effect of emotional state on cognitive performance and immunity in ms patients
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Publication
Journal: Chest
February/1/2010
Abstract
BACKGROUND
Sleep disorders are increasingly associated with insulin resistance, glucose intolerance, and type 2 diabetes mellitus. Whether the metabolic toll imposed by sleep-related disorders is caused by poor-quality sleep or due to other confounding factors is not known. The objective of this study was to examine whether experimental sleep fragmentation across all sleep stages would alter glucose metabolism, adrenocortical function, and sympathovagal balance.
METHODS
Sleep was experimentally fragmented across all stages in 11 healthy, normal volunteers for two nights using auditory and mechanical stimuli. Primary outcomes included insulin sensitivity (S(I)), glucose effectiveness (S(G)), and insulin secretion, as determined by the intravenous glucose tolerance test. Secondary outcomes included measures of sympathovagal balance and serum levels of inflammatory markers, adipokines, and cortisol.
RESULTS
Following two nights of sleep fragmentation, S(I) decreased from 5.02 to 3.76 (mU/L)(-1)min(-1) (P < .0001). S(G), which is the ability of glucose to mobilize itself independent of an insulin response, also decreased from 2.73 x 10(-2) min(-1) to 2.16 x 10(-2) min(-1) (P < .01). Sleep fragmentation led to an increase in morning cortisol levels and a shift in sympathovagal balance toward an increase in sympathetic nervous system activity. Markers of systemic inflammation and serum adipokines were unchanged with sleep fragmentation.
CONCLUSIONS
Fragmentation of sleep across all stages is associated with a decrease in S(I) and S(G). Increases in sympathetic nervous system and adrenocortical activity likely mediate the adverse metabolic effects of poor sleep quality.
Publication
Journal: Science Signaling
March/4/2010
Abstract
Glioblastoma, the most common malignant brain tumor, is among the most lethal and difficult cancers to treat. Although epidermal growth factor receptor (EGFR) mutations are frequent in glioblastoma, their clinical relevance is poorly understood. Studies of tumors from patients treated with the EGFR inhibitor lapatinib revealed that EGFR induces the cleavage and nuclear translocation of the master transcriptional regulator of fatty acid synthesis, sterol regulatory element-binding protein 1 (SREBP-1). This response was mediated by Akt; however, clinical data from rapamycin-treated patients showed that SREBP-1 activation was independent of the mammalian target of rapamycin complex 1, possibly explaining rapamycin's poor efficacy in the treatment of such tumors. Glioblastomas without constitutively active EGFR signaling were resistant to inhibition of fatty acid synthesis, whereas introduction of a constitutively active mutant form of EGFR, EGFRvIII, sensitized tumor xenografts in mice to cell death, which was augmented by the hydroxymethylglutaryl coenzyme A reductase inhibitor atorvastatin. These results identify a previously undescribed EGFR-mediated prosurvival metabolic pathway and suggest new therapeutic approaches to treating EGFR-activated glioblastomas.
Publication
Journal: PLoS Genetics
August/23/2011
Abstract
Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti-dsDNA autoantibody production, a SLE-related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti-dsDNA autoantibody positive (anti-dsDNA +, n = 811) and anti-dsDNA autoantibody negative (anti-dsDNA -, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti-dsDNA + SLE. Far fewer and weaker associations were observed for anti-dsDNA - SLE. For example, rs7574865 in STAT4 had an OR for anti-dsDNA + SLE of 1.77 (95% CI 1.57-1.99, p = 2.0E-20) compared to an OR for anti-dsDNA - SLE of 1.26 (95% CI 1.12-1.41, p = 2.4E-04), with p(heterogeneity)<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti-dsDNA + SLE and were not associated with anti-dsDNA - SLE. In conclusion, we identified differential genetic associations with SLE based on anti-dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti-dsDNA - SLE.
