Fbw7-dependent cyclin E regulation ensures terminal maturation of bone marrow erythroid cells by restraining oxidative metabolism.

The mechanisms that coordinate the final mitotic divisions of terminally differentiated bone marrow (BM) erythroid cells with components of their structural and functional maturation program remain largely undefined. We previously identified phenotypes resembling those found in early-stage myelodysplastic syndromes (MDS), including ineffective erythropoiesis, morphologic dysplasia and BM hyper-cellularity, in a knock-in mouse model in which cyclin E mutations were introduced at its two Cdc4 phosphodegrons (CPDs) to ablate Fbw7-dependent ubiquitination and degradation. Here, we have examined the physiologic consequences of cyclin E dysregulation in BM erythroid cells during terminal maturation in vivo. We found that cyclin E protein levels in BM erythroid cells are dynamically regulated in a CPD-dependent manner and that disruption of Fbw7-dependent cyclin E regulation impairs terminal erythroid cell maturation at a discrete stage before enucleation. At this stage of erythroid cell maturation, CPD phosphorylation of cyclin E regulates both cell-cycle arrest and survival. We also found that normal regulation of cyclin E restrains mitochondrial reactive oxygen species (ROS) accumulation and expression of genes that promote mitochondrial biogenesis and oxidative metabolism during terminal erythroid maturation. In the setting of dysregulated cyclin E expression, p53 is activated in BM erythroid cells as part of a DNA damage response-type pathway, which mitigates ineffective erythropoiesis, in contrast to the role of p53 induction in other models of dyserythropoiesis. Finally, cyclin E dysregulation and ROS accumulation induce histone H3 lysine 9 hyper-methylation and disrupt components of the normal terminal erythroid maturation gene expression program. Thus, ubiquitin-proteasome pathway control of G1-to-S-phase progression is intrinsically linked to regulation of metabolism and gene expression in terminally differentiating BM erythroid cells.

How migraines impact cognitive function: findings from the Baltimore ECA.

OBJECTIVE: To examine the cross-sectional and longitudinal relationship between migraine headaches and cognitive functioning. METHODS: The data were from Waves III (1993 through 1996) and IV (2004 through 2005) of the Baltimore Epidemiologic Catchment Area Study. Migraine headaches were diagnosed according to modified criteria of the International Headache Society. Scores on the immediate and delayed recall tests and the Mini-Mental State Examination (MMSE) were compared for migraineurs (n = 204) vs nonmigraineurs (n = 1,244). The longitudinal association between migraine and cognitive changes was assessed by generalized estimating equations. RESULTS: Migraineurs scored lower on tests of immediate and delayed memory at baseline, but declined by less over time than nonmigraineurs. These associations were specific to migraineurs with aura, who declined by 1.26 (p < 0.01) and 1.47 (p < 0.01) words less on the immediate and delayed recall tests over the 12 years of follow-up. The effects of migraine, specifically with aura, on the MMSE were restricted to those older than 50 years. Among those younger than 50 years, migraineurs with aura declined at the same rate on the MMSE as nonmigraineurs. However, among those older than 50 years, migraineurs with aura declined by 0.99 points (p < 0.01) less over the follow-up. CONCLUSIONS: Migraineurs, specifically those with aura, exhibited less decline on cognitive tests over time vs nonmigraineurs. For the Mini-Mental State Examination, these effects were only apparent among those who were older than 50 years.

Alcohol misuse by women.

Alcohol misuse among women is an important and growing problem. There is epidemiological and metabolic evidence that risk factors for and consequences of alcohol misuse are significantly different for women than for men. Understanding these differences is imperative if effective preventative and treatment interventions are to be undertaken. This article reviews the epidemiology of alcohol misuse by women, effects of alcohol misuse on women, fetuses, and relationships, and assessment and treatment strategies. We then suggest directions for future research in this field.

Genetic heterogeneity in schizophrenia II: conditional analyses of affected schizophrenia sibling pairs provide evidence for an interaction between markers on chromosome 8p and 14q.

