Brain neurons and glial cells express Neu differentiation factor/heregulin: a survival factor for astrocytes.

Neu differentiation factor (NDF, also called heregulin) was isolated from mesenchymal cells on the basis of its ability to elevate phosphorylation of ErbB proteins. Earlier in situ hybridization analysis showed that NDF was transcribed predominantly in the central nervous system during embryonic development. To gain insights into the role of NDF in brain we analyzed its distribution by immunohistochemistry and in situ hybridization. Late-gestation (day 17) rat embryos displayed high NDF immunoreactivity in both motor (e.g., putamen) and limbic (e.g., septum) regions. Lower levels of the factor were exhibited by adult brain, except for the cerebellum, where NDF expression was increased postnatally. Both neurons and glial cells were identified by immunohistochemistry as NDF-producing cells (e.g., pyramidal neurons in the cerebral cortex and glial cells in the corpus callosum). By establishment of primary cultures of rat brain cells we confirmed that NDF was expressed in neurons as well as in astrocytes. In addition, by using such primary cultures we observed that NDF treatment exerted only a limited mitogenic effect, which was accompanied by significant acceleration of astrocyte maturation. Furthermore, long-term incubation with the factor specifically protected astrocytes from apoptosis, implying that NDF functions in brain as a survival and maturation factor for astrocytes.     

Characteristics of human monocytes cultured in the Teflon culture bag.

Blood monocytes from healthy volunteers were isolated by Ficoll-Isopaque centrifugation and cultured (together with lymphocytes) in medium 199 with 20% heat-inactivated newborn calf serum in a Teflon culture bag. Quantifiable data on survival showed that up to 21 days of culture, approximately 40% of the initial number of monocytes were still viable. Such cultures could be maintained for more than 8 weeks without refeeding. The monocytes exhibited the morphology of macrophages after 5-7 days of culture, and increased in size during culture. Less than 1% of the cells became giant cells even after long culture periods. Almost all cultured monocytes were positive for alpha-naphthyl butyrate esterase, whereas the peroxidase-positive granules disappeared during the first week of culture. After long culture times increasing amounts of lysozyme and angiotensin-converting enzyme were detected in the culture supernatants. Phagocytosis of staphylococci did not decrease appreciably during culture, and the same holds for intracellular killing of these bacteria. Chemotactic activity decreased during culture, whereas the chemokinetic response of the monocytes persisted.     

Amino acid substitutions within the heptad repeat domain 1 of murine coronavirus spike protein restrict viral antigen spread in the central nervous system

Targeted recombination was carried out to select mouse hepatitis viruses (MHVs) in a defined genetic background, containing an MHV-JHM spike gene encoding either three heptad repeat 1 (HR1) substitutions (Q1067H, Q1094H, and L1114R) or L1114R alone. The recombinant virus, which expresses spike with the three substitutions, was nonfusogenic at neutral pH. Its replication was significantly inhibited by lysosomotropic agents, and it was highly neuroattenuated in vivo. In contrast, the recombinant expressing spike with L1114R alone mediated cell-to-cell fusion at neutral pH and replicated efficiently despite the presence of lysosomotropic agents; however, it still caused only subclinical morbidity and no mortality in animals. Thus, both recombinant viruses were highly attenuated and expressed viral antigen which was restricted to the olfactory bulbs and was markedly absent from other regions of the brains at 5 days postinfection. These data demonstrate that amino acid substitutions, in particular L1114R, within HR1 of the JHM spike reduced the ability of MHV to spread in the central nervous system. Furthermore, the requirements for low pH for fusion and viral entry are not prerequisites for the highly attenuated phenotype.     

Accumulation of closed-circular polyoma DNA molecules containing host DNA during serial passage of the virus

The high-multiplicity serial passage of plaque-purified polyoma virus in baby mouse kidney cultures results in the accumulation of closed-circular virus DNA molecules containing covalently linked sequences homologous to reiterated mouse cell DNA. Such molecules can be encapsidated within virions and are probably defective in plaque formation.     

The occurrence of the tropical bedbug (Cimex hemipterus, fabricius) in poultry barns in Israel

The occurrence of the tropical bedbug (Cimex hemipterus Fabricius) in poultry houses in Israel is described. Despite the heavy infestation serious losses have not been registered and no clinical signs observed. Treatment of the barns and accessories with 2% malathion emulsion gave good results. The parasite invaded human habitations as well.     

