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The amphibole asbestos, anthophyllite, is associated with asbestos-related disease in humans, along with mesothelioma in animal models. In humans, however, there are only three cases of histologically proven malignant mesothelioma of the pleura associated with anthophyllite that have been documented in the English-language literature. A fourth case is presented in a man who lived in South Africa and had anthophyllite in his lung. Anthophyllite was never commercially mined in South Africa. Using scanning electron microscopy, his lung fibre burden was calculated to be 358,000 fibres and 31,000 asbestos bodies per gram of dry weight of lung tissue. The mean aspect ratio of the anthophyllite fibres in the lung was 41.2 (SD = 28.8). No other types of asbestos were detected in the lung. His exposure was almost certainly occupational. He worked in the plastic manufacturing industry and was exposed to talc and asbestos blankets that were used to insulate machinery.

Nanoparticles are being used in ever increasing numbers in a range of industrial and medical products. Questions surrounding their potential to cause toxic effects in humans have been raised. Although animal experiments predict that nanoparticles are more toxic than their larger counterparts there are few descriptions in the literature of human exposure. A case described in 1994 has been re-examined from a pathology perspective. The subject, a 38-year-old previously healthy male, inhaled nanoparticles of nickel while spraying nickel onto bushes for turbine bearings using a metal arc process. He died 13 days after being exposed and the cause of death at autopsy was adult respiratory distress syndrome (ARDS). Nickel particles

Quantum superalgebras $su_{q}(m\mid n)$ are studied in the framework of $R$-matrix formalism. Explicit parametrization of $L^{(+)}$ and $L^{(-)}$ matrices in terms of $su_{q}(m\mid n)$ generators are presented. We also show that quantum deformation of nonsimple superalgebra $su(n\mid n)$ requires its extension to $u(n\mid n)$., 14 pages

Immunoreactive angiotensin I and angiotensin II were found in human urine that was purified on octadecasilylsilica cartridges. The daily excretion of angiotensin I and II in healthy volunteers was 189.00 (SE 38.36) and 17.54 (SE 3.07) pmol/24 h or 148.09 (SE 32.22) and 12.82 (SE 2.34) pmol/L, respectively (n = 12). No circadian rhythm was observed in the excretion patterns of angiotensin I and II. In vitro degradation of angiotensin I or II could not be detected in acidified urine samples. A marked increase in the excretion of angiotensin I and II could be demonstrated in patients with anaphylactoid reactions to drugs and food additives after oral challenge. Immunoreactive angiotensin I and II could be characterized by HPLC as Ile5-angiotensin I, Ile5-angiotensin II, and angiotensin II metabolites.

One hundred and forty-two coagulase-negative staphylococci (CNS) isolated from dialysate effluent or skin of patients receiving continuous ambulatory peritoneal dialysis (CAPD) were typed by extended antibiogram (16 antibiotics) and biotype (26 reactions). These isolates were then typed by supplementary methods to determine the most suitable typing method for an epidemiological study of antibiotic resistance. These included phage typing, reverse phage typing, plasmid typing, whole-cell protein typing by SDS-PAGE with analysis by densitometry, and immunoblotting. The percentage of isolates typed successfully by the supplementary methods were: phage typing 20%, reverse phage typing 0%, plasmid typing 66%, SDS-PAGE 100%, immunoblotting 100%. The discrimination of each method was: phage typing 20%, plasmid typing 37%, SDS-PAGE 69%, immunoblotting 57%. Reproducibility was 88% for phage typing and 97% for plasmid typing. The reproducibility of the whole-cell protein typing was 83% if the same extracts were used but only 43% when separate protein extracts were analysed on separate occasions. However, strain relatedness was highly reproducible. The determination of an antibiogram-biotype profile was not a sufficiently accurate typing method for an epidemiological study of antibiotic resistance. Whole-cell protein typing by SDS-PAGE or immunoblotting was technically demanding but was the most effective of the supplementary methods for detecting erroneous discrimination and false matching produced by antibiogram-biotype combinations.

Rates of resistance to 12 antibiotics were determined for 1,289 isolates of theBacteroides fragilis group submitted in 1988–1989 by 22 laboratories in 15 European countries. There was no resistance to metronidazole (breakpoint 8 mg/l) and only one isolate was resistant to chloramphenicol (breakpoint 8 mg/l). Resistance was uncommon for imipenem (0.3 % at > 4 mg/l), amoxicillin/clavulanate (1 % at > 8 mg/l), cefoxitin (3 % at > 32 mg/l), mezlocillin (6 % at > 64 mg/l) and clindamycin (9 % at > 4 mg/l). Resistance was the rule for ampicillin (93 % at > 4 mg/l), ciprofloxacin (56 % at > 4 mg/l) and tetracycline (64 % at > 4 mg/l).Bacteroides fragilis, the commonest species, was generally the most sensitive: resistance of this organism was uncommon for cefotetan (4 % at > 32 mg/l) and ceftazidime (12 % at > 32 mg/l) to which the other species were more often resistant. There were small but significant differences between laboratories and countries for many of the antibiotics. Regionally the most striking differences were for clindamycin where resistance inBacteroides fragilis was most common in the South and for tetracycline where resistance inBacteroides fragilis, Bacteroides thetaiotaomicron andBacteroides uniformis was least common in the North.

