Participation, retention and uptake in a multicentre pre-exposure prophylaxis cohort using online, smartphone-compatible data collection.

OBJECTIVES: The aim of the study was to assess the feasibility of a national pre-exposure prophylaxis (PrEP) programme using smartphone-compatible data collection. METHODS: This was a multicentre cohort study (NCT03893188) enrolling individuals interested in PrEP in Switzerland. All centres participate in the SwissPrEPared programme, which uses smartphone-compatible data collection. Feasibility was assessed after centres had enrolled at least one participant. Participants were HIV-negative individuals presenting for PrEP counselling. Outcomes were participation (number enrolled/number eligible), enrolment rates (number enrolled per month), retention at first follow-up (number with first follow-up/number enrolled), and uptake (proportion attending first visit as scheduled). Participant characteristics were compared between those retained after baseline assessment and those who dropped out. RESULTS: Between April 2019 and January 2020, 987 individuals were assessed for eligibility, of whom 969 were enrolled (participation: 98.2%). The median enrolment rate was 86 per month [interquartile range (IQR) 52-137]. Retention at first follow-up and uptake were both 80.7% (782/969 and 532/659, respectively). At enrolment, the median age was 40 (IQR 33-47) years, 95% were men who have sex with men, 47% had a university degree, and 75.5% were already taking PrEP. Most reported multiple casual partners (89.2%), previous sexually transmitted infections (74%) and sexualized drug use (73.1%). At baseline, 25.5% tested positive for either syphilis, gonorrhoea or chlamydia. Participants who dropped out were at lower risk of HIV infection than those retained after baseline assessment. CONCLUSIONS: In a national PrEP programme using smartphone-compatible data collection, participation, retention and uptake were high. Participants retained after baseline assessment were at considerable risk of HIV infection. Younger, less educated individuals were underrepresented in the SwissPrEPared cohort.

Using longitudinally sampled viral nucleotide sequences to characterize the drivers of HIV-1 transmission.

OBJECTIVES: Understanding the drivers of HIV-1 transmission is of importance for curbing the ongoing epidemic. Phylogenetic methods based on single viral sequences allow us to assess whether two individuals are part of the same viral outbreak, but cannot on their own assess who potentially transmitted the virus. We developed and assessed a molecular epidemiology method with the main aim to screen cohort studies for and to characterize individuals who are 'potential HIV-1 transmitters', in order to understand the drivers of HIV-1 transmission. METHODS: We developed and validated a molecular epidemiology approach using longitudinally sampled viral Sanger sequences to characterize potential HIV-1 transmitters in the Swiss HIV Cohort Study. RESULTS: Our method was able to identify 279 potential HIV-1 transmitters and allowed us to determine the main epidemiological and virological drivers of transmission. We found that the directionality of transmission was consistent with infection times for 72.9% of 85 potential HIV-1 transmissions with accurate infection date estimates. Being a potential HIV-1 transmitter was associated with risk factors including viral load [adjusted odds ratiomultivariable (95% confidence interval): 1.86 (1.49-2.32)], syphilis coinfection [1.52 (1.06-2.19)], and recreational drug use [1.45 (1.06-1.98)]. By contrast for the potential HIV-1 recipients, this association was weaker or even absent [1.18 (0.82-1.72), 0.89 (0.52-1.55) and 1.53 (0.98-2.39), respectively], indicating that inferred directionality of transmission is useful at the population level. CONCLUSIONS: Our results indicate that longitudinally sampled Sanger sequences do not provide sufficient information to identify transmitters with high certainty at the individual level, but that they allow the drivers of transmission at the population level to be characterized.

Rhinophototherapy in chronic rhinosinusitis: a double blind randomized placebo-controlled trial.

