TonEBP regulates the hyperosmotic expression of aquaporin 1 and 5 in the intervertebral disc.

The central region of the intervertebral disc (IVD) is rich in proteoglycans, leading to a hyperosmotic environment, which fluctuates with daily loading. The cells of the nucleus pulposus (NP cells) have adapted to this environment via the function of tonicity enhancer binding protein (TonEBP), and NP cells have been shown to express several water channels known as aquaporins (AQP). We have previously shown that AQP1 and 5 decrease during IVD degeneration. Here, the regulation of AQP1 and 5 by hyperosmotic conditions and the role of TonEBP in this regulation was investigated. AQP1 and 5 gene expression was upregulated by hyperosmotic conditions mimicking the osmolality of the healthy IVD, which was abrogated by TonEBP knockdown. Furthermore, AQP1 and 5 immunopositivity was significantly reduced in TonEBPΔ/Δ E17.5 mice when compared with wildtype controls, indicating in vivo expression of AQP1 and 5 is controlled at least in part by TonEBP. This hyperosmotic regulation of AQP1 and 5 could help to explain the decreased AQP1 and 5 expression during degeneration, when the osmolality of the NP decreases. Together this data suggests that TonEBP-regulated osmo-adaptation may be disrupted during IVD degeneration when the expression of both AQPs is reduced.

Genetic murine models of spinal development and degeneration provide valuable insights into intervertebral disc pathobiology.

Disc degeneration and associated back and neck pain elicits a substantial burden on healthcare systems and the individuals affected, necessitating the development of novel therapeutic strategies. This goal can only be achieved by a better understanding of intervertebral disc development, homeostasis and pathogenesis. A number of genetic and in-bred murine models are reviewed to underscore the importance of the mouse as an animal model of choice for the assessment of intervertebral disc pathobiology. Appraisals of the differences between mouse and human musculoskeletal systems and proteoglycan structures are also included. A number of important target pathways and molecules have been identified, many of which are worthy of further examination, requiring that the activity of these be confirmed in large animal models and assessed in the context of therapeutic intervention.

Cluster of serogroup W invasive meningococcal disease in a university campus.

INTRODUCTION: In France, the expansion of an hypervirulent strain causing serogroup W invasive meningococcal disease (MenW) has been observed since 2015/16. We describe a cluster of three MenW cases, causing two deaths, at the end of 2016 in a university campus, and the vaccination campaign which was consequently organized. METHODS: Epidemiological and microbiological analyses led a multidisciplinary expertise group to recommend the organization of a mass vaccination campaign using ACWY vaccine targeting more than 30,000 students and staff in the university campus. Individual data on vaccination was collected using the lists of students and staff registered at the university to estimate vaccine coverage. RESULTS: Three MenW cases occurred within a 2-month period among students in different academic courses. All three isolates were identical and belonged to the "UK-2013 strain" phylogenetic branch. The attack rate was 10.8/100,000 students. The vaccination campaign was organized only 15 days after the third case occurred. In total, 13,198 persons were vaccinated. Vaccine coverage was estimated at 41% for students of the university and 35% for university staff. CONCLUSION: Timely notification of cases to health authorities was essential for the detection of the cluster and the rapid implementation of the vaccination campaign. No further cases occurred in the campus in the year following the vaccination campaign. This episode is the second cluster of MenW caused by the "UK-2013 strain" in a university since 2016.

The food retail environment and its use in a deprived, urban area of Scotland.

OBJECTIVES: This study sought to describe the food retail environment and its use in a deprived urban area in Scotland by mapping all food outlets and determining where residents do their main food shopping as well as investigating the availability of fresh fruit and vegetables (F&V) (as an indicator of healthy eating) and takeaway food. STUDY DESIGN: Cross-sectional study. METHODS: The food retail environment, the number, size and food availability of all food outlets, was mapped in Viewpark, a small community located to the east of Glasgow. Subsequently a validated questionnaire was used to determined food shopping usage and habits. RESULTS: There was high availability of common fresh fruit and vegetables (F&V) and very high availability of fast food outlets. Only 9% of the sample shopped solely at local food outlets within Viewpark whilst 91% shopped at a large supermarket outside Viewpark (n = 106). Walking was significantly negatively associated (B = -3.555, P = 0.008) with shopping outside the community. The majority of respondents (80%) reported buying F&V weekly and 57% purchased takeaways at least once a week - these individuals were employed, over 45 years old and had at least one child. CONCLUSIONS: The use of the local retail environment in a deprived community is influenced by car accessibility.