Induction by the 4-quinolone group of antibacterial drugs of the umuC gene, the SOS function most involved in error-prone DNA repair (together with umuD), was assessed in a strain of Escherichia coli harbouring a umuC::lacZ gene fusion. All 4-quinolones tested induced this umuC::lacZ fusion, with maximum induction at 4-quinolone concentrations close to their minimum inhibitory concentrations for this strain, and the SOS Inducing Potential (SOSIP) was closely related to antibacterial activity. Mitomycin C, a known mutagen, was a slightly better inducer (in terms of SOSIP) than any of the quinolones. In contrast, induction by 4-quinolones of the sfiA (sulA) gene, an SOS function involved in cell division inhibition, was better than induction by mitomycin C in an E. coli strain harbouring an sfiA::lacZ gene fusion. The umuC gene fusion was induced at lower concentrations of 4-quinolone than was the sfiA gene fusion.

The immune system has been linked to the pathogenesis of hypertension in the spontaneously hypertensive rat (SHR). Recently interleukin-2 has been reported to inhibit the development of hypertension in the SHR, but no measures of different lymphocyte populations were made. To test the effect of interleukin-2 we repeated the protocol in the report by injecting forty two day old, male SHR and WKY rats, and in addition, analyzed lymphocyte subpopulations. Untreated, age matched rats of the same strain were used as a control. At three and four months of age blood was drawn from all animals. Monoclonal antibodies were used to fluorescently label different lymphocyte subpopulations. The populations examined were the total T-cells, T-nonhelper cells, T-helper cells and B-cells. Total numbers of lymphocytes and white blood cells were also examined. Blood pressures were measured in conscious, restrained animals at two and four months of age. The results showed no attenuation of blood pressure in the interleukin-2 treated SHR at either age. The interleukin-2 treated SHR had a decrease in the percentage of B-cells and an increase in the percentage of T-nonhelper cells relative to the control SHR. Both treated and untreated SHR had increased numbers of white blood cells and lymphocytes compared to both groups of WKY. We conclude that the interleukin-2 used was active but failed to have any effect on blood pressure or absolute numbers of white blood cells and lymphocytes in the treated animals.

Two plasmids containing the cloned Escherichia coli wild-type gyrA gene were used to transform ciprofloxacin-resistant Gram-negative clinical isolates to screen for DNA gyrase A-mediated quinolone resistance. The results show that the technique is simple and applicable to a wide range of Gram-negative species including E. coli, Enterobacter cloacae, Klebsiella aerogenes, Morganella morganii, Proteus mirabilis, Pseudomonas aeruginosa, Campylobacter jejuni and Neisseria gonorrhoeae. The use of an arithmetical MIC series of dilutions (as opposed to standard geometrical ones) was found to be essential during screening for the detection of altered gyrase A. The observations were consistent with the suggestion that DNA gyrase is highly conserved among different species of bacteria and that gyrase A-mediated resistance can occur in all.

Ocular tension recorded by pneumatonography was estimated at 4-hour intervals during six consecutive 24-hour periods in 8 New Zealand rabbits. The animals had been acclimatized for more than 8 weeks to artificial light from 08.00 to 20.00 h and dark for the other 12 h. Inter- and intrarabbit consistency was enough to allow the generalization that the lowest pressure occurred at noon (mean -0.8 mm Hg from baseline average), while the highest pressures (mean + 1.2 mm Hg above baseline average) occurred at 16.00 and 20.00 h. Only three other studies have measured rabbit ocular tensions throughout 24 h, but for shorter periods: one observed a light-induced rise as in the present study, but the other two studies found a rise during darkness.

A sensitive, specific, quantitative enzyme‐linked immunosorbent assay (ELISA) has been developed that can be used to determine the extent of mycelial growth of a sporulating thermophilic fungus, Humicola lanuginosa on the surface of rice grains. The assay employs a monoclonal antibody EC6, developed in a previous study, which does not recognize spores of the fungus. Using antigen‐coated wells, a direct linear relationship was established between dilutions of extracts from freeze‐dried mycelium (0.5 to 3 μg/ml) and absorbance values but to eliminate day‐to‐day variations it was found to be necessary to run a dilution series, prepared from stock freeze‐dried mycelium, with every test sample. The ELISA method was compared with conventional quantitative methods. Estimates of total mycelial length in freeze‐dried material by ELISA were found to be in the same order of magnitude as those determined by ergosterol and a theoretical calculation. The ELISA method also compared favourably with direct linear measurem...

The carotid body, jugulotympanic, vagal, and laryngeal paragangliomas are the most common paragangliomas respectively within the head and neck, although unusual examples in other sites have been described. Among these are several references in the literature to a mandibular or "alveolar body" paraganglioma, even though such an entity does not appear to have been adequately documented. This report describes a case which presented as an extensive osteoblastic tumor involving the mandible and which radiographically appeared as a typical osteosarcoma. However, the immunohistochemical and electron microscopic features were of a neuroendocrine tumor and the histologic pattern suggested a paraganglioma. The tumor was nonfunctional and an extensive search failed to reveal any further lesions. Eight months after resection of the lesion, metastatic deposits appeared within the left iliac crest and lumbar vertebra. The origin of this tumor is discussed.

Ciprofloxacin at a dose of 25 mg/L of dialysate was administered intraperitoneally for five days as a single agent for the empirical treatment of CAPD peritonitis. One hundred and seventeen consecutive episodes of peritonitis occurred in 65 patients during the study period, and 100 episodes were entered in the study. This therapy was successful in 79% of episodes. Resistant organisms (MIC greater than 4 mg/L) all of them coagulase-negative staphylococci, were isolated in nine (7.8%) of the 117 episodes. Mean ciprofloxacin concentrations in dialysate and serum on the last day of treatment were 6.1 mg/L (range 0.3-15.7) and 0.3 mg/L (range 0-0.9) respectively. No adverse effects were reported.

