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Objective. The main aim of this study was to assess through systematic review the efficacy of exercise and manual therapy (MT) interventions in individuals with primary headache. Methods. In this umbrella review, 2 authors reviewed systematic reviews by searching the Cochrane Database of Systematic Reviews, MEDLINE, PEDro, Web of Science, and Google Scholar. Systematic reviews that evaluated the effectiveness of MT. Exercise-based interventions, or both in patients with primary headaches were included. Methodological quality was analyzed using the ROBIS scale, and the strength of evidence was established according to the Grading Criteria of the Physical Activity Guidelines Advisory Committee. Results. Thirty-one systematic reviews containing 79 trials and involving 9103 patients were included. The 7 exercise-related systematic reviews reported beneficial effects on primary headache based on unclear to moderate evidence. Of the 23 MTrelated systematic reviews, 11 reported enhanced effectiveness compared with usual care; however, overall heterogeneity and risk of bias were high. Systematic reviews that evaluated the effectiveness of MT, exercise-based interventions, or both in patients with primary headaches were included. Conclusion. Results show that exercise could be an effective therapy for the treatment of primary headache, with moderate to limited quality of evidence regarding the positive effects in terms of pain intensity and frequency and duration of headache. Moderate quality of evidence was found regarding the ability of MT to reduce pain intensity in patients with tension-type headaches, but quality of evidence was limited in terms of frequency of headache and disability and pain reduction in patients with migraine. Impact. Exercise could be an effective treatment in patients with primary headache. Manual therapy showed limited evidence to reduce pain intensity in patients with tension-type headache. It is not possible to establish a preferential exercise protocol or MT program, so psychosocial and behavioral variables need to be considered in future studies. Keywords: Exercise, Manual Therapy, Migraine, Primary Headache, Tension-Type Headache, Umbrella Review, Introduction The International Classification of Headache Disorders defines primary headache as a headache disorder not caused by or attributed to another disorder. (1) Primary headache, and especially migraine and tension-type [...]

Objectives: The aim of this study was to compare outcomes of patients treated with the Cook Zenith Fenestrated (ZFEN) device for juxtarenal aortic aneurysms inside versus outside the IFU.Methods: We retrospectively reviewed our institutional ZFEN database for cases performed between 2012 and 2018, with analysis performed in 2020 in order to report midterm outcomes. The cohort was stratified based on treatment inside (IFU group) and outside (non-IFU group) the IFU for criteria involving the proximal neck: neck length 4 to 14 mm, neck diameter 19 to 31 mm, and neck angulation ≤45°. Patients with thoracoabdominal aneurysms or concurrent chimney grafting were excluded. The primary outcomes in question were mortality, type 1a endoleak, and reintervention. Univariate and multivariate analyses were performed to determine associations between adherence to IFU criteria and outcomes.Results: We identified 100 consecutive patients (19% female, mean age 73.6 years) for inclusion in this analysis. Mean follow-up was 21.6 months. Fifty-four patients (54%) were treated outside the IFU because of inadequate neck length (n=48), enlarged neck diameter (n=10), and/or excessive angulation (n=16). Eighteen patients were outside IFU for two criteria, and one patient was outside IFU for all three. Non-IFU patients were exposed to higher radiation doses (3652 vs 5445 mGy, p=0.008) and contrast volume (76 vs 95 mL, p=0.004). No difference was noted between IFU and non-IFU groups for 30-day mortality (0% vs 3.7%, p=0.18), or type 1a endoleak (0% vs 1.9%, p=0.41). Reintervention was also similar between cohorts (13% vs 27.8%, p=0.13). Being outside IFU for neck diameter or length was each borderline significant for higher reintervention on univariate analysis (p=0.05), but this was not significant on multivariate Cox proportional hazard modeling (HR 1.82 [0.53–6.25]; 2.03 [0.68–7.89]), respectively. No individual IFU deviations were associated with the primary outcomes on multivariate analysis, nor being outside IFU for multiple criteria.Conclusions: Patients with juxtarenal aortic aneurysms may be treated with the ZFEN device with moderate deviations from the IFU. While no differences were seen in mortality or proximal endoleak, larger studies are needed to examine the potential association between IFU nonadherence and reinterventions and close follow-up is warranted for all patients undergoing such repair.