Nationwide outbreak of Salmonella enterica serotype 4,[5],12:i:- infection associated with consumption of dried pork sausage, France, November to December 2011.

An outbreak of the monophasic variant of Salmonella enterica serotype 4,[5],12:i:- occurred in November and December 2011 in France. Epidemiological investigation and food investigation with the help of supermarket loyalty cards suggested dried pork sausage from one producer as the most likely source of the outbreak. Despite the absence of positive food samples, control measures including withdrawal and recall were implemented.

[Perception and understanding chronic heart failure by the patient. The impact of therapeutic education on the level of knowledge of patients. About 350 cases]. / Perception et compréhension de l'insuffisance cardiaque chronique par le patient. Impact d'une formation éducative sur les connaissances des patients. Etude médico-infirmière à propos de 35 cas.

UNLABELLED: Heart failure is a severe disease with a poor prognosis despite major therapeutic progresses achieved recently. A key factor is the high number of hospitalizations for heart failure, considered as being avoidable, since they are related to a lack of adequate management of the patients. Several therapeutic education programs focused on heart failure are in progress. Even though these programs aim at making patients an active agent managing the disease, data on patient's level of knowledge and experience regarding heart failure are scarce. The aim of our study was to analyze the patient's perception of the disease and his/her practices about this disease, as well as the treatments used. METHODS: we included 350 consecutive patients and analyzed their level of knowledge and experience using a questionnaire, as well as interviews performed by nurses and physicians. This initial assessment was followed by a second assessment after an 8-hours course in 2 days, made by the multidisciplinary education team of R. Dubos hospital (including physicians, nurses, physiotherapists, dietician). RESULTS: in contrast to tests assessing the knowledge on the disease, which were in overall satisfactory, the results on the level of knowledge on treatments and heart failure pathways were poor. The courses improve significantly the level of knowledge in all domains, whatever would the age and the level of patient's demand for information be. The analysis of the patient's conception of his/her own disease reveals the lack of knowledge on the severity of heart failure. Frequently, the effect of treatments is considered as poorly efficient, and a substantial fraction of these patients have underlying depressive moods. CONCLUSION: the understanding of the level of knowledge and the perception of the patient regarding his/her disease is primordial for setting educational structures and programs. However, the patient's conception of the disease is different from care providers. It is therefore essential to assess the patient's conception by an educational diagnosis prior to implement adapted education programs, in order to improve durably the patient's knowledge, at every age.

Detection of Legionella spp. by fluorescent in situ hybridization in dental unit waterlines.

AIMS: To confirm the presence of viable Legionella spp. in dental unit waterlines (DUWL) using fluorescent in situ hybridization (FISH) and compare this method with culture approach and also to validate the utility of an enrichment to increase FISH sensitivity. METHODS AND RESULTS: Water samples from 40 dental units were analysed. Three different techniques for detecting Legionella spp. were compared: (i) culture approach, (ii) direct FISH and (iii) FISH with a previous R2A medium enrichment (R2A/FISH). The FISH detection was confirmed by PCR. The use of the direct FISH does not improve significantly the detection of legionellae when compared with the culture. On the contrary, when R2A/FISH was performed, sensitivity was, respectively, two- and threefold higher than that with the direct FISH and culture approach. Using R2A/FISH, 63% of water samples analysed showed a contamination by legionellae. CONCLUSIONS: Legionellae detection by direct FISH and R2A/FISH in dental unit water is possible but is more rapid and more sensitive (R2A/FISH) than the culture approach. SIGNIFICANCE AND IMPACT OF THE STUDY: R2A/FISH showed that several pathogens present in DUWL are viable but may not be culturable. Unlike PCR, R2A/FISH is designed to detect only metabolically active cells and therefore provides more pertinent information on infectious risk.

Biphenyls as surrogates of the steroidal backbone. Part 1: synthesis and estrogen receptor affinity of an original series of polysubstituted biphenyls.

In the course of a programme aimed at discovering new ligands of the estrogen receptor, we explored a series of substituted biphenyls. Their synthesis and binding affinity are described.

