Effector T cells immune reactivity among patients with acute hepatitis E.

Hepatitis E virus (HEV) is a leading cause of acute viral hepatitis in several developing countries. Information on cellular immune responses during acute hepatitis E is limited. We therefore studied peripheral blood mononuclear cells (PBMCs) from patients with acute hepatitis E and healthy adult subjects who lacked anti-HEV antibodies for enumeration of various T-cell subsets using flow cytometry and to assess HEV-specific T effector cell responses using interferon-gamma ELISPOT assays. The patients showed increased numbers of CD8(+) cells and CD4(+) CD8(+) cells compared with healthy controls. In addition, the proportion of PBMCs that produced interferon-gamma in response to recombinant HEV open reading frame (ORF) 2 and ORF 3 proteins were found to be higher in patients than in healthy controls. Using pools of 15-mer overlapping peptides corresponding to these recombinant proteins, the immunodominant regions in these proteins for interferon-gamma-producing cells were mapped to regions corresponding to amino acids 181-249 and 301-489 of HEV ORF2 protein. These data provide evidence for the activation of effector T cells during acute hepatitis E. These responses may play a role in viral clearance from the host in patients with HEV infection.

Residual symptoms after remission of major depressive disorder with citalopram and risk of relapse: a STAR*D report.

BACKGROUND: Many patients with major depressive disorder (MDD) who experience full symptomatic remission after antidepressant treatment still have residual depressive symptoms. We describe the types and frequency of residual depressive symptoms and their relationship to subsequent depressive relapse after treatment with citalopram in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. METHOD: Participants in primary (n=18) and psychiatric (n=23) practice settings were openly treated with citalopram using measurement-based care for up to 14 weeks and follow-up for up to 1 year. We assessed 943 (32.8% of 2876) participants who met criteria for remission to determine the proportions with individual residual symptoms and any of the nine DSM-IV criterion symptom domains to define a major depressive episode. At each visit, the 16-item Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR16) and the self-report Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) scale were used to assessed depressive symptoms and side-effects respectively. RESULTS: More than 90% of remitters had at least one residual depressive symptom (median=3). The most common were weight increase (71.3%) and mid-nocturnal insomnia (54.9%). The most common residual symptom domains were sleep disturbance (71.7%) and appetite/weight disturbance (35.9%). Those who remitted before 6 weeks had fewer residual symptoms at study exit than did later remitters. Residual sleep disturbance did not predict relapse during follow-up. Having a greater number of residual symptom domains was associated with a higher probability of relapse. CONCLUSIONS: Patients with remission of MDD after treatment with citalopram continue to experience selected residual depressive symptoms, which increase the risk of relapse.

Painful physical symptoms and treatment outcome in major depressive disorder: a STAR*D (Sequenced Treatment Alternatives to Relieve Depression) report.

BACKGROUND: Painful physical symptoms (PPS) are both common and reduce the likelihood of remission in major depressive disorder (MDD), based upon results of clinical trials in selected populations. Whether PPS significantly contribute to poorer treatment outcome overall in primary or specialty psychiatric care settings remains unclear. METHOD: Out-patients (n=2876) with MDD were treated in the first step of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial with citalopram up to 60 mg/day for up to 14 weeks. Presence of painful symptoms, as well as severity of depression, physical illness, and demographic and treatment factors were examined. Time to and overall rates of remission were analysed in relation to the presence of PPS. RESULTS: Of the participants, 80% complained of PPS. These patients, both in primary and specialty psychiatric settings, had significantly lower remission rates and took longer to remit. Increasing severity of PPS was associated with greater physical illness burden, lower socio-economic status, absence of private insurance and being female, African-American or Hispanic. After adjustment for these factors, patients with PPS no longer had significantly poorer treatment outcomes. CONCLUSIONS: Presence and severity of PPS is an indicator of MDD that may have poorer treatment outcome with an initial selective serotonin reuptake inhibitor. These poorer treatment outcomes are multifactorial, however, and are not explained by the presence and severity of pain per se.

Indicators of pretreatment suicidal ideation in adults with major depressive disorder.

