Oxcarbazepine treatment of bipolar disorder

OBJECTIVE: To assess the effectiveness and safety of oxcarbazepine in bipolar disorder. METHOD: A chart review of naturalistic treatment with oxcarbazepine in 42 outpatients with DSM-IV bipolar disorder (10 males, 32 females; mean +/- SD age = 33.3 +/- 12.4 years; 25 with bipolar disorder type I, 4 with bipolar disorder type II, and 13 with bipolar disorder not otherwise specified) was conducted. Patients had received oxcarbazepine monotherapy or adjunctive therapy between April 2000 and April 2002. Treatment response was defined as a Clinical Global Impressions-Improvement scale score of 1 (marked improvement) or 2 (moderate improvement). RESULTS: Oxcarbazepine was moderately to markedly effective in 24 subjects (57%). Mixed symptoms were the most common indication (52% [22/42]). The mean oxcarbazepine dose was 1056.6 mg/day, and mean treatment duration was 16.2 weeks. Sedation (17/42, 40%) was the most common side effect, but 16 patients (38%) had no side effects. Twenty-two patients (52%) stopped treatment, mostly due to side effects (12/22). Males were more likely to respond than females (10/10 vs. 14/32, p =.006). Dose, bipolar subtype, indication, past nonresponse to mood stabilizers, concurrent mood stabilizer use, and monotherapy use of oxcarbazepine did not differentially predict response. CONCLUSION: Oxcarbazepine appeared effective in about one half of patients with bipolar disorder and was well tolerated.     

Understanding the basis of CD4(+) T-cell depletion in macaques infected by a simian-human immunodeficiency virus

The efficacy of candidate AIDS vaccines to mediate protection against viral infection and pathogenesis is evaluated, at a preclinical stage, in animal models. One model that is favored because the infecting virus is closely related to HIV-1 and because of the rapidity of pathogenic outcomes is the infection of Old World monkeys by simian-human immunodeficiency virus (SHIV) chimerae. We investigated the basis for the depletion of CD4(+) T lymphocytes in a SHIV-macaque model. Molecularly cloned SHIVs, SHIV-89.6 and SHIV-KB9, differ in the ability to cause CD4(+) T-cell loss at a given level of virus replication in monkeys. The envelope glycoproteins of the pathogenic SHIV-KB9 mediate membrane-fusion in cultured T lymphocytes more efficiently than the envelope glycoproteins of the non-pathogenic SHIV-89.6. The minimal envelope glycoprotein region that specifies this increase in membrane-fusing capacity was sufficient to convert SHIV-89.6 into a virus that causes profound CD4(+) T-cell depletion in monkeys. Conversely, two single amino acid changes that decrease the membrane-fusing ability of the SHIV-KB9 envelope glycoproteins also attenuated the CD4(+) T-cell destruction that accompanied a given level of virus replication in SHIV-infected monkeys. Thus, the ability of the HIV-1 envelope glycoproteins to fuse membranes, which has been implicated in the induction of viral cytopathic effects in vitro, contributes to the capacity of the pathogenic SHIV to deplete CD4(+) T lymphocytes in vivo.     

In vivo use of all-trans retinoic acid prior to induction chemotherapy improves complete remission rate and increases rhodamine 123 uptake in patients with de novo acute myeloid leukemia

All-trans retinoic acid (ATRA) is used in the treatment of acute promyelocytic leukemia. Because ATRA has effects (increase in apoptosis, suppression of bcl-2), it has also been used for the treatment of other French-American-British (FAB) subtypes of acute myelogenous leukemia (AML). To find out the in vivo and in vitro effects of ATRA in AML, we analyzed 37 patients with de novo AML. Twenty-seven patients received ATRA before remission-induction (RI) treatment (ATRA group). Results were compared to a control group (10 patients) that received induction without ATRA during the same time period. Bone marrow or peripheral blood samples were collected from all patients on d 0 and 4. The immunphenotype, myeloperoxidase (MPO), reaction and the efflux uptake of rhodamine 123 (Rh123) were analyzed on myeloblasts in these samples. In the myeloblasts from patients treated with ATRA, the uptake of Rh123 was increased significantly (p=0.026) from d 0 to d 4, and all other parameters remained unaltered. ATRA administration increased the complete remission (CR) rate (88%, 22/25 vs 55%, 5/9) significantly (p=0.042). Logistic regression analysis revealed that ATRA administration was the important factor in CR, among other potential factors including age, white blood count, bcl-2 expression, and the uptake and efflux of Rh123 (p=0.05). Estimated disease-free survival and overall survival were similar between these two groups (43% vs 37.5% and 51.2% vs 37.5%, respectively). In conclusion, ATRA treatment prior to RI treatment may improve the CR rate in patients with de novo AML, which seems to be related to its beneficial effect on multidrug resistance.     

