Miracle-dz/UniFAR-FTUs huggingface dataset:
Immunogenicity of sequential pneumococcal vaccination in subjects splenectomised for hereditary spherocytosis

Splenectomy predisposes for invasive pneumococcal disease. We investigated the immune response of splenectomised hereditary spherocytosis (HS) patients upon sequential pneumococcal vaccination. Thirty‐nine HS‐patients (2‐ to 18‐year‐old) had undergone near‐total or total splenectomy. All received one dose of 7‐valent pneumococcal conjugate vaccine (PCV‐7) and 23‐valent‐pneumococcal‐polysaccharide vaccine (PPV‐23) 2 months apart. Pneumococcal antibodies against serotypes 5/6B/7/14/18C/19F/23F and immunoglobulin serum concentrations were determined before PCV‐7 and 4 weeks after PPV‐23. Significant rises in antibody geometric mean concentrations were observed after PCV‐7 except for serotypes 5 and 7, which increased after PPV‐23. We found no impact of the mode of splenectomy.
Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-γ production in iNKT cells

Significance A unique characteristic of invariant natural killer T (iNKT) cells is their ability to immediately produce large amounts of interferon-gamma (IFN-γ) upon activation, which enables these cells to play critical roles in initiating immune responses in various pathological conditions. In this study, we demonstrate a previously unidentified mechanism mediated by basic helix–loop–helix transcription factor family, member e40 (Bhlhe40) for accelerating IFN-γ production in iNKT cells. Bhlhe40 is required for normal physiological functions in iNKT cells, where it positively regulates IFN-γ production. Bhlhe40 also contributes to acetylating histone H3-lysine 9 of the Ifng locus in iNKT cells. These findings may help in understanding the molecular mechanisms related to the biology of iNKT cells. Invariant natural killer T (iNKT) cells are a subset of innate-like T cells that act as important mediators of immune responses. In particular, iNKT cells have the ability to immediately produce large amounts of IFN-γ upon activation and thus initiate immune responses in various pathological conditions. However, molecular mechanisms that control IFN-γ production in iNKT cells are not fully understood. Here, we report that basic helix–loop–helix transcription factor family, member e40 (Bhlhe40), is an important regulator for IFN-γ production in iNKT cells. Bhlhe40 is highly expressed in stage 3 thymic iNKT cells and iNKT1 subsets, and the level of Bhlhe40 mRNA expression is correlated with Ifng mRNA expression in the resting state. Although Bhlhe40-deficient mice show normal iNKT cell development, Bhlhe40-deficient iNKT cells show significant impairment of IFN-γ production and antitumor effects. Bhlhe40 alone shows no significant effects on Ifng promoter activities but contributes to enhance T-box transcription factor Tbx21 (T-bet)-mediated Ifng promoter activation. Chromatin immunoprecipitation analysis revealed that Bhlhe40 accumulates in the T-box region of the Ifng locus and contributes to histone H3-lysine 9 acetylation of the Ifng locus, which is impaired without T-bet conditions. These results indicate that Bhlhe40 works as a cofactor of T-bet for enhancing IFN-γ production in iNKT cells.
Exploring diagnostic processes: social science perspectives

This review explores social science analyses of diagnosis of childhood neurological disabilities. The paper moves through three sections, which capture the historical and conceptual trends within the literature. The first focuses on work identifying the need to communicate effectively with parents when giving a diagnosis, the second explores the role parents can play as “partners” or contributors to diagnosis, and the final section goes further in exploring the social complexity of diagnoses in order to examine the embedded nature of social practices, power relations and hierarchies, and institutions in the diagnosis encounter.
Effects of low-dose, long-term formaldehyde exposure on the structure and functions of the ovary in rats

