle of cartilage sliding against opposing tissues. Specifically, in certain regions of the femoral condyle that were continuously or intermittently sliding against meniscus and tibial cartilage during CPM, chondrocyte PRG4 synthesis was higher with CPM than without. CONCLUSIONS: Rehabilitative joint motion, applied in the form of CPM, stimulates chondrocyte PRG4 metabolism. The stimulation of PRG4 synthesis is one mechanism by which CPM may benefit cartilage and joint health in post-operative rehabilitation.

Which aspects of ADHD are associated with tobacco use in early adolescence?

Several studies have found a relationship between attention-deficit hyperactivity disorder (ADHD) and substance use, primarily in the context of co-occurring conduct disorder (CD). However, very few have examined the associations between the individual dimensions of ADHD (hyperactivity-impulsivity and inattention) and substance use, even though these dimensions reflect distinct symptom groupings, both by clinical definition (DSM-IV, American Psychiatric Association, 1994) and through empirical demonstration (Lahey et al., 1988: McBurnett et al., 1999). This longitudinal study examines the relationship between dimensions of ADHD (as described by DSM) and substance use, accounting for other psychopathology and factors potentially related to substance use. Participants were 177 clinic-referred boys (initially between ages 7 and 12) followed up over nine annual phases until all participants had reached age 15. Annual assessment included structured clinical interviews with parent and child and self-report questionnaires of substance use, as well as questionnaires related to family factors and parenting behaviors. Seventy-eight per cent of participants reported use of tobacco, alcohol, marijuana, or other illicit drugs during adolescence, with 51% reporting any tobacco use. The inclusion of CD rendered all bivariate relationships with the full diagnosis of ADHD nonsignificant. However, adolescent inattention, considered independently, was associated with a 2.2 times greater risk for concurrent tobacco use, even after controlling for CD. Even when other factors, selected based on their associations with tobacco use in adolescence, were included in a regression model (concurrent adolescent CD odds ratio [OR] = 6.08), duration of tobacco use by age 12 (OR = 5.11), poor parental communication in childhood (OR = 2.9), African-American ethnicity (inversely predictive; OR = 0.15), inattention (OR = 2.3) remained significantly associated with tobacco use in early adolescence. These findings highlight the importance of considering the risks for comorbid substance use separately by individual dimensions of ADHD.

Development and utilization of paperless medical records: a unique approach.

The purpose of this article is to describe the development and utilization of a unique paperless medical record system in a large multispeciality group practice setting. The Scott and White integrated health care delivery system provides care over a 34-county area in Central Texas. Since 1988, clinicians at Scott and White have developed a text-based, content-searchable electronic medical record system known as EMRx. This system provides a single clinical data repository that allows patient care activities and aggregate data analyses to occur by using the same set of data on a daily basis. Use of this approach has led to the aggregation of over 9.8 million clinical documents since 1994. Over 1,845 health care providers used the system during May 2000 for direct patient care; 866,114 patient records have been accessed since January 1, 1999 to answer questions related to patient care, quality assurance, outcomes research, and accreditation.

Oppositional defiant and conduct disorder: a review of the past 10 years, part I.

OBJECTIVE: To review empirical findings on oppositional defiant disorder (ODD) and conduct disorder (CD). METHOD: Selected summaries of the literature over the past decade are presented. RESULTS: Evidence supports a distinction between the symptoms of ODD and many symptoms of CD, but there is controversy about whether aggressive symptoms should be considered to be part of ODD or CD. CD is clearly heterogenous, but further research is needed regarding the most useful subtypes. Some progress has been made in documenting sex differences. Symptoms that are more serious, more atypical for the child's sex, or more age-atypical appear to be prognostic of serious dysfunction. Progress has been made in the methods for assessment of ODD and CD, but some critical issues, such as combined information from different informants, remains to be addressed. A proportion of children with ODD later develop CD, and a proportion of those with CD later meet criteria for antisocial personality disorder. ODD and CD frequently co-occur with other psychiatric conditions. CONCLUSIONS: Although major advances in the study of the prevalence and course of ODD and CD have occurred in the past decade, some key issues remain unanswered.

