Genetics, recombination and clinical features of human rhinovirus species C (HRV-C) infections; interactions of HRV-C with other respiratory viruses

To estimate the frequency, molecular epidemiological and clinical associations of infection with the newly described species C variants of human rhinoviruses (HRV), 3243 diagnostic respiratory samples referred for diagnostic testing in Edinburgh were screened using a VP4-encoding region-based selective polymerase chain reaction (PCR) for HRV-C along with parallel PCR testing for 13 other respiratory viruses. HRV-C was the third most frequently detected behind respiratory syncytial virus (RSV) and adenovirus, with 141 infection episodes detected among 1885 subjects over 13 months (7.5%). Infections predominantly targeted the very young (median age 6–12 months; 80% of infections in those <2 years), occurred throughout the year but with peak incidence in early winter months. HRV-C was detected significantly more frequently among subjects with lower (LRT) and upper respiratory tract (URT) disease than controls without respiratory symptoms; HRV-C mono-infections were the second most frequently detected virus (behind RSV) in both disease presentations (6.9% and 7.8% of all cases respectively). HRV variants were classified by VP4/VP2 sequencing into 39 genotypically defined types, increasing the current total worldwide to 60. Through sequence comparisons of the 5′untranslated region (5′UTR), the majority grouped with species A (n = 96; 68%, described as HRV-Ca), the remainder forming a phylogenetically distinct 5′UTR group (HRV-Cc). Multiple and bidirectional recombination events between HRV-Ca and HRV-Cc variants and with HRV species A represents the most parsimonious explanation for their interspersed phylogeny relationships in the VP4/VP2-encoding region. No difference in age distribution, seasonality or disease associations was identified between HRV-Ca and HRV-Cc variants. HRV-C-infected subjects showed markedly reduced detection frequencies of RSV and other respiratory viruses, providing evidence for a major interfering effect of HRV-C on susceptibility to other respiratory virus infections. HRV-C's disease associations, its prevalence and evidence for interfering effects on other respiratory viruses mandates incorporation of rhinoviruses into future diagnostic virology screening

Evaluation of sleep, puberty and mental health in children with long-term melatonin treatment for chronic idiopathic childhood sleep onset insomnia

OBJECTIVES: To establish whether long-term use of melatonin influences pubertal development, sleep quality and mental health development in children as compared with the normal Dutch population of the same age. METHODS: This follow-up research study was conducted in children included in a previous melatonin dose-finding trial. Outcomes were measured using questionnaires (Strength and Difficulties Questionnaire (SDQ), Children's Sleep Habits Questionnaire (CSHQ) and Tanner Stages) adopted for Dutch children. Mean duration of therapy, persistence of effect, adverse events and (other) reasons leading to cessation of therapy were additional objectives of this study. RESULTS: Mean years of usage (n = 51) was 3.1 years (min 1.0 year, max 4.6 years), mean dose 2.69 mg (min 0.3 mg, max 10 mg). Mean SDQ score, mean CSHQ score and Tanner Stages standard deviation scores did not differ in a statistically significant way from published scores of the general Dutch population of the same age and sex. CONCLUSIONS: This follow-up study demonstrates that melatonin treatment in children can be sustained over a long period of time without substantial deviation of the development of children with respect to sleep quality, puberty development and mental health scores, as compared with the general Dutch population

Plasmodium vivax Sub-Patent Infections after Radical Treatment Are Common in Peruvian Patients: Results of a 1-Year Prospective Cohort Study

BACKGROUND: There is an increasing body of literature reporting treatment failure of the currently recommended radical treatment of Plasmodium vivax infections. As P. vivax is the main malaria species outside the African continent, emerging tolerance to its radical treatment regime could have major consequences in countries like Peru, where 80% of malaria cases are due to P. vivax. Here we describe the results of a 1-year longitudinal follow up of 51 confirmed P. vivax patients living around Iquitos, Peruvian Amazon, and treated according to the Peruvian national guidelines. METHODOLOGY: Each month a blood sample for microscopy and later genotyping was systematically collected. Recent exposure to infection was estimated by detecting antibodies against the P. vivax circumsporozoite protein (CSP) and all PCR confirmed P. vivax infections were genotyped with 16 polymorphic microsatellites. RESULTS: During a 1-year period, 84 recurrent infections, 22 positive also by microscopy, were identified, with a median survival time to first recurrent infection of 203 days. Most of them (71%) were asymptomatic; in 13 patients the infection persisted undetected by microscopy for several consecutive months. The genotype of mostly recurrent infections differed from that at day 0 while fewer differences were seen between the recurrent infections. The average expected heterozygosity was 0.56. There was strong linkage disequilibrium (I(A) (s) = 0.29, p<1.10(-4)) that remained also when analyzing only the unique haplotypes, suggesting common inbreeding. CONCLUSION: In Peru, the P. vivax recurrent infections were common and displayed a high turnover of parasite genotypes compared to day 0. Plasmodium vivax patients, even when treated according to the national guidelines, may still represent an important parasite reservoir that can maintain transmission. Any elimination effort should consider such a hidden reservoir