OBJECTIVE---Our laboratory has previously established in vitro that a caspase-generated RasGAP N[H.sub.2]-terminal moiety, called fragment N, potently protects cells, including insulinomas, from apoptotic stress. We aimed to determine whether fragment N can increase the resistance of pancreatic β-cells in a physiological setting. RESEARCH DESIGN AND METHODS--A mouse line, called rat insulin promoter (RIP)-N, was generated that bears a transgene containing the rat insulin promoter followed by the cDNA-encoding fragment N. The histology, functionality, and resistance to stress of RIP-N islets were then assessed. RESULTS--Pancreatic β-cells of RIP-N mice express fragment N, activate Akt, and block nuclear factor κB activity without affecting islet cell proliferation or the morphology and cellular composition of islets. Intraperitoneal glucose tolerance tests revealed that RIP-N mice control their glycemia similarly as wild-type mice throughout their lifespan. Moreover, islets isolated from RIP-N mice showed normal glucose-induced insulin secretory capacities. They, however, displayed increased resistance to apoptosis induced by a series of stresses including inflammatory cytokines, fatty acids, and hyperglycemia. RIP-N mice were also protected from multiple low-dose streptozotocin-induced diabetes, and this was associated with reduced in vivo β-cell apoptosis. CONCLUSIONS--Fragment N efficiently increases the overall resistance of β-cells to noxious stimuli without interfering with the physiological functions of the cells. Fragment N and the pathway it regulates represent, therefore, a potential target for the development of antidiabetes tools., Elimination of pancreatic β-cells by apoptosis is a culminating event leading to type 1 diabetes (1) and possibly type 2 diabetes (2,3). The development of tools favoring D-cell survival in [...]

This is the first study investigating qSOFA as a predictor for clinical outcomes in EGS. A new modified qSOFA (qadSOFA) was developed. The AUROC of qSOFA and qadSOFA for mortality was 0.715 and 0.859, respectively with an optimal cut-off value identified as qadSOFA≥3.

The elliptic problem -div⁡(μ⁢∇⁡u)=f-\operatorname{div}(\mu\nabla u)=fis considered, where μ>0\mu>0is smooth but strongly varying. Anisotropic a posteriori error estimates are derived, the effectivity index being bounded above and below by two constants independent of the data 𝑓, 𝜇, the mesh size and aspect ratio, up to higher order terms. Numerical experiments on non-adapted and adapted anisotropic meshes confirm these predictions.

Objective: Although genetic factors have been implicated in the etiology of bipolar disorder, no specific gene has been conclusively identified. Given the link between abnormalities in serotonergic neurotransmission and bipolar disorder, a candidate gene association approach was applied to study the involvement of the monoamine oxidase A (MAOA) gene, which codes for a catabolic enzyme of serotonin, in the susceptibility to bipolar disorder. Method: In France and Switzerland, 272 patients with bipolar disorder and 122 healthy subjects were typed for three polymorphic markers of the MAOA gene: the MAOA-CA repeat, the MAOA restriction fragment length polymorphism (RFLP), and a repeat directly adjacent to the variable number of tandem repeats (VNTR) locus. Results: A significant difference in the distribution of the alleles for the MAOA-CA repeat was observed between the female bipolar patients and comparison group. Conclusions: The results obtained in the French and Swiss population confirm findings from two studies conducted in the United Kingdom.

Objective: To determine to what extent human immunodeficiency type 1 (HIV-1) RNA levels and [CD4.sup.+] cell counts predict clinical outcomes in a general HIV-1-infected population. Methods: Community-based prospective study (Swiss HIV Cohort Study) including 394 HIV-1-infected patients, randomly selected from 4 strata of [CD4.sup.+] cell counts (0 to [is greater than or equal to] 0.50 x [10.sup.9]L). Levels of HIV-1 RNA, [CD4.sup.+] cell counts, and other variables were evaluated from samples collected between 1991 and 1993 for their ability to predict death and clinical progression. Results: Patients were followed up on average for 29 months. Baseline HIV-1 RNA levels, [CD4.sup.+] cell counts, clinical stage, and 02-microglobulin levels independently predicted survival, whereas only HIV-1 RNA levels and [CD4.sup.4] cell counts independently predicted clinical progression. Multivariate relative hazards it (RHs) for death ranged from 1.0 to 5.4 across quartiles of [CD4.sup.+] counts, but only from 1.0 to 1.8 across quartiles of HIV-1 RNA. For clinical progression, gradients of risk were similar for [CD4.sup.+] counts (1.0-4.2) and for HIV-1 RNA (1.0-3.1). In patients with [CD4.sup.+] cell counts less than 0.05 x [10.sup.9]/L HIV-1 RNA levels predicted neither death nor clinical progression. Finally, the number of HIV-1 RNA copies per [CD4.sup.+] cell was the best predictor of death (multivariate RH, 1.0-9.7 across quartiles) and clinical progression (multivariate RH, 1.0-4.1). Conclusions: Levels of HIV-1 RNA and CD41 cell counts provided independent and complementary information on clinical outcomes. The RNA/[CD4.sup.+] ratio was the best single predictor. In patients who had fewer than 0.05 x [10.sup.9]/L [CD4.sup.+] cells, HIV-1 RNA levels had little prognostic value. Arch Intern Med. 1998;158:247-252

