Olanzapine in the treatment of pervasive developmental disorders: a case series analysis

Controlling the symptoms that are characteristic of patients with pervasive developmental disorders is often challenging. We report on the safety and efficacy of olanzapine in the treatment of 7 patients with pervasive developmental disorders. The patients were all male and ranged in age from 8 to 52 years. They received olanzapine doses of 5-10 mg/d along with their various other drug regimens. Patients were monitored and evaluated for a mean duration of 17.7 (range 12-26) months while on olanzapine therapy. Very few side effects were observed during treatment. All patients showed clinically significant improvement on the Clinical Global Impressions scale, as well as an improved score as measured by the Global Assessment of Functioning scale. Our observations support the use of long-term olanzapine therapy for symptom control in patients with pervasive developmental disorders.     

History of childhood abuse in panic disorder,social phobia,and generalized anxiety disorder

The authors examined the prevalence of self-reported childhood physical or sexual abuse in a sample of adult patients presenting for treatment of panic disorder, social phobia, or generalized anxiety disorder. Regardless of the presence of comorbid anxiety disorders or comorbid depression, patients with panic disorder had significantly higher rates of past childhood physical or sexual abuse than patients with social phobia. Patients with generalized anxiety disorder had intermediate rates of past physical or sexual abuse that were not significantly different from the other two diagnostic groups. Anxiety disorder patients with a history of childhood abuse were also more likely to have comorbid major depression than those without. These findings are discussed in terms of biological and behavioral factors that may influence the development of anxiety disorders after the experience of a traumatic event.     

Direct relation of long-term synaptic potentiation to phosphorylation of membrane protein F1, a substrate for membrane protein kinase C

One hour after long-term potentiation (LTP) in the intact hippocampus, a selective increase in protein F₁ in vitro phosphorylation was observed in homogenate prepared from dorsal hippocampus. Protein F₁ phosphorylation was directly related to the magnitude and persistence of potentiation. No other phosphoprotein studied exhibited a relationship with synaptic enhancement. Low-frequency, non-potentiating stimulation did not increase protein F₁ phosphorylation, and phosphorylation of F₁ was not elevated when high-frequency stimulation did not produce potentiation. We also confirmed our earlier demonstration of a similar pattern of results 5 min after LTP. In related work we have previously observed: (1) that protein F₁ is a substrate for protein kinase C (PKC); (2) that membrane PKC activity was increased by translocation from the cytosol following LTP; and (3) that membrane PKC activity was directly related to the persistence of enhancement. We therefore predicted in the present study that protein F₁ phosphorylation in a dorsal hippocampal membrane fraction would be related to LTP. Hippocampal membrane protein F₁ was found to be directly related to both the magnitude and persistence of response enhancement. Thus the molecular events leading to prolonged potentiation may involve increased PKC/protein F₁ association. Persistence of potentiation may be related to synaptic growth processes involving the growth-associated function of protein F₁.     

Caveolin-1 expression is maintained in rat and human astroglioma cell lines

Caveolin-1 is the principal structural and functional component of caveolae, a plasmalemmal compartment that has been proposed to sequester lipid and protein components that participate in transmembrane signal transduction processes. Multiple studies reveal a reduction in the expression level of caveolin-1 mRNA and protein in many carcinomas as well as transformed cells. The human caveolin-1 gene is localized to a suspected tumor suppressor locus (7q31.1). Collectively, these data have been taken to imply that caveolin-1 may function in a tumor suppressor capacity. To determine if a reduction in the expression level of caveolin-1 mRNA and protein accompanied the transformation of astrocytes, we undertook studies of two transformed rat astroglial cell lines, C6 and DI TNC(1), as well as several cell lines derived from human glioblastoma tumors: T98G, U87MG, U118MG, U138MG, and U373MG. Ultrastructural, immunolocalization, immunoblot, and Northern blot analyses demonstrated that caveolin-1 message and protein were expressed in all rat and human glioma cells. The localization pattern, buoyant density, and detergent-insolubility property of caveolin-1 protein were indistinguishable from that determined for nontransformed type 1 astrocytes in culture. Nucleotide sequence analyses of caveolin-1 cDNAs indicate that mutations are not present in the caveolin-1 sequence in any of the glioma cell types. Taken together with previous analyses, these data indicate that, at least for astrocytes, the process of transformation in and of itself is not solely sufficient to reduce the level of caveolin-1 expression, and that caveolin-1 expression in and of itself is not solely sufficient to prevent the acquisition of a transformed phenotype.     