BACKGROUND: This study evaluated the efficacy of rhinophototherapy in patients with chronic rhinosinusitis (CRS) without nasal polyps. METHOD: In this randomized double-blind, placebo-controlled trial, CRS patients (n=50) received either mixed visible and ultraviolet (UVA and UVB) light source application (mUV/VIS) or visible light alone that served as placebo. Both groups were treated for 3 weeks. RESULTS: Results in the rhinophototherapy and placebo group were not significantly different and failed to reduce patient-reported outcomes measures (Rhinosinusits Disability Index, Visual Analogic Scale of symptom severity) and objective scores (rhinomanometry, olfactory thresholds, nasal Nitic Oxide concentrations), immediately and one month after treatment. CONCLUSIONS: The present data suggest that rhinophototherapy is not an efficient treatment for chronic rhinosinusitis without nasal polyps.

[Robotic-Assisted Oesophageal Surgery]. / Roboterchirurgie am Ösophagus.

BACKGROUND: Abdominothoracic oesophageal resections, also known as Ivor Lewis procedures, are complex visceral surgery procedures. In recent years, substeps have increasingly been performed using minimally invasive techniques. However, intrathoracic anastomosis is still a challenge given the instrumental and technological possibilities available to date. This article provides a detailed description of the use of the Da Vinci robotic system and our techniques in oesophageal surgery. METHODS: In a prospective data collection, we analysed the robotic-assisted oesophageal surgeries performed at the University Hospital of Schleswig-Holstein, Campus Kiel, between November 2013 and November 2015. RESULTS: A total of 56 patients underwent robotic-assisted oesophageal surgery, with 43 patients undergoing the Ivor Lewis technique, 10 patients undergoing the McKeown procedure and 3 patients undergoing enucleation of a leiomyoma. A complete tumour resection (R0 margin) was achieved in 53 patients (93.4%); the mean number of resected lymph nodes was 23 (14-75). Forty-five (80.5%) patients received an induction therapy. Mean operative time was 412 min (120-610); mean hospital stay was 19 days (4-145). A conversion to open surgery was necessary in 19 (34.1%) cases, most notably in the thoracic part of the surgical procedure (17 patients). Forty-three patients received intrathoracic oesophagogastrostomy; 4 out of 5 patients with an initial side-to-side anastomosis developed a leakage, whereupon the technique was switched to a hand-sewn procedure (leakage in 3 out of 20 patients). Other major morbidities included leakage of the gastric conduit in 2 patients (3.6%), airway fistula in 2 patients (3.6%), mesenteric ischaemia in one patient (1.8%), and peritonitis due to a dislocated feeding tube in one other patient. Pulmonary complications occurred in 19 patients (34%). Four patients (7.1%) died of pulmonary embolism, heart attack, and septic organ failure. CONCLUSION: Robotic-assisted, minimally invasive oesophagectomy is a feasible and useful approach for oncological surgery. This technique should be implemented in a structured program with an extensive and critical evaluation of the users' own results and an exchange with other experienced work teams. This helps to avoid pitfalls and to speed up the learning curve. Further technological developments and increasing experience might lead to a more widespread use of this technique.

Antimicrobial activity of hop extracts against foodborne pathogens for meat applications.

AIMS: The objective of this study was the fundamental investigation of the antimicrobial efficiency of various hop extracts against selected foodborne pathogens in vitro, as well as their activity against Listeria monocytogenes in a model meat marinade and on marinated pork tenderloins. METHODS AND RESULTS: In a first step, the minimum inhibitory concentrations (MIC) of three hop extracts containing either α- or ß-acids or xanthohumol were determined against test bacteria including L. monocytogenes, Staphylococcus aureus, Salmonella enterica and Escherichia coli by a colorimetric method based on the measurement of bacterial metabolic activity. Moreover, the influence of either lactic or citric acid on the antimicrobial activity of the hop extracts was evaluated. The efficiency of hop extracts as a natural food preservative was then tested in a model meat marinade at 2 and 8°C, respectively, and finally on marinated pork. The experiments showed that Gram-positive bacteria were strongly inhibited by hop extracts containing ß-acids and xanthohumol (MIC values of 6.3 and 12.5 ppm, respectively), whereas the antimicrobial activity of the investigated α-acid extract was significantly lower (MIC values of 200 ppm). Gram-negative bacteria were highly resistant against all tested hop extracts. Acidification of the test media led to a decrease of the MIC values. The inhibitory activity of the hop extracts against L. monocytogenes was strongly reduced in a fat-containing model meat marinade, but the efficiency of ß-acids in this matrix could be increased by lowering pH and storage temperatures. By applying 0.5 % ß-acids at pH = 5 in a model marinade, the total aerobic count of pork tenderloins was reduced up to 0.9 log10 compared with marinated pork without hop extract after 2 weeks of storage at 5°C. CONCLUSIONS: ß-acid containing hop extracts have proven to possess a high antimicrobial activity against Gram-positive bacteria in vitro and in a practice-related application for food preservation. SIGNIFICANCE AND IMPACT OF THE STUDY: Antimicrobial hop extracts could be used as natural preservatives in food applications to extend the shelf life and to increase the safety of fresh products.