IMRT in oral cavity cancer

BACKGROUND: Except for early T1,2 N0 stages, the prognosis for patients with oral cavity cancer (OCC) is reported to be worse than for carcinoma in other sites of the head and neck (HNC). The aim of this work was to assess disease outcome in OCC following IMRT. Between January 2002 and January 2007, 346 HNC patients have been treated with curative intensity modulated radiation therapy (IMRT) at the Department of Radiation Oncology, University Hospital Zurich. Fifty eight of these (16%) were referred for postoperative (28) or definitive (30) radiation therapy of OCC. 40 of the 58 OCC patients (69%) presented with locally advanced T3/4 or recurred lesions. Doses between 60 and 70 Gy were applied, combined with simultaneous cisplatin based chemotherapy in 78%. Outcome analyses were performed using Kaplan Meier curves. In addition, comparisons were performed between this IMRT OCC cohort and historic in-house cohorts of 33 conventionally irradiated (3DCRT) and 30 surgery only patients treated over the last 10 years. RESULTS: OCC patients treated with postoperative IMRT showed the highest local control (LC) rate of all assessed treatment sequence subgroups (92% LC at 2 years). Historic postoperative 3DCRT patients and patients treated with surgery alone reached LC rates of ~70–80%. Definitively irradiated patients revealed poorest LC rates with ~30 and 40% following 3DCRT and IMRT, respectively. T1 stage resulted in an expectedly significantly higher LC rate (95%, n = 19, p < 0.05) than T2-4 and recurred stages (LC ~50–60%, n = 102). Analyses according to the diagnosis revealed significantly lower LC in OCC following definitive IMRT than that in pharyngeal tumors treated with definitive IMRT in the same time period (43% vs 82% at 2 years, p < 0.0001), while the LC rate of OCC following postoperative IMRT was as high as in pharyngeal tumors treated with postoperative IMRT (>90% at 2 years). CONCLUSION: Postoperative IMRT of OCC resulted in the highest local control rate of the assessed treatment subgroups. In conclusion, generous indication for IMRT following surgical treatment is recommended in OCC cases with unfavourable features like tight surgical margin, nodal involvement, primary tumor stage >T1N0, or already recurred disease, respectively. Loco-regional outcome of OCC following definitive IMRT remained unsatisfactory, comparable to that following definitive 3DCRT

Identification of a Novel Gene Product That Promotes Survival of Mycobacterium smegmatis in Macrophages

BACKGROUND: Bacteria of the suborder Corynebacterineae include significant human pathogens such as Mycobacterium tuberculosis and M. leprae. Drug resistance in mycobacteria is increasingly common making identification of new antimicrobials a priority. Mycobacteria replicate intracellularly, most commonly within the phagosomes of macrophages, and bacterial proteins essential for intracellular survival and persistence are particularly attractive targets for intervention with new generations of anti-mycobacterial drugs. METHODOLOGY/PRINCIPAL FINDINGS: We have identified a novel gene that, when inactivated, leads to accelerated death of M. smegmatis within a macrophage cell line in the first eight hours following infection. Complementation of the mutant with an intact copy of the gene restored survival to near wild type levels. Gene disruption did not affect growth compared to wild type M. smegmatis in axenic culture or in the presence of low pH or reactive oxygen intermediates, suggesting the growth defect is not related to increased susceptibility to these stresses. The disrupted gene, MSMEG_5817, is conserved in all mycobacteria for which genome sequence information is available, and designated Rv0807 in M. tuberculosis. Although homology searches suggest that MSMEG_5817 is similar to the serine:pyruvate aminotransferase of Brevibacterium linens suggesting a possible role in glyoxylate metabolism, enzymatic assays comparing activity in wild type and mutant strains demonstrated no differences in the capacity to metabolize glyoxylate. CONCLUSIONS/SIGNIFICANCE: MSMEG_5817 is a previously uncharacterized gene that facilitates intracellular survival of mycobacteria. Interference with the function of MSMEG_5817 may provide a novel therapeutic approach for control of mycobacterial pathogens by assisting the host immune system in clearance of persistent intracellular bacteria

