ENT-specific therapy of obstructive sleep apnoea in adults : A revised version of the previously published German S2e guideline.

The German Society of Otorhinolaryngology, Head and Neck Surgery recently has released the abbreviated version of its scientific guideline "ENT-specific therapy of obstructive sleep apnoea (OSA) in adults", which has been updated in 2015 and can be found online at the Association of the Scientific Medical Societies (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). A summary of the main recommendations is provided in this revised English version. All recommendations are based on a systematic literature research of articles published up until March 2014. Literature research followed the Cochrane Handbook for Systematic Literature Research to create Guidelines published by the German Cochrane Centre. Studies were evaluated with respect to their scientific value according to the recommendations of the Oxford Centre for Evidence-based Medicine, and grades of recommendation are provided regarding each intervention.

[S2e-guideline: "ENT-specific therapy of obstructive sleep apnea in adults" short version : Sleep Medicine Task Force of the German Society for Otorhinolaryngology, Head and Neck Surgery]. / Leitlinie: "HNO-spezifische Therapie der obstruktiven Schlafapnoe bei Erwachsenen" Kurzfassung : ArGe Schlafmedizin der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie.

The present S2e-guideline is an update of the former S2e-guideline "treatment of obstructive sleep apnea in adults". The update was performed on behalf of the German Society for Otorhinolaryngology, Head and Neck Surgery by its Sleep Medicine Task Force. The long version of the guideline is valid from 5.9.2015 to 5.9.2020 and has been available (guideline No. 017-069) since November 2015 on the official AWMF website.The subsequently presented short version of the guideline summarizes the essentials in a legible way. For further information, please refer to the long version.

Are all health gains equally important? An exploration of acceptable health as a reference point in health care priority setting.

BACKGROUND: Accumulating evidence suggests that members of society prefer some QALY gains over others. In this paper, we explore the notion of acceptable health as a reference point in assessing the value of health gains. The value of health benefits may be assessed in terms of their position relative to this reference level, benefits above the level of acceptable health being valued differently from benefits below this level. In this paper we focus on assessing the level of acceptable health at different ages and associations with background variables. METHODS: We recruited a sample of the adult population from the Netherlands (n = 1067) to investigate which level of health problems they consider to be acceptable for people aged 40 to 90, using 10-year intervals. We constructed acceptable health curves and associated acceptable health with background characteristics using linear regressions. RESULTS: The results of this study indicate that the level of health problems considered acceptable increases with age. This level was associated with respondents' age, age of death of next of kin, health and health behaviour. CONCLUSIONS: Our results suggest that people are capable of indicating acceptable levels of health at different ages, implying that a reference point of acceptable health may exist. While more investigation into the measurement of acceptable health remains necessary, future studies may also focus on how health gains may be valued relative to this reference level. Gains below the reference point may receive higher weight than those above this level since the former improve unacceptable health states while the latter improve acceptable health states.

A cross-sectional study of tetanus and diphtheria antibody concentrations post vaccination among lung transplant patients compared with healthy individuals.

BACKGROUND: Lung transplant (LuTx) patients are routinely immunized against tetanus and diphtheria. However, few studies have been done to measure serologic immunity in the transplant population. OBJECTIVES: The primary objective of this study was to compare tetanus and diphtheria antibody concentrations in LuTx vs. healthy subjects. METHODS: Serum was used from an available sample of 111 total individuals (n = 36 healthy; n = 75 LuTx). Tetanus and diphtheria antibody concentrations were measured using an enzyme-linked immunosorbant assay method. RESULTS: A statistically significant difference in both tetanus and diphtheria antibody concentrations was found between the groups. The median concentration of tetanus antibody was higher for healthy individuals compared with the LuTx group (3.2 IU/mL [1.2-5.2 interquartile range {IQR}] vs. 1.3 IU/mL [0.4-2.6 IQR], respectively; P = 0.0001). No difference in time was found since the last tetanus-diphtheria vaccine or tetanus-diphtheria-pertussis vaccine dose between the groups (healthy 76.5 months [16-114 IQR] vs. LuTx 74.5 months [45-118 IQR]; P = 0.44). CONCLUSIONS: Tetanus and diphtheria immunizations are recommended for LuTx patients to reduce the risk of infection. Because the LuTx group has lower antibody concentrations, further studies should investigate the possible need for more frequent tetanus and diphtheria boosters.

