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.

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.

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.

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.

Inhibitory effect of shark serum on the Lewis lung carcinoma.

The growth and metastasis of transplanted Lewis lung carcinoma in C57BL/6J mice were inhibited by an ip injection of whole serum from Carcharhinus plumbeus, the sandbar shark. Tumors failed to develop in 69% of the animals inoculated with shark serum on days 0, 3, and 6 after tumor transplantation. Histologic examination of the tumor site at days 3 and 6 showed that tumor cells were pyknotic, and evidence of lysis of tumor cells and minor leukocytic infiltration existed. Tumor cells were not in tissue sections from day 15, and these animals still had no symptoms at day 216. The mean tumor volume of the remaining 31% of the treated animals was less than that of controls; they had a prolonged mean survival time, but ultimately they died from metastases, as did the controls. Urea- and hemoglobin-treated animals and those pretreated or intralesionally treated with shark serum were similar to the controls in both tumor kinetics and survival times.

Which short-term therapy? Matching patient and method.

In recent years, numerous forms of short-term psychotherapy have been developed, without clear guidelines for choosing among them. There are three major approaches in terms of both their techniques and their criteria for patient selection. The "interpretive" method stresses the use of insight produced by a therapist's interpretations, the "existential," the maturational effect of a brief empathic encounter with the therapist, and the "corrective," the behavioral changes resulting from patient management by the therapist. The question facing a short-term therapist is how to choose a particular method for a particular patient. A framework is proposed based on developmental phases of adult life to help therapists match patient and method.

Psychiatric disorders in primary care. Results of a follow-up study.

Despite extensive documentation of high rates of psychiatric morbidity among primary care patients, there have been, to our knowledge, no US studies following up these patients over time. We analyzed data based on two administrations of the Schedule for Affective Disorders and Schizophrenia-Life-time version (SADS-L) six months apart to 166 attenders at a primary care clinic in Marshfield, Wis. In the short span between interviews, 35% of the study group exhibited at least one Research Diagnostic Criteria disorder, and almost two thirds of these individuals had significant changes in diagnostic status based on SADS-L data. Diagnosis of these transient and episodic cases by the primary care physicians was under 10%, demonstrating the need for careful evaluation of the psychiatric status of primary care patients.

Age at onset of selected mental disorders in five community populations.

Using data collected in the National Institute of Mental Health Epidemiologic Catchment Area Program, we examined the reported age at onset of selected mental disorders using life table survival methods. The examination of hazard rates suggests that adolescence and young adulthood are important periods for the development of unipolar major depression, bipolar illness, phobias, and drug and alcohol abuse/dependence. Although there are limitations in using cross-sectional data for this purpose, the findings suggest the need for more attention to the development of mental disorders in childhood and adolescence.

Comparing age at onset of major depression and other psychiatric disorders by birth cohorts in five US community populations.

Using data collected in the National Institute of Mental Health (Rockville, Md) Epidemiologic Catchment Area Program, we examined the proposed hypothesis that there has been a shift in major depression to younger ages at onset, or increased prevalence in younger age periods, for recent birth cohorts. Life-table survival methods were used to examine the hazard rates for major depression as well as for other specific mental disorders. The findings are consistent with a gradual shift to increased rates for major depression between the ages of 15 and 19 years for Epidemiologic Catchment Area respondents born more recently. The findings also suggest a similar shift for drug abuse/dependence; similar but less pronounced changes were found for alcohol abuse/dependence and obsessive-compulsive disorder. However, in this study, bipolar disorder, panic disorder, and phobias did not exhibit a consistent increase in onset at younger ages. Further research is required to determine if the shifts in major depression, drug abuse/dependence, and possibly alcohol abuse/dependence are linked. It is important to note that these shifts to adolescent onset are occurring when nearly half the 31 million Americans without health insurance are aged 24 years or younger.

Recall and dating of psychiatric symptoms. Test-retest reliability of time-related symptom questions in a standardized psychiatric interview.