The association between melatonin and sleep stages in normal adults and hypogonadal men

The role of melatonin in normal sleep-wake regulation has been inferred from the temporal relationships between its cycle and the 24 h cycle in sleep propensity. Pharmacological doses of melatonin were reported to have sleep-inducing effects in insomniacs. The current study investigated the relationship between melatonin and sleep stages in groups of hypogonadal men with abnormal melatonin levels. We were also interested in examining what would happen to these relationships during testosterone replacement therapy. Male patients with hypogonadotropic hypogonadism (IGD, n = 6), constitutional delayed puberty (DP, n = 6), and Klinefelter's syndrome (KS, n = 5) before and during testosterone replacement therapy were studied. Six patients with KS and normal testosterone levels were also studied. Results were compared with those obtained in normal controls (n = 6). Serum samples were obtained at 15 min intervals from 1900-0700h in a controlled light-dark environment with simultaneous polysomnographic sleep recordings. Serum melatonin levels were the highest in IGD and DP and lowest in KS patients. A lower percentage of sleep stage 2 and higher percentage of stage 3/4 were observed in IGD and DP groups while KS patients had higher percentage of stage 2 and lower percentage of stage 3/4 as compared to controls. Slow wave sleep was the highest in IGD and the lowest in KS groups. Serum melatonin levels were lowest in KS groups. Serum melatonin levels were lowest in sleep stage 3/4, higher in stage 2 and highest in REM sleep when all groups were combined and averaged together. However, in the IGD group, melatonin levels were actually lowest in REM sleep. Also in the KS group, melatonin levels were lower in REM than during sleep stage 2. Serum melatonin levels were lowest in sleep stage 3/4 in all groups, higher in stage 2, and highest in REM sleep. During waking periods, melatonin levels were the highest in untreated IGD, DP and KS patients. Testosterone treatment given to these patients, although normalized, their melatonin levels did not statistically significantly change these correlations. These data demonstrate that relative melatonin concentrations are associated with sleep stages in hypogonadal and normal men. The results also indicate that the association between melatonin and the reproductive hormones are independent of the synchronizing effects of melatonin on sleep homeostasis.     

Nidovirus infections: experimental model systems of human neurologic diseases

The presence of terminally differentiated slow- and non-dividing cells in the central nervous system (CNS) provides a safe harbor for viral persistence and latency and constitutes a unique immunologic environment for viral infections. Studies of experimental model systems of viral infections of the CNS provide insight into mechanisms of viral persistence and immune-mediated pathology. Nidoviruses are comprised of 2 families of viruses, coronaviruses and arteriviruses, and are common pathogens of humans and a variety of animal species. Both families of viruses contain neurotropic strains that produce experimental neurologic diseases in rodents. These include acute meningitis and encephalitis; acute poliomyelitis; and chronic inflammatory, immune-mediated, demyelination. Coronavirus-induced demyelinating disease mimics many of the pathologic features of Multiple Sclerosis (MS).     

Adolescents on the Front Line: Exposure to Shelling Via Television and the Parental Role

Objectives: Research suggests that exposure to traumatic content via television inadvertently increases posttraumatic stress symptoms (PTSS) as well as psychological distress, especially among adolescent viewers. The aim of the current study was to assess the effect of news consumption on PTSS and general distress among adolescents who live in a war area, as well as to examine the role of parents as intermediaries of news broadcasting. Method: A total of 65 adolescents who live in a war zone filled out the Child Post Traumatic Stress Reaction Index, the Brief Symptoms Inventory, and a scale measuring the level of real-life exposure, news broadcast consumption, and parents as intermediaries of news broadcasting. Results: A main effect for real-life exposure on both PTSS and general distress was revealed. Interestingly, a three-way interaction between real-life exposure, television exposure, and parents as intermediators was found for general distress. Only under low real-life exposure did parents as intermediaries buffer the effect of television exposure on general distress. Conclusions: Parental intermediation of news broadcasting of traumatic events, especially in situations of continuous, real-life exposure, is essential.     

Impact of dosing regimen of custirsen,an antisense oligonucleotide,on safety,tolerability and cardiac repolarization in healthy subjects

Aims

Custirsen (OGX-011/TV-1011), a second-generation antisense oligonucleotide (ASO) that reduces clusterin production, is under investigation with chemotherapy in patients with solid tumours. Custirsen is associated with constitutional symptoms (CS) that may interfere with clinical pharmacology investigations, such as QT interval studies. Experience with other ASOs suggests NSAID premedication may ameliorate CS, but we observed suboptimal outcomes in healthy subjects given custirsen and NSAIDs. We sought to establish a custirsen regimen for future clinical pharmacology studies in healthy subjects.

Methods

Subjects received custirsen (640 mg intravenously over 120 min) with dexamethasone premedication or increasing doses (320, 480, 640 mg over 6 days) of custirsen with dexamethasone premedication, then one full custirsen dose without premedication on day 8. Incidence/severity of adverse events (AEs) and extensive electrocardiogram readings were evaluated. Pharmacokinetic parameters were estimated.

Results

AEs included CS, elevated transaminases and prolonged activated partial thromboplastin time (aPTT) that were predominantly grade 1/2. Administration of increasing custirsen doses and dexamethasone premedication reduced the incidence of CS associated with full dose custirsen. Transaminase elevation showed a dose-dependent effect (0% at days 2, 4, 27% at day 6) with the highest custirsen doses. Increasing doses of custirsen may have mitigated the severity but not incidence of aPTT prolongation. Neither regimen was associated with cardiac repolarization changes in QT values or concentration–effect analyses. The custirsen pharmacokinetic profile was consistent with previous experience.

Conclusion

Escalation of custirsen dose combined with dexamethasone premedication reduced CS associated with full dose custirsen and should be considered in future clinical pharmacology studies of custirsen.