Various arthroscopic meniscal repair techniques have been developed in recent years to preserve meniscal function. We report the case of a patient with a failed arthroscopic meniscal repair demonstrating an inflammatory foreign-body reaction to bioabsorbable meniscal arrows.

Fine needle aspiration of the male breast can present problems of diagnosis because the cytological presentation of gynaecomastia can be confused with that of adenocarcinoma. We reviewed breast aspirates from 24 male patients in order to determine the accuracy of cytology as a method of diagnosing gynaecomastia. Discrepancies were observed between the original cytology reports on one hand and the review cytology and biopsies on the other. Of the 24 aspirates from the male breast, the cytology was reported as negative in 16 cases, suspicious in three cases and malignant in five. In four cases of the negative group, a specific diagnosis of gynaecomastia was made. In two of the negative cases the subsequent biopsies revealed adenocarcinoma. Of the five cases reported on the original cytology as adenocarcinoma, two on review showed the features of florid gynaecomastia and this was confirmed on biopsy and three confirmed the initial diagnosis of adenocarcinoma. The cytological features of gynaecomastia which distinguish it from adenocarcinoma are discussed.

Monoclonal antibodies (mAbs) were raised against Penicillium islandicum, a fungus commonly isolated from stored rice grains in South-East Asia. Mice were immunized by a direct, simple method; fresh cell-free surface washings from a solid agar slant culture were injected directly into the peritoneum without prior concentration. Hybridoma supernatants were screened by ELISA. Most of the mAbs raised cross-reacted with other storage fungi and/or uninfected rice grains but there were species-specific. One of these, PI01, was used to develop ELISA and DIP-STICK assays for the detection of P. islandicum in individual grains. All inoculated grains and approximately 90% of grains in natural infected samples from Indonesia tested positively, by ELISA, for P. islandicum. This result and those obtained for discoloured grains from both Indonesia and the Philippines, 32% and 14% respectively, are higher than those obtained by direct plating of surface-sterilized grains. Heat and periodate treatment of the PI01 antigen and binding on Western blots indicate that it is a glycoprotein of Mr greater than 90,000. Hyphae of all ages stained uniformly by immunofluorescence using the PI01 antibody but mature conidia stained only weakly.

Ciprofloxacin was evaluated as single-agent therapy for the empirical treatment of patients presenting with CAPD peritonitis in an open, uncontrolled trial. Seventy-five episodes of peritonitis in 44 patients receiving continuous ambulatory peritoneal dialysis were entered in the study. The antibiotic was administered intraperitoneally, at a dose of 50 mg/l in each bag of dialysate, for seven days. Treatment with ciprofloxacin was appropriate (organisms isolated sensitive to ciprofloxacin) and successful (clinical and bacteriological cure of peritonitis) in 62 (83%) of the 75 episodes. The mean ciprofloxacin concentrations in serum and effluent were 1.1 mg/l (range 0-2.9 mg/l) and 10.0 mg/l (range 0.2-33.4 mg/l), respectively, with no evidence of accumulation. Side effects were seen in two patients only, and were mild and transitory.

Neuronal and glial cultures from the hypothalamic-brain stem areas of 1-day-old normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rat brains stained positively with atrial natriuretic peptide (ANP)-specific antibodies. The endogenous levels of the ANP immunoreactivity in WKY neuronal and glial cultures were 17.0 +/- 2.2 and 14.3 +/- 2.7 pg/mg, respectively. Comparable neuronal and glial cultures from SH rat brains contained a 48 to 70% decrease in the endogenous ANP immunoreactivity levels. Culture media from both brain cell types also contained ANP immunoreactivity, the levels of which are significantly higher than those found in the cells. However, similar to endogenous levels, the media levels of immunoreactive ANP in SH neuronal and glial cultures were significantly reduced compared with WKY brain cultures. These observations demonstrate that endogenous ANP-like immunoreactivity is found in neuronal and glial cells and is released into the media. The levels of peptide are reduced in cultures of SH compared with WKY cultures, suggesting a genetically controlled difference between the hypertensive and normotensive rat strains long before hypertension develops.

Newly replicated Plasmodium falciparum parasites escape from host erythrocytes through a tightly regulated process that is mediated by multiple classes of proteolytic enzymes. However, the identification of specific proteases has been challenging. We describe here a forward chemical genetic screen using a highly focused library of more than 1,200 covalent serine and cysteine protease inhibitors to identify compounds that block host cell rupture by P. falciparum. Using hits from the library screen, we identified the subtilisin-family serine protease PfSU B1 and the cysteine protease dipeptidyl peptidase 3 (DPAP3) as primary regulators of this process. Inhibition of both DPAP3 and PfSUB1 caused a block in proteolytic processing of the serine repeat antigen (SERA) protein SERA5 that correlated with the observed block in rupture. Furthermore, DPAP3 inhibition reduced the levels of mature PfSUB1. These results suggest that two mechanistically distinct proteases function to regulate processing of downstream substrates required for efficient release of parasites from host red blood cells.