The advent of more explicit diagnostic criteria and the growing interest in "lifetime" rates of mental disorders has made imperative an accurate determination of time-related diagnostic criteria. We used data from two independent test-retest studies of the Diagnostic Interview Schedule (DIS) and the Composite International Diagnostic Interview (CIDI) to study the reliability of different time-related questions in these fully standardized diagnostic interviews. With two exceptions (anxiety disorders and alcohol-related questions), the test-retest reliability of most time-related questions in both interviews was judged to be satisfactorily high. Furthermore, the validity of time-related questions in the DIS (age at symptom onset, duration and frequency of illness episodes) was examined by comparing them with detailed "consensus" ratings done independently by different clinicians for 207 former psychiatric inpatients. A surprisingly high concordance was found for former psychotic patients except for those still severely disturbed at the follow-up investigation. Some severe restrictions were also found for nonpsychotic disorders with regard to judgment of the age at onset of phobias, panic attacks, and depression. For a more valid assessment of time-related symptom information, the use of specific memory aids is suggested.

Anxiety and depression in a primary care clinic. Comparison of Diagnostic Interview Schedule, General Health Questionnaire, and practitioner assessments.

Over one half of all persons seen in a primary care clinic were identified as having anxiety or depressive disorder by the primary care provider, the General Health Questionnaire (GHQ), or the Diagnostic Interview Schedule (DIS). In only about 5% of all patients were findings positive on all three assessments concurrently. Both the GHQ and the practitioners identified over 30% of all patients as having a disorder, while about 8% had one or more of five DIS anxiety or depressive disorders (major depression, dysthymia, panic disorder, generalized anxiety disorder, or obsessive-compulsive disorder). Of the patients with DIS disorders 83% had positive GHQ scores, and 73% were identified by the practitioner as having a mental disorder.

Exclusion criteria of DSM-III. A study of co-occurrence of hierarchy-free syndromes.

The diagnostic criteria of the third edition of the DSM-III often state that one diagnosis cannot be made if it is "due to" another disorder. Using data from the National Institute of Mental Health Diagnostic Interview Schedule, with a sample of 11,519 subjects from a community population, we found that if two disorders were related to each other according to the DSM-III exclusion criteria, then the presence of a dominant disorder greatly increased the odds of having the excluded disorder. We also found that disorders, which DSM-III says are related to each other, were more strongly associated than disorders, which DSM-III says are unrelated. However, we also found there was a general tendency toward co-occurrence, so that the presence of any disorder increased the odds of having almost any other disorder, even if DSM-III does not list it as a related disorder. We concluded that empirical studies are needed to study the assumptions underlying the use of a diagnostic hierarchy.

Lifetime prevalence of specific psychiatric disorders in three sites.

Lifetime rates are presented for 15 DSM-III psychiatric diagnoses evaluated in three large household samples on the basis of lay interviewers' use of the Diagnostic Interview Schedule. The most common diagnoses were alcohol abuse and dependence, phobia, major depressive episode, and drug abuse and dependence. Disorders that most clearly predominated in men were antisocial personality and alcohol abuse and dependence. Disorders that most clearly predominated in women were depressive episodes and phobias. The age group with highest rates for most disorders was found to be young adults (aged 25 to 44 years). Correlates with race, education, and urbanization are presented.

One-month prevalence of mental disorders in the United States. Based on five Epidemiologic Catchment Area sites.

One-month prevalence results were determined from 18,571 persons interviewed in the first-wave community samples of all five sites that constituted the National Institute of Mental Health Epidemiologic Catchment Area Program. US population estimates, based on combined site data, were that 15.4% of the population 18 years of age and over fulfilled criteria for at least one alcohol, drug abuse, or other mental disorder during the period one month before interview. Higher prevalence rates of most mental disorders were found among younger people (less than age 45 years), with the exception of severe cognitive impairments. Men had higher rates of substance abuse and antisocial personality, whereas women had higher rates of affective, anxiety, and somatization disorders. When restricted to the diagnostic categories covered in international studies based on the Present State Examination, results fell within the range reported for European and Australian studies.

Six-month prevalence of psychiatric disorders in three communities 1980 to 1982.

Six-month prevalence rates for selected DSM-III psychiatric disorders are reported based on community surveys in New Haven, Conn, Baltimore, and St Louis. As part of the Epidemiologic Catchment Area program, data were gathered on more than 9,000 adults, employing the Diagnostic Interview Schedule to collect information to make a diagnosis. The most common disorders found were phobias, alcohol abuse and/or dependence, dysthymia, and major depression. The most common diagnoses for women were phobias and major depression, whereas for men, the most predominant disorder was alcohol abuse and/or dependence. Rates of psychiatric disorders dropped sharply after age 45 years.

