Influence Disease Severity Research Articles

Human herpesvirus 6 involvement in paediatric drug hypersensitivity syndrome.

Human herpesvirus (HHV)6 positivity in the context of drug hypersensitivity syndrome (DHS) may influence disease severity. Systemic corticosteroid treatment of those with DHS testing positive for HHV6 has been speculated to prolong the duration of disease. To evaluate whether paediatric HHV6-positive patients with DHS develop a more severe illness than those without presumed reactivation, and to evaluate the response to systemic corticosteroid treatment. A retrospective case series of 29 paediatric inpatients treated for DHS and tested for HHV6 was undertaken. HHV6-positive and -negative patients were identified and stratified into groups treated or not treated with systemic corticosteroids to examine their disease severity on the basis of hospital length of stay (LOS), total number of febrile days (Tfeb) and days until cessation of progression (CTP). Human herpesvirus6-positive patients had similar demographic characteristics to those of HHV6-negative patients, but had significantly longer hospital LOS (11·5 days vs. 5 days, P = 0·039), Tfeb (12·5 days vs. 3 days, P = 0·032) and CTP (4 days vs. 2 days, P = 0·014). All HHV6-positive patients and most (80%) of the HHV6-negative patients received systemic corticosteroids. Among the HHV6-negative patients, those who received corticosteroids showed significantly shorter CTP than those who did not (3 days vs. 2 days, P = 0·043). Additionally, there was a trend towards shorter hospital LOS and Tfeb among HHV6-negative patients who received corticosteroids vs. those who did not, although these differences were not statistically significant. The most common inciting drugs included trimethoprim-sulfamethoxazole (34%), phenytoin (10%) and amoxicillin (10%). Human herpesvirus6 positivity with DHS is associated with a more severe disease course. Treatment with systemic corticosteroids was associated with a trend towards reduced hospital LOS and Tfeb, and a significantly reduced number of days until cessation of progression.

Celastrol, a Chinese herbal compound, controls autoimmune inflammation by altering the balance of pathogenic and regulatory T cells in the target organ

Inflammation is an integral component of autoimmune arthritis. The balance of pathogenic T helper 17 (Th17) and protective T regulatory (Treg) cells can influence disease severity, and its resetting offers an attractive approach to control autoimmunity. We determined the frequency of Th17 and Treg in the joints of rats with adjuvant arthritis (AA), a model of rheumatoid arthritis (RA). We also investigated the impact of Celastrol, a bioactive compound from the traditional Chinese medicine Celastrus that can suppress AA, on Th17/Treg balance in the joints. Celastrol treatment reduced Th17 cells but increased Treg in the joints, and it inhibited Th17 differentiation but promoted Treg differentiation in vitro by blocking the activation of pSTAT3. Furthermore, Celastrol limited the production of Th17-differentiating cytokines and chemokines (CCL3, CCL5). Thus, Celastrol suppressed arthritis in part by altering Th17/Treg ratio in inflamed joints, and it should be tested as a potential adjunct/alternative for RA therapy.

Low Serum 25(OH)D Levels in Parkinson ’s Disease; a Non Specific Marker of Neurodegeneration?

Objective: Several investigations have recently inferred that a low serum vitamin D concentration may contribute to cognitive impairment in the elderly. Here, we assessed whether in a cohort of Parkinson’s disease (PD) patients attributable to any disease stage a deficit in serum 25-hydroxyvitamin D (25(OH) D) levels occurred as previously proposed and, more importantly, if it is correlated with cognitive impairment or disease duration. Methods: Our PD group (n=54) was compared to an age-matched control group (n= 30), but also to patients afflicted by Alzheimer’s disease (AD) (n= 17) and motor neuron disease (amyotrophic lateral sclerosis - ALS) (n=19). Results: Serum 25(OH)D levels > 30 ng/ml was found in 37% of PD patients (versus 76% in controls); in 34 out of 54 PD patients low 25(OH)D levels occurred (28,73 ± 20,22 ng/ml vs 44,52 ± 18,48 ng/ml in control group); however, no correlation with mini mental state examination (MMSE) or disease progression emerged in PD patients. AD cohort was characterized by a significantly lower vitamin D concentration (half manifesting severe deficiency below 10 ng/ml, in contrast with 18% amongst PD). To note, also in ALS, pathological low levels of vitamin D, comparable to PD, was found. Conclusion: Our findings highlight that vitamin D insufficiency or deficiency is shared by multiple neurodegenerative diseases, albeit a-specifically. In PD, 25(OH) D levels do not correlate with cognitive performance. On one hand, these data confirm the opportunity to restore vitamin D levels in a variety of neurological disorders; on the other, they suggest that, in PD, at contrast with AD, vitamin D insufficiency should not play a relevant role in influencing disease severity or unmasking an associated dementia.