Publication
Journal: Cancer Immunology, Immunotherapy
February/17/2005
Abstract
MUC1 is a glycoprotein overexpressed in tumors as a hypoglycosylated form. A vaccine composed of a 100-amino acid peptide corresponding to five 20-amino acid long repeats, and SB-AS2 adjuvant, was tested in a phase I study for safety, toxicity, and ability to elicit or boost MUC1-specific immune responses. Patients with resected or locally advanced pancreatic cancer without prior chemotherapy or radiotherapy were eligible. Escalating doses of the peptide (100, 300, 1,000, and 3,000 mug) were admixed with SB-AS2 and administered intramuscularly every 3 weeks for three doses, in cohorts of four patients. Sixteen patients were enrolled. Common adverse effects were grade 1 flu-like symptoms, tenderness, and erythema at the injection site. Delayed-type hypersensitivity (DTH) sites showed few or no T cells prevaccination (Pre V), but increased T-cell infiltration postvaccination (Post V). There was an increase in the percentage of CD8(+) T cells in the peripheral blood Post V. An increase in total MUC1-specific antibody was seen in some patients, and several patients developed IgG antibody. Two of 15 resected pancreatic cancer patients are alive and disease free at follow-up of 32 and 61 months. MUC1 100mer peptide with SB-AS2 adjuvant is a safe vaccine that induces low but detectable mucin-specific humoral and T-cell responses in some patients. No difference was seen between different peptide doses. Further evaluation is warranted to examine the effect on disease-free survival and overall survival, especially in early disease and in the absence of immunosuppressive standard therapy.
Publication
Journal: Cancer therapy
February/19/2017
Abstract
Pancreatic and biliary cancers are relatively resistant to chemotherapy and radiation and may therefore provide an opportunity for testing the potential of immunotherapy. MUC1 is an epithelial cell glycoprotein that is highly overexpressed and aberrantly glycosylated in many adenocarcinomas, including pancreatic tumors, providing a tumor specific antigen and target. We performed a Phase I/II clinical trial of a MUC1 peptide-loaded DC vaccine in 12 pancreatic and biliary cancer patients following resection of their primary tumors. The primary endpoints were vaccine toxicity and immunogenicity and the secondary endpoint was clinical outcome. The vaccine was well tolerated and no toxicity was observed. Three patients had pre-existing MUC1 antibody responses that remained stable post vaccination. MUC1-specific T cell responses were difficult to evaluate due to increases in activity of all CD8 and CD4 T cells following each vaccination. Prior to vaccination, patients entered onto this trial had a significantly higher percentage of FoxP3+CD4+ T cells compared to age matched healthy controls. The percentage of these cells also increased transiently following each injection, returning to baseline or below before the next injection. Vaccinated patients have been followed for over four years and four of the twelve patients are alive, all without evidence of recurrence. Study of the immune parameters in long-term survivors several years after vaccination may yield the sought after immune correlates of clinical responses that analysis of immune responses shortly after vaccination has not revealed.
Publication
Journal: Archives of general psychiatry
December/11/2006
Abstract
BACKGROUND
Working memory impairments are a central neurocognitive feature of schizophrenia. The nature of these impairments early in the course of illness and the impact of antipsychotic drug treatment on these deficits are not well understood. The oculomotor delayed response task is a translational spatial working memory paradigm used to characterize the neurophysiologic and neurochemical aspects of working memory in the primate brain.
OBJECTIVE
To examine oculomotor delayed response task performance in patients with first-episode schizophrenia before and after antipsychotic drug treatment.
METHODS
Twenty-five antipsychotic drug-naive, acutely ill patients with first-episode schizophrenia performed an oculomotor delayed response task at baseline before any drug treatment and again after 6 weeks of risperidone treatment. Twenty-five matched healthy controls were studied in parallel.
METHODS
Accuracy for remembered spatial locations on an oculomotor delayed response task.
RESULTS
Before treatment, patients demonstrated baseline impairment in the ability to maintain spatial location information in working memory at longer delay-period durations (8 seconds), when maintenance demands on working memory were greatest. After 6 weeks of risperidone treatment and significant clinical improvement, this pretreatment impairment worsened such that patients were uniformly impaired across all delay period durations (1-8 seconds). This occurred in the absence of any generalized adverse effect on oculomotor systems or significant extrapyramidal adverse effects.
CONCLUSIONS
Deficits in the maintenance of spatial information in working memory are present early in the course of illness. Risperidone treatment exacerbated these deficits, perhaps by impairing the encoding of information into working memory. Studies with nonhuman primates performing oculomotor delayed response tasks suggest that the apparent adverse effect of risperidone might result from treatment-related changes in modulatory functions of prefrontal D1 receptor systems.