[Impulsive-compulsive behaviours in a German Parkinson's disease outpatient sample]. / Impulsiv-zwanghafte verhaltensstörungen in einer deutschen stichprobe ambulant versorgter Parkinson-patienten.

BACKGROUND: Impulsive-compulsive behaviours (ICBs) are frequent complications of Parkinson's disease (PD), associated with treatment by dopamine agonists (DAs). These include impulse control disorders (ICDs), repetitive behaviour (RB) and the dopamine-dysregulation syndrome (DDS). METHODS: A subsample of 72 patients of a large longitudinal study (n = 739) was screened with the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease (QUIP). Results were associated with socio-demographic, clinical and neuropsychological parameters. RESULTS: A large proportion of the sample reported ICBs (60%), RBs were most frequent (47 %). Patients with ICBs consumed higher doses of DAs (343 ± 177 mg vs. 390 ± 153 mg; p < 0.01). Pramipexole was associated with RB but not ICDs (273 ± 225 mg and 53 ± 106 mg vs. 151 ± 209 mg in patients without ICB). Patients with ICDs reported more dyskinesias (UPDRS IV: 1.78 ± 1.6 vs. 0.55 ± 1.1 points; p = 0.012) and patients with multiple ICBs a longer duration of PD (9.3 ± 5.0 vs. 6.2 ± 4.0 years; p = 0.026) and worse quality of life (PDQ39: 29.9 ± 13.8 vs. 20.3 ± 13.4 points; p = 0.036) compared to patients without any ICB. CONCLUSIONS: ICBs are frequent even in outpatients with moderate duration and severity of PD and associated with DA dose. Because of possible serious psychosocial consequences, detecting and managing them is of high importance.

Comparative therapeutic efficacy and safety of type-II collagen (UC-II), glucosamine and chondroitin in arthritic dogs: pain evaluation by ground force plate.

The investigation was conducted on client-owned moderately arthritic dogs with two objectives: (i) to evaluate therapeutic efficacy of type-II collagen (UC-II) alone or in combination with glucosamine hydrochloride (GLU) and chondroitin sulphate (CHO), and (ii) to determine their tolerability and safety. Dogs in four groups (n = 7-10), were treated daily for a period of 150 days with placebo (Group-I), 10 mg active UC-II (Group-II), 2000 mg GLU + 1600 mg CHO (Group-III), and UC-II + GLU + CHO (Group-IV). On a monthly basis, dogs were evaluated for observational pain (overall pain, pain upon limb manipulation, and pain after physical exertion) using different numeric scales. Pain level was also measured objectively using piezoelectric sensor-based GFP for peak vertical force and impulse area. Dogs were also examined every month for physical, hepatic (ALP, ALT and bilirubin) and renal (BUN and creatinine) functions. Based on observations, significant (p < 0.05) reduction in pain was noted in Group-II, III, and IV dogs. Using GFP, significant increases in peak vertical force (N/kg body wt) and impulse area (N s/kg body wt), indicative of a decrease in arthritis associated pain, were observed in Group-II dogs only. None of the dogs in any group showed changes in physical, hepatic or renal functions. In conclusion, based on GFP data, moderately arthritic dogs treated with UC-II (10 mg) showed a marked reduction in arthritic pain with maximum improvement by day 150. UC-II, GLU and CHO operate through different mechanisms of action, and were well tolerated over a period of 150 days.