An integrated data warehouse system: development, implementation, and early outcomes.

This paper describes a generic vision of global information flow and the development of an integrated data warehouse system, using clinical data on all patient encounters and administrative data on all operating transactions as part of an integrated health care system. This new integrated data warehouse system has been successfully used for multiple purposes, including patient care, health services research, resource utilization and feasibility studies. During 1999, core analyses included the electronic abstraction, aggregation, and analysis of data on over 400,000 patients. This approach to building a centralized data system comprised of multiple repositories efficiently meets a variety of individual and aggregate information needs, while reducing the need to create duplicate databases.

A new standard of care: administration of preoperative antibiotics in the operating room.

Surgical site infections increase total hospital expenses and extend the length of hospital stay. Properly administered antibiotics are successful in minimizing postoperative subcutaneous wound infection secondary to perioperative bacterial contamination at the surgical site and are effective in most clean-contaminated surgical procedures. It is imperative that therapeutic levels of antibiotics be present during the time when the wound is open to maximize their effect to prevent the development of surgical wound infections. Only 32 per cent of 97 patients sampled from 1992 to 1994 at the Louisville Veterans Affairs Medical Center were administered preoperative antibiotics within 1 hour prior to surgical incision. Changing the responsibility for preoperative antibiotic administration from ward or holding room nurses to the anesthesiologist in the operating room rendered such antibiotics delivered closer to the induction of anesthesia and subsequent incision. Eighty-eight per cent of 220 patients sampled in 1995 had antibiotics administered within 1 hour of incision. This change in institutional policy of antibiotic administration maximizes the likelihood of appropriate antibiotic tissue levels and thereby their potential efficacy. Routine prophylaxis should be administered as close to the time of induction of anesthesia as possible to provide the best chance for appropriate tissue levels above the minimum inhibitory concentration for potential bacterial contamination.

Schizosaccharomyces pombe skp1+ encodes a protein kinase related to mammalian glycogen synthase kinase 3 and complements a cdc14 cytokinesis mutant.

We report the cloning of the skp1+ gene, a Schizosaccharomyces pombe homolog of the glycogen synthase kinase 3 (GSK-3) family whose members in higher eukaryotes are involved in cell fate determination, nuclear signalling, and hormonal regulation. skp1 is 67% identical to mammalian GSK-3 beta and displays similar biochemical properties in vitro. Like GSK-3 beta, skp1 is phosphorylated on a conserved tyrosine residue, and this phosphorylation is required for efficient activity. skp1 is also phosphorylated at a serine which has been identified as S-335. Phosphorylation at this site is likely to inhibit its function. Unlike the mammalian enzyme, skp1 both tyrosine autophosphorylates in yeast cells and can phosphorylate other proteins on tyrosine in bacteria. The skp1+ gene is not essential. However, cells with deletions in skp1+ are sensitive to heat shock and exhibit defects in sporulation. Overexpression of wild-type skp1+ specifically complements cdc14-118, one of several mutations causing a defect in cytokinesis. In addition, certain phosphorylation site mutants induce a delay or block in cytokinesis when overexpressed. Together, these data identify novel interactions of a fission yeast GSK-3 homolog with elements of the cytokinesis machinery.

Medical services use by patients before and after detoxification from benzodiazepine dependence.

OBJECTIVE: The authors examined use of medical and mental health services before and after detoxification among a group of patients detoxified from benzodiazepines to see if the data suggested a reduction in service use and costs after detoxification, the so-called offset effect observed for treatment of alcohol and mental disorders. METHODS: Through a medical record review, information was collected about medical service use for patients aged 40 and older who were detoxified from benzodiazepines at Scott and White Clinic and Hospital between 1987 and 1991. RESULTS: Among the 76 patients, medical and mental health outpatient visits fell from an average rate of 25.4 visits per year before detoxification to 4.4 per year after detoxification. For the 44 patients with at least one inpatient stay besides the admission for detoxification, the mean number of inpatient days remained constant at three days per year before and after detoxification. CONCLUSIONS: Although a retrospective record review suffers from a range of limitations, the findings suggest that detoxification from benzodiazepines may be effective in reducing use of outpatient medical and mental health services and presumably in reducing costs of care.