Introduction Despite 2008 NICE guidance on managing IBS in primary care, referrals to gastroenterology persist with baseline audit finding 14% of new outpatient slots in two DGHs were used by patients aged 16–45 years with no red flag symptoms where the GP felt diagnosis at referral was IBS. Given evidence for lifestyle and diet modification, we set out to help GPs avoid referral as outpatient review and investigation cost over £160,000 annually for these patients. Using potential savings, we funded direct GP access to faecal calprotectin (FC) testing and specialist IBS dietetic-led clinics in four centres across Somerset. Method We designed new care pathways for 16–45 year olds with no red flag symptoms with county-wide GP education using Rome III criteria to make a positive diagnosis of IBS and avoid missing red flags. Instead of referring to secondary care, GPs were asked to check FC, with Coeliac screen, FBC, CRP and TFT. If FC 50 µg/g, secondary care referral was appropriate to consider investigation, especially if FC >150 µg/g. A management algorithm provided symptom-based drug therapies. To aid implementation, the Somerset Pathway Navigator provided a single gateway to GP referrals. Results Outpatient data: Repeating our initial audit at 1 year showed referrals to secondary care for management and investigation fall from 14% to 9% of new appointments. Faecal calprotectin: 94 patients met this protocol; 64 patients had FC 150 µg/g. Even when FC 150 mg/g with 10 referred and 5 having Crohn’s or Ulcerative colitis. Specialist Dietetic outcomes: Over 12 months, 83 patients completed 8-week treatment courses including low FODMAP advice with statistically significant reductions in severity scores of all symptoms. After treatment, 65% reported satisfactory relief of IBS and 74% reported improved quality of life. Conclusion Providing GP education, developing new diagnosis and management pathways, introducing FC testing for GPs and effective dietetic treatments have encouraged self-management, provided cost-effective symptom resolution and reduced unnecessary secondary care referrals for likely IBS. Disclosure of interest None Declared. Reference Irritable bowel syndrome in adults (2008) CG61 NICE

This hypothesis is readily testable by replicating in additional well-characterized diabetic populations. Interestingly, raised fasting triglycerides and slightly increased fasting insulin have recently been associated with an mtDNA polymorphism at position 16 517 in a native American population[15xHegele, R. et al. Am. J. Hum. Genet. 1997; 60: 1552–1555Abstract | Full Text PDF | PubMedSee all References[15]. As this polymorphism is closely associated with the 16 189 variant in this group[16xTorroni, A. et al. Am. J. Hum. Genet. 1993; 53: 591–608PubMedSee all References[16], it is likely that the 16 189 variant and fasting insulin levels are associated in this population. Investigation of the effect of variation in the lengths of the homopolymeric tract on mitochondrial function might establish a mechanistic basis for this association.If correct, this hypothesis has important implications for clinicians and scientists in three separate fields of endeavour: diabetes research, biological anthropology and mitochondrial genetics. Firstly, if the 16 189 variant is a significant genetic predisposing factor for Type 2 diabetes, measures for preventing obesity could be targeted to individuals with the variant. Secondly, the variant might be a genetic determinant of metabolic thrift and, hence, have contributed to the successful colonization of Polynesia despite the adversity of the long sea voyages involved. Thirdly, by predisposing to Type 2 diabetes, the 16 189 variant might be responsible for orders of magnitude more morbidity than all other mitochondrial diseases put together.

Background Hand-arm vibration syndrome (HAVS) is associated with the use of hand-held vibrating tools. Affected workers may experience symptoms of tingling, numbness, loss of grip strength and pain. Loss of dexterity may impair everyday activities, and potentially increase the risk of occupational accidents. Although high vibration levels (up to 31 m/s 2 ) have been measured in association with rock drills, HAVS has not been scientifically evaluated in the South African mining industry. Aims The aim of this study was to determine the prevalence and severity of HAVS in South African gold miners, and to identify the tools responsible. Methods A cross-sectional study was conducted in a single South African gold-mine. Participants were randomly selected from mineworkers returning from annual leave, comprising 156 subjects with occupational exposure to vibration, and 140 workers with no exposure. Miners who consented to participate underwent a clinical HAVS assessment following the UK Health and Safety Laboratory protocol. Results The prevalence of HAVS in vibration-exposed gold miners was 15%, with a mean latent period of 5.6 years. Among the non-exposed comparison group, 5% had signs and symptoms indistinguishable from HAVS. This difference was statistically significant (P < 0.05). All the cases of HAVS gave a history of exposure to rock drills. Conclusions The study has diagnosed the first cases of HAVS in the South African mining industry. The prevalence of HAVS was lower than expected, and possible explanations for this may include a survivor population, and lack of vascular symptom reporting due to warm-ambient temperatures.

Corticosteroid-binding globulin (SERPINA6) deficiency is an extremely rare hereditary disorder characterized by reduced corticosteroid-binding capacity with normal or low plasma corticosteroid-binding globulin concentration, and normal or low basal cortisol levels associated with hypo-/hypertension and muscle fatigue. Here, we present a patient with severe muscle fatigue, normal blood pressure, and abnormal high saliva cortisol levels following a standardized stress test. This patient was found heterozygous for a de novo 367 asparagine-encoding variant of the corticosteroid-binding globulin gene, previously described as "transcortin Lyon". Both parents were homozygous for the ("wildtype") 367 aspartate-encoding allele. To the best of our knowledge, this case represents the first de novo mutation reported for corticosteroid-binding globulin deficiency, implicating a pathogenic role of variants of SERPINA6 in some cases of muscle fatigue.