Severe vitamin D deficiency is associated with frequent exacerbations and hospitalization in COPD patients.

BackgroundAcute exacerbations of COPD (AECOPD) are common and strongly influence disease severity and relative healthcare costs. Vitamin D deficiency is frequent among COPD patients and its contributory role in disease exacerbations is widely debated. Our aim was to assess the relationship of serum vitamin D levels with COPD severity and AECOPD.MethodsSerum vitamin D (25-hydroxyvitamin D) levels were measured in 97 COPD patients and related to lung function, comorbidities, FEV1 decline, AECOPD and hospital admission during the previous year.ResultsMost patients (96%) had vitamin D deficiency, which was severe in 35 (36%). No significant relationship was found between vitamin D and FEV1 or annual FEV1 decline. No difference between patients with and without severe vitamin D deficiency was found in age, gender, BMI, smoking history, lung function, and comorbidities, apart from osteoporosis (60.9% in severe deficiency vs 22.7%, p = 0.001). In multiple logistic regression models, severe deficiency was independently associated with AECOPD [adjusted odds ratios (aOR) of 30.5 (95% CI 5.55, 168), p < 0.001] and hospitalization [aOR 3.83 (95% CI 1.29, 11.4), p = 0.02]. The odds ratio of being a frequent exacerbator if having severe vitamin D deficiency was 18.1 (95% CI 4.98, 65.8) (p < 0.001), while that of hospitalization was 4.57 (95% CI 1.83, 11.4) (p = 0.001).ConclusionsIn COPD patients severe vitamin D deficiency was related to more frequent disease exacerbations and hospitalization during the year previous to the measurement of vitamin D. This association was independent of patients’ characteristics and comorbidities.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-014-0131-0) contains supplementary material, which is available to authorized users.

Targeted next-generation sequencing in steroid-resistant nephrotic syndrome: mutations in multiple glomerular genes may influence disease severity.

Genetic diagnosis of steroid-resistant nephrotic syndrome (SRNS) using Sanger sequencing is complicated by the high genetic heterogeneity and phenotypic variability of this disease. We aimed to improve the genetic diagnosis of SRNS by simultaneously sequencing 26 glomerular genes using massive parallel sequencing and to study whether mutations in multiple genes increase disease severity. High-throughput mutation analysis was performed in 50 SRNS and/or focal segmental glomerulosclerosis (FSGS) patients, a validation cohort of 25 patients with known pathogenic mutations, and a discovery cohort of 25 uncharacterized patients with probable genetic etiology. In the validation cohort, we identified the 42 previously known pathogenic mutations across NPHS1, NPHS2, WT1, TRPC6, and INF2 genes. In the discovery cohort, disease-causing mutations in SRNS/FSGS genes were found in nine patients. We detected three patients with mutations in an SRNS/FSGS gene and COL4A3. Two of them were familial cases and presented a more severe phenotype than family members with mutation in only one gene. In conclusion, our results show that massive parallel sequencing is feasible and robust for genetic diagnosis of SRNS/FSGS. Our results indicate that patients carrying mutations in an SRNS/FSGS gene and also in COL4A3 gene have increased disease severity.

CD8+ T cells prevent antigen-induced antibody-dependent enhancement of dengue disease in mice.