Publication
Journal: Bipolar Disorders
December/31/2009
Abstract
OBJECTIVE
Published studies suggest associations between circadian gene polymorphisms and bipolar I disorder (BPI), as well as schizoaffective disorder (SZA) and schizophrenia (SZ). The results are plausible, based on prior studies of circadian abnormalities. As replications have not been attempted uniformly, we evaluated representative, common polymorphisms in all three disorders.
METHODS
We assayed 276 publicly available 'tag' single nucleotide polymorphisms (SNPs) at 21 circadian genes among 523 patients with BPI, 527 patients with SZ/SZA, and 477 screened adult controls. Detected associations were evaluated in relation to two published genome-wide association studies (GWAS).
RESULTS
Using gene-based tests, suggestive associations were noted between EGR3 and BPI (p = 0.017), and between NPAS2 and SZ/SZA (p = 0.034). Three SNPs were associated with both sets of disorders (NPAS2: rs13025524 and rs11123857; RORB: rs10491929; p < 0.05). None of the associations remained significant following corrections for multiple comparisons. Approximately 15% of the analyzed SNPs overlapped with an independent study that conducted GWAS for BPI; suggestive overlap between the GWAS analyses and ours was noted at ARNTL.
CONCLUSIONS
Several suggestive, novel associations were detected with circadian genes and BPI and SZ/SZA, but the present analyses do not support associations with common polymorphisms that confer risk with odds ratios greater than 1.5. Additional analyses using adequately powered samples are warranted to further evaluate these results.
Publication
Journal: Hypertension
March/5/2007
Abstract
Activating angiotensin II type 1 autoantibodies (AT1-AAs) develop in women with preeclampsia and may contribute to the disorder. Insulin resistance and serum concentrations of the antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt-1) are also increased in women with preeclampsia compared with normal pregnancy. sFlt-1 and insulin resistance decrease substantially after delivery; however, significant group differences persist postpartum. Women who have had preeclampsia are at increased cardiovascular risk later in life. We measured AT1-AAs in groups of women with previous preeclampsia (n=29) and previous normal pregnancies (n=35) 18+/-9 months after the first completed pregnancy. These women had had sFlt-1, insulin resistance homeostasis model assessment score, and related cardiovascular risk factors measured. Activating antibodies were detected by the chronotropic response of cultured neonatal rat cardiomyocytes coupled with receptor-specific antagonists (losartan and prazosin). AT1-AAs were detected in 17.2% of women with previous preeclampsia versus 2.9% of women with previous uncomplicated pregnancies (P<0.05). In contrast, there was no difference in the prevalence of autoantibodies against the alpha1-adrenoceptor (10% of previous preeclamptic versus 14% of previous normal pregnant). Women with activating autoantibodies had significantly increased sFlt-1, reduced free vascular endothelial growth factor, and higher insulin resistance homeostasis model assessment values compared with autoantibody-negative women. These data suggest that, as with sFlt-1 and insulin resistance, the AT1-AA does not regress completely after delivery and, secondarily, that correlations exist among these variables. The impact of AT1-AA after preeclampsia, especially in the context of cardiovascular risk, remains to be determined.
Publication
Journal: Sleep
February/8/2009
Abstract
OBJECTIVE
To compare NREM EEG power in primary insomnia (PI) and good sleeper controls (GSC), examining both sex and NREM period effects; to examine relationships between EEG power, clinical characteristics, and self-reports of sleep.
METHODS
Overnight polysomnographic study.
METHODS
Sleep laboratory.
METHODS
PI (n=48; 29 women) and GSC (n=25; 15 women).
METHODS
None.
METHODS
EEG power from 1-50 Hz was computed for artifact-free sleep epochs across four NREM periods. Repeated measures mixed effect models contrasted differences between groups, EEG frequency bands, and NREM periods. EEG power-frequency curves were modeled using regressions with fixed knot splines.
RESULTS
Mixed models showed no significant group (PI vs. GSC) differences; marginal sex differences (delta and theta bands); significant differences across NREM periods; and group*sex and group*NREM period interactions, particularly in beta and gamma bands. Modeled power-frequency curves showed no group difference in whole-night NREM, but PI had higher power than GSC from 18-40 Hz in the first NREM period. Among women, PI had higher 16 to 44-Hz power than GSC in the first 3 NREM periods, and higher 3 to 5-Hz power across all NREM periods. PI and GSC men showed no consistent differences in EEG power. High-frequency EEG power was not related to clinical or subjective sleep ratings in PI.
