Scl-Ab reverts pro-osteoclastogenic signalling and resorption in estrogen deficient osteocytes.

BACKGROUND: Neutralising antibodies to sclerostin (Scl-Ab) have shown significant potential to induce bone formation and decrease bone resorption, increase strength and substantially reduce fracture risk in animal studies and clinical trials. Mechanical loading negatively regulates sclerostin expression, and sclerostin has been shown to induce RANKL synthesis in osteocytes. However, how Scl-Ab governs osteocyte regulation of osteoclast differentiation and function is not fully understood. We have recently discovered that osteoblasts and osteocytes alter osteoclastogenic signalling (RANKL/OPG) during estrogen-deficiency, and that osteoblast-induced osteoclastogenesis and resorption are exacerbated. However, it is not known whether estrogen deficient osteocytes exacerbate osteoclastogenesis. The aims of this study were to (1) establish whether osteocytes induce osteoclastogenesis and bone resorption during estrogen deficiency in vitro (2) investigate whether the sclerostin antibody can revert osteocyte-mediated osteoclastogenesis and resorption by attenuating RANKL/OPG expression. RESULTS: Using conditioned media and co-culture experiments we found increased osteocyte-induced osteoclastogenesis and bone resorption in estrogen deficient conditions. This is the first study to report that administration of Scl-Ab has the ability to revert osteocyte-mediated osteoclastogenesis and resorption by decreasing RANKL/OPG ratio expression and increasing WISP1 expression in estrogen deficient osteocytes. CONCLUSIONS: This study provides an enhanced understanding of the biological changes underpinning decreases in bone resorption following Scl-Ab treatment observed in vivo by revealing that Scl-Ab can reduce pro-osteoclastogenic cell signalling between osteocytes and osteoclasts.

Brief advice to tuberculosis patients in Nepal to stop smoking: a pilot study by the Britain Nepal Medical Trust.

SETTING: Tuberculosis (TB) treatment centres in Eastern Nepal. OBJECTIVE: To determine smoking cessation rates among TB patients advised to quit. DESIGN: One intervention and one control centre were studied. At the intervention centre, brief advice about smoking and cessation was given at the start of anti-tuberculosis treatment, and repeated 2 and 5 months later. After 6 months of standard treatment, patients were asked about quitting. Expired air carbon monoxide (CO) was measured in those claiming 6 months of abstinence. RESULTS: None of the 51 controls achieved 6 months of abstinence, whereas 77 (39%) of the 195 in the intervention group claimed at least 6 months of abstinence. All claims were verified by CO measurement in expired air (95%CI 31.4-47.6, P < 0.0001 for the difference in smoking cessation). CONCLUSION: Brief advice on smoking cessation to patients starting anti-tuberculosis treatment in the National Tuberculosis Programme (NTP) setting in Eastern Nepal led to 39% quitting for least 6 months. Our results should encourage randomised trials in smokers with TB in Nepal: if substantiated, smoking cessation advice should become a mandatory component of the NTP.

Maximizing the role of emergency departments in the prevention of violence: developing an approach in South London.

This article presents an overview of a partnership between public health teams in two primary care trusts in South East London, their local acute hospital trusts, and crime and disorder reduction partnerships to support the reduction of harm from violence. It discusses recent developments in violence prevention in emergency departments in the UK, and developments around outreach and case management, more common in the USA. It then outlines the elements of the violence prevention project being conducted in South East London.

Commentary. CT stroke window settings: an unfortunate misleading misnomer?

This commentary will discuss the use of the "stroke window" settings in the evaluation of CT head examinations and advocate their more widespread use in patients who present with neurological symptoms in addition to patients with suspected stroke. We present examples of the use of stroke windows, which revealed subtle abnormalities that were not readily apparent on default brain window settings and were subsequently confirmed on MRI or follow-up CT. As a result we suggest that stroke windows should be routine in the review of all CT head examinations.

Invasive cervical cancer audit: why cancers developed in a high-risk population with an organised screening programme.