Dengue virus (DENV) causes pathologies ranging from the febrile illness dengue fever to the potentially lethal severe dengue disease. A major risk factor for developing severe dengue disease is the presence of subprotective DENV-reactive Abs from a previous infection (or from an immune mother), which can induce Ab-dependent enhancement of infection (ADE). However, infection in the presence of subprotective anti-DENV Abs does not always result in severe disease, suggesting that other factors influence disease severity. In this study we investigated how CD8(+) T cell responses influence the outcome of Ab-mediated severe dengue disease. Mice were primed with aluminum hydroxide-adjuvanted UV-inactivated DENV prior to challenge with DENV. Priming failed to induce robust CD8(+) T cell responses, and it induced nonneutralizing Ab responses that increased disease severity upon infection. Transfer of exogenous DENV-activated CD8(+) T cells into primed mice prior to infection prevented Ab-dependent enhancement and dramatically reduced viral load. Our results suggest that in the presence of subprotective anti-DENV Abs, efficient CD8(+) T cell responses reduce the risk of Ab-mediated severe dengue disease.

Hispanic Ethnicity is Associated With Milder Disease Severity in Crohn’s Disease but not Ulcerative Colitis

Introduction: Inflammatory bowel disease (IBD) is increasing among Hispanic patients; however few studies have examined differences in epidemiology, disease severity, and treatment course between Hispanic and non-Hispanic patients. Our aim was to evaluate ethnicity as a clinically significant variable influencing disease severity, need for anti-TNF ±immunomodulator therapy, rates of surgery, and hospitalizations. Methods: A cohort of adult IBD patients followed in a large urban safety-net hospital between January 2007 and December 2012 was identified. The following variables were extracted from the electronic medical record: age, gender, race/ethnicity, disease type and severity, treatment regimens, steroid-free remission at 26 weeks, receipt of IBD-related surgery, and hospitalizations. Fisher exact and Mann-Whitney rank sum tests were used to compare categorical and continuous variables between Hispanic and non-Hispanic patients respectively. Results: We identified a total of 291 adult IBD patients, including 148 with Crohn’s Disease (CD), and 143 with ulcerative colitis (UC). Our cohort was 54% male and median age was 44 years. Our cohort was racially diverse with 32% white, 37% black, 28% Hispanic, and 2% Asian. Hispanic patients appeared to have a more benign disease course, with significantly less IBD-related surgeries (mean 0.4 vs. 1.1; p=0.001) and total hospitalizations (mean 2.1 vs. 2.9; p=0.04). Treatment regimens were significantly different between Hispanics and non-Hispanics (p=0.04), as Hispanic patients were less likely to require anti-TNF ± immunomodulator therapy (27% vs. 39%). On subgroup analysis, these differences were primarily noted among those with CD but not those with UC. Hispanic UC patients had a similar number of IBD-related surgeries (p=0.17) and hospitalizations (p=0.62), whereas Hispanic CD had lower rates of both IBD-related surgeries (mean 0.8 vs. 1.8; p=0.01) and total hospitalizations (mean 2.4 vs. 3.8; p=0.04). Hispanic patients with CD also were significantly less likely to require anti-TNF ± immunomodulator therapy (38% vs. 57%; p=0.05). Conclusion: Hispanic CD patients appear to have less severe disease than non-Hispanic patients, with lower rates of IBD-related surgery, hospitalization, and need for anti-TNF therapy. In contrast, Hispanic ethnicity does not appear to be associated with disease course severity in UC patients.

Mutation p.R156H of KRT10 responsible for severe phenotype of epidermolytic ichthyosis in a Chinese family.