CONCLUSIONS
Women with PI, but not men, showed increased high-frequency and low-frequency EEG activity during NREM sleep compared to GSC, particularly in early NREM periods. Sex and NREM period may moderate quantitative EEG differences between PI and GSC.
Publication
Journal: Psychological Medicine
August/2/2006
Abstract
BACKGROUND
Prefrontal cortical dysfunctions, including disturbances in adaptive context-specific behavior, have been reported in neuropsychological and brain imaging studies of schizophrenia. Some data suggest that treatment with antipsychotic medications may ameliorate these deficits.
METHODS
We investigated antisaccade performance in 39 antipsychotic-naive, first-episode schizophrenia patients who were re-evaluated 6 weeks after treatment initiation. A group of matched healthy subjects were examined at similar time-points. Patients and healthy individuals available for longer-term testing were re-assessed 26 and 52 weeks after initial testing.
RESULTS
Before treatment, patients showed elevated rates of response suppression errors and prolonged latencies of correct antisaccades. Increased rates of antisaccade errors were associated with faster response latencies during a separate, visually guided saccade task, but only prior to treatment. Throughout the 1-year follow-up, patients progressively improved in their ability to voluntarily suppress context-inappropriate behavior. Although treatment assignment was by clinician choice, results of exploratory analyses revealed that patients treated with risperidone progressively planned and initiated correct antisaccades more quickly than patients receiving haloperidol.
CONCLUSIONS
Deficits in the voluntary control of spatial attention are exaggerated during acute episodes of illness, but remain an enduring aspect of prefrontal dysfunction in schizophrenia even after treatment. During acute illness, speeded sensorimotor transformations may compound these deficits and contribute to the heightened distractibility associated with acute psychosis. Continued improvement in task performance throughout the 1-year follow-up suggests that partial normalization of prefrontal cognitive functions resulting from antipsychotic treatment may have a longer and more gradual time course than the reduction of acute psychotic symptoms.
Publication
Journal: Schizophrenia Research
March/20/2003
Abstract
Abnormalities in the structural integrity and connectivity of the medial temporal and the prefrontal cortex are well documented in schizophrenia, but it is unclear if they represent premorbid indicators of neuropathology. Studies of young relatives at high-risk for schizophrenia (HR) provide an opportunity to clarify this question. We herein provide data from a magnetic resonance imaging (MRI) study of these structures in young offspring of schizophrenia patients. A series of 17 young HR offspring of schizophrenic patients were compared with 22 healthy comparison subjects (HC). Morphometric comparisons of the right and left dorsolateral prefrontal cortex (DLPFC), and the anterior and posterior amygdala-hippocampal (A-H) complex were conducted using high-resolution whole brain T(1) weighted brain images. Compared with the HC group, HR subjects had significant decreases in intracranial volume. The volumes of the left anterior and posterior A-H complex were reduced in the HR subjects after adjusting for intracranial volume. HR subjects also showed a significant leftward (Right>Left) asymmetry of the anterior A-H complex compared to the HC subjects. No significant changes were seen in the DLPFC. Thus, lateralized alterations in the volume of the left A-H complex are evident in unaffected young offspring of schizophrenia patients and may be of neurodevelopmental origin. Follow-up studies are needed to examine the predictive value of these measures for future emergence of schizophrenia in at-risk individuals.
Publication
Journal: Psychiatry Research
December/21/2004
Abstract
Hippocampal volume reduction has been reported in patients with borderline personality disorder (BPD), and is hypothesized to be associated with traumatic childhood experiences. We extended this investigation to explore additional brain regions and other potential clinical correlates of structural brain changes in BPD. Ten unmedicated BPD subjects and 20 healthy controls were assessed for current and past Axis I and II comorbidities and histories of childhood abuse. All had magnetic resonance imaging (MRI) studies with a 1.5 T GE Signa Imaging System, performing three-dimensional-gradient echo imaging (SPGR) with the following parameters: TR=25 ms, TE=5 ms, and slice-thickness=1.5 mm. Compared with healthy controls, BPD subjects had significantly smaller right and left hippocampal volumes, most marked in subjects with childhood abuse, and significantly increased right and left putamen volumes, especially in subjects with substance use disorders. No significant differences between groups were found for caudate, amygdala, temporal lobes, dorsolateral prefrontal cortex and total brain volumes. This study replicated prior findings of diminished hippocampal volumes in subjects with BPD. Also, increased putamen volumes were found in BPD, a finding that has not been previously reported. Early traumatic experiences may play a role in hippocampal atrophy, whereas substance use disorders may contribute to putamen enlargement.