OBJECTIVES: To investigate why invasive cervical cancers developed in a high-risk urban population with an established screening programme and to place cancers in the context of high-grade cervical intraepithelial neoplasia (CIN) and cervical glandular intraepithelial neoplasia (CGIN) diagnosed during the same period of time. STUDY DESIGN: Observational study of CIN2+ (CGIN, CIN3 and CIN2) and invasive cervical cancer diagnosed at Guy's and St Thomas' NHS Foundation Trust in 1999-01, 2002-04 and 2005-07 and audit of screening histories of women with invasive cancer analysed according to route to diagnosis, histological type and International Federation of Obstetrics and Gynecology (FIGO) stage. RESULTS: There were 133 invasive cancers, 53 CGIN, 1502 CIN3 and 1472 CIN2. Screen-detected cancers in asymptomatic women comprised 48.9% of cancers and were successively more likely to be in younger age groups (P = 0.03); all except one were stage IA or IB1. Screen-detected IA cancers were more likely (P < 0.001) to be in women screened within 0.5-5.0 years (80.5%) than screen-detected fully invasive (58.3%) or symptomatic cancers (35.3%). Seventy-one (53.4%) women had been screened within 0.5-5.0 years; 11 had negative cytology within 0.5-3.5 years and two tests within 10 years. The other 60 had negative tests less frequently or had previous abnormal cytology, colposcopy or treatment. Potentially avoidable factors were often multiple, including false-negative cytology, high-grade cytology reported as low-grade and lapses in attendance either for routine or repeat screening, or for colposcopy or treatment. CONCLUSION: While often potentially avoidable, cancers in previously screened women tended to be early stage, detected by cytology and rare when compared with high-grade CIN.

Gender equity and trichiasis surgery in the Vietnam and Tanzania national trachoma control programmes.

AIMS: To calculate the gender distribution of trichiasis cases in trachoma communities in Vietnam and Tanzania, and the gender distribution of surgical cases, to determine if women are using surgical services proportional to their needs. METHODS: Population based data from surveys done in Tanzania and Vietnam as part of the national trachoma control programmes were used to determine the rate of trichiasis by gender in the population. Surgical records provided data on the gender ratio of surgical cases. RESULTS: The rates of trichiasis in both countries are from 1.4-fold to sixfold higher in females compared to males. In both countries, the female to male rate of surgery was the same or even higher than the female to male rate of trichiasis in the population. CONCLUSIONS: These data provide assurance of gender equity in the provision and use of trichiasis surgery services in the national programmes of these two countries. Such simple analyses should be used by other programmes to assure gender equity in provision and use of trichiasis surgery services.

Controlled management of public relations following a public health incident.

This paper describes the management of public relations following an outbreak of multidrug resistant TB at a London hospital. Eight patients were involved, all of the secondary cases occurred in HIV seropositive patients, and three cases died. The paper describes how the the Incident Committee undertook to recall contacts of the cases for screening, inform the general practitioners of all of the contacts about their patients' exposure, warn other organizations and professionals interested or involved in the management of HIV in the London area as to the nature of the incident, and establish a helpline, before informing a wider audience through the EPINET, Communicable Disease Report and national press.

An outbreak of multi-drug-resistant tuberculosis in a London teaching hospital.

We describe the epidemiology and control of a hospital outbreak of multi-drug-resistant tuberculosis (MDR-TB). A human immunodeficiency virus (HIV)-negative patient with drug-sensitive tuberculosis developed MDR-TB during a period of unsupervised therapy. She was admitted to an isolation room in a ward with HIV-positive patients, but the room, unbeknown to hospital staff, was at positive-pressure relative to the main ward. Seven HIV-positive contacts developed MDR-TB. The diagnosis in the second patient was delayed, partly because acid-fast bacilli in his sputum were assumed to be Mycobacterium avium-intracellulare. All the available Mycobacterium tuberculosis isolates were indistinguishable by molecular typing. Nearly 1400 staff and patient contacts were offered screening, but the screening programme detected only one of the cases. Despite therapy, the index patient and two of the contacts died. HIV-positive patients are more likely than others to develop tuberculosis after exposure, and the disease may progress more rapidly. In these patients the possibility that acid-fast bacilli may represent M. tuberculosis must always be considered. Patients with tuberculosis (suspected or proven) should not be nursed in the same wards as immunosuppressed patients, and should be isolated. MDR-TB cases must be isolated in negative-pressure rooms. Hospital side-rooms may be positive-pressure as a fire safety measure; infection control teams must be aware of the airflows in all isolation rooms, and must be consulted during the design of hospital buildings. Good communication between infection control teams and clinicians is important, and all medical and nursing staff must be aware of the principles of management of patients with proven or suspected tuberculosis and MDR-TB.