Persistence of influenza vaccine-induced antibodies in lung transplant patients between seasons.

BACKGROUND: Immunization policy-making bodies advised against immunizing too early before the influenza season because vaccine-specific antibody may wane before the end of the influenza season. Lung transplant patients are included in the group of high-risk patients for whom this recommendation had been made. We hypothesized that immunosuppressed lung transplant patients would maintain protective concentrations of influenza antigen-specific antibodies between seasons. METHODS: As part of a planned 5-year study of influenza vaccine responses in lung transplant patients, we measured influenza antibody concentrations by hemagglutination inhibition assay before influenza immunization annually. The fraction of lung transplant patients who maintained seroprotective levels (≥ 40 hemagglutination units) approximately 11 months from last season immunization was calculated. Antibody concentrations and response rates in lung transplant patients were compared with healthy individuals and those waiting for lung transplantation. RESULTS: The majority of lung transplant patients maintained seroprotective influenza antigen-specific antibody concentrations for approximately 11 months after immunization. Seroprotection rates varied greatly with influenza antigens (healthy 68-100%, pretransplant 44-100%, transplant 64-100%), and were similar when groups were compared. More than 70% of lung transplant patients maintained seroprotective antibody concentrations to 10 of 11 vaccine antigens. CONCLUSION: Seroprotective influenza antibody concentrations are maintained at very high rates among immunosuppressed lung transplant patients and depend more on the vaccine virus than the immunostatus of the vaccine recipient. Early seasonal influenza immunization of lung transplant patients is appropriate.

Secondhand smoke exposure in Alaskan households with children.

INTRODUCTION: Secondhand smoke (SHS) exposure causes premature death and disease in children and non-smoking adults; the home is the primary source of SHS exposure. The aim of this study was to assess variance in the prevalence of children's SHS exposure in Alaskan households with an adult smoker according to rurality, race/ethnicity, income and education, household age composition, marital status, amount smoked each day, and beliefs in SHS health consequences. METHOD: Telephone interviews were conducted between 2004 and 2007 on a population-based random sample of 1119 Alaskan adult smokers with children living in the household. RESULTS: Respondents living with children over 5 years of age reported a significantly (p <0.05) higher prevalence of home SHS exposure, compared with those living with younger children. Respondents 40 years and older reported significantly more exposure than others. Alaska Native smokers reported significantly lower SHS exposure in their homes than those of other races, as did those living in very rural areas. Respondents' heavier smoking was significantly associated with more SHS exposure. The sub-population of adults living without other adults was approximately 1.5 times more likely to report SHS exposure than those living with other adults. As expected, having a no-smoking rule in the home greatly lowered the risk of SHS exposure in the home. CONCLUSIONS: Although most smokers with children believed that SHS is harmful, some need to convert those beliefs into actions. The results from this study suggest that those with school-aged children, and moderate to heavy smokers should be targeted for intervention, given their high prevalence of home SHS exposure. Future work should examine reasons for low exposure levels among Alaska Native people to inform programmatic efforts in other communities.

Therapeutic efficacy of undenatured type-II collagen (UC-II) in comparison to glucosamine and chondroitin in arthritic horses.

