Synthesis of halogenated analogs of 5-(4-chlorophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo[2,1-a]-isoindole or mazindol for exploration of the dopamine transporter

In order to study the presynaptic dopamine transporter in the human brain by single photon emission tomography (SPET) or positron emission tomography (PET) we have developed new halogenated mazindol derivatives using a pathway involving a reaction between a dilithio derivative of 2-phenyl-2-imidazoline and appropriate methyl or ethyl halogenobenzoates. After HPLC purification and chemical characterization, the affinity for the dopamine transporter was studied in vitro with [³H]-GBR 12935 and compared to mazindol and nomifensine. Affinity potencies were determined as follow:- mazindol > brominated derivatives > iodinated derivatives > nomifensine > fluorinated derivatives. The properties were related to the structure of these compounds and showed the importance of the nature of the substituent on the primary phenyl ring of mazindol for affinity to the dopamine transporter.     

Inactivation of viruses in blood with aluminum phthalocyanine derivatives

The inactivation of viruses added to whole blood and a red cell concentrate with aluminum phthalocyanine and its sulfonated derivatives was studied. A cell-free form of vesicular stomatitis virus (VSV), used as a model, was completely inactivated (greater than 10(4) infectious units; TCID50) on treatment of whole blood with 10 microM (10 mumol/L) aluminum phthalocyanine chloride (AIPs) and visible light dosage of 88 to 176 J per cm2. At 44 J per cm2, complete VSV inactivation was achieved on raising the concentration of AIPc to 25 microM (25 mumol/L). Results at least as good were achieved on similar treatment of a red cell concentrate. Also inactivated were a cell-associated form of VSV and both cell-free and cell-associated forms of human immunodeficiency virus; encephalomyocarditis virus, used as a model for non-lipid-enveloped viruses, was not inactivated by this procedure. This inactivation of cell-free VSV suggests that a similar degree of inactivation could be achieved with a lower concentration of the sulfonated forms of aluminum phthalocyanine. Throughout the above studies, red cell integrity was well maintained, as judged by the absence of hemoglobin release (less than or equal to 2%) during the course of treatment or on subsequent storage. Red cell osmotic fragility was decreased on treatment of whole blood with AIPc. This study indicates that AIPc may be a promising method for the inactivation of viruses in cellular blood products.     

Low spatial frequency contrast sensitivity deficits in migraine are not visual pathway selective

Some people who experience migraine demonstrate reduced visual contrast sensitivity that is measurable between migraines. Contrast sensitivity loss to low spatial frequency gratings has been previously attributed to possible impairment of magnocellular pathway function. This study measured contrast sensitivity using low spatial frequency targets (0.25–4 c/deg) where the adaptation aspects of the stimuli were designed to preferentially assess either magnocellular or parvocellular pathway function (steady and pulsed pedestal technique). Twelve people with migraine with measured visual field abnormalities and 17 controls participated. Subjects were tested foveally and at 10° eccentricity. Foveally, there was no significant difference in group mean contrast sensitivity. At 10°, the migraine group demonstrated reduced contrast sensitivity for both the stimuli designed to assess magnocellular and parvocellular function ( P  < 0.05). The functional deficits measured in this study infer that abnormalities of the low spatial frequency sensitive channels of both pathways contribute to contrast sensitivity deficits in people with migraine.     

Hallucinogenic drug induced states resemble acute endogenous psychoses: results of an empirical study

Clinical evidence suggests that hallucinogenic drug-induced altered states of consciousness (ASCs) and the incipient, acute stages of endogenous psychoses share many common phenomenological features. The aim of our study was to assess hallucinogen-like phenomena in endogenous psychotic patients using standardised methods. We examined 93 endogenous psychotic patients, 50 healthy controls and a small group of drug induced psychotic patients (n = 7) with two ASC self-assessment scales (questionnaire APZ = Abnormer Psychischer Zustand = Altered State of Consciousness [Dittrich et al, 1985]; and questionnaire OAV = Abbreviation of the three subscales: Oceanic Boundlessness/Angst = Dread of Ego Dissolution/Visionary Restructuralisation [Bodmer 1989]). Patients were examined shortly after remission of their last acute psychotic episode and they answered the questionnaires referring to the early phase of this episode. Differences in the questionnaire scores were significant between psychotic patients and controls. Drug induced patients had numerically higher scores than endogenous psychotic patients, however these differences were only significant for the APZ total score and the undifferentiated items of the APZ, but not for the three APZ subscale and the OAV scores. More than 50% of the endogenous psychotic patients answered 26% of the APZ-and 43% of the OAV-items with “yes”. The OAV total score and the OSE (Ozeanische Selbstentgrenzung = oceanic boundlessness) scores of both questionnaires correlated significantly with BPRS Factor 3 (thought disturbance). Our results support the hypothesis that hallucinogen-like experiences represent common phenomena during the acute stages of endogenous psychoses. Remarkably, these phenomena include subjectively pleasant experiences of the OSE dimension. In the routine clinical assessment of endogenous psychotic patients experiences of this dimension may be more easily overlooked than the negative experiences of the AIA dimension (AIA: Angst vor der Ich-Auflösung = dread of ego dissolution).     