The effects of baicalein and baicalin on mitochondrial function and dynamics: A review

Mitochondria play an essential role in cell survival by providing energy, calcium buffering, and regulating apoptosis. A growing body of evidence shows that mitochondrial dysfunction and its consequences, including impairment of the mitochondrial respiratory chain, excessive generation of reactive oxygen species, and excitotoxicity, play a pivotal role in the pathogenesis of different diseases such as neurodegenerative diseases, neuropsychiatric disorders, and cancer. The therapeutical role of flavonoids on these diseases is gaining increasing acceptance. Numerous studies on experimental models have revealed the favorable role of flavonoids on mitochondrial function and structure. This review highlights the promising role of baicalin and its aglycone form, baicalein, on mitochondrial function and structure with a focus on its therapeutic effects. We also discuss their chemistry, sources and bioavailability

Drought Impact Is Alleviated in Sugar Beets (Beta vulgaris L.) by Foliar Application of Fullerenol Nanoparticles

Over the past few years, significant efforts have been made to decrease the effects of drought stress on plant productivity and quality. We propose that fullerenol nanoparticles (FNPs, molecular formula C-60(OH)(24)) may help alleviate drought stress by serving as an additional intercellular water supply. Specifically, FNPs are able to penetrate plant leaf and root tissues, where they bind water in various cell compartments. This hydroscopic activity suggests that FNPs could be beneficial in plants. The aim of the present study was to analyse the influence of FNPs on sugar beet plants exposed to drought stress. Our results indicate that intracellular water metabolism can be modified by foliar application of FNPs in drought exposed plants. Drought stress induced a significant increase in the compatible osmolyte proline in both the leaves and roots of control plants, but not in FNP treated plants. These results indicate that FNPs could act as intracellular binders of water, creating an additional water reserve, and enabling adaptation to drought stress. Moreover, analysis of plant antioxidant enzyme activities (CAT, APx and GPx), MDA and GSH content indicate that fullerenol foliar application could have some beneficial effect on alleviating oxidative effects of drought stress, depending on the concentration of nanoparticles applied. Although further studies are necessary to elucidate the biochemical impact of FNPs on plants; the present results could directly impact agricultural practice, where available water supplies are often a limiting factor in plant bioproductivity

Non-invasive cardiac imaging techniques and vascular tools for the assessment of cardiovascular disease in type 2 diabetes mellitus

Cardiovascular disease is the major cause of mortality in type 2 diabetes mellitus. The criteria for the selection of those asymptomatic patients with type 2 diabetes who should undergo cardiac screening and the therapeutic consequences of screening remain controversial. Non-invasive techniques as markers of atherosclerosis and myocardial ischaemia may aid risk stratification and the implementation of tailored therapy for the patient with type 2 diabetes. In the present article we review the literature on the implementation of non-invasive vascular tools and cardiac imaging techniques in this patient group. The value of these techniques as endpoints in clinical trials and as risk estimators in asymptomatic diabetic patients is discussed. Carotid intima–media thickness, arterial stiffness and flow-mediated dilation are abnormal long before the onset of type 2 diabetes. These vascular tools are therefore most likely to be useful for the identification of ‘at risk’ patients during the early stages of atherosclerotic disease. The additional value of these tools in risk stratification and tailored therapy in type 2 diabetes remains to be proven. Cardiac imaging techniques are more justified in individuals with a strong clinical suspicion of advanced coronary heart disease (CHD). Asymptomatic myocardial ischaemia can be detected by stress echocardiography and myocardial perfusion imaging. The more recently developed non-invasive multi-slice computed tomography angiography is recommended for exclusion of CHD, and can therefore be used to screen asymptomatic patients with type 2 diabetes, but has the associated disadvantages of high radiation exposure and costs. Therefore, we propose an algorithm for the screening of asymptomatic diabetic patients, the first step of which consists of coronary artery calcium score assessment and exercise ECG