Can valerian improve the sleep of insomniacs after benzodiazepine withdrawal?

PURPOSE: The authors studied the sleep of patients with insomnia who complained of poor sleep despite chronic use of benzodiazepines (BZDs). The sample consisted of 19 patients (mean age 43.3+/-10.6 years) with primary insomnia (DSM-IV), who had taken BZDs nightly, for 7.1+/-5.4 years. The control group was composed of 18 healthy individuals (mean age 37+/-8 years). Sleep electroencephalogram (EEG) of the patients was analyzed with period amplitude analysis (PAA) and associated algorithms, during chronic BZD use (Night 1), and after 15 days of a valerian placebo trial (initiated after washout of BZD, Night 2). Sleep of control subjects was monitored in parallel. RESULTS: Valerian subjects reported significantly better subjective sleep quality than placebo ones, after BZD withdrawal, despite the presence of a few side effects. However, some of the differences found in sleep structure between Night 1 and Night 2 in both the valerian and placebo groups may be due to the sleep recovery process after BZD washout. Example of this are: the decrease in Sleep Stage 2 and in sigma count; the increase in slow-wave sleep (SWS), and delta count, which were found to be altered by BZD ingestion. There was a significant decrease in wake time after sleep onset (WASO) in valerian subjects when compared to placebo subjects; results were similar to normal controls. Nonetheless, valerian-treated patients also presented longer sleep latency and increased alpha count in SWS than control subjects. CONCLUSIONS: The decrease in WASO associated with the mild anxiolytic effect of valerian appeared to be the major contributor to subjective sleep quality improvement found after 2-week of treatment in insomniacs who had withdrawn from BDZs. Despite subjective improvement, sleep data showed that valerian did not produce faster sleep onset; the increase in alpha count compared with normal controls may point to residual hyperarousabilty, which is known to play a role in insomnia. Nonetheless, we lack data on the extent to which a sedative drug can improve alpha sleep EEG. Thus, the authors suggest that valerian had a positive effect on withdrawal from BDZ use.     

Effects of combined conventional and modified ultrafiltration in adult patients

BACKGROUND: Modified ultrafiltration (MUF) improves hemodynamics and postoperative recovery in children. Ultrafiltration (UF) may have similar benefits in adults. The purpose of this study was to investigate the effects of UF in adult patients. METHODS: A total of 40 adult patients undergoing cardiac surgery were randomized into a study group of conventional UF during bypass + venovenous MUF after bypass and a control group with no UF. Perioperative clinical variables, cytokines, and endothelin-1 levels were compared between groups. RESULTS: There was no mortality in either group. The patients in the study group had a greater rise in hematocrit (5.7% +/- 2.4% vs 1.2% +/- 1.9%, p < 0.001), hemoglobin (1.7 +/- 0.8 mg/mL vs 0.5 +/- 0.6 mg/mL, p < 0.0005), and platelet levels (27,800 +/- 29,200 vs -9,000 +/- 30,970, p < 0.001). Mean arterial blood pressure and CI increased after MUF (from 64.2 +/- 16.9 mm Hg to 72.3 +/- 14.1 mm Hg, p = 0.05, and from 2.4 +/- 0.7 to 2.8 +/- 0.6, p < 0.03, respectively). Postoperative oxygenation was better in the study group (alveolo-arterial PO2 tension gradient 74.6 +/- 43.9 mm Hg vs 107.2 +/- 27.8 mm Hg, p = 0.03). Ultrafiltration reduced postoperative bleeding (522.2 +/- 233.4 mL vs 740 +/- 198.4 mL, p < 0.003). CONCLUSIONS: A combination of conventional and modified UF is effective and safe in adult patients undergoing cardiac surgery. Ultrafiltration improved hemodynamics, hemostatic, and pulmonary functions. We recommend the use of combined UF in high-risk adult patients.     

CpG oligonucleotides induce strong humoral but only weak CD4+ T cell responses to protein antigens in rhesus macaques in vivo

Oligonucleotides containing CpG motifs (CpG ODN) are strong adjuvants for humoral immune responses but data on cellular immune responses in primates are scarce. Rhesus macaque blood contained similar numbers of plasmacytoid dendritic cells and B cells, the key sensors of CpG ODN, as human blood, and these cells were activated by CpG-A and CpG-B in vitro. In vivo, both ODNs induced equal plasma levels of interferon-inducible protein 10 and similarly enhanced antibody responses following i.m. injections of the ODNs, protein antigen, and aluminium hydroxide into rhesus macaques, whereas antigen-specific CD4(+) T cell responses were only slightly increased by CpG ODN.     