Dear editor Epidermolytic ichthyosis is a rare genetic disorder characterized by diffuse erythroderma from the time of birth with subsequent appearance of thick, brown scales and occasional blister formation. Mutation has been found in keratin 1 (K1) and keratin 10 (K10) genes.1 Epidermolytic hyperkeratosis (EHK) is mostly inherited in a dominant mode. We report a Chinese family of EHK sufferers and their mutation findings. The pedigree of the EHK family showed an autosomal dominant inheritance pattern (Figure 1). The proband, a 41 year-old Chinese woman, had erythroderma on the head, trunk, and extremities. She exhibited skin blistering, erosions, erythrodermic, and hyperkeratosis on the skin since infancy and the blistering and erosion gradually diminished with age. Physical examination revealed hyperkeratosis of the entire body (Figure 2A) and desquamation of the palm (Figure 2B). Her son, a 13 year-old boy, has a similar history and clinical manifestation. He was born with typical extensive erythroderma and bullae, and his skin was covered with hyperkeratotic patches of scales. Hyperkeratotic plaques can be seen on the back of the hand (Figure 2C), this lesion healed quickly after retinoid acid treatment (Figure 2D). Pathological examination of the upper portion of his left arm showed granular degeneration in the suprabasal layers (Figure 2E). Figure 1 Pedigree figure. Figure 2 Clinical, histopathological, and gene sequencing of the patients. Direct sequencing of the whole coding regions of KRT1 and KRT10 was performed. A heterozygous KRT10 missense mutation c.467G>A(p.Arg156His) was identified in the proband and her son, while not in normal controls (Figure 2F and G). The mutation hotspots of EHK are located at the conserved sequences in helix initiative and helix terminal motifs of K1 and K10.2 The mutation of the reported family, c.467G>A, just occurred at the hotspots. A previous study has revealed that the relationship between the genotype and phenotype in these patients was complex, not only dependent on the position of the mutation but also on the actual amino acid substitution.3,4 The p.R156 of KRT10 can be substituted by many amino acids such as serine, glycine, cysteine, histidine, and leucine, of which histidine is the most similar to arginine. Theoretically, the p.Arg156His mutation should be accompanied by a mild clinical manifestation,3 but the reported patients experienced severe conditions. So we cannot conclude that the more similar between two amino acid substitution in the same codon, the milder consequence will be brought. The p.Arg156His mutation is rather common in previous reports,2,4 but the clinical manifestations vary greatly. Other genetic or epigenetic factors that were not identified may influence disease severity. In conclusion, we confirm the diagnosis of epidermolytic ichthyosis in the two patients according to the genetic testing and this is beneficial for their genetic counseling. The results reveal that the mutation p.R156H of KRT10 is responsible for severe clinical manifestations in a Chinese family with EHK, and also confirm the complexity of the genotype–phenotype correlation in EHK.

FTY720 (fingolimod) modulates the severity of viral-induced encephalomyelitis and demyelination.

BackgroundFTY720 (fingolimod) is the first oral drug approved by the Food and Drug Administration for treatment of patients with the relapsing-remitting form of the human demyelinating disease multiple sclerosis. Evidence suggests that the therapeutic benefit of FTY720 occurs by preventing the egress of lymphocytes from lymph nodes thereby inhibiting the infiltration of disease-causing lymphocytes into the central nervous system (CNS). We hypothesized that FTY720 treatment would affect lymphocyte migration to the CNS and influence disease severity in a mouse model of viral-induced neurologic disease.MethodsMice were infected intracranially with the neurotropic JHM strain of mouse hepatitis virus. Infected animals were treated with increasing doses (1, 3 and 10 mg/kg) of FTY720 and morbidity and mortality recorded. Infiltration of inflammatory virus-specific T cells (tetramer staining) into the CNS of FTY720-treated mice was determined using flow cytometry. The effects of FTY720 treatment on virus-specific T cell proliferation, cytokine production and cytolytic activity were also determined. The severity of neuroinflammation and demyelination in FTY720-treated mice was examined by flow cytometry and histopathologically, respectively, in the spinal cords of the mice.ResultsAdministration of FTY720 to JHMV-infected mice resulted in increased clinical disease severity and mortality. These results correlated with impaired ability to control viral replication (P < 0.05) within the CNS at days 7 and 14 post-infection, which was associated with diminished accumulation of virus-specific CD4+ and CD8+ T cells (P < 0.05) into the CNS. Reduced neuroinflammation in FTY720-treated mice correlated with increased retention of T lymphocytes within draining cervical lymph nodes (P < 0.05). Treatment with FTY720 did not affect virus-specific T cell proliferation, expression of IFN-γ, TNF-α or cytolytic activity. FTY720-treated mice exhibited a reduction in the severity of demyelination associated with dampened neuroinflammation.ConclusionThese findings indicate that FTY720 mutes effective anti-viral immune responses through impacting migration and accumulation of virus-specific T cells within the CNS during acute viral-induced encephalomyelitis. FTY720 treatment reduces the severity of neuroinflammatory-mediated demyelination by restricting the access of disease-causing lymphocytes into the CNS but is not associated with viral recrudescence in this model.