Medically unexplained somatic symptoms in different cultures. A preliminary report from phase I of the World Health Organization International Study of Somatoform Disorders.

The World Health Organization has recently launched an international study of somatoform disorders in different cultures. Five centres representing distinct cultures participated in phase I of the project, the main objective of which was to test the cross-cultural applicability and reliability of instruments for the assessment of somatoform disorders. The analysis of the assessed somatic symptoms showed that various aches and pains in different parts of the body represented cross-culturally the most frequent symptoms for which there was no medical explanation. Such symptoms may indicate the presence of an underlying mental disorder but can also represent a means for culture-specific expression of psychosocial distress. This bears particular significance for health professionals in primary and general medical care, who are most likely to encounter patients presenting with multiple, persistent and medically unexplained somatic symptoms.

The Schizosaccharomyces pombe cdc3+ gene encodes a profilin essential for cytokinesis.

The fission yeast Schizosaccharomyces pombe divides by medial fission and, like many higher eukaryotic cells, requires the function of an F-actin contractile ring for cytokinesis. In S. pombe, a class of cdc- mutants defective for cytokinesis, but not for DNA replication, mitosis, or septum synthesis, have been identified. In this paper, we present the characterization of one of these mutants, cdc3-124. Temperature shift experiments reveal that mutants in cdc3 are incapable of forming an F-actin contractile ring. We have molecularly cloned cdc3 and used the cdc3+ genomic DNA to create a strain carrying a cdc3 null mutation by homologous recombination in vivo. Cells bearing a cdc3-null allele are inviable. They arrest the cell cycle at cytokinesis without forming a contractile ring. DNA sequence analysis of the cdc3+ gene reveals that it encodes profilin, an actin-monomer-binding protein. In light of recent studies with profilins, we propose that Cdc3-profilin plays an essential role in cytokinesis by catalyzing the formation of the F-actin contractile ring. Consistent with this proposal are our observations that Cdc3-profilin localizes to the medial region of the cell where the F-actin contractile ring forms, and that it is essential for F-actin ring formation. Cells overproducing Cdc3-profilin become elongated, dumbbell shaped, and arrest at cytokinesis without any detectable F-actin staining. This effect of Cdc3-profilin overproduction is relieved by introduction of a multicopy plasmid carrying the actin encoding gene, act1+. We attribute these effects to potential sequestration of actin monomers by profilin, when present in excess.

Increased rates of drug abuse and dependence after onset of mood or anxiety disorders in adolescence.

OBJECTIVE: The aim of the study was to examine the relationship of prevalence and age at onset of drug abuse and dependence to mood and anxiety disorders, using epidemiologic data. METHODS: Life-table analyses using data collected on 20,745 respondents in the National Institute of Mental Health's Epidemiologic Catchment Area surveys were used to calculate the hazard rate for developing drug disorders subsequent to adolescent-onset or adult-onset mood and anxiety disorders. RESULTS: For respondents with onset of a mood disorder during adolescence, the peak age for developing drug abuse and dependence occurs between 15 and 19 years; when the mood disorder begins in adulthood, the peak onset for drug disorders is delayed to between 25 and 29 years of age. Similar but less striking results are found for onset of drug abuse and dependence following either panic or obsessive-compulsive disorder. CONCLUSIONS: These findings highlight the need for future prospective studies of children and adolescents to date the onset of mental disorders and substance use disorders. If prospective studies can confirm the apparent pattern of substance use disorders occurring subsequent to mental disorders, prevention and treatment strategies for youth at risk should be developed.