Does neoadjuvant treatment before oncologic esophagectomy affect the postoperative quality of life? A prospective, longitudinal outcome study.

To evaluate the cancer patients' quality of life (QoL) following esophagectomy the focus was placed on the impact of neoadjuvant treatment before surgery. For patients undergoing oncologic surgery, the QoL is generally accepted as an important outcome parameter in addition to clinical parameters. This prospective nonrandomized study evaluated QoL in patients treated by preoperative chemo(radio)therapy followed by either surgery or surgery alone with special focus on the postoperative course. QoL was assessed in 131 consecutive patients who underwent surgery for esophageal cancer. The EORTC-QLQ-C30 and a tumor-specific module were administered before surgery, at discharge, 3, 6, 12, and 24 months after surgery. Clinical data were collected prospectively and a follow up was performed every 6 months. The histological type of cancer was squamous cell carcinoma in 49.6% and adenocarcinoma in 50.4%. There was no significant difference between patients that were treated neoadjuvantly and those that were first operated on with regard to morbidity, mortality, and survival rates (5-year survival rate of 34%). Most QoL scores dropped significantly below the baseline in the early postoperative period and recovered slowly during the follow-up period to almost preoperative levels in many scores. There was no statistically significant difference in any of the QoL scales between neoadjuvantly treated or primary operated patients. Esophageal resections are associated with significant deterioration of QoL, which slowly recovers during the follow-up period to an almost preoperative level. Neoadjuvant treatment seems to not further negatively affect the QoL deterioration.

Single-dose rituximab for remission induction and maintenance therapy in ANCA-associated vasculitis: a retrospective analysis of 17 patients.

OBJECTIVES: The aim of this study was to evaluate the efficacy of a repeated single-dose rituximab (RTX) regimen for remission induction and maintenance in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHOD: We performed a retrospective analysis of all patients with an established diagnosis of AAV who were treated with single-dose RTX infusions at our institution. Clinical outcome data were assessed over a period of 24 months. RESULTS: Sixteen patients were treated for remission induction and maintenance and one patient was treated for only maintenance therapy. Remission (absence of disease activity during the past 3 months and a prednisolone dose of ≤ 7.5 mg) was achieved in 11 patients (68%) with a mean time to remission of 9.4 (range 3-24) months. At 6 months, six patients (37.5%) were in remission and the mean prednisolone dose of all responding patients was 8.2 mg. Five patients had treatment failure due to early relapsing (n = 4) or persistently active (n = 1) disease. At 24 months, nine of the 11 responding patients (82%) were in remission. All patients still had concomitant steroid and/or disease-modifying anti-rheumatic drug (DMARD) therapy at 24 months. Overall, 11 relapses were seen in nine patients (five non-responders and four responders) with a mean time to relapse of 5.3 (range 4-24) months. No major relapses were observed in the responding patients. Severe infections were only seen in patients who had been previously treated with cyclophosphamide (CYC). CONCLUSIONS: The combination of single-dose RTX with other immunosuppressants seems less effective than the standard RTX regimen for the induction of remission of AAV.

[Antiseptic anaphylaxis]. / Anaphylaxie aux antiseptiques.

Antiseptics are widely used in medical practice. Their cutaneous secondary effects such as allergic contact dermatitis are well known. However, anaphylactic reactions are less. The scope of this article is to describe antiseptics currently used which cause immediate hypersensitivity reactions. Finally, the diagnostic tools and therapeutic approach will be discussed.

