1,742 research outputs found
The importance of serological assays in diagnosing acute pulmonary histoplasmosis
Histoplasmosis is a systemic mycosis caused by inhalation of Histoplasma capsulatum microconidia. The disease does not normally affect immunocompetent individuals after a single, transient inhalation exposure. However, longer exposure may cause chronic or disseminated acute pulmonary infection. Herein, we report the case of a 24-year-old immunocompetent patient, who presented fever, cough and dyspnea for one month. The chest radiography revealed interstitial infiltrate and diffuse micronodules. The patient reported having had close and prolonged contact with bats. Diagnosis was confirmed by positive double immunodifusion and immunoblotting assays. She was treated with ketoconazole (400 mg) and there was complete resolution of the disease
Bowel Histology of CVID Patients Reveals Distinct Patterns of Mucosal Inflammation
Diarrhea is the commonest gastrointestinal symptom in patients with common variable immunodeficiency (CVID). Different pathologies in patients’ bowel biopsies have been described and links with infections have been demonstrated. The aim of this study was to analyze the bowel histology of CVID patients in the Royal-Free-Hospital (RFH) London CVID cohort. Ninety-five bowel histology samples from 44 adult CVID patients were reviewed and grouped by histological patterns. Reasons for endoscopy and possible causative infections were recorded. Lymphocyte phenotyping results were compared between patients with different histological features. There was no distinctive feature that occurred in most diarrhea patients. Out of 44 patients (95 biopsies), 38 lacked plasma cells. In 14 of 21 patients with nodular lymphoid hyperplasia (NLH), this was the only visible pathology. In two patients, an infection with Giardia lamblia was associated with NLH. An IBD-like picture was seen in two patients. A coeliac-like picture was found in six patients, four of these had norovirus. NLH as well as inflammation often occurred as single features. There was no difference in blood lymphocyte phenotyping results comparing groups of histological features. We suggest that bowel histology in CVID patients with abdominal symptoms falls into three major histological patterns: (i) a coeliac-like histology, (ii) IBD-like changes, and (iii) NLH. Most patients, but remarkably not all, lacked plasma cells. CVID patients with diarrhea may have an altered bowel histology due to poorly understood and likely diverse immune-mediated mechanisms, occasionally driven by infections
Altered Microbiota, Impaired Quality of Life, Malabsorption, Infection, and Inflammation in CVID Patients With Diarrhoea
© Copyright © 2020 van Schewick, Nöltner, Abel, Burns, Workman, Symes, Guzman, Proietti, Bulashevska, Moreira, Soetedjo, Lowe and Grimbacher. Background: Diarrhoea is the commonest gastrointestinal symptom in patients with common variable immunodeficiency (CVID). Objective: The aim of this study was to describe the prevalence and clinical presentation of chronic and recurrent diarrhoea in the Royal-Free-Hospital (RFH) London CVID cohort, including symptoms, infections, level of inflammation, and microbial diversity. Methods: A cross-sectional study of adult CVID patients (139 out of 172 diagnosed with CVID completed the screening questionnaire). Those with diarrhoea ≥6 days/month had stool and blood samples analysed and completed the short Inflammatory Bowel Disease Questionnaire (sIBDQ). BMI, spleen-size, lymphocytes and gut-microbial diversity were compared. Due to logistical and clinical restraints, not all patients could be analysed on all measures. Results: 46/139 (33.1%) patients had current significant diarrhoea. In patients with past or present diarrhoea, BMI was lower (median 23.7 vs. 26, p = 0.005), malabsorption more common (57.97 vs. 35.71%, p = 0.011). CD4+ lymphocytes were higher in patients with diarrhoea (p = 0.028; n = 138), but CD4+ naïve lymphocytes were significantly higher in non-diarrhoea patients (p = 0.009, N = 28). Nine patients had confirmed or probable current gastrointestinal infections. Calprotectin was >60 μg/g in 13/29 with significant diarrhoea including 9 without infection. SIBDQ revealed a low median score of 4.74. Microbial alpha diversity was significantly lower in CVID patients compared to healthy household controls. There was no significant difference in alpha diversity in relation to antibiotic intake during the 6 weeks prior to providing samples. Conclusion: Patients with CVID and significant diarrhoea had infections, raised calprotectin, malabsorption, a lower BMI, an impaired quality of life (comparable to active IBD), and they differed from non-diarrhoea patients in their lymphocyte phenotyping. Furthermore, microbial diversity was altered. These findings strongly imply that there may be an inflammatory nature and a systemic predisposition to diarrhoea in CVID, which necessitates further investigation
Confirmation of sexual dimorphism in Hoplias aimara (Valenciennes, 1847) (Erythrinidae: Characiformes) proposed by local expertise in Amapá, Brazil
Thermorheological and textural behaviour of gluten-free gels obtained from chestnut and rice flours
Nowadays, as celiac disease is becoming more
common the consumers’ demand for gluten-free products
with high nutritional and taste quality is increasing. This
work deals with the study of the impact of four novelty
gluten-free sources: chestnut flour (Cf), whole rice flour
(Rw), Carolino rice flour (Rc) and Agulha rice flour (Ra).