A 3-year cohort study of the natural history of spinocerebellar ataxia type 6 in Japan.

BackgroundOnly a few prospective studies have determined which clinical symptoms and factors are associated with the disease severity of spinocerebellar ataxia type 6 (SCA6). A multicenter longitudinal cohort study was conducted to clarify both the natural history of SCA6 in Japan and the factors influencing disease progression.MethodsPatients were consecutively recruited between 2007 and 2008. Scores from the Scale for the Assessment and Rating of Ataxia (SARA) and Barthel Index (BI) were collected prospectively each year. Additionally, data from the Japan intractable diseases research (IDR) registry were collected both retrospectively, from 2003 to 2006, and prospectively, from 2007 to 2010. As a result, we were able to collect 3 years of retrospective data and 4 years of prospective data during the course of 3 yearly visits.ResultsForty-six patients were registered. The follow-up rate of the third year was 93%. The SARA scores worsened significantly each year. Over 3 years, the decline of the SARA scores was 1.33 ± 1.40 points/year. The results of multivariate analysis of the decline of the SARA score were not significant. The IDR scores correlated well with the SARA and BI scores. Kaplan-Meier curves of 7 years of data from the IDR registry illustrated the correlation between the ability to walk and the time course of the disease.ConclusionsInformation regarding the progression of ataxia and the decline in the activities of daily living (ADL) in patients with SCA6 was obtained by a 3-year cohort study and a 7-year IDR study. The decline of the SARA score of patients with SCA6 was 1.33 ± 1.40 points/year. The results elucidate the natural history of SCA6, factors influencing disease severity, and utility of data from the IDR registry of Japan.

Influenza viruses

In the last decade, sporadic and lethal human disease caused by zoonotic avian influenza viruses, and the seasonal activity of human H1N1 2009 pandemic type have driven intense epidemiological and laboratory studies into the virus life cycle. This article highlights major developments from mid-2012 to early 2014. Advances in molecular techniques and efficient rollout of diagnostic tests have enabled the rapid identification of clinical cases and detailed genetic sequencing of viral genomes. Studies have contributed widely to the understanding of how and when influenza viruses circulate, what determines their innate pathogenicity in particular hosts and whether host cofactors influence disease severity. Other imperatives include investigations into how influenza can be better prevented by vaccination, or treated with antiviral drugs. Avian influenza viruses present a continuous threat to human populations. There is a need for sustained surveillance and downstream research to evaluate the potential for future pandemics.

Role of glutathione S-transferases in the spinocerebellar ataxia type 2 clinical phenotype

Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative and incurable hereditary disorder caused by a CAG repeat expansion mutation on ATXN2 gene. The identification of reliable biochemical markers of disease severity is of paramount significance for the development and assessment of clinical trials. In order to evaluate the potential use of glutathione-S-transferase (GST) activity as a biomarker for SCA2, a case–control study in 38 affected, presymptomatic individuals or healthy controls was conducted. An enlarged sample of 121 affected individuals was set to assess the impact of GST activity on SCA2 clinical expression. There was a significant increase in GST activity in affected individuals relative to controls, although sensibility and specificity were not high. GST activity was not significantly influenced by sex, age, disease duration or CAG repeat size and did not significantly influence disease severity markers. These findings show a disruption of in vivo GST activity in SCA2, suggesting a role for oxidative stress in the neurodegenerative process.