[Skin barrier defects in atopic dermatitis: new treatments?]. / Anomalies de la barrière cutanée dans la dermatite atopique: une piste pour de nouveaux traitements?

Atopic dermatitis (AD) is a chronic inflammatory skin disorder and the most frequent skin disease in children. Skin barrier defects play a crucial role in its pathogenesis. 50% of patients suffering from AD present mutations in the filaggrin gene, coding for a key protein of the upper layer of the skin. However these mutations alone are not sufficient for disease development, suggesting that environmental factors are also of great importance in the genesis of AD. In particular skin infections frequently provoke clinical exacerbations in patients suffering from AD. New insights into skin barrier dysfunctions have facilitated the development of drugs targeting the sustainable restitution of the skin's physiologic function. These agents could modify the pharmacological approach of AD treatments in the future.

[Meta-analysis to estimate the economic losses caused by reduced milk yield and reproductive performance associated with bovine paratuberculosis in Switzerland]. / Eine Meta-Analyse zur Schätzung der wirtschaftlichen Einbussen durch Milch- und Reproduktionsverluste infolge boviner Paratuberkulose in der Schweiz.

INTRODUCTION: Especially in regions with intensive cattle farming, paratuberculosis in ruminants can cause considerable economic losses for example through loss of sick animals, reduced milk yield and decreased reproduction performance. Although quantifying the actual economic losses is complex, this study attempts to quantify the losses caused by paratuberculosis in infected dairy farms in Switzerland by means of meta-analyses. For this purpose, in an elaborate selection process, data from 12 studies on milk yield and from three studies on the calving to conception interval were finally selected for further calculations. In addition, data from eight studies each on milk fat concentration and milk protein concentration were evaluated. For the meta-analyses, only studies in which «sick¼ (seropositive) and «healthy¼ (seronegative) animals based on the results of serum ELISA tests were compared at the individual animal level were considered. With a paratuberculosis prevalence of 5,99 % in cattle in Switzerland, a total loss of CHF 12 034 329,96 (95 % CI [CHF 8 625 406,02; CHF 16 409 276,30]; 11 095 652,20 € [7 952 624,35 €; 15 129 352,70 €]) per year was calculated for a population of 559 900 dairy cows. The main part of the losses is caused by an extended calving to conception interval: Seropositive animals need an average of 14,93 days longer (95 % CI [1,73; 28,13]) from calving to successful insemination as seronegative animals. This results in total costs for the extended calving to conception interval due to paratuberculosis of CHF 7 365 591,21 per year (95 % CI [CHF 900 394,95; CHF 14 838 087,61]; 6 791 075,10 € [830 164,14 €; 13 680 716,80 €]). Milk yield reduction based on a lactation period of 305 days results in an economic loss of CHF 4 668 738,75 per year (95 % CI [CHF 1 571 188,69; CHF 7 725 011,07]; 4 304 577,13 € [1 448 635,97 €; 7 122 460,21 €]). Milk fat and milk protein content were not found to be significantly changed. Despite a large number of studies in the screening phase, it was not possible to calculate all types of losses attributable to paratuberculosis due to lack of comparability between the studies, which is essential for meta-analyses. Nevertheless, it was possible to carry out four different meta-analyses, the results of which give a first impression of the economic importance of paratuberculosis in dairy cows in Switzerland.