Whole brain and regional [125I]-α-bungarotoxin binding in developing rat

These experiments were conducted in order to determine if the total number of binding sites for [¹²⁵I]-α-bungarotoxin ([¹²⁵I]-α-BGT) in rat brain increases and then decreases during postnatal development as predicted by comparison with skeletal muscle, and, if so, to determine at approximately what age the peak in binding occurs in the brain as a whole. A further purpose was to investigate the time-course of development of the [¹²⁵I]-α-BGT binding sites in several brain regions.Specific binding for [¹²⁵I]-α-BGT was studied using the pellets from a 20 min, 14,000 × g centrifugation of rat brain homogenates from 4 or 5 postnatal ages. At least three binding assays were done per region and per age, on cerebral cortex, cerebellum, caudate-putamen, posterior hippocampus, pons-medulla and whole brain. In most regions, the [¹²⁵I]-α-BGT specific binding is measurable, but is low at day one, peaks at about 12–20 days and declines by adulthood. With a few exceptions, these data hold true whether binding is expressed as specific binding per mg protein, specific binding per gram wet tissue, or total specific binding per brain region. The absolute number of specifically bound [¹²⁵I]-α-BGT molecules is undistorted by simultaneous or non-linear growth of cells uninvolved with α-BGT binding and, thus, is the measurement most useful in determining developmental changes. Whole brain has the same age-related pattern as in the majority of the brain regions, i.e., compared to 19–20 days, the adult brain actually has fewer total binding sites.     

gamma-H2AX foci formation in peripheral blood lymphocytes of tumor patients after local radiotherapy to different sites of the body: dependence on the dose-distribution, irradiated site and time from start of treatment

PURPOSE: To evaluate the relationship between an estimated integral total body radiation dose delivered and phosphorylated histone H2AX protein (gamma-H2AX) foci formation in peripheral blood lymphocytes of cancer patients. MATERIAL AND METHODS: gamma-H2AX formation was quantified as the mean number of foci per lymphocyte (N(meanH2AX)) and the percentage of lymphocytes with > or =n foci. The integrated total body radiation dose was estimated from the dose volume histogram of patient's body corrected for the proportion of the body scanned by computed tomography for 3D treatment planning. RESULTS: There was a strong linear correlation between the mean number of gamma-H2AX foci per lymphocyte in the peripheral blood sample and integrated total body radiation dose (r = 0.83, p < 0.0001). The slope of the relationship was dependent on the site of body irradiated. In comparison to chest irradiation with a slope of 8.7 +/- 0.8 foci Gy(-1), the slopes for brain, upper leg and pelvic sites were significantly shallower by -4.7, -4.3, and -3.8 Gy(-1), respectively (p < 0.0001), while the slope for upper abdomen irradiation was significantly larger by 9.1 +/- 2.6 Gy(-1) (p = 0.0007). There was a slight time effect since the start of radiotherapy on the slopes of the in vivo dose responses leading to shallower slopes (-1.5 +/- 0.7 Gy(-1), p = 0.03) later (> or =10 day) during radiotherapy. After in vitro irradiation, lymphocytes showed 10.41 +/- 0.12 foci per Gy with no evidence of inter-individual heterogeneity. CONCLUSIONS: gamma-H2AX measurements in peripheral lymphocytes after local radiotherapy allow the estimation of the applied integral body dose. The site and time dependence have to be considered.     

Hypobaric hypoxia modifies constitutive nitric oxide synthase activity and protein nitration in the rat cerebellum

Ischemic hypoxia provokes alterations in the production system of nitric oxide in the cerebellum. We hypothesize that the nitric oxide system may undergo modifications due to hypobaric hypoxia and that may play a role in high altitude pathophysiology. Therefore, changes in the nitric oxide system of the cerebellum of rats submitted to acute hypobaric hypoxia were investigated. Adult rats were exposed for 7 h to a simulated altitude of 8235 m (27000 ft.) and then killed after 0 h or 1, 3, 5 and 10 days of reoxygenation. Nitric oxide synthase calcium-dependent and -independent activity, immunoblotting and immunohistochemistry of neuronal, endothelial, and inducible nitric oxide synthase, and nitrotyrosine were evaluated. Immunoreactivity for neuronal nitric oxide synthase slightly increased in the baskets of the Purkinje cell layer and in the granule cells, after 0 h of reoxygenation, although no changes in neuronal nitric oxide synthase immunoblotting densitometry were detected. Calcium-dependent activity significantly rose after 0 h of reoxygenation, reaching control levels in the following points, and being coincident with a peak of eNOS expression. Nitrotyrosine formation showed significant increments after 0 h and 1 day of reoxygenation. Nitrotyrosine immunoreactivity showed an intracellular location change in the neurons of the cerebellar nuclei and in addition, an appearance of nitration in the soma of the Purkinje cells was detected. No changes in inducible nitric oxide synthase activity, immunoblotting or immunohistochemistry were detected. We conclude that at least part of the nitric oxide system is involved in cerebellum responses to hypobaric hypoxia.