The impact of socially-accountable, community-engaged medical education on graduates in the Central Philippines: Implications for the global rural medical workforce.

INTRODUCTION: Developing and retaining a high quality medical workforce, especially within low-resource countries has been a world-wide challenge exacerbated by a lack of medical schools, the maldistribution of doctors towards urban practice, health system inequities, and training doctors in tertiary centers rather than in rural communities. AIM: To describe the impact of socially-accountable health professional education on graduates; specifically: their motivation towards community-based service, preparation for addressing local priority health issues, career choices, and practice location. METHODS: Cross-sectional survey of graduates from two medical schools in the Philippines: the University of Manila-School of Health Sciences (SHS-Palo) and a medical school with a more conventional curriculum. RESULTS: SHS-Palo graduates had significantly (p < 0.05) more positive attitudes to community service. SHS-Palo graduates were also more likely to work in rural and remote areas (p < 0.001) either at district or provincial hospitals (p = 0.032) or in rural government health services (p < 0.001) as Municipal or Public Health Officers (p < 0.001). Graduates also stayed longer in both their first medical position (p = 0.028) and their current position (p < 0.001). CONCLUSIONS: SHS-Palo medical graduates fulfilled a key aim of their socially-accountable institution to develop a health professional workforce willing and able, and have a commitment to work in underserved rural communties.

The Early External Cephalic Version (ECV) 2 Trial: an international multicentre randomised controlled trial of timing of ECV for breech pregnancies.

OBJECTIVE: To investigate whether initiating external cephalic version (ECV) earlier in pregnancy might increase the rate of successful ECV procedures, and be more effective in decreasing the rate of non-cephalic presentation at birth and of caesarean section. DESIGN: An unblinded multicentred randomised controlled trial. SETTING: A total of 1543 women were randomised from 68 centres in 21 countries. POPULATION: Women with a singleton breech fetus at a gestational age of 33(0/7) weeks (231 days) to 35(6/7) weeks (251 days) of gestation were included. METHODS: Participants were randomly assigned to having a first ECV procedure between the gestational ages of 34(0/7) (238 days) and 35(6/7) weeks of gestation (early ECV group) or at or after 37(0/7) (259 days) weeks of gestation (delayed ECV group). MAIN OUTCOME MEASURES: The primary outcome was the rate of caesarean section; the secondary outcome was the rate of preterm birth. RESULTS: Fewer fetuses were in a non-cephalic presentation at birth in the early ECV group (314/765 [41.1%] versus 377/768 [49.1%] in the delayed ECV group; relative risk [RR] 0.84, 95% CI 0.75, 0.94, P=0.002). There were no differences in rates of caesarean section (398/765 [52.0%] versus 430/768 [56.0%]; RR 0.93, 95% CI 0.85, 1.02, P=0.12) or in risk of preterm birth (50/765 [6.5%] versus 34/768 [4.4%]; RR 1.48, 95% CI 0.97, 2.26, P=0.07) between groups. CONCLUSION: External cephalic version at 34-35 weeks versus 37 or more weeks of gestation increases the likelihood of cephalic presentation at birth but does not reduce the rate of caesarean section and may increase the rate of preterm birth.

Thioredoxin peroxidase is required for the transcriptional response to oxidative stress in budding yeast.

A genetic screen was performed in Saccharomyces cerevisiae to identify mechanisms important for the transcriptional activation of genes encoding antioxidant proteins. Thioredoxin peroxidase, Tsa1p, of the thioredoxin system, was found to be essential for the transcriptional induction of other components of the thioredoxin system, TRX2 (thioredoxin) and TRR1 (thioredoxin reductase), in response to H(2)O(2). The expression of TRX2 and TRR1 is known to be regulated by the transcription factors Yap1p and Skn7p in response to H(2)O(2), and the Tsa1p-dependent regulation of TRX2 requires the Yap1p/Skn7p pathway. The data suggest that expression of components of the thioredoxin system is dependent on the activity of Tsa1p in response to H(2)O(2) in a Yap1p/Skn7p-dependent pathway.

Double filtration plasmapheresis in a dog with multiple myeloma and hyperviscosity syndrome.

A 12 year old, 38 kg, mix-breed, intact male dog presented with a 20 day history of clinical signs consistent with hyperviscosity syndrome secondary to multiple myeloma. The dog received three double filtration plasmapheresis treatments on day 0, 7 and 22 after presentation. A significant (p<0.05) reduction in serum total protein, alpha-2 and gamma globulins was found following each treatment. These reductions were accompanied by a complete resolution, although temporary, of the clinical signs of hyperviscosity syndrome. The present study reported for the first time the use of double filtration plasmapheresis to reduce clinical signs of hyperviscosity syndrome in a dog with multiple myeloma.

E-Cadherin and EpCAM expression by NSCLC tumour cells associate with normal fibroblast activation through a pathway initiated by integrin αvß6 and maintained through TGFß signalling.