Crowded outpatient departments in city hospitals of developing countries: a case study from Lesotho.

'Overuse' of hospital outpatient departments in urban areas of developing countries is perceived as a problem by many health planners. The World Health Organization is promoting advanced health centres, or 'reference centres', as part of a strategy to develop urban health systems and to reduce primary contact care at hospitals. However, hospital-based information to assist city health service planning is limited in many countries. This study examined user characteristics, patient flow and prescribing quality at the national referral hospital in Maseru, Lesotho, using simple and replicable methods. The study found that most users were self-referred and came from the city. The majority of respondents were aware of their local health centre but reported they would normally use the hospital when they were ill. Examination of patient flow showed that, on average, patients spent a total of 3.7 h waiting. Quality of care was compromised by a tendency to over-prescribe, particularly antibiotics and sedatives. The study suggests that in Maseru, the perception of 'overuse' is due to congestion and that improved patient flow management will reduce the numbers of patients waiting. Quality of care could be strengthened by regular audit of prescribing practices by clinicians in the hospital.

Can the solar cycle and climate synchronize the snowshoe hare cycle in Canada? Evidence from tree rings and ice cores.

Dark marks in the rings of white spruce less than 50 yr old in Yukon, Canada, are correlated with the number of stems browsed by snowshoe hares. The frequency of these marks is positively correlated with the density of hares in the same region. The frequency of marks in trees germinating between 1751 and 1983 is positively correlated with the hare fur records of the Hudson Bay Company. Both tree marks and hare numbers are correlated with sunspot numbers, and there is a 10-yr periodicity in the correlograms. Phase analysis shows that tree marks and sunspot numbers have periods of nearly constant phase difference during the years 1751-1787, 1838-1870, and 1948 to the present, and these periods coincide with those of high sunspot maxima. The nearly constant phase relations between the annual net snow accumulation on Mount Logan and (1) tree mark ratios, (2) hare fur records before about 1895, and (3) sunspot number during periods of high amplitude in the cycles suggest there is a solar cycle-climate-hare population and tree mark link. We suggest four ways of testing this hypothesis.

Relationship of dietary iodide and drinking water disinfectants to thyroid function in experimental animals.

The importance of dietary iodide on the reported hypothyroid effect of drinking water disinfectants on thyroid function was investigated. Previous studies have also showed differences in the relative sensitivity of pigeons and rabbits to chlorinated water. Pigeons and rabbits were exposed for 3 months to diets containing high (950 ppb) or low (300 ppb) levels of iodide and to drinking water containing two levels of chlorine. Results showed that the high-iodide diet prevented the hypothyroid effect observed in pigeons given the low-iodide diet and chlorinated drinking water. Similar trends were observed in rabbits exposed to the same treatment; however, significant hypothyroid effects were not observed in this animal model. The factor associated with the observed effect of dietary iodide on the chlorine-induced change in thyroid function is unknown, as is the relative sensitivity of rabbits and pigeons to the effect of chlorine. Several factors may explain the importance of dietary iodide and the relative sensitivity of these species. For example, the iodine formed by the known reaction of chlorine with iodide could result in a decrease in the plasma level of iodide because of the relative absorption rates of iodide and iodine in the intestinal tract, and the various types and concentrations of chloroorganics (metabolites) formed in the diet following the exposure of various dietary constituents to chlorine could affect the thyroid function. The former factor was investigated in the present studies. Results do not confirm a consistent, significant reduction in the plasma level of iodide in rabbits and pigeons exposed to chlorinated water and the low-iodide diet. The latter factor is being investigated.

Relationship of drinking water disinfectants to plasma cholesterol and thyroid hormone levels in experimental studies.

The effects of drinking water containing 2 or 15 ppm chlorine (pH 6.5 and 8.5), chlorine dioxide, and monochloramine on thyroid function and plasma cholesterol were studied because previous investigators have reported cardiovascular abnormalities in experimental animals exposed to chlorinated water. Plasma thyroxine (T4) levels, as compared to controls, were significantly decreased in pigeons fed a normal or high-cholesterol diet and drinking water containing these drinking water disinfectants at a concentration of 15 ppm (the exception was chlorine at pH 6.5) for 3 months. In most of the treatment groups, T4 levels were significantly lower following the exposure to drinking water containing the 2 ppm dose. Increases in plasma cholesterol were frequently observed in the groups with lower T4 levels. This association was most evident in pigeons fed the high-cholesterol diet and exposed to these disinfectants at a dose of 15 ppm. For example, after 3 months of exposure to deionized water or water containing 15 ppm monochloramine, plasma cholesterol was 1266 +/- 172 and 2049 +/- 212 mg/dl, respectively, a difference of 783 mg/dl. The factor(s) associated with the effect of these disinfectants on plasma T4 and cholesterol is not known. We suggest however that these effects are probably mediated by products formed when these disinfectants react with organic matter in the upper gastrointestinal tract.