On-line hemodiafiltration does not induce inflammatory response in end-stage renal disease patients: results from a multicenter cross-over study

BACKGROUND: On-line hemodiafiltration (HDF) represents the supreme blood purification modality for end-stage renal disease (ESRD) patients. Large-volume infusion of on-line prepared substitution fluid may, however, expose patients to inflammatory contaminants. As a result, on-line HDF might aggravate chronic inflammation, which correlates with malnutrition, cardiovascular disease, and mortality among ESRD patients. METHODS: In a multicenter cross-over study, 27 ESRD patients were randomly assigned to treatment with on-line HDF and low-flux hemodialysis (HD). After 6 months, patients were crossed to the other treatment modality, and treatment continued for another 6 months. Both on-line HDF and low-flux HD were conducted with polysulfone membranes and ultrapure dialysis fluid. Samples were drawn at the end of each treatment period. RESULTS: Inflammatory parameters were elevated in the study population when compared to healthy controls. Induction of interleukin-1 receptor antagonist (IL-1Ra) and tumor necrosis factor alpha (TNF-alpha) was comparable for on-line HDF and low-flux HD, and there was no intradialytic increase in cytokine production. As a result, interleukin-6 (IL-6) plasma levels did not differ significantly between the two treatment modalities. Similarly, no difference between on-line HDF and low-flux HD was observed for C-reactive protein (CRP) and albumin. Markers of endothelial cell activation (soluble intercellular and vascular cell adhesion molecules sICAM-1 and sVCAM-1) as well as the cardiovascular risk marker cardiac troponin T (cTnT) remained elevated compared to healthy subjects, but showed no difference between the two treatment modalities. CONCLUSIONS: On-line HDF, as the most effective renal replacement therapy, does not provoke inflammatory response and is both safe and highly biocompatible.     

Evoked electromyographic technique for quantitative assessment of the innervation status of laryngeal muscles

OBJECTIVES: The purpose of this study was to develop a minimally invasive, noninjurious evoked electromyographic technique that could accurately quantitate the level of innervation of laryngeal muscles with recurrent laryngeal nerve stimulation. METHODS: A four-phase study was conducted in 24 canines, including 1) identification of the best stimulation-recording configuration, 2) statistical analysis of sensitivity and accuracy, 3) evaluation of safety, and 4) identification of the laryngeal muscle(s) that contribute to the evoked response. RESULTS: The results demonstrated that an entirely noninvasive technique is not feasible. The stimulating cathode must be invasive to ensure discrete activation of the recurrent laryngeal nerve, whereas both recording electrodes should remain on the surface with one overlying the thyroid ala. This configuration proved to be highly accurate, with an error rate of only 6% to 7%, and with sensitivity sufficient to detect a signal in a nerve with fewer than 1% of the axons intact. There was no evidence of nerve injury in any animal over the course of 350 stimulus needle penetrations. By use of neuromuscular blockade to identify those muscles generating the surface response, the thyroarytenoid muscle was found to be the primary contributor, whereas the posterior cricoarytenoid muscle was uninvolved. CONCLUSIONS: This evoked electromyographic technique could provide quantitative information regarding the extent of muscle innervation during denervation and regeneration in case of laryngeal paralysis.     

Heart rate variability, sympathetic and vagal balance and EEG arousals in upper airway resistance and mild obstructive sleep apnea syndromes

BACKGROUND AND PURPOSE: We questioned the role of respiratory events in obstructive sleep apnea syndrome (OSAS) and of upper airway resistance syndrome (UARS) on heart rate (HR) during sleep, paying specific attention to the termination of the abnormal breathing events and examining the presence of arousals or termination with only central nervous system (CNS) activation. PATIENTS AND METHODS: Twenty patients, 10 with UARS and 10 with mild OSAS, were studied. A nocturnal polysomnogram was performed including measurement of respiratory variables and pulse transit time (PTT). According to the presence or absence of a PTT event indicative of autonomic nervous system (ANS) activation, 148 events were extracted after having been randomly chosen in each represented sleep stage, with or without an electroencephalogram (EEG) arousal >1.5s. RR interval (RRI) in electrocardiogram (ECG) recordings, as well as heart rate variability, was calculated during 60 and 120s, respectively. Period amplitude analysis (PAA) was applied for RR-interval analysis, and fast Fourier transformation (FFT) was applied to perform HR variability analysis. RESULTS: Visually scored EEG arousal was significantly associated with an increase in sympathetic index of heart rate, while PTT was associated with a drop in parasympathetic index, after the respiratory events. Patients with mild OSAS presented persistently shorter RRI when compared to patients with UARS. The latter also exhibited a significant decrease in parasympathetic index (High Frequency (HF)) at the termination of a respiratory event. CONCLUSION: The HF component was only significantly decreased in patients with UARS, which indicates a predominant involvement of the parasympathetic tone in patients with UARS in comparison to those with OSAS.