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.     

Anaphylaxis to omeprazole: diagnosis and desensitization protocol.

BACKGROUND: Omeprazole is an inhibitor of the parietal cell enzyme H+/K+ adenosine triphosphatase. Immediate-type hypersensitivity reactions, such as urticaria, angioedema, and hypotension, induced by omeprazole and other proton pump inhibitors are rare. OBJECTIVES: To confirm the immediate-type mechanism of recurrent anaphylactic reactions to the repeated administration of omeprazole using skin testing and to enable safe administration of the drug after successful oral desensitization. METHODS: Intradermal skin tests were performed with omeprazole (0.04 and 0.4 mg/mL) prepared from the oral and intravenous commercial preparations and with pantoprazole (0.02 and 0.2 mg/mL) prepared from the oral commercial preparation. Skin tests were repeated after completion of the desensitization. Oral desensitization was applied at a starting dose of 0.001 mg of omeprazole, and a full dose of 16 mg was achieved after 5.6 hours (cumulative dose of 32.6 mg). RESULTS: Intradermal skin test results were positive to omeprazole and pantoprazole at all tested concentrations. After successful desensitization, omeprazole was administered in the full dose uneventfully. The wheal size of the intradermal skin tests performed after completion of the desensitization was significantly reduced. CONCLUSION: When indicated, this newly designed desensitization protocol may be used in patients with omeprazole-induced anaphylaxis.     

Pathological confirmation of cystic fibrosis in the fetus following prenatal diagnosis

Prenatal diagnosis of cystic fibrosis is presently based on the determination of microvillar enzyme activities in the amniotic fluid. However, there seems to be no accurate means for confirming the diagnosis of the aborted fetus. During the past year we performed pathological and histopathological examinations on 7 fetuses diagnosed in the second trimester of pregnancy to be affected by cystic fibrosis and compared them with 4 control age-matched fetuses. Glycol-methacrylate-embedded 2-3-mu thick sections of the pancreas, lungs, bronchial tree, and GI tract were stained with toluidine blue, H&E, PAS, and AB-PAS, and examined microscopically. In the controls, PAS-positive granules were dispersed throughout the cytoplasm of most pancreatic acinar and tracheal submucosal glandular cells. In the affected fetuses 2 distinct groups were identified. In one group of 4 fetuses, the pancreatic and tracheal submucosal glands were dilated and contained a weak PAS-positive material. The glandular epithelial cells had very little PAS-positive granules. In this group, the tracheal epithelium was either atrophic or metaplastic and devoid of microvilli. In the second group of 3 fetuses there was less dilation of the glands, and both pancreatic acinar cells and tracheal submucosal glandular epithelial cells contained few PAS-positive granules, which were confined mainly to a perinuclear location. The tracheal epithelial cells contained few microvilli which, when present, appeared thicker and shorter as compared to controls. We feel that histochemical evaluation of pancreatic and bronchial tissue may be of help in the pathological confirmation of cystic fibrosis in human fetuses where the results of the biochemical studies are suggestive of the disease.     

Computerized cognitive testing in patients with type I Gaucher disease: effects of enzyme replacement and substrate reduction.

PURPOSE: Because of concern for drug-induced cognitive dysfunction during clinical trials using substrate reduction therapy (miglustat) in type 1 Gaucher disease and because it has been suggested that some patients with type 1 Gaucher disease may develop neurocognitive impairment as part of the natural history, two different batteries of neuropsychological tests were devised to examine these issues. Using these tests, cognitive function was assessed in patients treated with miglustat, in patients receiving enzyme replacement (standard care for symptomatic patients), and in untreated (milder) patients. METHODS: For this study, 55/60 patients exposed to miglustat in Israel participated in psychologist-administered testing; 36/55 participated in computerized testing. Of these, 31 enzyme-treated patients and 22 untreated patients participated in the psychologist-administered testing, and 15 enzyme-treated patients and 18 untreated patients participated in computerized testing. The psychologist-administered battery consisted of 18 standard neuropsychological subtests specific to executive and visuospatial functioning. The computerized battery (Mindstreams, NeuroTrax Corp., New York, NY) consisted of 10 subtests tapping multiple cognitive domains. Between-group analyses for each modality compared cognitive performance. RESULTS: In the psychologist-administered testing, patients exposed to miglustat performed significantly less well than the other groups in 5/18 subtests. On the computerized tests, all patients performed comparably to normal controls. Scores in patients exposed to miglustat were higher than in untreated patients, particularly in visuospatial function, whereas enzyme-treated patients performed less well. However, with the exception of visuospatial function, these results were not statistically significant. CONCLUSIONS: It is unclear why different testing methods yielded discordant results. Any dysfunction suggested by the current study is apparently subtle and of doubtful clinical relevance given that cognitive status did not interfere with patients' daily intellectual function. The computerized battery has methodological advantages (e.g., language options, objectivity, brevity, and ease of use) that make it well-suited for longitudinal studies, for long-term surveillance of substrate reduction therapy as well as for comparisons with other lysosomal storage disorders and other chronic diseases. These preliminary findings should allay fears of cognitive dysfunction due to short-term miglustat therapy.     

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.     

Utilization of the 2017 diagnostic criteria for hEDS by the Toronto GoodHope Ehlers–Danlos syndrome clinic: A retrospective review

The new 2017 diagnostic criteria for hypermobile Ehlers–Danlos Syndrome (hEDS) provide a framework for diagnosing hEDS but are more stringent than the previous Villefranche criteria. Our clinical experience at the GoodHope EDS clinic was that the 2017 criteria left many highly symptomatic patients without a diagnosis of hEDS. We conducted a retrospective cohort study to confirm our clinic experience and assess the accuracy of the 2017 diagnostic criteria for hEDS in patients who had a previous hEDS diagnosis based on the Villefranche criteria. Our study found that 15% (n = 20 of 131) of patients with a prior diagnosis of hEDS met the 2017 diagnostic criteria, and many of the traits used to distinguish hEDS were not significantly more frequent in patients who met 2017 criteria versus those who did not. In both groups objective systemic manifestations were found less frequently than subjective systemic manifestations. Beighton score (BS) as assessed by primary care practitioner was found to be higher than assessment by EDS practitioner in 81% (n = 74 of 91) of cases. Generalized joint hypermobility was confirmed in only 46% (n = 51 of 111) of patients who had a previous diagnosis of hEDS. Higher BS did not correlate with increased number of systemic manifestations in our cohort. Common comorbidities of hEDS were found with similar frequency in those who met 2017 criteria and those who did not. Based on our cohort, the 2017 hEDS diagnostic criteria require refinement to improve its diagnostic accuracy.     

Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide

Three random basic copolymers of amino acids were tested for their effect on experimental allergic encephalomyelitis (EAE). One of these copolymers denoted as Cop 1, composed of alanine, glutamic acid, lysine and tyrosine, with a molecular weight of 23 000, showed a marked suppressive effect on the disease. The intravenous administration of Cop 1 in physiological saline, as late as 5 days following the challenge with the disease-inducing dose of the basic encephalitogenic protein, reduced the clinical incidence of EAE from 64% in the control group to 22%; the histological lesions were also decreased both in prevalence and in severity. The suppressive effect on the disease attained by the synthetic copolymer is of the same order of magnitude as that previously reported for the basic encephalitogen. The effect of the copolymers appears to be specific, since neither an acidic amino acid copolymer, nor unrelated basic proteins, had any protective action. On the other hand, a second batch of Cop 1 showed activity identical to that of the first batch. The potential applicability of this non-encephalitogenic and non-immunosuppressive material is discussed.     

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.