Peripheral blood gene expression profiling in Sjögren's syndrome.

Sjögren's syndrome (SS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands. The affected cases commonly present with oral and ocular dryness, which is thought to be the result of inflammatory cell-mediated gland dysfunction. To identify important molecular pathways involved in SS, we used high-density microarrays to define global gene expression profiles in the peripheral blood. We first analyzed 21 SS cases and 23 controls, and identified a prominent pattern of overexpressed genes that are inducible by interferons (IFNs). These results were confirmed by evaluation of a second independent data set of 17 SS cases and 22 controls. Additional inflammatory and immune-related pathways with altered expression patterns in SS cases included B- and T-cell receptor, insulin-like growth factor-1, granulocyte macrophage-colony stimulating factor, peroxisome proliferator-activated receptor-alpha/retinoid X receptor-alpha and PI3/AKT signaling. Exploration of these data for relationships to clinical features of disease showed that expression levels for most interferon-inducible genes were positively correlated with titers of anti-Ro/SSA (P<0.001) and anti-La/SSB (P<0.001) autoantibodies. Diagnostic and therapeutic approaches targeting interferon-signaling pathway may prove most effective in the subset of SS cases that produce anti-Ro/SSA and anti-La/SSB autoantibodies. Our results strongly support innate and adaptive immune processes in the pathogenesis of SS, and provide numerous candidate disease markers for further study.

Human influenza viral infection in utero alters glial fibrillary acidic protein immunoreactivity in the developing brains of neonatal mice.

Epidemiological reports describe a strong association between prenatal human influenza viral infection and later development of schizophrenia. Postmodern human brain studies, however, indicate a lack of gliosis in schizophrenic brains presumably secondary to absence of glial cells during the second trimester viral infection in utero. We hypothesized that human influenza infection in day 9 pregnant mice would alter the expression of glial fibrillary acidic protein (GFAP, an important marker of gliosis, neuron migration, and reactive injury) in developing brains of postnatal days 0, 14 and 35 mice. Determination of cellular GFAP immunoreactivity (IR) expressed as cell density in cortex and hippocampus of control and experimental brains showed increases in GFAP-positive density in exposed cortical (P = 0.03 day 14 vs control) and hippocampal cells (P = 0.035 day 14, P = 0.034 day 35). Similarly, ependymal cell layer GFAP-IR cell counts showed increases with increasing brain age from day 0, to days 14 and 35 in infected groups (P = 0.037, day 14) vs controls. The GFAP-positive cells in prenatally exposed brains showed 'hypertrophy' and more stellate morphology. These results implicate a significant role of prenatal human influenza viral infection on subsequent gliosis, which persists throughout brain development in mice from birth to adolescence.

Venlafaxine and bupropion combination therapy in a case of treatment-resistant depression.

OBJECTIVE: To report the therapeutic efficacy of venlafaxine and bupropion in a patient with treatment-refractory major depression. CASE SUMMARY: A 21-year-old white woman with chronic and recurrent major depression presented with lack of response to several antidepressants. On examination, the patient exhibited neurovegetative signs of depression, guilt feelings, and suicidal ideation. The patient was administered venlafaxine 75 mg three times daily. The dose was titrated to 150 mg three times daily over the next month. Later bupropion was instituted up to 100 mg three times daily over a four-month period. The patient responded favorably to combination therapy and has remained free of depression for approximately 23 months. DISCUSSION: Venlafaxine and bupropion are antidepressant agents with unique pharmacologic profiles, each effective in the treatment of depression. Recent data indicate that combinations of selective serotonin-reuptake inhibitors and bupropion can convert partial response to full response in patients with treatment-resistant depression. We considered whether a combination of venlafaxine and bupropion would reduce the depressive symptoms of a patient who was unresponsive to various classes of psychotropic agents. Gradual administration of venlafaxine and bupropion acted synergistically to significantly reduce depressive symptoms (p < 0.002) and significantly increase social function (p < 0.002) over a period of eight months. CONCLUSIONS: To our knowledge this is the first report of successful combination therapy with venlafaxine and bupropion in treatment of chronic recurrent and refractory major depression.

Defective corticogenesis and reduction in Reelin immunoreactivity in cortex and hippocampus of prenatally infected neonatal mice.

Recent reports indicate an association between second trimester human influenza viral infection and later development of schizophrenia. Postmortem human brain studies also provide evidence for reduction in Reelin mRNA (an important secretory protein responsible for normal lamination of the brain) in schizophrenic brains. We hypothesized that human influenza infection in day 9 pregnant mice would alter the expression of reelin in day 0 neonatal brains. Prenatally-infected murine brains from postnatal day 0 showed significant reductions in reelin-positive cell counts in layer I of neocortex and other cortical and hippocampal layers when compared to controls. Whereas layer I Cajal-Retzius cells produced significantly less Reelin in infected animals, the same cells showed normal production of calretinin and nNOS when compared to control brains. Moreover, prenatal viral infection caused decreases in neocortical and hippocampal thickness. These results implicate a potential role of prenatal viral infection in causation of neuronal migration abnormalities via reduction in Reelin production in neonatal brains.

Is it time to have another look at lithium maintenance therapy in bipolar disorder?

1. Bipolar disorder is typically a chronic disease entailing an episodes course, whereby psychiatric status alternates between periods of normal functioning and periods of illness. Lithium is well established and approved for the treatment of bipolar disorder. However, its efficacy in practice is not as great as expected. This retrospective record study was undertaken to determine the efficacy of lithium in bipolar disorders. 2. 48 patients who met DSM-III-R diagnostic criteria for bipolar I disorder and had been admitted once before lithium therapy and twice or more after that, were included in this study. 3. No significant difference in length between episode (frequency) was observed before and after lithium maintenance therapy. In addition, the percentages of manic episode after lithium therapy were much greater than before that. 4. The results indicate that it is worth re-examining the efficacy of lithium in bipolar disorders.

The lithium ratio and the incidence of side effects.

1. During a prospective and outpatient study the correlation between the lithium ratio and the incidence of lithium side effects and type of comedications was studied in 51 Iranian bipolar patients by using new direct method of measuring erythrocyte lithium concentration. 2. Results revealed that patients who received lithium alone the incidence of lithium side effects was extremely lower than those with lithium and neuroleptics in combination. Both neurological and renal side effects of lithium were higher in patients who received lithium in combination with neuroleptics. 3. In patients on lithium alone the lithium ratio among patients with side effects were significantly lower than those without side effects, and the plasma lithium concentrations were significantly higher in those with side effects. In patients who received neuroleptics in combination with lithium, the lithium ratios were also significantly lower in those with serious side effects than those with slight side effects, but there were no significant correlation in plasma lithium concentrations between them. 4. Previous studies about the correlation of the lithium ratio and incidence of side effects have yielded inconsistent results, and methodological problems may be a reason for these discrepancies. By using the new direct method of measuring erythrocyte lithium concentration, repetition of previous studies on lithium ratio may elucidate its value as a tool in daily practice.