Cannabinoid receptor 1 inhibition improves the intestinal microcirculation in experimental endotoxemia

Impairment of the intestinal microcirculation in endotoxemia may cause a deterioration of the mucosal barrier function thus releasing intraluminal bacteria and their toxins into the systemic circulation. In clinical sepsis this mechanism may influence disease severity and outcome. The aim of the study was to investigate the impact of cannabinoid receptor 1 (CB1R) modulation within the intestinal microcirculation with regard to leukocyte activation and capillary perfusion, and on intestinal histology in experimental endotoxemia in rats. Endotoxemia was induced by intravenous lipopolysaccharide (LPS) administration. We studied 5 groups of animals: controls (CON), LPS, LPS + CB1R agonist (ACEA, 2.5 mg/kg), LPS + CB1R antagonist (AM281, 2 mg/kg) and LPS + CB1R agonist (ACEA, 2.5 mg/kg) + CB1R antagonist (AM281, 2 mg/kg). Intestinal intravital microscopy (IVM) was performed two hours following LPS/placebo administration. Intestinal leukocyte adhesion in submucosal venules and functional capillary density (FCD) of the intestinal wall was quantified using IVM. Histological changes were assessed using a standardized injury score. After two hours of endotoxemia, we observed a significant increase of leukocyte adhesion in intestinal submucosal venules. Administration of the CB1R antagonist in endotoxemic animals significantly reduced the number of adhering leukocytes (p < 0.05). The CB1R agonist did not further increase leukocyte adhesion. FCD was significantly improved by the CB1R antagonist (p < 0.05). Administration of the CB1R agonist, ACEA, reversed the beneficial effect of the CB1R antagonist, AM281. CB1R inhibition significantly improved intestinal microcirculation by reducing leukocyte adhesion and increasing FCD in acute endotoxemia in rats. The data supports the involvement of the CB1R signaling in leukocyte activation during sepsis. Drugs targeting the CB1R may have therapeutic potential in systemic inflammation, such as sepsis.

An overview of calf diarrhea - infectious etiology, diagnosis, and intervention.

Calf diarrhea is a commonly reported disease in young animals, and still a major cause of productivity and economic loss to cattle producers worldwide. In the report of the 2007 National Animal Health Monitoring System for U.S. dairy, half of the deaths among unweaned calves was attributed to diarrhea. Multiple pathogens are known or postulated to cause or contribute to calf diarrhea development. Other factors including both the environment and management practices influence disease severity or outcomes. The multifactorial nature of calf diarrhea makes this disease hard to control effectively in modern cow-calf operations. The purpose of this review is to provide a better understanding of a) the ecology and pathogenesis of well-known and potential bovine enteric pathogens implicated in calf diarrhea, b) describe diagnostic tests used to detect various enteric pathogens along with their pros and cons, and c) propose improved intervention strategies for treating calf diarrhea.

The importance of a large sample cohort for studies on modifier genes influencing disease severity in FAP patients