INTRODUCTION: La paratuberculose des ruminants cause, particulièrement dans les régions ayant une industrie laitière intensive, des pertes économiques considérables, par exemple par la perte d'animaux malades, la réduction de la production laitière et une reproduction diminuée. Malgré la complexité de la quantification des pertes économiques effectives, on a essayé dans l'étude présentée ici de calculer les pertes causées par la paratuberculose dans les exploitations laitières en Suisse au moyen de méta-analyses. Dans ce but, des données extraites par un processus de sélection compliqué de 12 études sur la production laitière et de trois études sur la période de tarissement ont été utilisées pour calculer les pertes dues à la paratuberculose. De plus, huit études chacune sur la concentration de graisse et des protéines du lait ont été prises en compte. Seules des études où les animaux étaient classifiés comme «sains¼ (séronégatifs) et «malades¼ (séropositifs) sur la base d'un test ELISA sérique ont été prises en considération pour les méta-analyses. Pour une prévalence de la paratuberculose de 5,99 % chez les bovins en Suisse, on a pu calculer pour une population de 559 900 vaches laitières une perte totale de 12 034 329,96 CHF (IC 95 % [8 625 406,02 CHF; 16 409 276,30 CHF]; 11 095 652,20 € [7 952 624,35 €; 15 129 352,70 €]) par année. La plus grande partie de ces pertes sont dues à une période de tarissement prolongée: les vaches séropositifs ont besoin en moyenne de 14,93 jours de plus (IC 95 % [1,73; 28,13]) du vêlage à une insémination menant à une gestation que les animaux séronégatifs. Il en résulte des coûts dus à la paratuberculose en raison d'une période de tarissement prolongée de 7 365 591,21 CHF par année (IC 95 % [900 394,95 CHF; 14 838 087,61 CHF]; 6 791 075,10 € [830 164,14 €; 13 680 716,80 €]). La diminution de la production laitière cause pour une durée de lactation de 305 jours une perte économique de 4 668 738,75 CHF par année (IC 95 % [1 571 188,69 CHF; 7 725 011,07 CHF]; 4 304 577,13 € [1 448 635,97 €; 7 122 460,21 €]). Les pertes en valeurs de graisse et de protéines du lait n'étaient pas significatives. Malgré le nombre élevé d'études prises en compte dans la phase de recherche de publications pertinentes, il n'a pas été possible de calculer tous les types de pertes, car les études n'étaient pas suffisamment comparables entre elles, ce qui est une condition essentielle pour une méta-analyse. Il a cependant été possible de procéder à quatre méta-analyses différentes, dont les résultats donnent une idée de l'importance économique des pertes liées à la paratuberculose chez les vaches laitières en Suisse.

Tumor necrosis factor is a critical mediator in hapten induced irritant and contact hypersensitivity reactions.

We examined the role of cytokines in the cutaneous response to the application of trinitrochlorobenzene (TNCB) in both nonsensitized and sensitized mice, i.e., in the irritant reaction (IR) and contact hypersensitivity reactions (CH). When administered immediately before challenge, anti-tumor necrosis factor (TNF) antibody abrogated the ear swelling response in CH; antibody directed against interferon gamma or antibodies to both granulocyte/macrophage colony-stimulating factor and interleukin 3 (IL-3) had a partial inhibitory effect; anti-IL-2 receptor antibody had no effect. Anti-TNF prevented the various features of the CH, as seen on histological sections, e.g., leukocyte infiltration and hemorrhages within the dermis and keratinocytes necrosis. Anti-TNF antibody also prevented the IR. The presence of TNF mRNA was evaluated on Northern blots; TNF-alpha mRNA was detectable in an untreated ear, increased after the application of TNCB in nonsensitized mice, and was highest in sensitized mice. TNF mRNA accumulation, which was evident 0.5 h after hapten application and lasted greater than 72 h, was abolished by treatment with anti-TNF antibody, thus suggesting an auto-amplification of TNF production. The cellular origin of TNF mRNA was explored by in situ hybridization; basal keratinocytes showed the highest labeling, but TNF mRNA was also detectable in cells of the dermal infiltrate. After hapten (TNCB) application at sites susceptible (the ear) or resistant (the foot pad) to CH or IR, a close correlation was observed between TNF mRNA accumulation and the intensity of the inflammatory reaction. The major role played by TNF in both the CH and the IR explains the histologically similar aspects of these reactions and the extreme variability of these reactions at various anatomical sites.

Circulating allergen-reactive T cells from patients with atopic dermatitis and allergic contact dermatitis express the skin-selective homing receptor, the cutaneous lymphocyte-associated antigen.