Grapevine red blotch virus (GRBV) is a recently identified virus that infects grapevine and has a severe impact on the grape industry in North America. Since the first description of the virus 8 years ago, clear progress has been made regarding our understanding of the GRBV pathosystem. However, questions remain regarding the origin of this pathogen and its spread outside North America, especially in Europe. In this study, we present the results of a large-scale GRBV survey in two European repositories; we targeted Vitisspp. accessions with diverse geographical origins. Of 816 accessions from different origins (50 different countries around the world), six accessions were infected by GRBV, all of which originated from the United States. We investigated the DNA virome of 155 grapevine accessions from the Swiss grapevine collection using high-throughput sequencing. We observed that virome of the Swiss grapevine collection was composed of several RNA viruses. In contrast, we did not detect any DNA viruses in the 155 Swiss grapevine accessions. This finding suggests that the abundance of DNA viruses infecting grapevines in Switzerland is either very low or non-existent. Our results and the findings of studies published since 2008 show that GRBV most likely originated in North America and subsequently spread to other viticultural areas in the world via unintentional movement of infected cuttings. According to our data, the most plausible scenario for the origin of GRBV is that the virus evolved from non-Vitis viniferahosts and underwent a host jump to Vitis viniferaafter its introduction to North America in the 1600s.

Early use of effective antimicrobial treatments is critical for the outcome of infections and the prevention of treatment resistance. Antimicrobial resistance testing enables the selection of optimal antibiotic treatments, but current culture-based techniques can take up to 72 hours to generate results. We have developed a novel machine learning approach to predict antimicrobial resistance directly from matrix-assisted laser desorption/ionization–time of flight (MALDI-TOF) mass spectra profiles of clinical isolates. We trained calibrated classifiers on a newly created publicly available database of mass spectra profiles from the clinically most relevant isolates with linked antimicrobial susceptibility phenotypes. This dataset combines more than 300,000 mass spectra with more than 750,000 antimicrobial resistance phenotypes from four medical institutions. Validation on a panel of clinically important pathogens, including Staphylococcus aureus, Escherichia coliand Klebsiella pneumoniae, resulting in areas under the receiver operating characteristic curve of 0.80, 0.74 and 0.74, respectively, demonstrated the potential of using machine learning to substantially accelerate antimicrobial resistance determination and change of clinical management. Furthermore, a retrospective clinical case study of 63 patients found that implementing this approach would have changed the clinical treatment in nine cases, which would have been beneficial in eight cases (89%). MALDI-TOF mass spectra-based machine learning may thus be an important new tool for treatment optimization and antibiotic stewardship.

Rat bite fever is a rarely reported acute febrile bacterial illness caused by, Streptobacillus moniliformis or Spirillum minus following a rat bite. It is classically characterised by abrupt onset of [...]

To report renal outcomes including long-term patency, secondary interventions, and related renal function after fenestrated endovascular aortic repair (fEVAR).

A space-time adaptive algorithm to solve the motion of a rigid disk in an incompressible Newtonian fluid is presented, which allows collision or quasi-collision processes to be computed with high accuracy. In particular, we recover the theoretical result proven in [M. Hillairet, Lack of collision between solid bodies in a 2D incompressible viscous flow, Comm. Partial Differential Equations 32 2007, 7–9, 1345–1371], that the disk will never touch the boundary of the domain in finite time. Anisotropic, continuous piecewise linear finite elements are used for the space discretization, the Euler scheme for the time discretization. The adaptive criteria are based on a posteriori error estimates for simpler problems.

Short-term outcomes in patients with all forms of TOS have been widely reported in the literature and have established that rib resection can be beneficial in decompressing the thoracic outlet and relieving pressure on traversing structures. We sought to determine long-term functional outcomes using the Disability of the Arm, Shoulder, and Hand (QuickDASH) survey in patients with TOS who underwent rib resection.

The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of nintedanib in subgroups based on ILD diagnosis.

Rib resection in venous thoracic outlet syndrome (vTOS) may be approached via a transaxillary, supraclavicular, or infraclavicular approach based on surgeon preference. The purpose of this study was to evaluate long-term postoperative quality of life function after surgery for vTOS and to determine if there were long-term patency differences associated with the surgical approach or whether prophylactic postoperative venography was performed.

The Octopus endovascular strategy involves placement of multiple, stacked bifurcated grafts in the thoracic segment of a thoracoabdominal aneurysm (TAAA) to facilitate deployment of multiple parallel covered stents for visceral perfusion. This study aimed to review early outcomes of the Octopus TAAA repair strategy at a tertiary, high-volume referral center.