Information from multiple genome scans and collaborative efforts suggests that schizophrenia is a heterogeneous, complex disorder with polygenic and environmental antecedents. In a previous paper we demonstrated that stratification of families on the basis of co-segregating phenotypes (psychotic affective disorders (PAD) and schizophrenia spectrum personality disorders (SSPD) in first-degree relatives of schizophrenic probands increased linkage evidence in the chromosome 8p21 region (D8S1771) among families with co-segregating SSPD. We have now applied a method of conditional analysis of sib-pairs affected with schizophrenia, examining shared alleles identical-by-descent (IBD) at multiple loci. The method yields enhanced evidence for linkage to the chromosome 8p21 region conditioned upon increased allele sharing at a chromosome 14 region. The method produces a more refined estimate of the putative disease locus on chromosome 8p21, narrowing the region from 18 cM (95% confidence interval) in our previous genome scan, to approximately 9.6 cM. We have also shown that the affected siblings sharing two alleles IBD at the chromosome 8p21 region and one allele IBD at the chromosome 14 region differ significantly in clinical symptoms from non-sharing affected siblings. Thus the analysis of allele sharing at a putative schizophrenia susceptibility locus conditioned on allele sharing at other loci provides another important method for dealing with heterogeneity.

A conceptual structure and methodology for the systematic approach to the evaluation and treatment of patients with chronic dizziness.

The patient with chronic dizziness should never be labeled with psychogenic dizziness. Chronic does not mean psychogenic. Chronic means that health care has been unsuccessful. A systematic approach that yields a comprehensive formulation and rational treatment plan will increase the probability of a successful outcome and return to health. The four perspectives of diseases, life stories, dimensions, and behaviors provide a comprehensive yet flexible methodology for the evaluation of the patient in distress with chronic and disabling dizziness. The design of a comprehensive treatment plan involves the determination of each perspective's contribution to the patient's distress and to what relative degree. This process recognizes that the perspectives are distinct from one another but complementary in illuminating the various reasons for a patient's distress. The perspectives come together as the formulation of the patient's case and offer a recipe for treatment rather than just a list of ingredients such as bio, psycho, and social.

Genetic heterogeneity in schizophrenia: stratification of genome scan data using co-segregating related phenotypes.

Despite considerable effort to identify susceptibility loci for schizophrenia, none have been localized. Multiple genome scans and collaborative efforts have shown evidence for linkage to regions on chromosomes 1q, 5q, 6q, 8p, 13q, 10p and 22q.(1-9) Heterogeneity is likely. We previously mapped schizophrenia susceptibility loci (SSL) to chromosomes 13q32 (P = 0.00002) and 8p21-22 (P= 0.0001) using 54 multiplex pedigrees and suggested linkage heterogeneity. We have now stratified these families based on co-segregating phenotypes in non-schizophrenic first degree relatives (schizophrenia spectrum personality disorders (SSPD); psychotic affective disorders (PAD)). Genome scans were conducted for these phenotypic subgroups of families and broadened affected phenotypes were tested. The SSPD group provided its strongest genome-wide linkage support for the chromosome 8p21 region (D8S1771) using either narrow (non-parametric lod (NPL) P= 0.000002) or broadened phenotypes (NPL P = 0.0000008) and a new region of interest on 1p was identified (P = 0.006). For PAD families, the peak NPL in the genome scan occurred on chromosome 3p26-p24 (P = 0.008). The identification of multiple susceptibility loci for schizophrenia may be enhanced by stratification of families using psychiatric diagnoses of the non-schizophrenic relatives.

Mental disorders and the incidence of migraine headaches in a community sample: results from the Baltimore Epidemiologic Catchment area follow-up study.

BACKGROUND: The cross-sectional relation between migraine headaches and affective disorders has been demonstrated in studies of clinical and community populations. Few studies have investigated the prospective relation between psychiatric disorders and migraine headaches. METHODS: A prospective follow-up of the Baltimore, Md, cohort of the Epidemiologic Catchment Area Study assessed psychopathologic features in 1981 and again between 1993 and 1996. Interviews included a history of headaches at baseline and self-reported assessment of migraine headaches at follow-up. Risk estimates for incident migraine headaches by 1981 demographic variables and psychopathologic features were calculated. The cross-sectional association between prevalent migraine and lifetime psychiatric diagnoses was estimated. RESULTS: In the at-risk population of 1343, there were 118 incident cases of migraine headaches. The age- and sex-specific incident rates of migraine headaches followed the expected patterns, with younger age and female sex identified as risk factors. In cross-sectional analyses, major depression (odds ratio, 3.14; 95% confidence interval, 2.03-4. 84) and panic disorder (odds ratio, 5.09; 95% confidence interval, 2. 65-9.79) had the strongest associations, and alcohol and other substance abuse were not associated. In logistic regression models including age, sex, and psychiatric illness in 1981, only phobia was predictive of incident migraines (odds ratio, 1.70; 95% confidence interval, 1.11-2.58). Affective disorders were not predictive of incident migraine headaches. Including a history of tricyclic antidepressant use did not change the results. CONCLUSIONS: There is a strong cross-sectional relation between affective disorders and migraine headaches in this cohort. However, there is no association between antecedent affective disorders and incident migraine headaches in this population-based prospective study.