The cutaneous lymphocyte-associated antigen (CLA) is the major T cell ligand for the vascular adhesion molecule E-selectin, and it has been proposed to be involved in the selective targeting of memory T cells reactive with skin-associated Ag to cutaneous inflammatory sites. To further investigate the relation of CLA and cutaneous T cell responses, we analyzed the CLA phenotype of circulating memory T cells in patients with allergic contact dermatitis and atopic dermatitis (AD) alone vs in patients manifesting bronchopulmonary atopy (asthma with or without AD) and nonallergic individuals. Significant T cell proliferative responses to Ni, a contact allergen, and to the house dust mite (HDM), an allergen to which sensitization is often observed in AD and/or asthma, was noted only in allergic and atopic individuals, respectively. When the minor circulating CLA+CD3+CD45RO+ subset was separated from the major CLA-CD3+CD45RO+ subpopulation in Ni-sensitive subjects, the Ni-dependent memory T cell response was largely confined to the CLA+ subset. A similar restriction of the T cell proliferative response to the CLA+ memory subset was observed for HDM in patients with AD alone. In HDM-sensitive patients with asthma with or without AD, however, the CLA- subset exhibited a strong antigen-dependent proliferation, in contrast to patients with AD alone, whose CLA- subset proliferated very weakly to HDM. In asthma with or without AD, the HDM-dependent proliferation slightly predominated in the CLA- when compared to the CLA+ subset. The functional linkage between CLA expression and disease-associated T cell effector function in AD was also demonstrated by the finding that the circulating CLA+ T cell subset in AD patients, but not nonatopic controls, selectively showed both evidence of prior activation (human histocompatibility antigen-DR expression) and spontaneous production of interleukin 4 but not interferon-gamma. Taken together, these observations demonstrate the correlation of CLA expression on circulating memory T cells and disease-associated memory T cell responses in cutaneous hypersensitivity, and they suggest the existence of mechanisms capable of sorting particular T cell Ag specificities and lymphokine patterns into homing receptor-defined memory subsets.

Maturation of dendritic cells is accompanied by rapid transcriptional silencing of class II transactivator (CIITA) expression.

Cell surface expression of major histocompatibility complex class II (MHCII) molecules is increased during the maturation of dendritic cells (DCs). This enhances their ability to present antigen and activate naive CD4(+) T cells. In contrast to increased cell surface MHCII expression, de novo biosynthesis of MHCII mRNA is turned off during DC maturation. We show here that this is due to a remarkably rapid reduction in the synthesis of class II transactivator (CIITA) mRNA and protein. This reduction in CIITA expression occurs in human monocyte-derived DCs and mouse bone marrow-derived DCs, and is triggered by a variety of different maturation stimuli, including lipopolysaccharide, tumor necrosis factor alpha, CD40 ligand, interferon alpha, and infection with Salmonella typhimurium or Sendai virus. It is also observed in vivo in splenic DCs in acute myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalitis. The arrest in CIITA expression is the result of a transcriptional inactivation of the MHC2TA gene. This is mediated by a global repression mechanism implicating histone deacetylation over a large domain spanning the entire MHC2TA regulatory region.

Cefepime neurotoxicity: thresholds and risk factors. A retrospective cohort study.

OBJECTIVES: Toxic serum cefepime trough concentrations are not well defined in the current literature. We aimed to define a more precise plasma trough concentration threshold for this antibiotic's neurological toxicity and to identify individuals at risk for developing neurotoxic side effects. METHODS: Retrospective study including all individuals who underwent cefepime therapeutic drug monitoring (TDM) between 2013 and 2017. Individuals with cefepime concentrations other than trough were excluded. The primary outcome was to assess the incidence of neurotoxicity and its relationship with cefepime plasma trough concentrations. Secondary outcomes were the relationship of renal function, cefepime daily dose, age, and cerebral and general co-morbidities with the occurrence of neurotoxicity. We also compared the mortality rate during hospitalization in individuals with and without neurotoxicity, and the possible impact of neuroprotective co-medications on outcomes. RESULTS: Cefepime concentrations were determined in 584 individuals. Among 319 individuals with available trough concentrations included, the overall incidence of neurotoxicity was 23.2% (74 of 319 individuals). Higher cefepime plasma trough concentrations were significantly associated with risk of neurotoxicity (no neurotoxicity 6.3 mg/L (interquartile range (IQR) 4.1-8.6) versus with neurotoxicity 21.6 mg/L (IQR 17.0-28.6), p <0.001). Individuals with presumed cefepime neurotoxicity had a significantly lower renal function (estimated glomerular filtration rate 82.0 mL/min/1.73 m2 (IQR 45.0-105.0) versus 35.0 mL/min/1.73 m2 (IQR 23.3-53.3], p <0.001), and significantly higher in-hospital mortality (19 (7.8%) versus 26 (35.1%) individuals, p <0.001). No neurotoxic side effects were seen below a trough concentration of 7.7 mg/L. Levels ≥38.1 mg/L always led to neurological side effects. CONCLUSION: In individuals with risk factors for cefepime neurotoxicity, such as renal insufficiency, TDM should be systematically performed, aiming at trough concentrations <7.5 mg/L.