Formaldehyde (FA) is a ubiquitous environmental pollutant. However, the effects of FA exposure on reproduction are still a matter of scientific controversy. In this study, we assessed the ovarian toxicity of long-term, low-dose FA exposure in rats and explored the potential oxidative stress mechanisms. A total of 30 Sprague-Dawley female rats were randomly allotted to three groups, in which rats were exposed to FA at a dose of 0 mg/m3 (control), 0.5 mg/m3 and 2.46 mg/m3, respectively, by inhalation consecutively for 60 days. The results showed that the ovarian toxicity of FA is dose dependent. Ovarian structure and function in the group of rats exposed to 0.5 mg/m3 FA showed no obvious difference when compared with those in the control group. However, the activity of superoxide dismutase was significantly decreased, whereas the level of malondialdehyde was significantly increased in ovaries of rats exposed to 2.46 mg/m3 FA. Moreover, histopathological results demonstrated that the number and size of mature follicles significantly decreased, vascular congestion and interstitial edema in the ovaries of rats exposed to 2.46 mg/m3 FA. In conclusion, this study may suggest that the FA level of 0.5 mg/m3 can be considered as a safe level for FA exposure, but long-term FA exposure at a dose of 2.46 mg/m3 has a harmful effect on ovary by inducing oxidative stress.
Parasite plastids: approaching the endgame

Considerable work still needs to be done to understand more fully the basic processes going on inside the non‐photosynthetic plastid organelle of Plasmodium spp. , the causative agent of malaria. Following an explosion of genomic and transcriptional information in recent years, research workers are still analysing these data looking for new material relevant to the plastid. Several metabolic and housekeeping functions based on bacterial biochemistry have been elucidated and this has given impetus to finding lead inhibitors based on established anti‐microbials. Structural investigations of plastid‐associated enzymes identified as potential targets have begun. This review gives a perspective on the research to date and hopes to emphasize that a practical outcome for the clinic should be an important focus of future efforts. Malaria parasites have become resistant to front‐line anti‐malarials that are widely used and were formerly dependable. This has become a worrying problem in many regions where malaria is endemic. The time lag between hunting for new inhibitors and their application as Pharmaceuticals is so long and costly that a steady stream of new ventures has to be undertaken to give a reasonable chance of finding affordable and appropriate antimalarials for the future. Attempts to find inhibitors of the plastid organelle of the malaria parasite should be intensified in such programmes.
Decreased zinc and downregulation of ZIP3 zinc uptake transporter in the development of pancreatic adenocarcinoma

Pancreatic adenocarcinoma is an untreatable deadly cancer. The factors involved in its early development remain unknown; which contributes to the absence of biomarkers for early detection of malignancy or at-risk subjects, and the absence of efficacious therapeutic agents. Because zinc changes are implicated in some cancers, we determined if it might be involved in the development of pancreatic adenocarcinoma. With in situ Dithizone and Zinquin staining of normal pancreas and adenocarcinoma tissue sections, we show for the first time, a consistent major loss of zinc in ductal and acinar epithelium in adenocarcinoma compared to the normal epithelium. This decrease in zinc is evident in well-differentiated through poorly-differentiated stages of malignancy. Immunohistochemistry identified ZIP3 as the basilar membrane zinc uptake transporter in normal ductal/acinar epithelium; and that the transporter is absent in adenocarcinoma. In situ Rt-PCR revealed that ZIP3 gene expression is silenced in adenocarcinoma. The ZIP3 down regulation accompanied the loss of zinc in early and progressing malignancy. RREB1 transcription factor was down regulated along with ZIP3; and might be involved in the silencing of ZIP3 expression. Zinc treatment was cytotoxic to malignant Panc1 cells. The combination of concurrent zinc, ZIP3, and RREB-1 changes represent early events in the development of adenocarcinoma; and suggest that zinc might be a tumor suppressor of pancreatic cancer. This report provides the clinical foundation for further mechanistic studies that will provide important insight into pancreatic carcinogenesis, and can lead to the development of effective early biomarkers and effective therapeutic agents for pancreatic cancer.
Combination of Eribulin and Aurora A Inhibitor MLN8237 Prevents Metastatic Colonization and Induces Cytotoxic Autophagy in Breast Cancer