OBJECTIVE: In order to evaluate the presence of treatment emergent suicidal ideation (SI), it becomes necessary to identify those patients with SI at the onset of treatment. The purpose of this report is to identify sociodemographic and clinical features that are associated with SI in major depressive disorder (MDD) patients prior to treatment with a selective serotonin reuptake inhibitor. METHOD: This multisite study enrolled 265 out-patients with non-psychotic MDD. Sociodemographic and clinical features of participants with and without SI were compared post hoc. RESULTS: Social phobia, bulimia nervosa, number of past depressive episodes, and race were independently associated with SI by one or more SI measure. CONCLUSION: Concurrent social phobia and bulimia nervosa may be potential risk factors for SI in patients with non-psychotic MDD. Additionally, patients with more than one past depressive episode may also be at increased risk of SI.

Electroconvulsive therapy is equally effective in unipolar and bipolar depression.

OBJECTIVE: To determine the relative efficacy of electroconvulsive therapy (ECT) in the treatment of bipolar (BP) and unipolar (UP) depressive illness and clarify its role in BP depression. METHOD: Patients referred for ECT with both UP and BP depressions. [classified by Structured Clinical Interview for DSM (SCID-I) criteria for history of mania] were included in a multi-site collaborative, double-masked, randomized controlled trial of three electrode placements - right unilateral, bifrontal or bitemporal - in a permutated block randomization scheme. RESULTS: Of 220 patients, 170 patients (77.3%) were classified as UP and 50 (22.7%) as BP depression in the intent-to-treat sample. The remission and response rates and numbers of ECT for both groups were equivalent. CONCLUSION: Both UP and BP depressions remit with ECT. Polarity is not a factor in the response rate. In this sample ECT did not precipitate mania in depressed patients. Treatment algorithms for UP and BP depression warrant re-evaluation.

Co-infection by Semliki forest virus and malarial parasite modulates viral multipucation, pathogenesis and cytokines in mice.

Environmental, technological and societal factors continue to have a dramatic effect on infectious diseases worldwide and are considered to be facilitating the emergence of several infectious diseases at a time. Co-infection with different species of viral and malaria infections are currently emerging problems of dual infection in the developing as well as developed countries. Understanding of interactions between the host, malaria and virus infection is of current concern and we have initiated studies to delineate the mechanisms involved during the progression of Semliki forest virus (SFV) and Plasmodium yoelii (P. yoelii) infection in mice. Enhanced virus multiplication and up-regulation of cytokine mRNA level in P. yoelii and SFV co-infected mice were observed on day 4 post-infection compared to respective controls. Collectively, our observations indicate that malaria infection may influence virus multiplication, pathogenesis and up-regulation of cytokine mRNA during co-infection in mice.

Prostate cancer chemoprevention by green tea: in vitro and in vivo inhibition of testosterone-mediated induction of ornithine decarboxylase.

Recently, we have shown that ornithine decarboxylase (ODC), a rate-controlling enzyme in the polyamine biosynthetic pathway, is overexpressed in prostate cancer (PCA) and prostatic fluid in humans (R. R. Mohan et al., Clin. Cancer Res., 5: 143-147, 1999). ODC is also characterized as an androgen-responsive gene, and the androgenic stimulation regulates the development and growth of both normal and tumorigenic prostate cells. Thus, chemopreventive approaches aimed toward the modulation of ODC could be effective against PCA. Green tea polyphenols (GTPs) possess strong chemopreventive properties against a variety of animal tumor models and in some human epidemiological studies. At least two epidemiological studies have suggested that people who consume tea regularly may have a decreased risk of PCA. In this study, we investigated the effect of GTPs against testosterone-mediated induction of ODC in human prostate carcinoma cells, LNCaP as an in vitro model, and in Cpb:WU rats and C57BL/6 mice as in vivo models. Treatment of LNCaP cells with testosterone resulted in induction of ODC activity in a dose-dependent manner. Pretreatment of the cells with GTPs resulted in a significant inhibition of testosterone-caused induction of ODC activity in a dose-dependent manner. Similar effects of GTPs were observed in anchorage-independent growth assay of LNCaP cells where pretreatment of the cells with GTP was found to result in dose-dependent inhibition of colony formation. Testosterone treatment of the cells resulted in a significant increase in the level of ODC mRNA, and this increase was almost completely abolished by prior treatment of the cells with GTPs. The administration of testosterone (10 mg/kg body weight, i.p.) to sham-operated and castrated Cpb:WU rats resulted in 2- and 38-fold increases in ODC activity, respectively, in the ventral prostate. Oral feeding of 0.2% GTPs in drinking water for 7 days before testosterone administration resulted in 20 and 54% decreases in testosterone-caused induction of ODC activity in sham-operated and castrated rats, respectively. Similar results were obtained with C57BL/6 mice, where testosterone treatment at similar dosage resulted in a 2-fold increase in ODC activity in the ventral prostate and prior oral feeding with 0.2% GTPs resulted in 40% inhibition in this induction.