SV40 has been implicated in the etiology of 40% to 60% of human mesotheliomas. These studies could have important medical implications concerning possible sources of human infection and potential therapies if human tumors are induced by this agent. We did PCR-based analysis to detect SV40 large T antigen DNA in human mesotheliomas. None of 69 tumors in which a single copy gene was readily amplified contained detectable SV40 large T antigen sequences. Under these conditions, it was possible to detect one copy of integrated SV40 DNA per cell in a mixture containing a 5,000-fold excess of normal cells using formalin-fixed preparations. Kidney, a known reservoir of SV40 in monkeys, from some of these individuals were also negative for SV40 large T antigen sequences. A subset of mesotheliomas was analyzed for SV40 large T antigen expression by immunostaining with a highly specific SV40 antibody. These tumors as well as several human mesothelioma cell lines previously reported to contain SV40 large T antigen were negative for detection of the virally encoded oncoprotein. Moreover, mesothelioma cell lines with wild-type p53 showed normal p53 function in response to genotoxic stress, findings inconsistent with p53 inactivation by the putative presence of SV40 large T antigen. Taken together, these findings strongly argue against a role of SV40 by any known transformation mechanism in the etiology of the majority of human malignant mesotheliomas.

Three of the papers contained in this supplement cover aspects of a symposium titled ‘The modern gladiatorial arena: Gram-positive pathogens versus new therapies’ which was held at the 14th European Congress of Clinical Microbiology and Infectious Diseases in Prague, Czech Republic, in May 2004. These papers review the prevalence of resistant pathogens in Europe, the effectiveness of currently available therapies, areas of unmet clinical need, and the way in which unmet needs might be addressed in the future. They are preceded by a fourth paper which provides a review of the mechanisms of antibiotic resistance in Gram-positive bacteria. One of the antibiotics that promises to be relevant to unmet needs is daptomycin, an agent with a unique mode of bactericidal action. The antibiotic was discovered by Eli Lilly and Company (Lilly) in the early 1980s and was under development as LY146032, for the intravenous treatment of serious Gram-positive infections. Despite promising trials for the treatment of skin and soft tissue infections and endocarditis Lilly suspended trials in 1991 because of concerns regarding skeletal muscle toxicity. Later in the decade, interest in daptomycin returned because of the increasing prevalence of infections caused by Gram-positive pathogens that were resistant to many antibiotics. In 1997, Cubist Pharmaceuticals received rights to the drug on the premise that modified dosing regimens would be clinically effective without the risk of skeletal muscle toxicity. Clinical trials (at a dosage of 4 mg/kg once daily) supported this premise and in September 2003 the drug was approved by the US Food and Drug Administration for the treatment of complicated skin and soft tissue infections caused by susceptible Gram-positive bacteria, including methicillin-resistant and methicillinsusceptible Staphylococcus aureus. Chiron Biopharmaceuticals has in-licensed the commercial rights to daptomycin in Western and Eastern Europe, Australia, New Zealand, India and certain Central American, South American and Middle Eastern countries. Daptomycin is currently undergoing further trials to assess its potential to address unmet needs, particularly in the treatment of serious skin and soft tissue infections.

In a rural community in South Africa historically exposed to asbestos environmentally and occupationally, 200 women who had worked with asbestos and applied for medical examination to determine compensable asbestos disease were evaluated. Clinical and radiologic evaluation, sputum collection, and microscopic analysis were done. A questionnaire elicited type of exposure, duration, decade of first work exposure, and environmental exposure. Crackles were present in the lungs of 166 women and asbestos fibers and ferruginous bodies were present in 122. Asbestosis was identified in 26 and plural plaques in 62. Auscultation for crackles (rales) is useful in the initial examination of former asbestos workers in rural communities of developing countries.

The success of gene therapy requires specific targets. For the potential treatment of cardiovascular disease by gene therapy, the renin-angiotensin system offers targets that are know to be effective based on pharmaceutical drugs that have targeted angiotensin-converting enzyme (ACE) angiotensin type I receptors (AT1R). Other targets include renin and angiotensinogen. It is clear that lowering overactive amounts of angiotensin II has positive effects on reducing high blood pressure, decreasing left ventricular hypertrophy, and lowering the risk of heart attacks, stroke, and kidney failure. To inhibit the RAS system we have used antisense (AS) inhibitors which can be delivered either as oligonucleotides and used like small molecule drugs or in vectors with a sequence of DNA in the antisense direction. This review summarizes the effects of these two approaches on reducing high blood pressure. Gene therapy with antisense offers long-lasting, highly specific inhibition of gene products such as the components of RAS when their overactivity needs to be reduced in order to ameliorate disease.

In two U.S. studies about medical errors in 2000 and 2001, family physicians offered their ideas on how to prevent, avoid, or remedy the five most often reported medical errors. Almost all reports (94 percent) included at least one idea on how to overcome the reported error. These ideas ranged from "do not make errors" (34 percent of all solutions offered to these five error types) to more thoughtfully proposed solutions relating to improved communication mechanisms (30 percent) and ways to provide care differently (26 percent). More education (7 percent) and more resources such as time (2 percent) were other prevention ideas.

Background The use of early warning system scores and track & trigger charts is widespread in adult and paediatric hospitalised patients. Its use in neonatal group is not well recognized. Lack of well established normal ranges for biophysical variables in preterm/term neonates illustrate difficulties in establishing a scoring system that can potentially be used on the neonatal units and postnatal wards. Aim To develop neonatal track and trigger observation chart in order to enable early identification of neonates in need of urgent medical assessment and intervention. Methods A core group involving local paediatricians, neonatal nurses and midwifery sister was established to lead the project. The group contacted various neonatal units in different newborn networks in England seeking information if early warning scores or track & trigger system was being developed or already well established. Literature search was carried out to identify studies related to newborn early warning system scores. Results One relevant published study was retrieved from Medline search (Roland 2010). None of the neonatal units contacted had an established early warning neonatal scoring system. Group developed newborn observation chart for “At Risk” and “High Risk” Infants. It was based on neurophysiological parameters, intervention criteria and staff concerns. A decision tree was devised based on trigger scores. Conclusions Prospectively evaluation of Burton neonatal track and trigger observation chart is required to ascertain its efficacy. If found to be reliable and valid, it will facilitate observation of neonates deemed to be at risk and prompt an early review in triggered neonates.