ABSTRACTBiomethanization is a new technology used for green-waste valorization where organic waste is biodegraded by microbial communities under anaerobic conditions. The main product of this type of anaerobic digestion is a biogas used as an energy source. Moving and handling organic waste may lead to the emission of high concentrations of bioaerosols. High exposure levels are associated with adverse health effects amongst green environment workers. Fungal spores are suspected to play a role in many respiratory illnesses. There is a paucity of information related to the detailed fungal diversity in biomethanization facilities. The aim of this study was to provide an in-depth description of fungal bioaerosols in biomethanization work environments using a next-generation sequencing approach combined with real-time polymerase chain reaction (PCR). Two biomethanization facilities treating different wastes were visited during the sampling campaign (n = 16). Quantification of Penicillium/Aspergillusand Aspergillus fumigatusrevealed a greater exposure risk during summer for both facilities visited. Concentrations of Penicilliumand Aspergilluswere similar in all work areas in both biomethanization facilities. Taxonomy analyses showed that the type of waste treated affects the fungal diversity of aerosols emitted. Although eight classes were evenly distributed in all samples, Eurotiomycetes were more dominant in the first facility and Agaricomycetes were dominant in the second one. A large diversity profile was observed in bioaerosols from both facilities showing the presence of pathogenic fungi. The following fungi detected are known allergens and/or are opportunistic pathogens: Aspergillus, Malassezia, Emericella, Fusarium, Acremonium, and Candida. Daily exposure to these fungi may put workers at risk. The information from this study can be used as a reference for minimizing occupational exposure in future biomethanization facilities.Implications: Biomethanization is a new technology used for green-waste valorization where organic waste is biodegraded by microbial communities. Effective waste management is increasingly recognized as a strategic approach for achieving newly created regulations concerning the disposal of organic residues; therefore, an expansion of facilities is expected. Workers’ exposure to diverse fungal communities is certain, as fungi are ubiquitous and necessary in organic matter decomposition. Monitoring this occupational exposure is important in order to prevent workers’ health problems.

Alcohol owes its origin to the ancient alchemists' quest to develop elixirs they believed were liquid roadmaps to divinity and had healing powers for both the body and the soul. [...]

ABSTRACTThis study sought to fill the gap in information about the type and the concentration of bioaerosols present in the air of biomethanization facilities (BF). Evaluation of bioaerosol composition and concentration was achieved in two biomethanization facilities located in Eastern Canada, during summer and winter. In order to have a thorough understanding of the studied environment, the methodology combined culture of bacteria and molds, qualitiative polymerase chain reaction (qPCR) for specific microorganisms, endotoxin quantification, and next-generation sequencing (NGS) for bacterial diversity. Results revealed that workers in biomethanization facilities are exposed to bioaerosols and pathogenic microorganisms similar to those found in composting plants. However, human exposure levels to bioaerosols are lower in BF than in composting plants. Despite these differences, use of personal protective equipment is recommended to lower the risks of health problems.Implications: Biomethanization is a new technology used in eastern Canada for waste management. In the next few years, it is expected that there will be an expansion of facilities in response of tight governmental regulations. Workers in biomethanization facilities are exposed to various amounts of bioaerosols composed of some harmful microorganisms. Therefore, monitoring this occupational exposure could be an interesting tool for improving worker’s health.

The bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 (PFKFB4) controls metabolic flux through allosteric regulation of glycolysis. Here we show that p53 regulates the expression of PFKFB4 and that p53-deficient cancer cells are highly dependent on the function of this enzyme. We found that p53 downregulates PFKFB4 expression by binding to its promoter and mediating transcriptional repression via histone deacetylases. Depletion of PFKFB4 from p53-deficient cancer cells increased levels of the allosteric regulator fructose-2,6-bisphosphate, leading to increased glycolytic activity but decreased routing of metabolites through the oxidative arm of the pentose-phosphate pathway. PFKFB4 was also required to support the synthesis and regeneration of nicotinamide adenine dinucleotide phosphate (NADPH) in p53-deficient cancer cells. Moreover, depletion of PFKFB4-attenuated cellular biosynthetic activity and resulted in the accumulation of reactive oxygen species and cell death in the absence of p53. Finally, silencing of PFKFB4-induced apoptosis in p53-deficient cancer cells in vivoand interfered with tumour growth. These results demonstrate that PFKFB4 is essential to support anabolic metabolism in p53-deficient cancer cells and suggest that inhibition of PFKFB4 could be an effective strategy for cancer treatment.

Recent empirical studies have highlighted the large degree of analytic flexibility in data analysis that can lead to substantially different conclusions based on the same data set. Thus, researchers have expressed their concerns that these researcher degrees of freedom might facilitate bias and can lead to claims that do not stand the test of time. Even greater flexibility is to be expected in fields in which the primary data lend themselves to a variety of possible operationalizations. The multidimensional, temporally extended nature of speech constitutes an ideal testing ground for assessing the variability in analytic approaches, which derives not only from aspects of statistical modeling but also from decisions regarding the quantification of the measured behavior. In this study, we gave the same speech-production data set to 46 teams of researchers and asked them to answer the same research question, resulting in substantial variability in reported effect sizes and their interpretation. Using Bayesian meta-analytic tools, we further found little to no evidence that the observed variability can be explained by analysts’ prior beliefs, expertise, or the perceived quality of their analyses. In light of this idiosyncratic variability, we recommend that researchers more transparently share details of their analysis, strengthen the link between theoretical construct and quantitative system, and calibrate their (un)certainty in their conclusions.