Magnetic resonance imaging of the caudate nuclei in depression. Preliminary observations.

A role of the caudate nucleus in depression has been suggested from relevant clinical conditions, such as patients with Huntington's disease or caudate infarcts, as well as animal studies. Correlations of caudate nucleus disease with depressive symptoms have been limited to autopsy studies and cases of gross pathological disorder, such as large infarcts. We used serial axial high-field magnetic resonance images and an unbiased stereological technique to estimate the volumes of the caudate nuclei in 50 patients who met DSM-III criteria for major depression (23 men, 48.3 +/- 17 years old) in comparison with 50 age- and gender-matched normal controls free of major neurological and psychiatric disorders. Depressed patients had smaller caudate nucleus volumes (5.2 +/- 1.6 cm3) compared with controls (6.2 +/- 1.7 cm3). Right and left caudate nucleus volumes were smaller in depressed patients compared with controls. Age was negatively correlated with caudate nucleus volumes in depressed patients as well as in controls. Caudate nucleus volumes in depressed patients were inversely correlated with the bicaudate and bifrontal indices. These results may be the first demonstration of diminished caudate nucleus volumes in depression and suggest a role for the caudate nucleus in the pathogenesis of major depression.

Differential antiproliferative and apoptotic response of sanguinarine for cancer cells versus normal cells.

Sanguinarine, derived from the root of Sanguinaria canadendid, has been shown to possess antimicrobial, anti-inflammatory, and antioxidant properties. Here we compared the antiproliferative and apoptotic potential of sanguinarine against human epidermoid carcinoma (A431) cells and normal human epidermal keratinocytes (NHEKs). Sanguinarine treatment was found to result in a dose-dependent decrease in the viability of A431 cells as well as NHEKs albeit at different levels because sanguinarine-mediated loss of viability occurred at lower doses and was much more pronounced in the A431 carcinoma cells than in the normal keratinocytes. DNA ladder assay demonstrated that compared to vehicle-treated control, sanguinarine treatment of A431 cells resulted in an induction of apoptosis at 1-, 2-, and 5-microM doses. Sanguinarine treatment did not result in the formation of a DNA ladder in NHEKs, even at the very high dose of 10 microM. The induction of apoptosis by sanguinarine was also evident by confocal microscopy after labeling the cells with annexin V. This method also identified necrotic cells, and sanguinarine treatment also resulted in the necrosis of A431 cells. The NHEKs showed exclusively necrotic staining at high doses (2 and 5 microM). We also explored the possibility of cell cycle perturbation by sanguinarine in A431 cells. The DNA cell cycle analysis revealed that sanguinarine treatment did not significantly affect the distribution of cells among the different phases of the cell cycle in A431 cells. We suggest that sanguinarine could be developed as an anticancer drug.

Hydroxyl radical formation resulting from the interaction of nickel complexes of L-histidine, glutathione or L-cysteine and hydrogen peroxide.

L-histidine, L-cysteine, reduced glutathione (GSH) and other bioligands, which are ubiquitously present in biological systems, are recognized as antioxidants. Studies have shown that nickel (II) complexed with these ligands catalyzes the disproportionation of H2O2, leading to the generation of hydroxyl radicals (OH radical). However, none of the studies could provide information regarding effective concentrations at which these ligands act either as pro-oxidant or antioxidant. Therefore, the observed paradoxical behaviour of biological antioxidants in nickel-induced oxidative response was evaluated. Benzoic acid (BA) is hydroxylated by OH radical to form highly fluorescent dihydroxy benzoate (OH-BA). We used this model to study the effect of nickel complexes of L-histidine, GSH or L-cysteine on the hydroxylation of BA. The concentration-dependent effect of L-histidine, GSH and L-cysteine, or nickel on the hydroxylation of BA was studied. The hydroxylation of BA was significantly enhanced up to 1:0.5 molar ratio (Ni:hist or GSH). However, beyond 1:0.5 molar ratios, histidine/GSH inhibited the hydroxylation and complete inhibition was observed at 1:1 molar ratios. Sorbitol and caffeic acid, considered as scavengers of hydroxyl radicals, inhibited nickel-induced hydroxylation of BA. The present study demonstrates paradoxical behaviour of these bioligands. They act as pro-oxidant at lower ligand ratios and as antioxidant at higher ligand ratios. The redox properties of nickel complexes with histidine, GSH or cysteine reported here may be crucial for the toxicity of nickel.