A corner is modelled as the intersection of two lines. A corner point is that point on an input digital arc whose a posteriori probability of being a corner is the maximum among all the points on the arc. The performance of the corner detector is characterized by its false alarm rate, misdetection rate, and the corner location error all as a function of the noise variance, the included corner angle, and the arc length. Theoretical expressions for the quantities compare well with experimental results. >

Background Sudden cardiac death in young people accounts for about 45 deaths per year in Wales. Early intervention with defibrillation improves survival for cardiac arrest. A recent intervention providing an automated external defibrillator (AED) to every high school in New York state, USA, eliminated sudden cardiac death in young people under 19 years over a 2-year period. We conducted a postal survey to establish whether secondary schoolteachers in South Wales had life support training and access to an AED. Methods All physical education departments in South Wales secondary schools (n=158, identified from Welsh Audit Office data) were sent postal questionnaires in May, 2014. Teachers were asked to provide information including the level of life support training and access to an AED. Completed questionnaires returned within 14 days were included in the study. Findings Responses were received from 35 schools (22%). Responses are representative of 2133 teachers who are responsible for 30 000 pupils aged 11–18 years. 200 teachers (9·6%) reported having in-date life support training and a further 21 (1·0%) had training that included use of an AED. Ten schools had an AED on site with a further two that had AEDs located at an adjacent leisure centre. Three of the schools with AEDs had no trained staff (odds ratio 1·04, 95% CI 0·58–1·90, p=0·89). 73% of the respondents (115/158) agreed that life support training should be a mandatory part of training. Interpretation The results suggest that only a small number of teachers in South Wales have life support training and access to an AED, and yet most teachers questioned expressed a desire to be trained in life support and to have access to an AED. Limitations to this study include the low response rate, which could reflect an inherent bias in the methodology whereby only interested teachers or schools with AEDs on site replied to the survey. These initial findings warrant further investigation at a national level, which would include a feasibility study exploring the implementation of a nationwide AED provision and training programme in schools. Funding None.

Background Use of early warning system scores and track and trigger charts is widespread in adult and paediatric hospitalised patients. Its use in neonatal group is not well recognised. Lack of well established normal ranges for biophysical variables in preterm/term neonates illustrate difficulties in establishing a scoring system that can potentially be used on the neonatal units (NNU) and postnatal wards (PNW). We have recently developed NOTT chart for use in newborn babies on PNW. Aim To validate NOTT chart in order to enable early identification of neonates in need of urgent medical assessment and intervention. Methods A service evaluation was carried out to evaluate the efficacy of NOTT chart. All admissions from PNW to NNU (Feb–Aug 2013) were evaluated. Notes of all babies on PNW (2 weeks duration in Nov 2013) were also reviewed. Results There were 24 NNU admissions from PNW between Feb–Aug 2013. Sensitivity of NOTT chart’s ‘medium’ and ‘high’ score was 96% (22/23). Charts of 42 babies on PNW were examined in Nov 2013. 7/42 babies scored ‘medium’ or ‘high’ out of which, 3 were admitted to NNU. Specificity of NOTT chart was 90%. Positive and negative predictive value was 43% and 100% respectively. Conclusions NOTT is an effective screening tool to identify any deterioration in the condition of a new born so prompt and timely assessment and medical intervention could be carried out. It is a useful tool for information sharing and provides a one stop solution for unifying all neonatal observations on PNW.

Interluekin-6 (IL-6) plays an important role in immunological, inflammatory and metabolic responses to exercise. The downstream effects of IL-6 signalling are dependent on the binding to its receptors, both soluble (sIL-6R) and membrane bound. There is evidence that sIL-6R concentrations change in response to exercise and are related to exercise load and fatigue. However, considerably less is known about the sIL-6R response to prolonged exercise training. Knowledge of the receptor response to training may provide insight into the mechanisms underlying cytokine regulation of a number of biological processes. This study investigated the effect of a prolonged period of training on sIL-6R and how this related to perceptions of fatigue. Ten (7 females, 3 males) highly trained swimmers participated. sIL-6R was determined from capillary blood samples collected prior to training each week for a period of 18 weeks. Participants also completed a subjective wellbeing-monitoring questionnaire once a week prior to training. sIL-6R was negatively correlated to weekly training volume (r = -0.68, r 2 = 0.47, p

Defects of both sodium-hydrogen exchange (NHE) and sodium-lithium countertransport (SLC) have been described in subjects at increased risk of coronary heart disease (CHD). Sodium transport is linked to the regulation of cell volume, intracellular pH and cell growth, which may explain aspects of this association. However, impaired growth in early life is also linked to adult CHD, and 'programmed' alterations of cell behaviour are postulated to be responsible for this. In this study, therefore, we examined whether NHE or SLC in adults are predicted by anthropometric measures at birth, as well as being associated with insulin resistance syndrome (IRS) variables in adulthood. Red cell SLC was measured in 26 adults, and NHE in dermal fibroblasts from another 15 subjects characterized anthropometrically at birth. SLC activity correlated with LDL cholesterol, triglycerides and urate (r=0.42 - 0.49; 0.05P0.01), but not birth anthropometry. NHE V(max) correlated with plasma insulin (r=0.80; P0.001), but birth weight was unrelated to V(max), K(m) or Hill coefficient for H(i)(+). However, pH(i) correlated with birth weight (r=0.74; P=0.002), insulin sensitivity (r=0.52; P0.05), fasting glucose (r=-0.52; P0.05) 2 h insulin (r=0.51; P0.05) 2 h glucose (r=-0.54; P0.05). In conclusion, red cell SLC is related to IRS variables, but not with birth weight measures. In contrast, low intracellular pH(i) is related to both low birth weight and adult insulin resistance, suggesting it might be a 'programmed' cell phenotype, although this is not apparently explained by altered NHE kinetics.