The present investigation evaluated arthritic pain in horses receiving daily placebo, undenatured type II collagen (UC-II) at 320, 480, or 640 mg (providing 80, 120, and 160 mg active UC-II, respectively), and glucosamine and chondroitin (5.4 and 1.8 g, respectively, bid for the first month, and thereafter once daily) for 150 days. Horses were evaluated for overall pain, pain upon limb manipulation, physical examination, and liver and kidney functions. Evaluation of overall pain was based upon a consistent observation of all subjects during a walk and a trot in the same pattern on the same surface. Pain upon limb manipulation was conducted after the walk and trot. It consisted of placing the affected joint in severe flexion for a period of 60 sec. The limb was then placed to the ground and the animal trotted off. The response to the flexion test was then noted with the first couple of strides the animal took. Flexion test was consistent with determining clinically the degree of osteoarthritis in a joint. Horses receiving placebo showed no change in arthritic condition, while those receiving 320 or 480 or 640 mg UC-II exhibited significant reduction in arthritic pain (P < 0.05). UC-II at 480 or 640 mg dose provided equal effects, and therefore, 480 mg dose was considered optimal. With this dose, reduction in overall pain was from 5.7 +/- 0.42 (100%) to 0.7 +/- 0.42 (12%); and in pain upon limb manipulation from 2.35 +/- 0.37 (100%) to 0.52 +/- 0.18 (22%). Although glucosamine and chondroitin treated group showed significant (P < 0.05) reduction in pain compared with pretreated values, the efficacy was less compared with that observed with UC-II. In fact, UC-II at 480 or 640 mg dose was found to be more effective than glucosamine and chondroitin in arthritic horses. Clinical condition (body weight, body temperature, respiration rate, and pulse rate), and liver (bilirubin, GGT, and ALP) and kidney (BUN and creatinine) functions remained unchanged, suggesting that these supplements were well tolerated.

[Guideline: Treatment of obstructive sleep apnea in adults]. / Leitlinie: Therapie der obstruktiven Schlafapnoe des Erwachsenen.

The current guideline discusses conservative and surgical therapy of obstructive sleep apnea (OSA) in adults from the perspective of the ear, nose and throat specialist. The revised guideline was commissioned by the German Society of Ear-Nose-Throat, Head-Neck Surgery (DG HNO KHC) and compiled by the DG HNO KHC's Working Group on Sleep Medicine. The guideline was based on a formal consensus procedure according to the guidelines set out by the German Association of Scientific Medical Societies (AWMF) in the form of a"S2e guideline". Research of the literature available on the subject up to and including December 2008 forms the basis for the recommendations. Evaluation of the publications found was made according to the recommendations of the Oxford Centre for Evidence-Based Medicine (OCEBM). This yielded a recommendation grade, whereby grade A represents highly evidence-based studies and grade D those with a low evidence base.

A novel pathway for secretory proteins?

In eukaryotes, most proteins which are transported to the extracellular space, into mitochondria or into chloroplasts are synthesized as precursor polypeptides containing cleavable N-terminal signal or targeting sequences. We have searched the literature for proteins that are exported from the cytosol without being proteolytically processed. Some of these proteins contain uncleaved signal or targeting sequences. However, among secretory proteins there is a class that does not possess hydrophobic signal sequences and appears to leave the cell by a secretory pathway clearly distinct from the classical route through the endoplasmic reticulum and Golgi apparatus.

Therapeutic targeting of necroptosis by Smac mimetic bypasses apoptosis resistance in acute myeloid leukemia cells.

Resistance to apoptosis, for example due to overexpression of Inhibitor of Apoptosis (IAP) proteins, is associated with poor prognosis in acute myeloid leukemia (AML). Here, we identify that Smac mimetics such as BV6, which antagonizes IAP proteins, elicit necroptosis in AML cells, in which apoptosis is inhibited pharmacologically by caspase inhibitors or genetically by caspase-8 knockdown. Importantly, BV6 triggers necroptosis also in apoptosis-resistant patient-derived AML blasts, underlining the clinical relevance of our findings. Mechanistically, we show that BV6-induced cell death depends on key components of necroptosis signaling such as RIP1, RIP3 and MLKL, since pharmacological or genetic inhibition of these proteins significantly protects AML cells from BV6-mediated cell death, whereas PGAM5 is dispensable. Interestingly, we identify constitutive tumor necrosis factor-alpha (TNFα) secretion and an autocrine/paracrine TNFα loop as critical mediators of BV6-induced necroptosis in AML cell lines and patient-derived blasts, as the TNFα-blocking antibody Enbrel or tumor necrosis factor-alpha receptor 1 (TNFR1) knockdown significantly rescue cell death. Notably, AML cells exhibit high basal levels of TNFα compared to non-malignant CD34+ cells, which is further increased by BV6. In conclusion, this is the first report showing that Smac mimetics circumvent apoptosis resistance in AML cells by inducing necroptosis in a TNFα-dependent manner, which has important implications for the development of new strategies to overcome treatment resistance in AML.