Pituitary size in depression.

Magnetic resonance images centered at the pituitary stalk were used to measure pituitary gland size in 19 patients with major depression compared with that in age- and sex-matched controls. Depressed patients had significantly greater pituitary cross-sectional area (P = 0.0009) and volume (P = 0.007) than the controls. This difference was particularly prominent in elderly depressed patients compared to elderly controls. These results provide the first demonstration of structural alterations in the pituitary gland in major depression.

In vivo assessment of pituitary gland volume with magnetic resonance imaging: the effect of age.

We used sagittal and coronal T1 weighted magnetic resonance images, at 1.5 Tesla, to measure the height, width, length, and cross-sectional area and to generate two estimates of pituitary gland volume in 35 normal volunteers aged 26-79 yr (19 females and 16 males). Subjects over 50 yr of age had significantly smaller pituitary gland height (P = 0.03), area (P = 0.04), and volume (P = 0.04) than those under 50 yr (by two-tailed t test). Overall, age was negatively correlated with pituitary volume (V1: r = -0.51; P = 0.003; V2: r = -0.47; P = 0.008), area (r = -0.43; P = 0.009), and height (r = -0.46; P = 0.005), but not with pituitary length or width. There were no statistically significant differences in pituitary size between men and women (by two-tailed t test). These findings suggest that pituitary gland height provides a good single measure for the assessment of pituitary gland size and that age must be controlled for in studies of pituitary gland size.

Cerebral white matter disease in late-onset paranoid psychosis.

We examined magnetic resonance (MR) scans of the heads of 8 patients with late onset psychosis and 8 aged controls. Although some patients had mild cognitive impairment, none had depression or a history or examination suggesting focal brain disease. Thus, all patients met DSM-III-R criteria for late-onset schizophrenia. All 8 patients showed significant leukoencephalopathy or vascular pathology on MR imaging, and temporoparietal and occipital lesions were especially prominent. Little such pathology was evident on control scans. We suggest that focal brain disease of vascular origin may be associated with late-onset psychosis, and that MR scanning of such cases may provide important clues to pathogenesis.

Magnetic resonance findings in patients with early-onset Alzheimer's disease.

The magnetic resonance scans of 22 patients with early-onset Alzheimer's disease (AD) were compared to 16 age-matched neurologically normal controls for the presence of white matter subcortical hyperintensities (SCH) and periventricular hyperintensities (PVH). Patients with AD were significantly more likely to have evidence of PVH (p less than 0.01) than age-matched controls. There was no significant difference between the two groups in either the frequency of SCH or the size of the largest lesion. Within the AD group, there was no difference demonstrated in the location of the SCH, either in the anterior-posterior plane or between the two hemispheres. Patients with AD more frequently demonstrated ventriculomegaly (p less than 0.001) and sulcal widening (p less than 0.05) compared with controls. This study suggests that the SCH seen in early-onset AD patients on MRI are related more to the aging process than to the AD process and that the increased frequency of PVH may have a relationship to the disease process.

Platelet [3H]-imipramine binding and leukoencephalopathy in geriatric depression.

We examined the relationship between platelet [3H]-imipramine binding and leukoencephalopathy as assessed by 1.5 Tesla Magnetic Resonance Imaging (MRI) in 21 elderly depressed patients who satisfied DSM-III criteria for major depression. Both drug-free platelet [3H]-imipramine binding and brain MRI studies were obtained during the same episode of depression. Our findings show a significant inverse relationship between frequency of subcortical hyperintensity (SCH) and the number (Bmax) of platelet [3H]-imipramine binding sites. Patients with Bmax less than 850 fmol/mg protein had significantly larger SCH compared with patients with a higher Bmax. These data provide further support to the potential use of platelet [3H]-imipramine binding studies and brain MR imaging as diagnostic adjuncts in geriatric depression and suggest, moreover, that these two biological markers may be linked in geriatric patients with depression.

In vitro 1H-magnetic resonance spectroscopy of postmortem brains with schizophrenia.