Mesothelioma has not been found in South African chrysotile miners and millers despite decades of producing about 100000 tons of the mineral per year. One possible explanation for the scarcity or absence of the cancer may be a relative lack of contaminating fibrous tremolite, an amphibole that variably occurs with chrysotile ores. The fibre content in the lungs of nine former chrysotile mine workers was ascertained by transmission electron microscopy. Despite fairly long service in most cases (median 9.5 yr; range 32-4 yr) the concentrations of chrysotile fibres were relatively low: only two cases exceeded 1.14 million fibres/g dried lung. Tremolite fibre levels were even lower: less than 1 million fibres/g dried lung in all but one case. Tremolite fibre concentrations exceeded those of chrysotile in only two cases. These results support the contention that South African chrysotile is not heavily contaminated by tremolite.

Many kinds of drugs are used for the treatment of hypertension, but they are all short-acting (or = 24 h) and patient compliance is poor. Gene therapy offers the advantage of producing long-term effects with high specificity, which should increase efficacy and reduce side effects. An antisense oligodeoxynucleotide (AS ODN) is a single-stranded oligonucleotide containing a gene-specific sequence of nucleotides, which is used to inhibit translation of mRNA. The application of AS ODNs for the treatment of hypertension began with targeting the renin-angiotensin system. Other genes, such as that coding for the beta1-adrenoceptor, have recently been targeted with AS ODNs in an attempt to reduce blood pressure. Strategies for the application of antisense technologies can be classified in two ways: the direct application of AS ODNs, and the production of AS by AS-cDNA inserted into viral vectors. Promising preclinical results from basic research have made feasible the possibility for antisense gene therapy of hypertension in the future.

Mesothelioma has not been found in South African chrysotile miners and millers despite decades of producing about 100 000 tons of the mineral per year. One possible explanation for the scarcity or absence of the cancer may be a relative lack of contaminating fibrous tremolite, an amphibole that variably occurs with chrysotile ores. The fibre content in the lungs of nine former chrysotile mine workers was ascertained by transmission electron microscopy. Despite fairly long service in most cases (median 9.5 yr; range 32–4 yr) the concentrations of chrysotile fibres were relatively low: only two cases exceeded 1.14 million fibres/g dried lung. Tremolite fibre levels were even lower: less than 1 million fibres/g dried lung in all but one case. Tremolite fibre concentrations exceeded those of chrysotile in only two cases. These results support the contention that South African chrysotile is not heavily contaminated by tremolite.

AIMS: An association between Chlamydia pneumoniae and atherosclerosis is now well established. The finding of C. pneumoniae in atherosclerotic lesions has led to the hypothesis that this organism may have an aetiological role in atherogenesis. The implications of such a concept are enormous, but to date the pathological features of the lesion have not been examined in the light of this new hypothesis. This study was designed to determine the pathological basis of the association between C.pneumoniae and atherosclerotic lesions. METHODS: The pathological features of 50 atherosclerotic lesions from 50 different patients, in which C.pneumoniae had been demonstrated by immunocytochemistry and PCR techniques, were examined using light and electron microscopy techniques. In 20 cases the lesions were fatty streaks, 20 were fibro-atheroma lesions, and 10 were advanced, complicated lesions. RESULTS: Intimal smooth-muscle cells infected with C. pneumoniae exhibit vacuolation, loss of myofilaments, an increase in lipid, rupture and fragmentation. Macrophages phagocytose these muscle cell fragments, lipid and C. pneumoniae. Large numbers of extracellular C. pneumoniae organisms were identified in the central necrotic core, in areas of fibrosis, in areas of fragmentation of the internal elastic lamina, and in ceroid bodies. Neither pathological changes nor organisms were seen in the endothelium. CONCLUSIONS : C. pneumoniae infection of intimal smoothhypen; muscle cells is accompanied by cytoplasmic alterations and damage. The fatty streak appears to be formed by a macrophage response to this muscle damage. C. pneumoniae is found in early, mature and advanced lesions. This is the first study of the pathology of atherosclerosis suggesting that the lesion be interpreted as an infective chlamydial granuloma.

There can no longer be any doubt that viable Chlamydia pneumoniae organisms are present in atherosclerotic lesions. Indeed, the endovascular presence of C. pneumoniae in coronary artery disease (CAD) is common. The fact that this lesion, which is the major cause of stroke, coronary heart disease ( CHD), peripheral vascular disease and aortic aneurysm, can no longer be regarded as sterile has prompted a good deal of study and speculation. Atherosclerotic lesions have been studied in detail, but until recently histological descriptions of the lesion have not included C. pneumoniae organisms. Reviews and analysis of the literature confirm the association between C. pneumoniae and atherosclerotic lesions and CHD. The possibility that C. pneumoniae plays a causal or contributory role in the development of atherosclerotic lesions has been debated. It is of major importance as there is already evidence that antibiotic therapy may be of clinical benefit in patients with CHD. Large clinical trials using antichlamydial agents have been embarked upon which may provide further evidence of a causal role for C. pneumoniae. The underlying mechanism of how C. pneumoniae contributes to lesions and the effect of antibiotic therapy on lesions remain unknown. The association between C. pneumoniae and atherosclerosis is reviewed. Particular attention is paid to the lesion itself and the presence of C. pneumoniae. Potential areas of study that may contribute to this rapidly expanding area of research is explored.