Evidence for a link between atmospheric thermonuclear detonations and nitric acid.

Suitably located glacier cores, obtained from high-altitude, low-temperature sites, can reveal detailed information about atmospheric air chemistry at sub-annual resolution1. Such data may provide input to climate-change models, the study of acid precipitation patterns and many other phenomena. Here I present data from an ice core which show that during the era of intense atmospheric thermonuclear weapons testing (ATWT) a significant part of the nitrate content in the snow was modulated by the intensity of the nuclear detonations. The fixation of nitrogen by nuclear fireballs leads to NOx gases in the atmosphere2 and ultimately to nitric acid in precipitation. At certain concentrations, these gases and the associated aerosols may perturb the climate3,4.

Modification of apolipoprotein C-II with 1,2-cyclohexanedione and 2,3-butanedione. Role of arginine in the activation of lipoprotein lipase.

Apolipoprotein C-II, the activator protein of lipoprotein lipase, contains 78 amino acids with a single residue of arginine at position 49. Chemical modification of apolipoprotein C-II with 1,2-cyclohexanedione or 2,3-butanedione results in a loss of both the arginine residue and the ability of the protein to enhance the activity of bovine milk lipoprotein lipase toward a trioleoylglycerol substrate; removal of the modifying group restores arginine and more than 70% of the activating property of the apolipoprotein. Arginine modification of apolipoprotein C-II does not effect its lipid-binding properties as assessed by its association to sonicated vesicles of dimyristoylphosphatidylcholine. Furthermore, secondary structure associated with complex formation with dimyristoylphosphatidylcholine are nearly identical for the unmodified, 1,2-cyclohexanedione-modified or modified-reversed proteins. These results suggest that arginine-49 of apolipoprotein C-II is situated at or near an amino acid sequence domain involved in the activation of lipoprotein lipase. However, a guanidinium group is not required for lipid binding.

Effect of a high carbohydrate diet on the content of apolipoproteins C-II, C-III and E in human plasma high density lipoprotein subfractions.

The effect of isocaloric high and low carbohydrate (Carb) diets on the structure and apoprotein composition of plasma high density lipoproteins (HDL) was assessed in four healthy men. The high Carb diet contained 65% calories as Carb and 15% as fat; the low Carb was 15% and 65%, respectively, with protein fixed at 20% of calories in each case. Cholesterol was 400 mg/day and the P/S ratio of the fat was 0.4. Each diet was sequentially consumed for periods of 3 weeks. At the end of each 3-week study period, plasma HDL2 and HDL3 were isolated by zonal ultracentrifugation and their apoprotein and lipid compositions were determined. Compared to the low Carb diet, the high Carb diet was associated with an increase in the size of HDL2 (116.0 +/- 1.8 vs. 109.1 +/- 1.8 A) and in the content (mean weight % +/- SEM) of apoE (2.81 +/- 0.71 vs. 1.79 +/- 0.49, P less than 0.01) and of apoC-II (1.73 +/- 0.09 vs. 1.11 +/- 0.12, P less than 0.01). HDL2 apoC-III content was not significantly different on the two diets (6.49 +/- 0.50 vs. 7.42 +/- 1.21). On the two diets, HDL3 size and HDL3 apoE content were not significantly changed. HDL3 apoC-II and apoC-III, however, were higher on the high Carb diet, P less than 0.05. The ratio (by weight) of HDL2 apoE/HDL2 apoC-II + C-III increased on the high Carb diet compared to the low Carb diet (0.344 +/- 0.058 vs. 0.228 +/- 0.053, P less than 0.01). We suggest that the increased amount of apolipoprotein E in HDL2 may influence its rate of catabolic clearance and may account for the well-known decrease in plasma HDL-cholesterol in subjects on high Carb diets.