Some evidence suggests that thalamic dysfunction could explain some of the signs and symptoms of schizophrenia. We measured the absolute concentrations of amino acid metabolites in thalamus, frontal pole, and cerebellar vermis in extracts of postmortem brains from 8 schizophrenics and 10 controls using high-resolution 1H-magnetic resonance spectroscopy. The concentrations of N-acetyl aspartate, glutamate, and valine tended to be reduced in the thalamus of the schizophrenic group. Although it is difficult to ascribe significance to the "tendencies," these data may tend to support other data suggesting decreased thalamic volume or neuronal number in schizophrenia.

A brain magnetic resonance imaging study of pituitary gland morphology in anorexia nervosa and bulimia.

Magnetic resonance imaging (MRI) of the brain was used to examine the morphology and dimensions of the pituitary gland in 18 patients with eating disorders (8 anorectics and 10 bulimics), in comparison with 13 healthy volunteers. None of the 18 patients with anorexia or bulimia had any radiological evidence suggestive of pituitary macroadenoma, cyst, or empty sella. Measurements revealed that the anorectics and bulimics had smaller pituitary gland cross-sectional areas (p less than 0.05) and smaller pituitary gland heights, compared with healthy controls. These preliminary findings in anorectics and bulimics are suggestive of pituitary atrophy secondary to nutritional or endocrine alterations, rather than a primary pituitary pathology.

Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study.

BACKGROUND: Vagus Nerve Stimulation (VNS) delivered by the NeuroCybernetic Prosthesis (NCP) System was examined for its potential antidepressant effects. METHODS: Adult outpatients (n = 30) with nonpsychotic, treatment-resistant major depressive (n = 21) or bipolar I (n = 4) or II (n = 5; depressed phase) disorders who had failed at least two robust medication trials in the current major depressive episode (MDE) while on stable medication regimens completed a baseline period followed by NCP System implantation. A 2-week, single-blind recovery period (no stimulation) was followed by 10 weeks of VNS. RESULTS: In the current MDE (median length = 4.7 years), patients had not adequately responded to two (n = 9), three (n = 2), four (n = 6), or five or more (n = 13) robust antidepressant medication trials or electroconvulsive therapy (n = 17). Baseline 28-item Hamilton Depression Rating Scale (HDRS(28)) scores averaged 38.0. Response rates (> or =50% reduction in baseline scores) were 40% for both the HDRS(28) and the Clinical Global Impressions-Improvement index (score of 1 or 2) and 50% for the Montgomery-Asberg Depression Rating Scale. Symptomatic responses (accompanied by substantial functional improvement) have been largely sustained during long-term follow-up to date. CONCLUSIONS: These open trial results suggest that VNS has antidepressant effects in treatment-resistant depressions.

Vagus nerve stimulation: a new tool for brain research and therapy.

Biological psychiatry has a long history of using somatic therapies to treat neuropsychiatric illnesses and to understand brain function. These methods have included neurosurgery, electroconvulsive therapy, and, most recently, transcranial magnetic stimulation. Fourteen years ago researchers discovered that intermittent electrical stimulation of the vagus nerve produces inhibition of neural processes, which can alter brain electrical activity and terminate seizures in dogs. Since then, approximately 6000 people worldwide have received vagus nerve stimulation for treatment-resistant epilepsy. We review the neurobiology and anatomy of the vagus nerve and provide an overview of the vagus nerve stimulation technique. We also describe the safety and potential utility of vagus nerve stimulation as a neuroscience research tool and as a putative treatment for psychiatric conditions. Vagus nerve stimulation appears to be a promising new somatic intervention that may improve our understanding of brain function and has promise in the treatment of neuropsychiatric disorders.

Assessment of posterior fossa structures with midsagittal MRI: the effects of age.

Midsagittal magnetic resonance (MR) images of 36 normal volunteers, ranging in age from 26 to 79 years, were used to evaluate the effects of age on the size of posterior fossa structures (cerebellar vermis, midbrain, pons, medulla and fourth ventricle). Our results demonstrate a highly statistically significant age-related decline in the cross-sectional area of the midbrain (r = -.44, p less than 0.007), a less prominent decline in the area of the anterior cerebellar vermis (r = -.33, p less than 0.05) and striking intercorrelations between the dimensions of the pons, medulla and cerebellar vermis. To the best of our knowledge, this is the first MRI demonstration of midbrain atrophy during aging in normal adults.