Biphenyls as surrogates of the steroidal backbone. Part 2: discovery of a novel family of non-steroidal 5-alpha-reductase inhibitors.

A new family of non-steroidal 5-alpha-reductase inhibitors was designed by replacing the steroid skeleton of an inhibitor related to estrone by a biphenyl moiety. This hypothesis originated from the reported estrogenic activity of a few biphenyl compounds (see Part 1 of this paper; Lesuisse et al. Bioorg. Med. Chem. Lett. 2001, 11, 1709). Two compounds turned out to be potent type 2 5-alpha-reductase inhibitors with IC(50)'s of inhibition in the nanomolar range. These are to our knowledge amongst the most potent non-steroidal 5-alpha-reductase inhibitors described to date.

Cumulative inactivation of the outward potassium current: a likely mechanism underlying electrical memory in human atrial myocytes.

The influence of the mode of cell stimulation on the outward K+ current (I(o)) was studied in whole-cell patch-clamped human atrial myocytes. Acceleration of the rate of membrane depolarization at 1 Hz or during prolonged 5-s test pulses at 0.1 Hz increased the rate and extent of I(o) inactivation, resulting in enhanced inactivating (4.9+/-0.6 v 6.3+/-0.7 pA/pF) and suppressed maintained (5.9+/-1.2 v 3.2+/-0.3 pA/pF) current components. These alterations were associated with a leftward shift of the voltage-dependency of I(o), and persisted on returning to a control depolarization protocol (750-ms test pulses delivered at 0.1 Hz). The effects of increasing external K+ concentrations (40 m m) on the kinetics of I(o) were more pronounced following both rapid and prolonged depolarization (changes in I(t)/I(o)caused by 40 m m K+: 8.9+/-3.5% v 15.5+/-3.1% before and after prolonged depolarization; and 9.2+/-1.2% v 15.4+/-1.7% before and after rapid depolarization). The phosphatase inhibitor, okadaic acid, enhanced the effect of rapid and prolonged depolarization on I(o)whereas the inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMK-II) with KN-62 or KN-93, or by intracellular application of the autocamtide-2-related inhibitory peptide, suppressed it. In conclusion, rapid and prolonged membrane depolarization both cause a cumulative increase in the rate and extent of I(o)inactivation. This process involves slow potassium channel inactivation mechanisms, is regulated by CaMK-II, and may contribute to the electrical memory of the atrial myocardium.

The clinical effectiveness of cognitive behaviour therapy for chronic insomnia: implementation and evaluation of a sleep clinic in general medical practice.

Chronic insomnia is a very common clinical condition which may respond well to non-pharmacological treatment. Indeed, the literature supports the efficacy of cognitive behaviour therapy (CBT). However, there has been no substantial study of clinical effectiveness. Since insomniacs typically present in general medical practice this is a crucial gap in the outcome research. This study, therefore, specifically investigated the clinical effectiveness of CBT delivered by Health Visitors (primary care nurses) trained as therapists. One hundred and thirty-nine insomniacs (mean age 51 yr) were randomised to CBT or Self-Monitoring Control (SMC) in a controlled trial. CBT comprised six group sessions (n=4 to 6 patients). After the controlled phase, SMC patients entered deferred treatment (CBT-DEF), allowing both treatment replication and long-term outcome to be investigated for a sizeable, treated sample. Repeated measures ANOVAs demonstrated superiority of CBT over SMC in substantially reducing sleep latency and wakefulness during the night. CBT-DEF replicated similar effects and maintained improvement was observed in both groups one year later. Furthermore, total sleep increased significantly during follow-up and 84% of patients initially using hypnotics remained drug-free. Results suggest that CBT administered by Health Visitors offers a clinically effective treatment for insomnia.

A qualitative study of general practitioners' and practice nurses' attitudes to obesity management in primary care.