Acceptable health and priority weighting: Discussing a reference-level approach using sufficientarian reasoning.

Health care systems are challenged in allocating scarce health care resources, which are typically insufficient to fulfil all health care wants and needs. One criterion for priority setting may be the 'acceptable health' approach, which suggests that society may want to assign higher priority to health benefits in people with "unacceptable" than in people with "acceptable" health. A level of acceptable health then serves as a reference point for priority setting. Empirical research has indicated that people may be able and willing to define health states as "unacceptable" or "acceptable", but little attention has been given to the normative implications of evaluating health benefits in relation to a reference level of acceptable health. The current paper aims to address this gap by relating insights from the distributive justice literature, i.e. the sufficientarian literature, to the acceptable health approach, as we argue that these approaches are related. We specifically focus on the implications of an 'acceptability' approach for priority weighting of health benefits, derived from sufficientarian reasoning and debates, and assess the moral implications of such weighting.

Methotrexate cross-resistance in a mitoxantrone-selected multidrug-resistant MCF7 breast cancer cell line is attributable to enhanced energy-dependent drug efflux.

Cellular resistance to the antifolate methotrexate (MTX) is often caused by target amplification, uptake defects, or alterations in polyglutamylation. Here we have examined MTX cross-resistance in a human breast carcinoma cell line (MCF7/MX) selected in the presence of mitoxantrone, an anticancer agent associated with the multidrug resistance (MDR) phenotype. Examination of protein expression and enzyme activities showed that MCF7/MX cells displayed none of the classical mechanisms of MTX resistance. They did, however, exhibit an ATP-sensitive accumulation defect accompanied by reduced polyglutamylation. Although the kinetics of drug uptake was similar between parental and resistant cells, the resistant cells exhibited increased energy-dependent drug efflux. This suggested the involvement of an ATP-binding cassette (ABC) transporter. However, cells transfected with the breast cancer resistance protein (BCRP)-the ABC transporter known to be highly overexpressed in MCF7/MX cells and to confer mitoxantrone resistance (D. D. Ross et al., J. Natl. Cancer Inst. 91: 429-433, 1999)-were not MTX resistant, which suggested that this transporter is not involved in MTX cross-resistance. Moreover, members of the MRP protein family of transport proteins, which had previously been implicated in MTX resistance, were not found to be overexpressed in the MCF7/MX cells. Thus, our data suggest that a novel MTX-specific efflux pump may be involved in this unusual cross-resistance phenotype.

DNA nanotechnology for nucleic acid analysis: multifunctional molecular DNA machine for RNA detection.

The Nobel prize in chemistry in 2016 was awarded for 'the design and synthesis of molecular machines'. Here we designed and assembled a molecular machine for the detection of specific RNA molecules. An association of several DNA strands, named multifunctional DNA machine for RNA analysis (MDMR1), was designed to (i) unwind RNA with the help of RNA-binding arms, (ii) selectively recognize a targeted RNA fragment, (iii) attract a signal-producing substrate and (iv) amplify the fluorescent signal by catalysis. MDMR1 enabled detection of 16S rRNA at concentrations ∼24 times lower than that by a traditional deoxyribozyme probe.

Strong indication for a breast cancer susceptibility gene on chromosome 8p12-p22: linkage analysis in German breast cancer families.

