The epidemiology of hepatitis A infection in Palestine: a universal vaccination programme is not yet needed.

In Palestine, there has been an increase in the reported incidence of acute hepatitis A virus (HAV) infection since 1995. Since overt clinical disease occurs only among adults, questions were raised whether or not a shift in the epidemiology of HAV has occurred. This is generally characterized by a decrease in the overall incidence rate and a shifting in the mean age of infection towards adolescence and early adulthood. The need for a vaccination programme is being discussed. To resolve this issue, we examined the prevalence of anti-HAV in a representative sample of 396 school children in the Gaza Strip. The prevalence of anti-HAV was 93.7% (95% CI: 91.3, 96.1%). Stratifying the prevalence by age showed that 87.8% (95% CI: 78.6, 97%) were HAV antibody positive by the age of 6. By the age of 14, almost 98% (95% CI: 92.7, 100%) were HAV antibody positive. This means that the majority of HAV infection is still taking place in early childhood, when it is usually asymptomatic and of little clinical significance. The results refuted the shifting epidemiology theory and we recommend that a vaccination programme against HAV infection is not yet needed. Alternative explanations for the increase in reported cases are discussed.     

Substances from the medicinal mushroom Daedalea gibbosa inhibit kinase activity of native and T315I mutated Bcr-Abl

Human chronic myelogenous leukemia (CML) is a malignancy of pluripotent hematopoietic cells characterized by a distinctive cytogenetic abnormality resulting in the creation of a p210 Bcr-Abl fusion protein with abnormal tyrosine kinase activity. Recently, a selective Abl kinase inhibitor, Imatinib mesylate, was introduced as a first line therapy for CML. Despite the initial response, CML patients develop a resistantance to Imatinib, which is mediated mainly by point mutations within the Abl protein. Herein, we describe the identification of mycelium organic extracts of Daedalea gibbosa with selective anti-proliferating and apoptosis-inducing activities against K562 cells and other laboratory model of CML. Using activity-guided purification, we isolated an active fraction, F6, which inhibits in vitro kinase activity of recombinant Abl. The active fraction significantly inhibits the autophosphorylation of native and mutated Bcr-Abl, which are resistant to Imatinib treatment including the T315I mutation. Using a colony-forming assay, we demonstrated that the active fraction is effective in inhibiting the colony formation of the Ba/F3 cell line harboring either native Bcr-Abl or its mutations, including the T315I mutation. Our data illustrated the potential of natural products in cancer therapeutics.     

Progression of retinopathy during pregnancy in type 1 diabetes mellitus

PURPOSE: The incidence and risk factors for progression of retinopathy during pregnancy in women with type 1 diabetes mellitus were retrospectively evaluated. METHODS: Fifty-four insulin-dependent diabetic patients at a teaching hospital in Saudi Arabia were followed throughout the pregnancy/puerperium with serial ophthalmic examination. Dilated fundus examination was performed in each trimester and puerperium. RESULTS: Progression of diabetic retinopathy in the study occurred in 13/54 (24%) patients--2/22 (9.1%) patients had no diabetic retinopathy initially, 4/20 (20%) had non-proliferative diabetic retinopathy (NPDR) and 7/12 (58.3%) had proliferative diabetic retinopathy (PDR). Of the eight patients with PDR who had no laser treatment before pregnancy, six (75%) showed progression but only one of the four patients who had PDR and laser treatment prior to pregnancy experienced progression of retinopathy. Eight patients in total received panretinal photocoagulation to arrest the progression of retinal disease during pregnancy and only one of them had laser treatment prior to pregnancy. CONCLUSION: Laser photocoagulation for severe NPDR or early PDR prior to pregnancy may protect against rapid progression of PDR. Visual impairment resulting from progression of PDR can be prevented by aggressive laser treatment during pregnancy. Duration of diabetes>15 years, poor glycaemic control and hypertension are high-risk factors in the progression of diabetic retinopathy in pregnancy.     

Application of a Machine Learning Algorithm for Structural Brain Images in Chronic Schizophrenia to Earlier Clinical Stages of Psychosis and Autism Spectrum Disorder: A Multiprotocol Imaging Dataset Study

Background and HypothesisMachine learning approaches using structural magnetic resonance imaging (MRI) can be informative for disease classification; however, their applicability to earlier clinical stages of psychosis and other disease spectra is unknown. We evaluated whether a model differentiating patients with chronic schizophrenia (ChSZ) from healthy controls (HCs) could be applied to earlier clinical stages such as first-episode psychosis (FEP), ultra-high risk for psychosis (UHR), and autism spectrum disorders (ASDs).Study DesignTotal 359 T1-weighted MRI scans, including 154 individuals with schizophrenia spectrum (UHR, n = 37; FEP, n = 24; and ChSZ, n = 93), 64 with ASD, and 141 HCs, were obtained using three acquisition protocols. Of these, data regarding ChSZ (n = 75) and HC (n = 101) from two protocols were used to build a classifier (training dataset). The remainder was used to evaluate the classifier (test, independent confirmatory, and independent group datasets). Scanner and protocol effects were diminished using ComBat.Study ResultsThe accuracy of the classifier for the test and independent confirmatory datasets were 75% and 76%, respectively. The bilateral pallidum and inferior frontal gyrus pars triangularis strongly contributed to classifying ChSZ. Schizophrenia spectrum individuals were more likely to be classified as ChSZ compared to ASD (classification rate to ChSZ: UHR, 41%; FEP, 54%; ChSZ, 70%; ASD, 19%; HC, 21%).ConclusionWe built a classifier from multiple protocol structural brain images applicable to independent samples from different clinical stages and spectra. The predictive information of the classifier could be useful for applying neuroimaging techniques to clinical differential diagnosis and predicting disease onset earlier.     