OBJECTIVES: To examine general practitioners' (GPs) and practice nurses' (PNs) perceptions of obesity, their strategies and attitudes towards weight management, and their views on the major obstacles to (and need for) better weight management in primary care. METHOD: A qualitative study was carried out using semi-structured interviews with GPs and PNS within the Greater Glasgow Healthboard area. RESULTS: GPs and PNs understood the problem of obesity but generally had little enthusiasm for weight management. Most of the GPs felt it was an inappropriate use of their time and passed obese patients onto the PNs; the PNs felt that obese patients were "off-loaded" onto them. Stated management objectives were aimed at "healthy lifestyle" rather than "unrealistic" weight loss, yet frustration at "lack of success" was a major theme. Lack of motivation on the part of the patient was seen as the major problem. GPs were keener to be directly involved when a concomitant disease was present. Suggested requirements to improve weight management at the level of primary care included more time, better facilities, community dieticians and more training courses. However, many felt that Government, media and public health had to take a leading role in order to deal with the problem effectively. CONCLUSIONS: A comprehensive and integrative primary care-led approach to weight management may be possible but will need substantial shifts of resources, organisation, training and attitudes in order to maximise its potential impact.

Development of a photolabile ligand for the endothelin-A receptor of endothelin.

Actions of endothelin (ET) are usually mediated through the so-called endothelin-A or -B (ET(A) or ET(B))-receptors. As part of our ongoing research program, we are studying the characterization of the ET(A)-receptor using specific photolabile ligands. Starting with the ET(A)-specific antagonist TTA-386 as a leading compound we developed new ET(A)-specific antagonists containing the photolabile amino acid, p-benzoyl-phenylalanine (Bpa). Following a Bpa peptide scan, with either the L- or D-isomer, we found that D-phenylalanine-6 of TTA-386 can be substituted with either L- or D-Bpa and gives analogs showing antagonistic properties, in an ET(A)-receptor preparation (rat aorta), very similar to those of TTA-386 itself. No agonistic or antagonistic properties were measured with these derivatives in an ET(B) pharmacological preparation (guinea pig lung parenchyma). Thus, these new ligands appear as very promising probes for the characterization of the ET(A)-receptor.

An improved procedure for the preparation of the endothelin-B-receptor ligand sarafotoxin 6c.

Sarafotoxin 6c (S6c) is a specific agonist for the endothelin-B- (ETB) receptor, being largely used as a standard compound in pharmacological studies related to ETB-receptors. We have developed an improved peptide synthesis prncedure. Using the Fmoc chemistry methodology and an appropriate orthogonal protection scheme, we obtained a crude peptide with a major component identified as [Cys(Acm)(1,15)]S6c. A silver salt (AgBF4) treatment of this crude material completely removed the Acm moieties without the appearance of any major side-products. The free peptide was cyclized using a Fe3+/Fe2+ oxidizing method. Besides the formation of the bridges, no other modification was observed. Thus, the peptide purification was facilitated and an excellent yield of pure sarafotoxin was obtained. The material was characterized by analytical reverse phase-high performance liquid chromatography (RP-HPLC) and matrix assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry. Pharmacological properties of the peptide were evaluated in an ETB preparation (guinea pig lung parenchyma strips) and were identical to those of an S6c standard.

The demand and supply of nutritional advice and guidance in Scottish family planning services.

Recent changes to the health services have led to an increased provision of clinical care in family planning clinics. While some women may only require contraceptive services, others may demand advice on a breadth of lifestyle issues, including diet and nutrition. Obesity affects 17% of women of childbearing age in Scotland and being overweight during pregnancy has significant health risks. A postal survey of 227 nurses identified as working in family planning clinics in Scotland was conducted in 1998. After a mail shot and one reminder, a net response rate of 64% (n = 145) was achieved. Overall, it was found that obesity was perceived as the most extensive problem in women of childbearing age. Seventy nurses (48%) reported that, in addition to offering family planning services, they gave dietary advice 'frequently' or 'always' to their clients without being asked. There were differences in nutrition-related activities in consultations between nurses offering family planning services only and those who routinely offered nutritional advice. Over half (61%) of the nurses reported that they would give advice regarding weight management even if the patients were not seeking help, although there was no significant difference between the two comparison groups. In some cases, the nutritional advice offered to clients highlighted a deficit in training. Most nutrition education came from diploma and/or training courses and scientific literature, followed by 'experience'. Those nurses already embracing a nutritional advice and guidance role were more interested in further nutrition training (p = 0.018) than the other nurses. However, overall, 67% of the nurses wished to train further in nutrition and weight management. The findings suggest that family planning nurses should be supported to develop nutritional advice and guidance skills, and that there is a pressing need for training in public health nutrition and weight management for nurses working in family planning services.