Publication
Journal: Social Work
March/19/2008
Abstract
Women disadvantaged by poverty, as well as racial or ethnic minority status, are more likely to experience depression than the rest of the U.S. population. At the same time, they are less likely to seek or remain in treatment for depression in traditional mental health settings. This article explores a therapeutic, psychosocial engagement strategy developed to address the barriers to treatment engagement and the application of this strategy to a special population--women of color and white women who are depressed and living on low incomes. The conceptual foundations of this intervention-ethnographic and motivational interviewing--as well as its key techniques and structure are reviewed. Finally, a case example description and promising pilot data demonstrate the usefulness of this strategy.
Publication
Journal: Schizophrenia Research
September/25/2008
Abstract
BACKGROUND
A broad range of psychopathology, including externalizing disorders is seen in offspring at genetic risk for schizophrenia. However, it is unclear whether such psychopathology may underlie a higher predisposition to the premorbid antecedents of schizophrenia. We examined the prevalence and correlates of psychopathology in an ongoing study of offspring genetically at risk for schizophrenia.
METHODS
Seventy five consenting high risk offspring (HR: offspring, age 15.68+/-3.27 years; male/female 34/41) and 82 matched comparison subjects (40 males and 42 females; age 15.92+/-3.0 years) participated in this study. Diagnoses were ascertained using structured psychiatric interviews and consensus meetings, including all available clinical information.
RESULTS
Sixty (60%) of the HR offspring had one or more lifetime diagnosis of axis I psychiatric disorder. HR subjects with axis I psychopathology had significantly more soft neurological signs, poorer premorbid adjustment, and higher schizotypy scores as measured by Chapman psychosis proneness scales. Among those with psychopathology, HR subjects with externalizing disorders showed the most abnormal scores in schizotypy.
CONCLUSIONS
A substantial proportion of HR offspring of parents with schizophrenia manifest a broad range of childhood psychiatric disorders. Psychopathology, especially externalizing disorders such as attention deficit hyperactivity disorder (ADHD) may represent a subgroup with an increased risk for schizophrenia spectrum disorders. This possibility needs to be examined by prospective follow-up studies, and would be of considerable importance to early diagnosis and intervention efforts in schizophrenia.
Publication
Journal: Diabetes Care
December/15/2014
Abstract
OBJECTIVE
We examined the effects of an intensive lifestyle intervention (ILI), compared with a diabetes support and education (DSE) control intervention, on long-term changes in depression symptoms, antidepressant medication (ADM) use, and health-related quality of life (HRQoL) in overweight/obese individuals with type 2 diabetes.
METHODS
Look AHEAD was a multisite randomized controlled trial of 5,145 overweight/obese participants assigned to ILI (designed to produce weight loss) or DSE and followed for a median of 9.6 years. The Beck Depression Inventory (BDI) was administered at baseline, annually at years 1-4, and again at year 8. Mean BDI scores and incidence of BDI scores ≥10, indicative of likely mild or greater depression, were examined. Annually through year 10, participants reported their ADM use and completed the Medical Outcomes Study Short Form 36 (SF-36) questionnaire, which yields physical component summary (PCS) and mental component summary (MCS) scores.
RESULTS
ILI significantly reduced the incidence of mild or greater depression symptoms (BDI scores ≥10) compared with DSE (hazard ratio [HR] = 0.85; 95% CI 0.75-0.97; P = 0.0145). Although SF-36 PCS scores worsened over time in both groups, ILI participants reported better physical function than DSE throughout the first 8 years (all P values <0.01). There were no significant differences between treatment arms in the proportion of participants who used ADMs or in SF-36 MCS scores.
CONCLUSIONS
ILI for overweight/obese patients with type 2 diabetes may reduce the risk of developing clinically significant symptoms of depression and preserve physical HRQoL. These findings should be considered when evaluating the potential benefits of ILIs.
Publication
Journal: Journal of Clinical Oncology
August/13/2006
Abstract
OBJECTIVE
A phase II study was undertaken in patients with recurrent malignant glioma to determine the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, dosed at the respective maximum-tolerated dose (MTD) for patients receiving and not receiving enzyme-inducing antiepileptic drugs (EIAEDs). Because tipifarnib undergoes extensive hepatic metabolism, MTD is doubled in patients on EIAEDs. The population included 67 patients with glioblastoma multiforme (GBM) and an exploratory group of 22 patients with anaplastic glioma (AG).