The clinician-researcher in psychiatry.

As clinical research in psychiatry has grown in importance and promise in the past decade, the need for a growing pool of skilled clinician-researchers has been increasingly recognized. Compared with physicians in other specialties, psychiatrists in academic positions have less training in research and devote less time to it, which is reflected in the growing concentration of research funds from the National Institute of Mental Health in just a few of the strongest medical school departments. To focus attention on the need for developing the role of clinician-researchers, the authors examine four major tasks faced by clinician-researchers and present a developmental perspective on the transition to research.

Changes in children's behavior after a natural disaster.

Five months after a severe winter storm, a survey of children whose behavior had been assessed by means of a parent rating scale during a Head Start program 6 months before the disaster showed that some problem-behavior scores had increased significantly. The subgroups of children at higher risk were boys, whose Anxiety scale scores increased, and children accepted for Head Start only because their parents said they had special needs, whose Aggressive Conduct scale scores increased. For the entire group of children, school behavior improved. The findings support previous impressions that parents deny their children's problems after a natural disaster.

Epidemiologic evidence for early onset of mental disorders and higher risk of drug abuse in young adults.

Data from the National Institute of Mental Health (NIMH) Epidemiologic Catchment Area Program, an epidemiologic survey of five communities, showed that four major disorders commonly begin in late adolescence or young adulthood. The median age at onset for anxiety disorders is 15 years; for major depressive episode, 24 years; for drug abuse or dependence, 19 years; and for alcohol abuse or dependence, 21 years. Findings also suggest that for respondents 18-30 years old, having a major depressive episode or anxiety disorder doubles the risk for later drug abuse or dependence.

The NIMH Depression Awareness, Recognition, and Treatment Program: structure, aims, and scientific basis.

Unrecognized, untreated, and undertreated depressive disorders extract an inordinate human and economic cost, despite the availability of an extensive array of effective clinical interventions. To enhance the availability and quality of care, the National Institute of Mental Health launched the Depression Awareness, Recognition, and Treatment Program, a multiphase information and education program designed to alert health professionals and the general public to the fact that depressive disorders are common, serious, and treatable. The authors review the development of this program, describing the professional education efforts it supports in anticipation of increased demand for services, the public education campaign launched in May 1988, and highlights of the scientific advances that make the program feasible and timely.

Mental health problems among children seen in pediatric practice: prevalence and management.

An ambulatory care survey involving 40% of all pediatricians in Monroe County, NY, was conducted between January and December 1979 to obtain an estimate of the prevalence of mental health problems among children seen by pediatricians. If a child with such a problem was identified, the pediatrician described the problem in detail, its impact on the family and the patient, and the action taken to handle the problem. The weighted 40% probability sample was representative of all pediatric practices in the county. During the 2 months for which each of the 30 pediatricians reported on all visits, there were 21,575 visits made by 18,351 children. There were 935 children detected at their first visit as having a problem, and another 48 children at a repeat visit during the reporting period. This is equivalent to a point prevalence at time of first visit of 5.09%. There was considerable variation between pediatricians: group practitioners reported a point prevalence of 4.06%, solo practitioners reported 5.06%, and health center pediatricians reported 7.33%. High rates were reported among children 7 to 14 years old (8.0%), boys (6.2%) compared with girls (3.9%), those on Medicaid (8.3%), and those whose presenting complaint was a chronic physical disorder (13.1%). The slightly higher rate among blacks than whites appeared to be related to the generally lower socioeconomic status among blacks. The rate among children in one-parent families was twice as high as in two-parent families. With regard to the mental health problem, most frequent diagnoses (primary or secondary) were adaptation reaction (31.5% of "problem" children), speech and language disorder (18.4%), other specific learning disorder (17.1%), hyperkinetic disorder (16.8%), and conduct disorder (14.7%). Functional impairment was moderate or severe in more than half the affected children; most frequent treatment provided by the pediatricians was supportive therapy or counseling (81.4%); drugs were prescribed for 11.3% of the affected children, amphetamines for 4.7%.