BackgroundFamilial adenomatous polyposis (FAP) is usually characterised by the appearance of hundreds-to-thousands of adenomas throughout the colon and rectum and if left untreated the condition will develop into CRC with close to 100% penetrance. Germline mutations in the APC gene, which plays an integral role in the Wnt-signalling pathway, have been found to be responsible for 70-90% of FAP cases. Several studies suggest that modifier genes may play an important role in the development of CRC and possible modifiers for FAP have been suggested. Interestingly, a study has found that SNPs within ATP5A1 is associated with raised levels of ATP5A1 expression and high expression levels may facilitate CRC development. We aimed to determine if SNPs in ATP5A1 modify the risk of developing CRC/adenomas in FAP patients.MethodsGenomic DNA from 139 Australian FAP patients with a germline APC mutation underwent genotyping at the Australian Genome Research Facility (AGRF) utilising iPLEX GOLD chemistry with Sequenom MassArray on an Autoflex Spectrometer for 16 SNPs in the ATP5A1 gene. Association between ages of diagnosis/risk of CRC/adenomas was tested with Kaplan-Meier estimator analysis, logistic regression and cox proportional hazard regression.ResultsAn association between age of diagnosis of CRC and genotypes was observed for SNP rs2578189 (p = 0.0014), with individuals harbouring the variant genotype developing CRC 29 years earlier than individuals harbouring the wildtype genotype. Individuals harbouring the variant genotype of SNP rs2578189 were also at increased risk of CRC (HR = 13.79, 95% CI = 2.36-80.64, p = 0.004). We used an independent Dutch FAP cohort (n = 427) to validate our results; no association between SNP rs2578189 and CRC was observed.ConclusionThese results highlight the difficulties in studying a disease that has a high degree of intervention and also emphasize the importance of large sample sizes when searching for modifier genes in patients with an inherited predisposition to disease. To fully determine if there are genetic modifiers of disease in FAP we would encourage people that are interested in collaborating in future studies into the role of modifier genes in disease expression in FAP to join forces.

Childhood Anemia at High Altitude: Risk Factors for Poor Outcomes in Severe Pneumonia

Pneumonia is the leading cause of mortality in young children globally, and factors that affect tissue delivery of oxygen may affect outcomes of pneumonia. We studied whether altitude and anemia influence disease severity and outcomes in young children with World Health Organization-defined severe pneumonia. We analyzed data from the SPEAR (Severe Pneumonia Evaluation Antimicrobial Research) study, a World Health Organization- and USAID-sponsored multinational randomized controlled trial of antibiotics for severe pneumonia among children aged 2 to 59 months in resource-poor settings. The trial enrolled 958 children in 8 sites at varying elevations, classified as high (≥ 2000 m) or low (<2000 m) altitude. We compared illness severity and assessed the effect of anemia on treatment outcome at high and low altitudes, adjusting for potential confounders and study site. Children at high altitudes had significantly lower oxygen saturation on presentation, more cyanosis, lower systolic blood pressure, and higher hemoglobin. After adjusting for potential confounders, anemia predicted treatment failure in children living at high altitude (relative risk: 4.07; 95% confidence interval: 2.60-6.38) but not at low altitude (relative risk: 1.12; 95% confidence interval: 0.96-1.30). Children at high altitude took longer to reach normoxemia than did children at lower altitudes (5.25 vs 0.75 days; P < .0001). Children at high altitude present with more severe disease, and children with anemia at high altitude are at greater risk of poor outcome when being treated for severe pneumonia. Given the high global prevalence of anemia among young children, prevention and treatment of anemia should be a priority in children living at high altitude and could improve outcomes of pneumonia.

Complement alternative pathway genetic variation and Dengue infection in the Thai population

Dengue disease is a mosquito-borne infection caused by Dengue virus. Infection may be asymptomatic or variably manifest as mild Dengue fever (DF) to the most severe form, Dengue haemorrhagic fever (DHF). Mechanisms that influence disease severity are not understood. Complement, an integral component of the immune system, is activated during Dengue infection and the degree of activation increases with disease severity. Activation of the complement alternative pathway is influenced by polymorphisms within activation (factor B rs12614/rs641153, C3 rs2230199) and regulatory [complement factor H (CFH) rs800292] proteins, collectively termed a complotype. Here, we tested the hypothesis that the complotype influences disease severity during secondary Dengue infection. In addition to the complotype, we also assessed two other disease-associated CFH polymorphisms (rs1061170, rs3753394) and a structural polymorphism within the CFH protein family. We did not detect any significant association between the examined polymorphisms and Dengue infection severity in the Thai population. However, the minor allele frequencies of the factor B and C3 polymorphisms were less than 10%, so our study was not sufficiently powered to detect an association at these loci. We were also unable to detect a direct interaction between CFH and Dengue NS1 using both recombinant NS1 and DV2-infected culture supernatants. We conclude that the complotype does not influence secondary Dengue infection severity in the Thai population.