Textural, thermorheological and stability performance of
gluten-free gels using different experimental techniques
were evaluated. Mixed gels were also produced for comparison.
Texture parameters were determined from the texture
profile analysis using a texturometer. Thermorheological
oscillatory measurements were conducted in a stresscontrolled
rheometer in order to clarify the kinetics of gel
formation and to characterise the structure of the matured
gels. The stability of the gels was evaluated using transmittance
profiling of the gels under gravitational fields
(LUMiSizer®). Texture studies suggested that gels from mixtures of chestnut flour at 30 % and rice flour at 20 %
showed the right texture to develop gel-based new desserts.
Rheological results showed that the thermal profiles on
heating of Cf gels were similar to those obtained for Rw
and Ra, whereas Rc gels exhibited a particular pattern. Once
the final gelatinisation temperature was achieved, no significant
differences on the viscoelastic properties were noticed
for all the tested gels. Stability tests showed that gels with
Rc should present an industrial advantage over the other
assayed formulations, since the stability of these gels is of
the order of four times larger
Synthesis, G-Quadruplex Stabilisation, Docking Studies, and Effect on Cancer Cells of Indolo[3,2-b]quinolines with One, Two, or Three Basic Side Chains.
G-quadruplex (G4) DNA structures in telomeres and oncogenic promoter regions are potential targets for cancer therapy, and G4 ligands have been shown to modulate telomerase activity and oncogene transcription. Herein we report the synthesis and G4 thermal stabilisation effects, determined by FRET melting assays, of 20 indolo[3,2-b]quinolines mono-, di-, and trisubstituted with basic side chains. Molecular modelling studies were also performed in an attempt to rationalise the ligands' binding poses with G4. Overall, the results suggest that ligand binding and G4 DNA thermal stabilisation increase with an N5-methyl or a 7-carboxylate group and propylamine side chains, whereas selectivity between G4 and duplex DNA appears to be modulated by the number and relative position of basic side chains. From all the indoloquinoline derivatives studied, the novel trisubstituted compounds 3 d and 4 d, bearing a 7-(aminoalkyl)carboxylate side chain, stand out as the most promising compounds; they show high G4 thermal stabilisation (ΔTm values between 17 and 8 °C) with an inter-G4 ΔTm trend of Hsp90A>KRas21R≈F21T>c-Kit2, 10-fold selectivity for G4 over duplex DNA, and 100-fold selectivity for the HCT116 cancer cell line (IC50 and IC90 : <10 μM) over primary rat hepatocytes. Compounds 3 d and 4 d also decreased protein expression levels of Hsp90 and KRas in HCT116 cancer cells
Treatment of Highly Drug-Resistant Pulmonary Tuberculosis
BACKGROUND
Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes.
METHODS
In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs — bedaquiline, pretomanid, and linezolid — that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated.
RESULTS
A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid.
CONCLUSIONS
The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799. opens in new tab.
Deriving a mutation index of carcinogenicity using protein structure and protein interfaces
With the advent of Next Generation Sequencing the identification of mutations in the genomes of healthy and diseased tissues has become commonplace. While much progress has been made to elucidate the aetiology of disease processes in cancer, the contributions to disease that many individual mutations make remain to be characterised and their downstream consequences on cancer phenotypes remain to be understood. Missense mutations commonly occur in cancers and their consequences remain challenging to predict. However, this knowledge is becoming more vital, for both assessing disease progression and for stratifying drug treatment regimes. Coupled with structural data, comprehensive genomic databases of mutations such as the 1000 Genomes project and COSMIC give an opportunity to investigate general principles of how cancer mutations disrupt proteins and their interactions at the molecular and network level. We describe a comprehensive comparison of cancer and neutral missense mutations; by combining features derived from structural and interface properties we have developed a carcinogenicity predictor, InCa (Index of Carcinogenicity). Upon comparison with other methods, we observe that InCa can predict mutations that might not be detected by other methods. We also discuss general limitations shared by all predictors that attempt to predict driver mutations and discuss how this could impact high-throughput predictions. A web interface to a server implementation is publicly available at http://inca.icr.ac.uk/
Cytotaxonomy of Parodon nasus and Parodon tortuosus (Pisces, Characiformes): A case of synonymy confirmed by cytogenetic analyses
Phenoloxidase activity acts as a mosquito innate immune response against infection with semliki forest virus
Several components of the mosquito immune system including the RNA interference (RNAi), JAK/STAT, Toll and IMD pathways have previously been implicated in controlling arbovirus infections. In contrast, the role of the phenoloxidase (PO) cascade in mosquito antiviral immunity is unknown. Here we show that conditioned medium from the Aedes albopictus-derived U4.4 cell line contains a functional PO cascade, which is activated by the bacterium Escherichia coli and the arbovirus Semliki Forest virus (SFV) (Togaviridae; Alphavirus). Production of recombinant SFV expressing the PO cascade inhibitor Egf1.0 blocked PO activity in U4.4 cell- conditioned medium, which resulted in enhanced spread of SFV. Infection of adult female Aedes aegypti by feeding mosquitoes a bloodmeal containing Egf1.0-expressing SFV increased virus replication and mosquito mortality. Collectively, these results suggest the PO cascade of mosquitoes plays an important role in immune defence against arboviruses
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