Quercetin alters the DNA damage response in human hematopoietic stem and progenitor cells via TopoII‐ and PI3K‐dependent mechanisms synergizing in leukemogenic rearrangements

Quercetin (Que) is an abundant flavonoid in the human diet and high‐concentration food supplement with reported pro‐ and anti‐carcinogenic activities. Topoisomerase II (TopoII) inhibition and subsequent DNA damage induction by Que was implicated in the mixed lineage leukemia gene (MLL) rearrangements that can induce infant and adult leukemias. This notion raised concerns regarding possible genotoxicities of Que in hematopoietic stem and progenitor cells (HSPCs). However, molecular targets mediating Que effects on DNA repair relevant to MLL translocations have not been defined. In this study we describe novel and potentially genotoxic Que activities in suppressing non‐homologous end joining and homologous recombination pathways downstream of MLL cleavage. Using pharmacological dissection of DNA‐PK, ATM and PI3K signalling we defined PI3K inhibition by Que with a concomitant decrease in the abundance of key DNA repair genes to be responsible for DNA repair inhibition. Evidence for the downstream TopoII‐independent mutagenic potential of Que was obtained by documenting further increased frequencies of MLL rearrangements in human HSPCs concomitantly treated with Etoposide and Que versus single treatments. Importantly, by engaging a tissue engineered placental barrier, we have established the extent of Que transplacental transfer and hence provided the evidence for Que reaching fetal HSPCs. Thus, Que exhibits genotoxic effects in human HSPCs via different mechanisms when applied continuously and at high concentrations. In light of the demonstrated Que transfer to the fetal compartment our findings are key to understanding the mechanisms underlying infant leukemia and provide molecular markers for the development of safety values.     

Digestive tract microflora liberates low molecular weight peptides with immunotriggering activity

Antibiotic digestive tract decontamination in BALB/c-mice resulted in a significant reduction of peritoneal macrophage function and lymphocyte proliferation. Considerable evidence has accumulated showing that certain species of the indigenous gastrointestinal (GI)-tract microflora, e.g. Bacteroides sp., Clostridium sp., Lactobacillus sp., and Propionibacterium sp., liberate low molecular weight peptides which are able to trigger basic immune responses. Eradication of the GI-tract microflora apparently results in a lack of peptide production correlating to immunosuppression in experimental BALB/c-mice. Substitution of peptides in GI-tract decontaminated mice reconstituted macrophage function as well as proliferation of lymphatic tissue.     

Tuberculous meningitis--clinical and laboratory review of 100 patients

In developing countries tuberculous meningitis is a difficult infection to differentiate from other central nervous system (CNS) infections. This paper presents the history, physical findings, laboratory data, and clinical course of 100 patients who were admitted to a special ward and had CSF cultures positive for Mycobacterium tuberculosis. Fifty-four patients were comatose when admitted and 76 had meningeal signs. Mean admission CSF values were WBC 531, glucose 23 mg/dl, and protein 166 mg/dl. Only two CSF AFB smears were positive. Sixty-one percent of the chest X-rays taken were consistent with pulmonary tuberculous and 39% were normal. Twenty-four patients died within the first week after admission, before the clinical diagnosis was made and anti-tuberculous therapy could be started. Fifty-three of 76 patients given antituberculous therapy died. Neurologic sequelae developed in 48% of the survivors. The high mortality and morbidity rates in this patient-group were due to the severity of illness on admission and the predominance of children (54%).     

Action of alpha-methyldopa on human umbilical circulation in vitro.

To determine the possible effects of alpha-methyldopa on the motility of human umbilical artery, a total of 53 arterial segments were perfused with different concentrations of the drug as follows: 38 segments with 125, 250 and 500 ng/ml of the drug, 9 segments with 500 ng/ml alpha-methyldopa in combination with 10(-7) M yohimbine, and 6 segments with 10(-7) M yohimbine alone. alpha-Methyldopa had a vasoconstrictor effect at all doses employed, with a clear dose-effect correlation (p less than 0.01). The vasoconstrictor effect of 500 ng/ml alpha-methyldopa was fully inhibited in the presence of 10(-7) M yohimbine. These results suggest that alpha 2-adrenergic receptors are present in the umbilical circulation and that alpha-methyldopa may play a role in the control of this circulation.