The G263X MYBPC3 mutation is a common and low-penetrant mutation for hypertrophic cardiomyopathy in the region of Asturias (Northern Spain)

Hypertrophic cardiomyopathy (HCM) is characterised by wide disease manifestations, ranging from severe left ventricular septum (LVS) size and incapacitating symptoms to normal LVS and no symptoms at all. In addition to life style and other non-genetic factors, the phenotype variability could be explained in part by the heterogeneous genetic background of MCH [ 1 Keren A. Syrris P. McKenna W.J. Hypertrophic cardiomyopathy: the genetic determinants of clinical disease expression. Nat Clin Pract Cardiovasc Med. 2008; 5: 158-168 Crossref PubMed Scopus (161) Google Scholar , 2 Bos J.M. Towbin J.A. Ackerman M.J. Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J Am Coll Cardiol. 2009; 54: 201-211 Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar , 3 Richard P. Charron P. Carrier L. et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003; 107: 2227-2232 Crossref PubMed Scopus (983) Google Scholar ]. Moreover, the mutated gene and the type of mutation could also influence disease severity. The myosin binding protein C3 (MYBPC3) is the most frequently mutated gene and has been linked to a delayed expression of HCM. In the other hand, cardiac beta-myosin heavy chain (MYH7) mutations are commonly found among patients with early onset symptoms and severe disease manifestations [ 3 Richard P. Charron P. Carrier L. et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003; 107: 2227-2232 Crossref PubMed Scopus (983) Google Scholar , 4 García-Castro M. Coto E. Reguero J.R. et al. Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy. Rev Esp Cardiol. 2009; 62: 48-56 Crossref PubMed Scopus (55) Google Scholar ].

Impact of temperature stress and validamycin A on compatible solutes and fumonisin production in F. verticillioides: Role of trehalose-6-phosphate synthase

Fusarium verticillioides is a pathogen of maize that causes root, stalk and ear rot and produces fumonisins, toxic secondary metabolites associated with disease in livestock and humans. Environmental stresses such as heat and drought influence disease severity and toxin production, but the effects of abiotic stress on compatible solute production by F. verticillioides have not been fully characterized. We found that decreasing the growth temperature leads to a long-term reduction in polyol levels, whereas increasing the temperature leads to a transient increase in polyols. The effects of temperature shifts on trehalose levels are opposite the effects on polyols and more dramatic. Treatment with validamycin A, a trehalose analog with antifungal activity, leads to a rapid reduction in trehalose levels, despite its known role as a trehalase inhibitor. Mutant strains lacking TPS1, which encodes a putative trehalose-6-phosphate synthase, have altered growth characteristics, do not produce detectable amounts of trehalose under any condition tested, and accumulate glycogen at levels significantly higher than wild-type F. verticillioides. TPS1 mutants also produce significantly less fumonisin than wild type and are also less pathogenic than wild type on maize. These data link trehalose biosynthesis, secondary metabolism, and disease, and suggest that trehalose metabolic pathways may be a viable target for the control of Fusarium diseases and fumonisin contamination of maize.

Association of microRNAs genes polymorphisms with rheumatoid arthritis in Egyptian female patients

ObjectiveTo investigate whether miRNA-499 (rs3746444) and miRNA-146a (rs2910164) genes polymorphisms are independent factors for rheumatoid arthritis (RA) in Egyptians, and whether they influence disease severity and activity. MethodsTwo hundred and seventeen RA patients and 245 healthy controls were enrolled in this study. Polymorphisms of miRNA-146a and miRNA-499 genes were detected using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). ResultsThe miRNA-499 CT genotype was an independent factor of RA. The miRNA-499 CT, CC genotypes and C allele frequencies were significantly increased in erosive RA group. Moreover, the heterozygote CT had more severe and more active form of the disease compared with homozygote CC or TT. However, we did not find any significant association of miRNA-146a polymorphism with RA risk, severity, and activity. ConclusionThe miRNA-499 polymorphism is an independent factor of RA, and influences disease severity and activity.