We summarize previous field effect studies in high-Tccuprates and then discuss our method to smoothly tune the carrier concentration of a cuprate film over a wide range using an applied electric field. We synthesized epitaxial one-unit-cell thick films of La2−xSrxCuO4and from them fabricated electric double layer transistor devices utilizing various gate electrolytes. We were able to vary the carrier density by about 0.08 carriers per Cu atom, with the resulting change in Tcof 30 K. The superconductor-insulator transition occurred at the critical resistance very close to the quantum resistance for pairs, RQ= h/(2e)2= 6.5 kΩ. This is suggestive of a quantum phase transition, possibly driven by quantum phase fluctuations, between a “Bose insulator” and a high-Tcsuperconductor state.

This work combines hyper-Rayleigh scattering (HRS) experiments performed in the NIR range (1.30 and 1.60 μm) and quantum chemical calculations to provide a comprehensive description of the second harmonic generation (SHG) responses of donor–acceptor Stenhouse adducts (DASAs). Representative derivatives of the three generations of DASAs, which differ by the nature of their electron-donating and withdrawing moieties and also include clickable species, have been synthesized and their photoswitching behavior fully characterized. The HRS measurements allow us to establish relationships between the magnitude of the SHG response of open forms and the nature of the donor and acceptor groups. The largest SHG responses are obtained for derivatives incorporating either a barbituric acid or an indanedione acceptor unit, while N-methylaniline appears as the most efficient donor group. The calculations support well the experimental data and show that high hyperpolarizabilities are associated to low excitation energies and large extent of the photoinduced intramolecular charge transfer, which enhances the dipole moment variation between the ground and first dipole-allowed electronic excited state. In addition, a complete investigation of the photoswitching kinetics of DASAs in chloroform solution shows important differences, highlighting in particular the role of the donor group on the photoswitching efficiency.

Since the first implantation of an endograft in 1991, endovascular aneurysm repair (EVAR) rapidly gained recognition. Historical trials showed lower early mortality rates but these results were not maintained beyond 4 years. Despite newer-generation devices, higher rates of reintervention are associated with EVAR during follow-up. Therefore, the best therapeutic decision relies on many parameters that the physician has to take in consideration. Patient’s preferences and characteristics are important, especially age and life expectancy besides health status. Aneurysmal anatomical conditions remain probably the most predictive factor that should be carefully evaluated to offer the best treatment. Unfavorable anatomy has been observed to be associated with more complications especially endoleak, leading to more re-interventions and higher risk of late mortality. Nevertheless, technological advances have made surgeons move forward beyond the set barriers. Thus, more endografts are implanted outside the instructions for use despite excellent results after open repair especially in low-risk patients. When debating about AAA repair, some other crucial points should be analysed. It has been shown that strict surveillance is mandatory after EVAR to offer durable results and prevent late rupture. Such program is associated with additional costs and with increased risk of radiation. Moreover, a risk of loss of renal function exists when repetitive imaging and secondary procedures are required. The aim of this article is to review the data associated with abdominal aortic aneurysm and its treatment in order to establish selection criteria to decide between open or endovascular repair.

Intimal hyperplasia (IH) is the major cause of stenosis of vein grafts. Drugs such as statins prevent stenosis, but their systemic administration has limited effects. We developed a hyaluronic acid hydrogel matrix, which ensures a controlled release of atorvastatin (ATV) at the site of injury. The release kinetics demonstrated that 100% of ATV was released over 10 hours, independent of the loading concentration of the hydrogel. We investigated the effects of such a delivery on primary vascular smooth muscle cells isolated from human veins. ATV decreased the proliferation, migration, and passage of human smooth muscle cells (HSMCs) across a matrix barrier in a similar dose-dependent (5–10 µM) and time-dependent manner (24–72 hours), whether the drug was directly added to the culture medium or released from the hydrogel. Expression analysis of genes known to be involved in the development of IH demonstrated that the transcripts of both the gap junction protein connexin43 (Cx43) and plasminogen activator inhibitor-1 (PAI-1) were decreased after a 24–48-hour exposure to the hydrogel loaded with ATV, whereas the transcripts of the heme oxygenase (HO-1) and the inhibitor of tissue plasminogen activator were increased. At the protein level, Cx43, PAI-1, and metalloproteinase-9 expression were decreased, whereas HO-1 was upregulated in the presence of ATV. The data demonstrate that ATV released from a hydrogel has effects on HSMCs similar to the drug being freely dissolved in the environment.