METHODS
Patients received tipifarnib (300 and 600 mg bid for 21 days every 4 weeks in non-EIAED and EIAED patients, respectively). All patients were assessable for efficacy and safety.
RESULTS
Two AG patients (9.1%) and eight GBM patients (11.9%) had progression-free survival (PFS) more than 6 months. Among the latter eight GBM patients, six of 36 patients (16.7%; 95% CI, 7% to 32%) were not receiving EIAEDs and two of 31 patients (6.5%; 95% CI, 1% to 20%) were receiving EIAEDs. Four patients had partial responses in group A GBM and one patient had a partial response group B GBM. An exploratory comparison of PFS between GBM groups A and B was statistically significant (P = .01). Patients not receiving EIAEDs had a higher incidence and increased severity of hematologic events. However, the incidence and severity of rash (the previously determined dose-limiting toxicity in patients receiving EIAEDs) seemed similar in EIAED and non-EIAED subgroups.
CONCLUSIONS
Tipifarnib (300 mg bid for 21 days every 4 weeks) shows modest evidence of activity in patients with recurrent GBM who are not receiving EIAEDs and is generally well tolerated in this population.
Publication
Journal: International Journal of Epidemiology
September/26/2007
Abstract
BACKGROUND
Preeclampsia (PE), especially severe or early PE, is a leading cause of morbidity and mortality among mothers and infants. We estimated the population attributable fractions of severe or early PE associated with pre-existing conditions among nulliparous and multiparous women.
METHODS
Among 70 924 women in the Danish National Birth Cohort, we used hospital discharge data to identify 2117 cases of PE, of which 449 were early (<37 weeks), 426 were severe (clinically diagnosed) and 228 were both early and severe. Prospective interview data were supplemented with hospital registry data to identify women with pre-existing conditions. Generalized estimating equations were utilized to estimate adjusted relative risks, and population attributable fractions were calculated with 95% CI.
RESULTS
Pre-existing hypertension, diabetes, obesity or multiple gestation were associated with 22.3% (19.8-24.9) of all PE cases among nulliparous women. These conditions, or a prior preeclamptic pregnancy, were associated with 52.2% (46.4-57.9) of PE among multiparous women. Early PE was preceded by these pre-existing conditions among 34% (28.3-40.0) of affected nulliparous women and among 50% (37.5-63.4) of multiparous women. The fraction of severe PE associated with these conditions was 23% among nulliparas and 59% among multiparas. Being obese or overweight was associated with 15-17% of the population risk of early PE among nulliparous and multiparous women.
CONCLUSIONS
Pre-existing maternal and obstetric conditions are associated with a high proportion of severe or early cases of PE. Obesity and overweight contributed independently to the risk of pre-term PE, a finding with potentially profound public health implications.
Publication
Journal: Fertility and Sterility
November/8/2006
Abstract
OBJECTIVE
To report the baseline characteristics and racial differences in the polycystic ovary syndrome (PCOS) phenotype from a large multicenter clinical trial (PPCOS).
METHODS
Double-blind, randomized trial of three treatment regimens (with extended release metformin or clomiphene citrate).
METHODS
Academic medical centers.
METHODS
Six hundred twenty-six infertile women with PCOS, aged 18-39 years, with elevated T levels and oligomenorrhea (exclusion of secondary causes), seeking pregnancy, with>> or = 1 patent fallopian tube, normal uterine cavity, and a partner with sperm concentration>> or = 20 x 10(6)/mL in>> or = 1 ejaculate.
METHODS
Baseline characterization.
METHODS
Historical, biometric, and biochemical measures of PCOS.
RESULTS
There were no significant differences in baseline variables between treatment groups. The overall mean (+/-SD) age of the subjects was 28.1 +/- 4.0 years, and the mean body mass index was 35.2 kg/m2 (+/-8.7). Polycystic ovaries (PCOs) were present in 90.3% of the subjects, and the mean volume of each ovary was 10 cm3 or more. Of the subjects, 7% had ovaries that were discordant for PCO morphology. At baseline, 18.3% of the subjects had an abnormal fasting glucose level >> 100 mg/dL). Asians tended to have a milder phenotype, and whites and African Americans were similar in these measures.