Cryptosporidiosis among children with acute gastroenteritis in the pediatric ward in the General Hospital, Penang

Stool samples from 836 cases with diarrhea and acute gastroenteritis from the Pediatric ward, Penang General Hospital, were examined for Cryptosporidium oocysts. A dimethyl sulfoxide modified acid fast technique was used for the identification of the parasites. 36 samples or 4.3% were found to be positive for Cryptosporidium. The prevalence of infection was higher (2.39%) in children with diarrhea and vomiting than in children with acute gastroenteritis alone (0.8%). Stool examination and cultures from the Cryptosporidium positive samples revealed no other parasites, rotavirus or enteropathogenic bacteria. This suggests that Cryptosporidium may be an important agent in the causation of diarrhea in young children. A routine laboratory examination for the detection of Cryptosporidium in the search for causal agents of childhood diarrhea in our environment may, therefore, be significant.     

Pro-inflammatory cytokines and the pathogenesis of Gaucher's disease: increased release of interleukin-6 and interleukin-10

Gaucher's disease is characterized by hepatosplenomegaly, bone-marrow infiltration, osteonecrosis and bone thinning, associated with the presence of pathological macrophages that contain undegraded glycosphingolipids. To investigate the possible role of cytokines in the systemic and local manifestations of established Gaucher's disease, interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF alpha) and interleukin-10 (IL-10) were measured in freshly-separated serum. Samples from eight male and 14 female patients with type 1 Gaucher's disease were compared with sera from 22 healthy age- and sex-matched controls. Concentrations of IL-6 and IL-10 were significantly elevated in sera from patients with Gaucher's disease (11.9 +/- 1.8 (SEM) pg/ml and 5.4 +/- 0.5 (SEM) pg/ml, respectively) compared with those of controls (4.1 +/- 0.9 (SEM) and 0.8 +/- 0.3 (SEM) pg/ml, p < 0.0001). No significant differences in concentrations of TNF alpha or IL-1 beta were identified. IL-6 has been implicated in the development of localized osteolysis in multiple myeloma and in the development of post-menopausal osteoporosis. High concentrations of IL- 6 in the serum of patients with Gaucher's disease may thus reflect the development of the bone lesions commonly associated with this disorder. Since IL-6 and IL-10 are important regulators of lymphocyte growth and differentiation, and IL-6 concentrations were significantly raised in patients with oligo- or polyclonal increases in serum immunoglobulins, enhanced release of these cytokines from pathological macrophages provides a pathological link between Gaucher's disease and associated lympho-proliferative disorders.      

Autosomal recessive cerebellar hypoplasia

Cerebellar hypoplasia is found in association with a variety of neurologic and systemic disorders. It is the primary finding in the uncommonly reported condition of autosomal recessive cerebellar hypoplasia. We describe two siblings with cerebellar hypoplasia documented in both by magnetic resonance imaging (MRI) and review the clinical features of previously reported cases of autosomal recessive cerebellar hypoplasia. The most common findings in this disorder are nonprogressive ataxia, strabismus, mental retardation, and speech delay with dysarthria. Previously reported cases have been confirmed by autopsy, pneumoencephalography, or computed tomographic (CT) scans. MRI clearly documents diffuse cerebellar hypoplasia and aids in distinguishing autosomal recessive cerebellar hypoplasia from other disorders. The pathophysiology of this disorder is uncertain, however, studies of the weaver mutant mouse (an animal model of autosomal recessive cerebellar hypoplasia) suggest that an abnormality of the Bergmann glia may lead to the observed granule cell layer deficiency in these patients. This diagnosis should be considered for children with nonprogressive ataxia and families should be made aware of the 25% recurrence risk.     

Aneuploidy and percentage of S-phase cells determined by flow cytometry correlate with cell phenotype in childhood acute leukemia

Cellular DNA content distributions of propidium-iodide-stained bone marrow blasts were determined by flow cytometry (FCM) for 225 untreated children with acute leukemia and were correlated with leukemia cell phenotype and karyotype. Aneuploidy of the primary malignant stem line was detected in 54 cases (24%): 51 hyperdiploid and 3 hypodiploid. A second stem line with approximately twice the DNA content of the primary stem line was recognized by FCM in 28 cases (23 ALL, 5 ANLL) and may be an important source of leukemia cell heterogeneity. The degree of DNA content abnormality detected by FCM was highly correlated (r = 0.98) with the number of whole chromosome gains or losses in the leukemia karyotype. Aneuploidy detectable by FCM was more frequent in acute lymphoblastic leukemia (ALL) (52 of 173, 30.1%) than in acute nonlymphoblastic leukemia (2 of 52, 3.8%) (p less than 0.001). In the ALL group, aneuploidy was significantly correlated with the cell surface expression of common ALL antigen: 46 of 127 antigen-positive cases were aneuploid compared to 6 of 46 antigen-negative cases (p less than 0.003). Only 2 of 21 cases of T-cell ALL without common ALL antigen had detectable aneuploidy, which was significantly less than in the common ALL group (p = 0.02). The median percentage of cells in S- phase was significantly greater for B-cell and erythrocyte rosette- positive T-cell ALL, than for the other phenotypic subgroups. We conclude that aneuploidy and S-phase cell percentage are correlated with the state of leukemia cell differentiation. The biologic basis for the correlation is not established, but may be linked to the process of malignant transformation.