ABSTRACTBacterial factors may contribute to the global emergence and spread of drug-resistant tuberculosis (TB). Only a few studies have reported on the interactions between different bacterial factors. We studied drug-resistant Mycobacterium tuberculosisisolates from a nationwide study conducted from 2000 to 2008 in Switzerland. We determined quantitative drug resistance levels of first-line drugs by using Bactec MGIT-960 and drug resistance genotypes by sequencing the hot-spot regions of the relevant genes. We determined recent transmission by molecular methods and collected clinical data. Overall, we analyzed 158 isolates that were resistant to isoniazid, rifampin, or ethambutol, 48 (30.4%) of which were multidrug resistant. Among 154 isoniazid-resistant strains, katGmutations were associated with high-level and inhApromoter mutations with low-level drug resistance. Only katG(S315T) (65.6% of all isoniazid-resistant strains) and inhApromoter −15C/T (22.7%) were found in molecular clusters. M. tuberculosislineage 2 (includes Beijing genotype) was associated with any drug resistance (adjusted odds ratio [OR], 3.0; 95% confidence interval [CI], 1.7 to 5.6; P< 0.0001). Lineage 1 was associated with inhApromoter −15C/T mutations (OR, 6.4; 95% CI, 2.0 to 20.7; P= 0.002). We found that the genetic strain background influences the level of isoniazid resistance conveyed by particular mutations (interaction tests of drug resistance mutations across all lineages; P< 0.0001). In conclusion, M. tuberculosisdrug resistance mutations were associated with various levels of drug resistance and transmission, and M. tuberculosislineages were associated with particular drug resistance-conferring mutations and phenotypic drug resistance. Our study also supports a role for epistatic interactions between different drug resistance mutations and strain genetic backgrounds in M. tuberculosisdrug resistance.

Molecular beam epitaxy technique has enabled synthesis of atomically smooth thin films, multilayers, and superlattices of cuprates and other complex oxides. Such heterostructures show high temperature superconductivity and enable novel experiments that probe the basic physics of this phenomenon. For example, it was established that high temperature superconductivity and anti-ferromagnetic phases separate on �ngström scale, while the pseudo-gap state apparently mixes with high temperature superconductivity over an anomalously large length scale (the "Giant Proximity Effect"). We review some recent experiments on such films and superlattices, including X-ray diffraction, atomic force microscopy, angle-resolved time of flight ion scattering and recoil spectroscopy, transport measurements, highresolution transmission electron microscopy, resonant X-ray scattering, low-energy muon spin resonance, and ultrafast photo-induced reflection high energy electron diffraction. The results include an unambiguous demonstration of strong coupling of in-plane charge excitations to out-of-plane lattice vibrations, a discovery of interface high temperature superconductivity that occurs in a single CuO2plane, evidence for local pairs, and establishing tight limits on the temperature range of superconducting fluctuations.

Cough is a common symptom of diseases such as asthma and COPD and also presents as a disease in its own right. Treatment options are limited; a recent meta-analysis concluded that over-the-counter remedies are ineffective, and there is increasing concern about their use in children. Transient receptor potential cation channel, subfamily A, member 1 (TRPA1) channels are nonselective cation channels that are activated by a range of natural products (eg, allyl isothiocyanate), a multitude of environmental irritants (eg, acrolein, which is present in air pollution, vehicle exhaust, and cigarette smoke), and inflammatory mediators (eg, cyclopentenone prostaglandins). TRPA1 is primarily expressed in small-diameter, nociceptive neurons where its activation probably contributes to the perception of noxious stimuli. Inhalational exposure to irritating gases, fumes, dusts, vapors, chemicals, and endogenous mediators can lead to the development of cough. The respiratory tract is innervated by primary sensory afferent nerves, which are activated by mechanical and chemical stimuli. Recent data suggest that activation of TRPA1 on these vagal sensory afferents by these irritant substances could lead to central reflexes, including dyspnea, changes in breathing pattern, and cough, which contribute to the symptoms and pathophysiology of respiratory diseases.

RasGAP bears two caspase-3 cleavage sites that are used sequentially as caspase activity increases in cells. When caspase-3 is mildly activated, RasGAP is first cleaved at position 455. This leads to the production of an N-terminal fragment, called fragment N, that activates the Ras-PI3K-Akt pathway and that promotes cell survival. At higher caspase activity, RasGAP is further cleaved at position 157 generating two small N-terminal fragments named N1 and N2. We have now determined the contribution of this second cleavage event in the regulation of apoptosis using cells in which the wild-type RasGAP gene has been replaced by a cDNA encoding a RasGAP mutant that cannot be cleaved at position 157. Our results show that cleavage of fragment N at position 157 leads to a marked reduction in Akt activity. This is accompanied by efficient processing of caspase-3 that favors cell death in response to various apoptotic stimuli. In nontumorigenic cells, fragments N1 and N2 do not modulate apoptosis. Therefore, the role of the second caspase-mediated cleavage of RasGAP is to allow the inactivation of the antiapoptotic function of fragment N so that caspases are no longer hampered in their ability to kill cells.