Rescue of the cardiac defect in ErbB2 mutant mice reveals essential roles of ErbB2 in peripheral nervous system development.

ErbB2 receptor tyrosine kinase plays a role in neuregulin signaling and is expressed in the developing nervous system. We genetically rescued the cardiac defect of erbB2 null mutant embryos, which otherwise died at E11. These rescued erbB2 mutant mice die at birth and display a severe loss of both motor and sensory neurons. Motor and sensory axons are severely defasciculated and aberrantly projected within their final target tissues. Schwann cells are completely absent in the peripheral nerves. Schwann cell precursors are present within the DRG and proliferate normally, but their ability to migrate is decreased. Acetylcholine receptors cluster within the central band of the mutant diaphragm muscle. However, these clusters are dispersed and morphologically different from those in control muscle. Our results reveal an important role for erbB2 during normal peripheral nervous system development.

Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development.

Corticotropin releasing factor (CRF) is a major integrator of adaptive responses to stress. Two biochemically and pharmacologically distinct CRF receptor subtypes (CRFR1 and CRFR2) have been described. We have generated mice null for the CRFR1 gene to elucidate the specific developmental and physiological roles of CRF receptor mediated pathways. Behavioral analyses revealed that mice lacking CRFR1 displayed markedly reduced anxiety. Mutant mice also failed to exhibit the characteristic hormonal response to stress due to a disruption of the hypothalamic-pituitary-adrenal (HPA) axis. Homozygous mutant mice derived from crossing heterozygotes displayed low plasma corticosterone concentrations resulting from a marked agenesis of the zona fasciculata region of the adrenal gland. The offspring from homozygote crosses died within 48 hr after birth due to a pronounced lung dysplasia. The adrenal agenesis in mutant animals was attributed to insufficient adrenocorticotropic hormone (ACTH) production during the neonatal period and was rescued by ACTH replacement. These results suggest that CRFR1 plays an important role both in the development of a functional HPA axis and in mediating behavioral changes associated with anxiety.

[Chronic urticaria]. / Urticaire chronique.

Chronic urticaria (CU) is a common disease of unknown origin. Its impact on the quality of life is significant. Antibodies to high affinity receptors expressed on mast cells and basophiles (FcepsilonRI) are found in 30% of cases and may be associated with more severe and prolonged symptoms. A wide variety of disorders can be associated with CU. However, in the absence of suggestive signs or symptoms, an extensive workup rarely permits the diagnosis of an underlying pathology. In this case, the work up should be minimal. The newer generation oral anti-histamines represent the first line treatment. In the refractory cases, other drugs may be considered but few controlled studies support their use.

Danger signals from mitochondrial DAMPS in trauma and post-injury sepsis.