Recent findings suggest that the inhibition of Aurora A (AURKA) kinase may offer a novel treatment strategy against metastatic cancers. In the current study, we determined the effects of AURKA inhibition by the small molecule inhibitor MLN8237 both as a monotherapy and in combination with the microtubule-targeting drug eribulin on different stages of metastasis in triple-negative breast cancer (TNBC) and defined the potential mechanism of its action. MLN8237 as a single agent and in combination with eribulin affected multiple steps in the metastatic process, including migration, attachment, and proliferation in distant organs, resulting in suppression of metastatic colonization and recurrence of cancer. Eribulin application induces accumulation of active AURKA in TNBC cells, providing foundation for the combination therapy. Mechanistically, AURKA inhibition induces cytotoxic autophagy via activation of the LC3B/p62 axis and inhibition of pAKT, leading to eradication of metastases, but has no effect on growth of mammary tumor. Combination of MLN8237 with eribulin leads to a synergistic increase in apoptosis in mammary tumors, as well as cytotoxic autophagy in metastases. These preclinical data provide a new understanding of the mechanisms by which MLN8237 mediates its antimetastatic effects and advocates for its combination with eribulin in future clinical trials for metastatic breast cancer and early-stage solid tumors. Mol Cancer Ther; 15(8); 1809–22. ©2016 AACR.
Campylobacter Epidemiology - Insights from Subtyping by Pulsed-Field Gel Electrophoresis

Hook, H. 2005. Campylobacter epidemiology – insights from subtyping by pulsed-field gel electrophoresis. Doctoral thesis. ISSN 1652-6880, ISBN 91-576-6988-0 Campylobacter jejuni and Campylobacter coli are frequent worldwide causes of food-borne gastroenteritis. Poultry is regarded as the most important infection source. In temperate countries, a marked seasonal variation of human campylobacteriosis is seen, with most cases occurring during the warmer season. In this PhD project, pulsed-field gel electrophoresis, PFGE, was used to explore the genetic and epidemiological relationships among both campylobacters colonising broilers and campylobacters causing sporadic infection in humans. In a commercial broiler flock, a subsequent addition of genotypes occurred during rearing, with two types found at two weeks of age and six types on the day before slaughter. Two new types were found in the slaughter samples. In two-thirds of the individual birds sampled the day before slaughter, more than one type were found. In two separate studies, Campylobacter isolates from humans infected in Sweden were characterised by PFGE. Although a large variation in distinct restriction patterns was found, most isolates could be sorted into clusters based on pattern similarities. Isolates in some clusters and subclusters were significantly more seasonally concentrated than other isolates. A sequenced strain of C. jejuni, NCTC 11168, was used as a reference strain and molecular size marker for PFGE. Using a Campylobacter strain for this purpose may be advantageous compared with using commercially available molecular markers, as the more sample-like DNA migration patterns facilitate and refine interpretation and analysis. In conclusion, PFGE was found to be a useful tool for investigating Campylobacter epidemiology in both broilers and humans. The results show that multiple genotypes of C. jejuni may be present in a commercial broiler flock during rearing and even in gastrointestinal tracts of individual birds. Both recurring environmental exposure and genetic changes within the population may explain the genotype diversity. Although a large number of genotypes may be found among Campylobacter strains infecting humans, a large proportion of these may be genetically related. It seems that certain Campylobacter genotypes infect humans in the regions studied during a short period of the year, and that these genotypes account for a substantial proportion of the cases during the season (summer and early autumn) with highest campylobacteriosis incidence.
The TO strains of Theiler's viruses cause “slow virus—like” infections in mice

Intracerebral inoculation of mice with tissue culture–adapted TO strains of Theiler's mouse encephalomyelitis viruses results in a clinical disease consisting of spastic paralysis due to demyelination after a lengthy incubation period. Thus, in effect, these ordinary picornaviruses are capable of causing a slow infection in their natural host, the mouse. In addition, through the use of tissue culture–adapted virus stocks, virus content in mouse tissues now can be accurately quantified by standard plaque assay.
Differential Utilization of CD134 as a Functional Receptor by Diverse Strains of Feline Immunodeficiency Virus