Plant secondary metabolism significantly contributes to defensive measures against adverse abiotic and biotic cues. To investigate stress-induced, transcriptional alterations of underlying effector gene families, which encode enzymes acting consecutively in secondary metabolism and defense reactions, a DNA array (MetArray) harboring gene-specific probes was established. It comprised complete sets of genes encoding 109 secondary product glycosyltransferases and 63 glutathione-utilizing enzymes along with 62 cytochrome P450 monooxygenases and 26 ABC transporters. Their transcriptome was monitored in different organs of unstressed plants and in shoots in response to herbicides, UV-B radiation, endogenous stress hormones, and pathogen infection. A principal component analysis based on the transcription of these effector gene families defined distinct responses and crosstalk. Methyl jasmonate and ethylene treatments were separated from a group combining reactions towards two sulfonylurea herbicides, salicylate and an avirulent strain of Pseudomonas syringaepv. tomato. The responses to the herbicide bromoxynil and UV-B radiation were distinct from both groups. In addition, these analyses pinpointed individual effector genes indicating their role in these stress responses. A small group of genes was diagnostic in differentiating the response to two herbicide classes used. Interestingly, a subset of genes induced by P. syringaewas not responsive to the applied stress hormones. Small groups of comprehensively induced effector genes indicate common defense strategies. Furthermore, homologous members within branches of these effector gene families displayed differential expression patterns either in both organs or during stress responses arguing for their non-redundant functions.

The aims of this study were to relate heart morphology and functions changes to heart rate variability (HRV) components after acclimatization to high altitude and to define whether preadaptation to hypoxia could modulate HRV responses to acute hypoxic stress. Doppler-echocardiographic studies of the left ventricle were performed in female Wistar rats before, during, and after a 10-week exposure to moderate hypobaric hypoxia (CH rats, ~4000 m simulated) or normoxia (N rats, ~55 m). Right ventricular morphology and function and pulmonary artery pressure were evaluated using heart catheterization. Spectral analysis of HRV was studied after exposure in conscious unrestrained rats in normoxia and during acute hypoxic stress. Necropsy right ventricular hypertrophy and intraventricular and pulmonary artery hypertension were found in CH rats compared with N rats. Echocardiographic left ventricular morphology and functions were similar between the groups after exposures. Compared to the control group, CH rats had similar heart rates and HRV components when measured in normoxia. During acute hypoxic stress, HRV decreased in all rats, but less in CH rats. These results support the hypothesis that long-term mild hypoxia may moderate sympathetic activation induced by acute hypoxia and that right ventricular hypertrophy cannot be the direct cause of such a shift in sympathovagal nerve interaction during acute hypoxic stress.

High tensions of carbon monoxide (CO), relative to oxygen, were used as a tool to investigate the mechanism of chemotransduction. In an in vitrowhole organ, rat carotid body preparation, CO increased sinus nerve chemoafferent discharge in the dark, an effect that was significantly reduced (by ca70 %) by bright white light and by the removal of extracellular Ca2+from the superfusate or by the addition of either Ni2+(2 mM) or methoxyverapamil (100 μM). Addition of the P2purinoceptor antagonist pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (50 μM) also significantly reduced the neural response to CO. In perforated patch, whole‐cell recordings of isolated rat type I cells, CO induced a depolarisation of ca11 mV and a decrease in the amplitude of an outward current around and above the resting membrane potential. Membrane conductance between ‐50 and ‐60 mV was significantly reduced by ca40 % by CO. These effects were not photolabile and were present also when a ‘blocking solution’ containing TEA, 4‐AP, Ni2+and zero extracellular Ca2+was used. In conventional whole‐cell recordings, CO only decreased current amplitudes above +10 mV and was without effect around the resting membrane potential. These data demonstrate a direct effect of CO upon type I cell K+conductances and strongly suggest an effect upon a background, leak conductance that requires an intracellular mediator. The photolabile effect of CO only upon afferent neural discharge adds further evidence to a dual site of action of CO with a separate action at the afferent nerve terminal that, additionally, requires the permissive action of the neurotransmitter ATP.

Objective:This study aimed at the evaluation of the subjective experience and long-term behavioral and psychological effects of precocious puberty (PP). Methods:19 female patients who had been treated with GnRH agonists participated in a semistructured interview and completed two standardized checklists. Their parents completed the Child Behavior Checklist (CBCL). Results:The CBCL yielded significantly elevated Internalizing and Total Behavior Problem scores. An elevated risk was found for patients with short adult stature and a relatively late onset of PP. The latter tended to neuroticism, to accentuation of their physical appearance, and felt significantly more insecure than age-related non-PP girls. Conclusion:Our findings suggest that PP can lead to specific behavioral problems, and that patients with a risk factor may need psychosocial support.