Incidence of DIS/DSM-IV social phobia in adults.

OBJECTIVE: The aim of the study was to estimate the incidence of social phobia in the general population. METHOD: The Baltimore cohort of 3481 subjects, sampled during the 1981 Epidemiologic Catchment Area study, was traced. A total of 1920 subjects were re-interviewed from 1993 to 1996 using the Diagnostic Interview Schedule (DIS). A subsample of 349 subjects was interviewed by psychiatrists using the Schedules for Clinical Assessment in Neuropsychiatry. RESULTS: The estimated incidence of DIS/DSM-IV social phobia is 4-5/1000/year. New cases were found in all age groups, with the highest rates in subjects with baseline depressive and panic disorders. Psychiatric evaluations showed broad diagnostic concordance with DIS diagnoses in incident cases. However, validity indices were highly dependent on diagnostic thresholds. None of the psychiatrist-ascertained social phobics had received treatment for the disorder, although the majority were considered likely to benefit from treatment. CONCLUSION: New cases of social phobia occur in adults of all age groups, and are often secondary to other psychiatric conditions.

Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21.

Schizophrenia is a common disorder characterized by psychotic symptoms; diagnostic criteria have been established. Family, twin and adoption studies suggest that both genetic and environmental factors influence susceptibility (heritability is approximately 71%; ref. 2), however, little is known about the aetiology of schizophrenia. Clinical and family studies suggest aetiological heterogeneity. Previously, we reported that regions on chromosomes 22, 3 and 8 may be associated with susceptibility to schizophrenia, and collaborations provided some support for regions on chromosomes 8 and 22 (refs 9-13). We present here a genome-wide scan for schizophrenia susceptibility loci (SSL) using 452 microsatellite markers on 54 multiplex pedigrees. Non-parametric linkage (NPL) analysis provided significant evidence for an SSL on chromosome 13q32 (NPL score=4.18; P=0.00002), and suggestive evidence for another SSL on chromosome 8p21-22 (NPL=3.64; P=0.0001). Parametric linkage analysis provided additional support for these SSL. Linkage evidence at chromosome 8 is weaker than that at chromosome 13, so it is more probable that chromosome 8 may be a false positive linkage. Additional putative SSL were noted on chromosomes 14q13 (NPL=2.57; P=0.005), 7q11 (NPL=2.50, P=0.007) and 22q11 (NPL=2.42, P=0.009). Verification of suggestive SSL on chromosomes 13q and 8p was attempted in a follow-up sample of 51 multiplex pedigrees. This analysis confirmed the SSL in 13q14-q33 (NPL=2.36, P=0.007) and supported the SSL in 8p22-p21 (NPL=1.95, P=0.023).

The Yale Global Tic Severity Scale: initial testing of a clinician-rated scale of tic severity.

Despite the overt nature of most motor and phonic tic phenomena, the development of valid and reliable scales to rate tic severity has been an elusive goal. The Yale Global Tic Severity Scale (YGTSS) is a new clinical rating instrument that was designed for use in studies of Tourette's syndrome and other tic disorders. The YGTSS provides an evaluation of the number, frequency, intensity, complexity, and interference of motor and phonic symptoms. Data from 105 subjects, aged 5 to 51 years, support the construct, convergent, and discriminant validity of the instrument. These results indicate that the YGTSS is a promising instrument for the assessment of tic severity in children, adolescents and adults.

Effects of sulfur-containing analogues of stearic acid on growth and fatty acid biosynthesis in the protozoan Crithidia fasciculata.

A variety of analogues of stearic acid in which one of the methylene groups was replaced by a sulfur atom were examined as inhibitors of growth and fatty acid biosynthesis in the trypanosomatid protozoan Crithidia fasciculata. The 8-, 9-, 10-, and 11-thiastearic acids were found to suppress the synthesis of the cyclopropane-containing fatty acid dihydrosterculic acid (9,10-methyleneoctadecanoic acid) at micromolar concentrations in the growth medium, and all but the 9-thiastearate were found to inhibit the growth of the protozoa at concentrations. The most potent inhibitor, 8-thiastearic acid (I50 for growth = 0.8 microM; I50 dihydrosterculate synthesis = 0.4 microM), was also observed to inhibit the synthesis of gamma-linolenic acid at a similar concentration. The sulfoxide derivatives of the 9- and 10-thiastearates were found to have little effect on growth or fatty acid synthesis, and several long-chain amides of 3-amino-1,2-propanediol were found to have effects similar to those of the fatty acids from which they were derived.