Still hungry in hospital: identifying malnutrition in acute hospital admissions.

We assessed the prevalence, methods for recognition and clinical management of malnutrition in acute admissions in a large academic inner-city hospital. Of a total of 337 patients, it was possible to measure both height and weight in 219 patients (65% of admissions). As an alternative for bed-bound patients, mid-upper arm circumference was not very reliable in predicting BMI (sensitivity 98%; specificity 65%), and waist circumference even less so. Of these, 13% were malnourished (body mass index BMI <18.5 kg/m(2) or BMI 18.5-20 kg/m(2) with reported weight loss >3 kg in the last 3 months). Six patients (31% of those with BMI <18.5 kg/m(2)) and one with BMI 18.5-20 kg/m(2) were recognized as suffering from malnutrition and referred to the dietitian. Review of case records could not establish if the diagnosis was missed in the remainder, or if a conscious decision was taken not to manage malnutrition actively. Malnutrition in acute hospital admissions goes apparently unrecognized and unmanaged in 70% of cases. Since there are serious consequences, and effective simple treatment is readily available, increased awareness is required, with routine assessment of nutritional status in all patients.

Insomniacs' attributions. psychometric properties of the Dysfunctional Beliefs and Attitudes about Sleep Scale and the Sleep Disturbance Questionnaire.

OBJECTIVE: Mental overactivity has been widely implicated in the development and maintenance of insomnia, making the accurate and valid measurement of cognitive variables of some importance. The purpose of this study was to investigate the psychometric properties of two existing attributional scales. METHODS: Data are presented from 178 clinic attending insomniacs who completed the Dysfunctional Beliefs and Attitudes about Sleep Scale (DBAS) and the Sleep Disturbance Questionnaire (SDQ). Standard procedures for the psychometric evaluation of scales were adopted. RESULTS: The internal consistency of the DBAS (30 items) was reasonable (Cronbach's alpha = 0.72); however, a revised ten-item short form (DBAS-10) demonstrated a more robust principal component structure than the original scale (three relatively "pure" factors explained 55% of the variance). The derived subscales achieved satisfactory internal consistency, and the DBAS-10 demonstrated treatment-related measurement sensitivity. The DBAS-10, nevertheless, correlated highly (r = 0.826) with the DBAS. A four-factor solution for the SDQ is also presented (61% explained variance) with alpha = 0.67. Internal consistency of these subscales ranged from 0.59 to 0.82. The association between the SDQ and DBAS-10 was modest (r = 0.28), suggesting that the scales have some independence. CONCLUSIONS: The scales offer potential for clinical and research work on insomnia and possible applications are discussed.

Tyrosine kinase and protein kinase C regulate L-type Ca(2+) current cooperatively in human atrial myocytes.

The effects of tyrosine protein kinases (TK) on the L-type Ca(2+) current (I(Ca)) were examined in whole cell patch-clamped human atrial myocytes. The TK inhibitors genistein (50 microM), lavendustin A (50 microM), and tyrphostin 23 (50 microM) stimulated I(Ca) by 132 +/- 18% (P < 0.001), 116 +/- 18% (P < 0.05), and 60 +/- 6% (P < 0.001), respectively. After I(Ca) stimulation by genistein, external application of isoproterenol (1 microM) caused an additional increase in I(Ca). Dialyzing the cells with a protein kinase A inhibitor suppressed the effect of isoproterenol on I(Ca) but not that of genistein. Inhibition of protein kinase C (PKC) by pretreatment of cells with 100 nM staurosporine or 100 nM calphostin C prevented the effects of genistein on I(Ca). The PKC activator phorbol 12-myristate 13-acetate (PMA), after an initial stimulation (75 +/- 17%, P < 0.05), decreased I(Ca) (-36 +/- 5%, P < 0.001). Once the inhibitory effect of PMA on I(Ca) had stabilized, genistein strongly stimulated the current (323 +/- 25%, P < 0.05). Pretreating myocytes with genistein reduced the inhibitory effect of PMA on I(Ca). We conclude that, in human atrial myocytes, TK inhibit I(Ca) via a mechanism that involves PKC.