In all multicellular organisms, immediate host responses to both sterile and infective threat are initiated by very primitive systems now grouped together under the general term 'danger responses'. Danger signals are generated when primitive 'pattern recognition receptors' (PRR) encounter activating 'alarmins'. These molecular species may be of pathogenic infective origin (pathogen-associated molecular patterns) or of sterile endogenous origin (danger-associated molecular patterns). There are many sterile and infective alarmins and there is considerable overlap in their ability to activate PRR, but in all cases the end result is inflammation. It is the overlap between sterile and infective signals acting via a relatively limited number of PRR that generally underlies the great clinical similarity we see between sterile and infective systemic inflammatory responses. Mitochondria (MT) are evolutionarily derived from bacteria, and thus they sit at the crossroads between sterile and infective danger signal pathways. Many of the molecular species in mitochondria are alarmins, and so the release of MT from injured cells results in a wide variety of inflammatory events. This paper discusses the known participation of MT in inflammation and reviews what is known about how the major.

Cooperative DNA binding of the human HoxB5 (Hox-2.1) protein is under redox regulation in vitro.

The human HoxB5 (Hox-2.1) gene product is a sequence-specific DNA binding protein. Cooperative interactions stabilize in vitro DNA binding of the HoxB5 protein to tandem binding sites by at least 100-fold relative to binding to a single site. The HoxB5 homeodomain is sufficient for sequence-specific DNA binding but not for cooperative DNA binding. Here we report that the additional protein sequence required for cooperativity is a small domain adjacent to the homeodomain on the amino-terminal side. We further show that cooperative DNA binding is under redox regulation. The HoxB5 protein binds to DNA in vitro both when oxidized or reduced but binds cooperatively only when oxidized. Mutational analysis has revealed that the cysteine residue in the turn between homeodomain helices 2 and 3 is necessary for cooperative binding and redox regulation. The enhanced DNA binding of oxidized HoxB5 protein is the opposite of the redox regulation reported for other mammalian transcription factors such as Fos, Jun, USF, NF-kappa B, c-Myb, and v-Rel, in which oxidation of cysteine residues inhibits DNA binding. Thus, specific oxidation of nuclear proteins is a potential regulatory mechanism that can act to either decrease or increase their DNA binding activity.

Functional domains of the human orphan receptor ARP-1/COUP-TFII involved in active repression and transrepression.

The orphan receptor ARP-1/COUP-TFII, a member of the chicken ovalbumin upstream promoter transcription factor (COUP-TF) subfamily of nuclear receptors, strongly represses transcriptional activity of numerous genes, including several apolipoprotein-encoding genes. Recently it has been demonstrated that the mechanism by which COUP-TFs reduce transcriptional activity involves active repression and transrepression. To map the domains of ARP-1/COUP-TFII required for repressor activity, a detailed deletion analysis of the protein was performed. Chimeric proteins in which various segments of the ARP-1/COUP-TFII carboxy terminus were fused to the GAL4 DNA binding domain were used to characterize its active repression domain. The smallest segment confering active repressor activity to a heterologous DNA binding domain was found to comprise residues 210 to 414. This domain encompasses the region of ARP-1/COUP-TFII corresponding to helices 3 to 12 in the recently published crystal structure of other members of the nuclear receptor superfamily. It includes the AF-2 AD core domain formed by helix 12 but not the hinge region, which is essential for interaction with a corepressor in the case of the thyroid hormone and retinoic acid receptor. Attachment of the nuclear localization signal from the simian virus 40 large T antigen (Flu tag) to the amino terminus of ARP-1/COUP-TFII abolished its ability to bind to DNA without affecting its repressor activity. By using a series of Flu-tagged mutants, the domains required for transrepressor activity of the protein were mapped. They include the DNA binding domain and the segment spanning residues 193 to 399. Transcriptional activity induced by liver-enriched transactivators such as hepatocyte nuclear factor 3 (HNF-3), C/EBP, or HNF-4 was repressed by ARP-1/COUP-TFII independent of the presence of its cognate binding site, while basal transcription or transcriptional activity induced by ATF or Sp1 was not perturbed by the protein. In conclusion, our results demonstrate that the domains of ARP-1/COUP-TFII required for active repression and transrepression do not coincide. Moreover, they strongly suggest that transrepression is the predominant mechanism underlying repressor activity of ARP-1/COUP-TFII. This mechanism most likely involves interaction of the protein with one or several transcriptional coactivator proteins which are employed by various liver-enriched transactivators but not by ubiquitous factors such as Sp1 or ATF.