A 39-year-old black South African man with no recognised risk factors for coronary hart disease (CHD) except hypertension, died of a myocardial infarct (MI). The case was unusual because although hypertension is common, MI is rare in black South Africans. Serology indicated that the subject had previously had a Chlamydia pneumoniae infection. The primary lesion in the left anterior descending branch of the coronary artery was a ruptured atherosclerotic plaque in which C. pneumoniae was indentified by immunocytochemical, electron microscopic and polymerase chain reaction techniques. The organisms were detected in smooth-muscle cells, foam cells and interstitially, but not in adjacent unaffected tissue. C. pneumoniae DNA was also detected in the myocardium of the left ventricle in an area of the infarct. It is postulated that debris from the ruptured plaque was deposited in the muscle. The observations support the association between C. pneumoniae and CHD; for the first time the organism is identified in a lesion that ruptured and caused an MI.

This paper describes work being undertaken as part of the WebSET (Web-based Standard Educational Tools) project. The project is producing a standardised suite of interactive three-dimensional educational tools, delivered across the WWW. The major focus will be the use of open technology and standards, and the production of learning components that can be used as building blocks for further development in a wide range of application areas. Two learning disciplines have been selected for the development of the WebSET tools: surgical training, and physiological education. A high quality consortium from across Europe has been assembled with complementary skills in the technologies needed by the project. The project is partly funded by the European Commission.

Recent studies have shown that intrauterine growth retardation or fetal distress in human infants is associated with a pronounced reduction in melatonin secretion during the first 3 months of life. It is not known whether these associations persist beyond infancy. We have therefore examined the relationship between birthsize and melatonin secretion in 159 men and women aged 20, born in Adelaide, South Australia. Melatonin secretion was estimated by analysing the overnight urinary excretion of 6-sulphatoxymelatonin. The overnight excretion ranged from 1.7 to 128.9 nmoles/subject, was higher in women than in men (46.5 vs 34.1 nmoles, P = 0.003) and was significantly negatively correlated with the body mass index (P = 0.006). Excretion correlated with both birthweight and ponderal index at birth (P = 0.04 and P = 0.01 respectively after adjustment for gestational age) and also fell with increased duration of gestation (P = 0.007). The effects of adult body mass index added to that of low birthweight in predicting 6-sulphatoxymelatonin excretion. These data suggest that urinary 6-sulphatoxymelatonin excretion was impaired in adults who were growth restricted prenatally or were delivered after 40 weeks gestation.

It has been suggested that increased activity of the hypothalamic-pituitary-adrenal axis may link low birth weight with subsequent development of cardiovascular risk factors and disease. Two hundred and five men, aged 66-77 yr, who were born and still live in East Hertfordshire underwent an overnight very low dose (0.25 mg) dexamethasone suppression test followed by a low dose 1-microgram ACTH-(1-24) stimulation test. A 24-h urine sample was collected for analysis of cortisol metabolites by gas chromatography/electron impact mass spectrometry. Men with lower birth weight had enhanced responses of plasma cortisol to ACTH-(1-24) (P = 0.03), increased total urinary cortisol metabolite excretion (after adjustment for confounding effects of increased obesity and lean body mass in high birth weight men; P = 0.04), but no difference in plasma cortisol after dexamethasone. Features of the metabolic syndrome were independently associated with enhanced adrenal responsiveness to ACTH-(1-24) (raised blood pressure, P = 0.02; glucose intolerance, P = 0.09; hypertriglyceridemia, P = 0.02), with trends to increased urinary cortisol metabolite excretion, but not with differences in plasma cortisol after dexamethasone. Men with low birth weight and/or the metabolic syndrome have increased activity of the hypothalamic-pituitary-adrenal axis. This may be an important mechanism underpinning the effects of events in early life on later cardiovascular disease.

To determine whether poor fetal growth, as determined by size at birth, is associated with an increased risk of age-related cataract.A total of 741 men and women born in Sheffield, England between 1922 and 1930 and whose size at birth was available were traced and invited to take part in the study. Of these, 392 (53%) attended for ophthalmic examination. Lens opacity in these volunteers was graded using the Lens Opacities Classification System (LOCS) III.After adjusting for age, gender, gestational age, and risk factors for cataract there were no consistent associations between size at birth and age-related cataract. However, the odds ratio for nuclear cataract (opalescence) among subjects whose birth weight was more than 8 lb was 2.4 (95% CI 1.2 to 5.0) compared with those who weighed under 6 lb 12 oz at birth. Risk of cortical cataract by contrast fell with increasing birth weight, but the trend was not significant and became weak after adjusting for gestational age and other risk factors for cataract. No relation was evident between risk of posterior subcapsular cataract and size at birth.There is no consistent association between size at birth and age-related cataract. The higher risk of nuclear cataract with increased birth weight was contrary to the expected trend. The apparent difference in direction of the relation between birth weight and different subtypes of cataract may be a chance finding but warrants further exploration.