CONCLUSIONS
The treatment groups were well matched for baseline parameters, and we have added further information to the PCOS phenotype.
Publication
Journal: American Journal of Obstetrics and Gynecology
December/1/2003
Abstract
OBJECTIVE
We assessed the relationship between interleukin-6 (IL-6) promoter -174 polymorphism and spontaneous preterm birth (sPTB) less than 34 weeks and the relationship of polymorphism status with race.
METHODS
Polymerase chain reaction was used to evaluate DNA from 156 controls who delivered after spontaneous labor at term and 51 subjects who had sPTB less than 34 weeks.
RESULTS
Among the 156 controls, the C/C variant was present in 30 (19.2%). Among the 51 subjects, the C/C variant was present in 2 (6.3%) (odds ratio 0.17, 95% CI 0.04-0.74). Among white women, the C/C variant was present in 30 (27.2%) controls but only 2 (5.2%) cases. No African American women carried the C/C variant. The racial disparity was statistically significant. (P<.001)
CONCLUSIONS
The IL-6 promoter -174 allelic variant C/C is significantly less frequent among women with sPTB less than 34 weeks. There is a dramatic racial disparity in the distribution of allelic variants of this polymorphism.
Publication
Journal: Schizophrenia Research
February/5/2007
Abstract
BACKGROUND
Atypical antipsychotics clozapine, olanzapine, and quetiapine have significant affinity for the muscarinic receptors in vitro, while aripiprazole, risperidone, and ziprasidone do not. Dissimilarity in binding profiles may contribute to the reported differences in the anticholinergic effects of these antipsychotics. However, it is difficult with the available data to predict the likelihood of anticholinergic effects occurring with various doses of an atypical antipsychotic.
METHODS
We developed a model to assess the potential anticholinergic activity (AA) of atypical antipsychotics at therapeutic doses. A radioreceptor assay was used to measure in vitro AA at 6 clinically relevant concentrations of aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone. Using published pharmacokinetic data, in combination with the measured in vitro AA, dose-AA curves were generated.
RESULTS
Clozapine, and to a lesser extent olanzapine and quetiapine showed dose-dependent increases in AA. At therapeutic doses, the AA (in pmol/mL of atropine equivalents) was estimated to range from 27-250, 1-15, and 0-5.4 pmol/mL for clozapine, olanzapine, and quetiapine, respectively. Aripiprazole, risperidone, and ziprasidone did not demonstrate AA at any of the concentrations studied.
CONCLUSIONS
Therapeutic doses of clozapine, olanzapine, and, to a lesser extent, quetiapine are associated with clinically relevant AA.
Publication
Journal: Cell Metabolism
February/9/2011
Abstract
Paget's disease (PD) is characterized by abnormal osteoclasts (OCL) that secrete high IL-6 levels and induce exuberant bone formation. Because measles virus nucleocapsid gene (MVNP) and the p62(P392L) mutation are implicated in PD, marrows from 12 PD patients harboring p62(P392L) and eight normals were tested for MVNP expression and pagetic OCL formation. Eight out of twelve patients expressed MVNP and formed pagetic OCL in vitro, which were inhibited by antisense-MVNP. Four out of twelve patients lacked MVNP and formed normal OCL that were hyperresponsive to RANKL but unaffected by antisense-MVNP. Similarly, mice expressing only p62(P394L) formed normal OCL, while mice expressing MVNP in OCL, with or without p62(P394L), developed pagetic OCL and expressed high IL-6 levels dependent on p38MAPK activation. IL-6 deficiency in MVNP mice abrogated pagetic OCL development in vitro. Mice coexpressing MVNP and p62(P394L) developed dramatic Paget's-like bone lesions. These results suggest that p62(P394L) and IL-6 induction by MVNP play key roles in PD.
Publication
Journal: Schizophrenia Research
February/23/2006
Abstract
Prospective studies of young relatives at risk for schizophrenia (high-risk studies, HR) can shed light on premorbid precursors of schizophrenia. Early HR studies pointed to a wide prevalence of schizophrenia spectrum psychopathology among young relatives at increased genetic risk. Recent studies suggest that young HR relatives have neurobehavioral deficits and structural, physiological, and neurochemical brain abnormalities that may date back to childhood or earlier. In this paper, we provide a selected overview of the lessons and limitations of early "first generation" studies and the beginning insights from recent "second generation" studies. We also provide an interim summary of data from the ongoing studies of young relatives at risk for schizophrenia in Pittsburgh. Collectively, such data may help us to predict the eventual emergence of schizophrenia, and schizophrenia spectrum or non-spectrum psychopathology.