ABSTRACT The feline homologue of CD134 (fCD134) is the primary binding receptor for feline immunodeficiency virus (FIV), targeting the virus preferentially to activated CD4+ helper T cells. However, with disease progression, the cell tropism of FIV broadens such that B cells and monocytes/macrophages become significant reservoirs of proviral DNA, suggesting that receptor utilization may alter with disease progression. We examined the receptor utilization of diverse strains of FIV and found that all strains tested utilized CD134 as the primary receptor. Using chimeric feline × human CD134 receptors, the primary determinant of receptor function was mapped to the first cysteine-rich domain (CRD1) of fCD134. For the PPR and B2542 strains, the replacement of CDR1 of fCD134 (amino acids 1 to 64) with human CD134 (hCD134) alone was sufficient to confer nearly optimal receptor function. However, evidence of differential utilization of CD134 was revealed, since strains GL8, CPGammer (CPG41), TM2, 0827, and NCSU1 required determinants in the region spanning amino acids 65 to 85, indicating that these strains may require a more stringent interaction for infection to proceed.
Use of the automated fragmented red cell count for monitoring patients with thrombotic thrombocytopenic purpura

Sir, Herein we report a single academic center’s experience of schistocyte monitoring in ten patients with thrombotic thrombocytopenic purpura (TTP). TTP is a hematological emergency. In untreated cases, the mortality rate in patients with TTP approaches 90%, and thus, accurate and immediate identification and quantitation of schistocytes, in conjunction with a thrombocytopenia and elevated lactate dehydrogenase (LDH), is required to initiate plasma exchange [1]. The diagnostic criteria for identification and quantitation of schistocytes have been standardized by the International Council for Standardization in Hematology (ICSH) [2]. However, laboratory surveys in France indicate that the morphologic identification of schistocytes remains subjective [3]. Further, the precision of the test is limited by counting up to 1000 red blood cells (RBC) [4]. More recently, the automated fragmented red cell (FRC) parameter is available on new-generation automated hematology analyzers. Measurement of the FRC is performed by two-dimensional optical analysis on the ADVIA (Siemens Diagnostics, NY, USA) analyzer. This corresponds to the refractive index and volume on the platelet scatter plot which allows for distinction between platelets and small RBC. On the Sysmex (Roche Diagnostics, Kobe, Japan) analyzer, red cell fragments are counted in the reticulocyte channel by analysis of forward light scatter and fluorescent intensity. The FRC corresponds to events with a volume smaller than a RBC and with RNA content lower than platelets. The FRC count offers several advantages for routine use including improved precision, immediate availability, and relatively good agreement with microscopy in patients with suspected TTP [5–7]. The sensitivity and specificity varies according to the selected cutoff. However, the reported sensitivity is high (100% at a cutoff of 0.25% on the ADVIA analyzer) [5]. The FRC count therefore represents a promising tool for the follow-up of true-positive samples [7]. In this study, the accuracy of the automated FRC was compared with the microscopic schistocyte count for the diagnosis and monitoring of patients with TTP.
GE 132 + Natural : Novel promising dietetic supplement with antiproliferative influence on prostate , colon , and breast cancer cells

Purpose: Natural products have been investigated for promising new leads in pharmaceutical development. The purpose of this study was to analyze the biological effect of GE132+Natural, a novel supplement consisting of 5 compounds: Resveratrol, Ganoderma lucidum, Sulforaphane, Lycopene and Royal jelly. Methods: The antiproliferative activity of GE132+Natural was tested on 3 different human cancer cell lines: MCF7 (breast cancer cells), PC3 (prostate cancer cells), and SW480 (colon cancer cells), as well as on EA.hy 926 (normal human endothelial cell line). In addition, the cytotoxicity of GE132+Natural on the proliferation of primary human mesenchymal stem cells isolated from dental pulp (DP-MSC), along with its in vitro impact on different peripheral blood parameters, was determined. Results: The results revealed high antiproliferative activity of GE132+Natural on all tested cancer cell lines (PC3, MCF7 and SW480), as well as on the EA.hy 926 endothelial cell line in a dose-dependent manner. However, applied in a wide range of concentrations GE132+Natural did not affect both the proliferation of primary mesenchymal stem cells and the peripheral blood cells counts. Conclusion: The data obtained demonstrated that GE132+Natural is effective in inhibiting cancer cell proliferation, indicating its potential beneficial health effects. In addition, the results pointed that adult mesenchymal stem cells might be valuable as a test system for evaluating the toxicity and efficacy of new medicines or chemicals.
Rhinovirus-mediated endosomal release of transfection complexes