Self-related Experience in the Training of Behavior Therapists: Overview and First Evaluation of a ProgramBackground: During the past years, a growing body of research has documented the importance of scientific evaluation of selfrelated experience (SE) as an element in the training and education of behavior therapists. After a survey of the literature this paper describes the SE concept developed through our research group and a first attempt of its evaluation. Method: Our primary interest was to assess the group experience over the course of 100 hours distributed over 4 weekends. The main focus was on the third weekend, which included an additional evaluation process of participants and group leaders. We further assessed the participants’ expectations as well as their ratings after participation. Results: Results of the group experience indicate that the evaluation on the third weekend stimulated a reflection of intra- and interindividual processes and facilitated new learning experiences. Before starting the SE group, participants mainly expected a development of their basic therapeutic skills (e.g. empathy, positive regard). However, according to the retrospective ratings of the participants, personal aspects of self-experience have been addressed more intensively and their conveyance was rated as more effective. The expectations before beginning SE were generally higher than the ratings of the perceived contents after participation. Conclusions: The results suggest that the value of SE depend on participants’ experience as therapists as well as on duration and level of their training as behavior therapists. Accordingly, the contents of SE should be adapted in a flexible way.

Lipoteichoic and teichoic acids are components of the cell wall of Streptococcus pneumoniae.A recently developed enzyme immunoassay was used in patients with pneumococcal meningitis to investigate lipoteichoic and teichoic acid concentrations in CSF at the first lumbar puncture in relation to the clinical outcome determined by the Glasgow Outcome Scale. Lipoteichoic and teichoic acid concentrations in CSF were significantly associated with neurologic sequelae and mortality in S. pneumoniaemeningitis.

The most potent corticosteroids are 11β-hydroxylated compounds. In humans, two cytochrome P450 isoenzymes with 11β-hydroxylase activity, catalysing the biosynthesis of cortisol and aldosterone, are present in the adrenal cortex. CYP11B1, the gene encoding 11β-hydroxylase (P450c11), is expressed on high levels in the zona fasciculata and is regulated by ACTH. CYP11B2, the gene encoding aldosterone synthase (P450c11Aldo), is expressed in the zona glomerulosa under primary control of the renin-angiotensin system. Aldosterone synthase has 11β-hydroxylase activity as well as 18-hydroxylase activity and 18-oxidase activity. The substrate for CYP11B2 is 11-deoxycorticosterone, that of CYP11B1 is 11-deoxycortisol. Mutations in CYP11B1 cause congenital adrenal hyperplasia (CAH) due to 11β-hydroxylase deficiency. This disorder is characterized by androgen excess and hypertension. Mutations in CYP11B2 cause congenital hypoaldosteronism (aldosterone synthase deficiency) which is characterized by life-threatening salt loss, failure to thrive, hyponatraemia and hyperkalaemia in early infancy. Both disorders have an autosomal recessive inheritance. Classical and nonclassical forms of 11β-hydroxylase deficiency can be distinguished. Studies in heterozygotes for classical 11β-hydroxylase deficiency show inconsistent results with no or only mild hormonal abnormalities (elevated plasma levels of 11-deoxycortisol after ACTH stimulation). In infants with congenital hypoaldosteronism, a comparable frequency of 18-hydroxylase deficiency (aldosterone synthase deficiency type I) and of 18-oxidase deficiency (aldosterone synthase deficiency type II) can be found. Molecular genetic studies of the CYP11B1 and CYP11B2 genes in 11β-hydroxylase deficiency or aldosterone synthase deficiency have led to the identification of several mutations. Transfection experiments showed loss of enzyme activity in vitro. In some of the patients with 18-oxidase deficiency (aldosterone synthase deficiency type II) no mutations in the CYP11B2 gene were identified. Refined methods for steroid determination are the basis for the diagnosis of inborn errors of steroidogenesis. Molecular genetic studies are complementary; on the one hand, they have practical importance for the prenatal diagnosis of virilizing CAH forms and on the other hand, they are of theoretical importance in terms of our understanding of the functioning of cytochrome P450 enzymes.

Beta vulgaris cells were cultured in specially constructed fluidized bed reactors on Murashige and Skoog medium with 3% sucrose as a carbon source. Biomass density levels of approximately 17–18 g dry cell weight liter-1 for 5 liter fermenters and 9–10 g dry cell weight liter-1 for 50 liter reactor were observed. Depending on particular cell line, cell content of betalains reached levels ranging from 12 to 25 mg g dry cell weight-1, representing the productivities of 14 to 17 mg of pigments per liter and day.