Publication
Journal: Journal of Clinical Oncology
October/28/2010
Abstract
OBJECTIVE
Vorinostat is the first US Food and Drug Administration-approved histone deacetylase inhibitor and is indicated for the treatment of refractory cutaneous T-cell lymphoma. We conducted a phase I study to determine the maximum-tolerated dose and pharmacokinetics of vorinostat in patients with hepatic dysfunction.
METHODS
Patients had solid malignancies and acceptable bone marrow and renal function. Hepatic dysfunction was categorized as mild, moderate, or severe by the National Cancer Institute Organ Dysfunction Working Group criteria. Fifteen patients with normal liver function were enrolled as controls. All patients received a single 400-mg dose of vorinostat for pharmacokinetic studies. One week later, daily vorinostat dosing was begun and continued until toxicity or disease progression occurred. The daily vorinostat dose was escalated within each hepatic dysfunction category. Vorinostat plasma concentrations were quantitated by a validated liquid chromatography-tandem mass spectrometry assay and modeled noncompartmentally.
RESULTS
Fifty-seven patients were enrolled (median age, 59 years; females, n = 24); 42 patients had hepatic dysfunction (16 mild, 15 moderate, and 11 severe). Eight of nine patients with dose-limiting toxicity had grade 4 thrombocytopenia. The recommended vorinostat doses in mild, moderate, and severe hepatic dysfunction were 300, 200, and 100 mg, respectively, on the daily continuous schedule. There were no significant differences in vorinostat pharmacokinetic parameters among the normal or hepatic dysfunction categories. Disease stabilization was noted in 12 patients. Of five patients with adenoid cystic carcinoma, one patient had a partial response, and four patients had stable disease. A patient with papillary thyroid carcinoma had stable disease for more than 2 years.
CONCLUSIONS
Patients with varying degrees of hepatic dysfunction require appropriate dose reduction even though vorinostat pharmacokinetics are unaltered.
Publication
Journal: Clinical Pharmacology and Therapeutics
January/13/2005
Abstract
OBJECTIVE
The activity of cytochrome P450 (CYP) enzymes, which determine the rate of elimination of lipid-soluble drugs, demonstrates considerable interindividual variability. The extent to which age and sex influence CYP activity remains unclear in humans. Our objectives were to determine whether in vivo activity of selected CYP enzymes is affected by age or sex and to evaluate sex bioequivalence in a large sample size.
METHODS
We have assessed in vivo activity of the CYP1A2, 2C19, 2D6, 2E1, and 3A4 enzymes in 161 normal subjects (51% female subjects and 40% aged >50 years). After simultaneous administration of a cocktail of selective probes (caffeine, mephenytoin, debrisoquin [INN, debrisoquine], chlorzoxazone, and dapsone, respectively), phenotypic indices for metabolism of these drugs were used as measures of individual CYP activity. Sex bioequivalence analysis used the bootstrap method.
RESULTS
There were no sex differences associated with CYP1A2 activity. A significant negative correlation (r = -0.572, P < .01) between enzyme activity and age was observed for CYP2C19, but there were no sex differences. CYP2D6 activity showed no dependence on age or sex. In contrast, CYP2E1 activity showed an age-associated increase (r = 0.393, P < .01), which developed earlier in life in male subjects compared with female subjects. These results were further supported by the sex bioequivalence analysis of CYP phenotypic activity, which revealed that sexes were equivalent with respect to CYP2C19 (90% confidence interval [CI], 0.874-1.04), CYP3A4 (90% CI, 0.95-1.176), and CYP2D6 (90% CI, 0.928-1.09) phenotype and just exceeded the 0.8 to 1.25 limits to be equivalent with respect to CYP2E1 (90% CI, 0.785-1.08) and CYP1A2 (90% CI, 0.736-1.03) phenotype.
CONCLUSIONS
These observations suggest that the presence of selective mechanisms of regulation for individual CYP enzymes can be influenced by age and sex. However, we suggest that sex has a limited ability to explain intersubject variation of activity for these phenotypic measures of CYP enzyme activity.
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