Endocytosis is an efficient method for transfer of genes into mammalian cells. Incorporation of adenovirus particles into gene transfer complexes greatly enhances gene delivery, probably by the release of endocytosed DNA into the cytoplasm. We report here that two different serotypes of human rhinovirus (HRV), HRV2 and HRV14, are also able to enhance receptor-mediated gene transfer. The effect of several compounds known to inhibit viral infection on HRV2- and HRV14-enhanced transfection was examined. WIN I(s) and WIN IV, two compounds which inhibit viral uncoating, had different effects on HRV2- and HRV14-enhanced gene transfer to NIH 3T3 cells. While HRV14-enhanced gene transfer was severely reduced in the presence of these compounds, virtually no effects were observed when HRV2 was used. The use of antiviral compounds thus allowed transfection of human cells, which are normally lysed rapidly upon infection with HRV. Viral activity could be mimicked by using a peptide derived from the N terminus of VP1 of HRV2. This peptide possesses pH-dependent membrane-disrupting activity and enhances gene transfer to NIH 3T3 and HeLa cells.
Novel cerebral physiologic monitoring to guide low-flow cerebral perfusion during neonatal aortic arch reconstruction.

OBJECTIVE This study was undertaken to describe the combined measurement of cerebral blood flow velocity and cerebral oxygen saturation as a guide to bypass flow rate for regional low-flow perfusion during neonatal aortic arch reconstruction. METHODS Data were prospectively collected from 34 patients undergoing neonatal aortic arch reconstruction with regional low-flow perfusion. Cerebral oxygen saturation and blood flow velocity were measured by near-infrared spectroscopy and transcranial Doppler ultrasonography, respectively, throughout cardiopulmonary bypass. After cooling to 17 degrees C to 22 degrees C, baseline values of cerebral oxygen saturation and blood flow velocity were recorded during full-flow bypass. Regional low-flow perfusion was instituted for aortic arch reconstruction, and bypass flow rate was adjusted to maintain cerebral oxygen saturations and blood flow velocities within 10% of baseline recorded during cold full-flow bypass. Cerebral oxygen saturations and blood flow velocities were recorded again after repair during full-flow hypothermic bypass. Bypass flow during regional low-flow perfusion was recorded, as were arterial pressure and blood gas data. One-way repeated measures analysis of variance was used to determine differences in values during regional low-flow perfusion relative to baseline and after perfusion. RESULTS A mean bypass flow of 63 mL/(kg x min) was required to maintain cerebral oxygen saturations and blood flow velocities within 10% of baseline. Mean arterial pressure had a poor correlation with the required bypass flow rate (r(2) = 0.006 by linear regression analysis). Fourteen of 34 patients had a cerebral oxygen saturation of 95% during regional low-flow perfusion, placing them at risk for cerebral hyperperfusion if the cerebral oxygen saturation had been used alone to guide bypass flow. Pressure was detected in the umbilical or femoral artery catheter (mean 12 mm Hg) in all patients during regional low-flow perfusion. CONCLUSIONS Cerebral blood flow velocity, as determined by transcranial Doppler ultrasonography, adds valuable information to cerebral oxygen saturation data in guiding bypass flow during regional low-flow perfusion. Its most important use may be prevention of cerebral hyperperfusion during periods with high near-infrared spectroscopic saturation values.
Term pregnancies and the clinical characteristics of multiple sclerosis: a population based study

Objective Pregnancy has a well documented effect on relapse risk in multiple sclerosis (MS). Prospective studies have reported a significant decline by two-thirds in the rate of relapses during the third trimester of pregnancy and a significant increase by two-thirds during the first 3 months postpartum. However, it is unclear as to whether there are any long term effects on disability. Methods Data were collated from clinical records and family histories systematically collected from the University of British Columbia MS Clinic. Results Clinical and term pregnancy data were available from 2105 female MS patients. MS patients having children after MS onset took the longest time to reach an Expanded Disability Status Scale (EDSS) score of 6 (mean 22.9 years) and patients having children before MS onset were the quickest (mean 13.2 years). However, these effects were not related to term pregnancy and were fully accounted for by age of MS onset. Conclusions Pregnancy had no effect on the time to reach an EDSS score 6. As MS predominantly affects women of childbearing age, women with MS can be reassured that term pregnancies do not appear to have any long term effects on disability.