Chromosomal losses involving the short arm of chromosome 8 are frequent in a variety of tumor types, including breast cancer, suggesting the presence of one or more tumor suppressor genes in this region. Previous linkage analysis and studies of loss of heterozygosity (LOH) have suggested the presence of a putative third breast cancer susceptibility gene around D8S505 at 8p12-p22. We have performed linkage analysis in two German breast cancer families, showing negative lod scores with 17q and 13q markers, using seven adjacent microsatellite markers from 8p12-p22. Incorporating LOH data from tumors of the affected family members a maximum cumulative three-point lod score of 3.30 at theta = 0.00 was obtained with D8S137 and D8S131. Our findings considerably strengthen the evidence for a third breast cancer susceptibility locus (BRCA3) mapping to the short arm of human chromosome 8.

Relationship of polymorphisms in the renin-angiotensin system and in E-selectin of patients with early severe coronary heart disease.

Previous association studies between angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) polymorphisms and several cardiovascular diseases have reported variable results. Therefore we examined the association of the DNA variants of ACE and AGT with early, severe coronary heart disease (CHD). In addition, we compared the genotypes of both polymorphisms and the recently discovered polymorphism in the E-selectin gene in both patients and an unselected population. This study included 113 patients with severe CHD (50 years old or less) and up to 197 control subjects. The frequencies of the ACE I/D variants were 48% I and 52% D in the controls and 46% I and 54% D in the patients. The frequencies of the AGT-M235T polymorphism were 60.8% M and 39.2% T in controls and 49.1% M and 50.9% T in the patients. The frequencies of the S128R polymorphism of the E-selectin were 91.3% S and 8.7% R in controls and 84.5% S and 15.5% R in the patients. In our studies the DD genotype of ACE was not associated with early severe CHD. We found a correlation between the M235T molecular variant of AGT and the S128R variant of E-selectin to early severe CHD.

Do people desire to be healthier than other people? A short note on positional concerns for health.

Contrary to traditional economic postulates, people do not only care about their absolute position but also about their relative position. However, empirical evidence on positional concerns in the context of health is scarce, despite its relevance for health care policy. This paper presents a first explorative study on positional concerns in the context of health. Using a 'two-world' survey method, a convenience sample of 143 people chose between two options (having more in absolute terms or having more in relative terms) in several health and non-health domains. Our results for the non-health domains compare reasonably well to previous studies, with 22-47% of respondents preferring the positional option. In the health domain, these percentages were significantly lower, indicating a stronger focus on absolute positions. The finding that positional concerns are less prominent in the health domain has important implications for health policy, for instance in balancing reduction of socio-economic inequalities and absolute health improvements.

Haplotyping and estimation of haplotype frequencies for closely linked biallelic multilocus genetic phenotypes including nuclear family information.

With the discovery of single nucleotide polymorphisms (SNP) along the genome, genotyping of large samples of biallelic multilocus genetic phenotypes for (fine) mapping of disease genes or for population studies has become standard practice. A genetic trait, however, is mainly caused by an underlying defective haplotype, and populations are best characterized by their haplotype frequencies. Therefore, it is essential to infer from the phase-unknown genetic phenotypes in a sample drawn from a population the haplotype frequencies in the population and the underlying haplotype pairs in the sample in order to find disease predisposing genes by some association or haplotype sharing algorithm. Haplotype frequencies and haplotype pairs are estimated via a maximum likelihood approach by a well-known expectation maximization (EM) algorithm, adapting it to a large number (up to 30) of biallelic loci (SNP), and including nuclear family information, if available, into the analysis. Parents are treated as an independent sample from the population. Their genotyped offspring reduces the number of potential haplotype pairs for both parents, resulting in a higher accuracy of the estimation, and may also reduce computation time. In a series of simulations our approach of including nuclear family information has been tested against both the EM algorithm without nuclear family information and an alternative approach using GENEHUNTER for the haplotyping of the families, using the locus-by-locus allele counts of the sample. Our new approach is more precise in haplotyping in cases of a high number of heterozygous loci, whereas for a moderate number of heterozygous positions in the sample all three different approaches gave the same perfect results.