Fibroblasts in the tumour stroma (cancer-associated fibroblasts) influence tumour progression and response to therapeutics; little is known about the mechanisms through which the tumour cell co-opts a normal fibroblast. To study the activation of fibroblasts by tumour cells, a panel of non-small cell lung cancer (NSCLC) cell lines and normal human dermal fibroblasts were co-cultured. A subset of the NSCLC cells induced an activated cancer-associated fibroblast-like fibroblast phenotype defined by induction of fibroblast α-smooth muscle actin expression. Tumour cells that activated fibroblasts were associated with E-Cadherin and EpCAM expression and expression of integrin αvß6. Co-culture of activating tumour cells with fibroblasts resulted in induction of transcripts associated with tumour cell invasion and growth, TGFß1 and TGFBR1, SERPINE-1, BMP6, SPHK1 and MMP9. Fibroblast activation was inhibited by an αvß6/8 integrin blocking antibody (264RAD) and a small molecule inhibitor of the TGF-beta type I receptor activin-like kinase (ALK5) (SB431542), demonstrating that transactivation of the TGFß pathway initiates fibroblast activation. Both integrin and ALK5 antagonists inhibited initiation. Only ALK5 was effective when added after 3 days of co-culture. This suggests that although activation is αvß6-dependent, once fibroblasts are activated alternative TGFß pathway regulators maintain an activation loop. In co-culture activating cells had reduced sensitivity to selumetinib, AZD8931 and afatinib compared with mono-culture. In contrast, non-activating cells were insensitive to selumetinib and AZD8931 in both mono-culture and co-culture. In conclusion NSCLC cell lines, positive for E-Cadherin, EpCAM and αvß6 expression, activate normal fibroblasts through avß6/TGFß signalling in vitro, and influence both gene expression and response to therapeutic agents.

Preservation of famous person knowledge in a patient with severe post anoxic amnesia.

A 58 year old patient (ES) suffered severe anterograde and retrograde amnesia following prolonged cardiac arrest with presumed hypoxic brain damage. Personally relevant autobiographical memory was severely impaired as was knowledge of public events. In contrast, knowledge of famous people was very well preserved. This findings has implications for the organisation of remote memory. Knowledge of people is clearly represented independently from autobiographical memory. We argue that this pattern of profound autobiographical amnesia may result from either multifocal neocortical damage (as in this case) or a failure of the "thematic framework" system involved in the active reconstruction of autobiographical memory, as hypothesised in another patient with thalamic infarction who showed a similar pattern of results (Hodges and McCarthy, 1993).

Identifying asthmatic patients in the community: a new method.

Identifying a random sample of patients in the community has long proved problematic. In 1989 changes were made in the management of adult asthmatic patients referred to specialist clinics in the Grampian Health Board area. In order to estimate the effect of these changes on the management of patients not referred, it was necessary to identify two random samples of adult asthmatic patients treated solely in general practice. As it was felt that existing methods were open to bias and other errors, a method using National Health Service drug prescription forms was devised. Following the computerization of the Pharmacy Practice Division in Aberdeen, a similar method for the identification of a follow-up sample had to be devised. Nearly 400 general practitioners (86% of those eligible) took part in the first sampling in 1989; 96% of those contacted participated in the second sampling in 1991. Both methods were effective in identifying asthmatic patients in the community. Computerization has made the task simpler, less time consuming and, as a consequence, most cost effective.

Open mesh versus non-mesh for repair of femoral and inguinal hernia.

BACKGROUND: Inguinal hernia repair is the most frequent operation in general surgery. Until recently the standard procedure has been open musculo-aponeurotic repair using sutures under tension to close the defect but 'tension-free' repair using prosthetic mesh is becoming increasingly common in many countries. OBJECTIVES: The purpose of this review is to evaluate open mesh techniques in comparison with open non-mesh techniques for the surgical repair of groin hernia. SEARCH STRATEGY: Electronic databases were searched and further trials were sought from the reference lists of reports of known trials. Through the EU Hernia Trialists Collaboration authors of identified randomised controlled trials were asked for information on any other trials known to them. There was no language restriction. SELECTION CRITERIA: Studies were eligible for inclusion if they were randomised or quasi-randomised trials comparing either a) open mesh with open non-mesh repair of groin hernia or b) open flat mesh repair with plug and mesh repair of groin hernia. DATA COLLECTION AND ANALYSIS: For each outcome the results were derived using data from the best available source. The majority of data for this review came from individual patient data (IPD) supplied by the trialists. When these were unavailable data came from additional aggregated information or from published trial reports. All trials were analysed using the 'intention to treat' principle. MAIN RESULTS: Twenty trials comparing open mesh with open non-mesh repair were identified. Open mesh methods, on average, took 7-10 minutes less to perform than Shouldice procedures, but took 1-4 minutes longer than other non-mesh methods. There were no clear differences between mesh and non-mesh groups for haematomas, seromas or wound/superficial infections. Three serious operative complications were reported after open mesh repair and three following non-mesh repair. Overall, those in the mesh groups had a shorter length of hospital stay and quicker return to usual activities, but this pattern was not observed for all trials. There was a suggestion that persisting pain was less frequent after mesh repair than after non-mesh repair but this result was dependent on one trial and data were not available for 11 trials. There was no evidence of a difference between the groups with respect to persisting numbness. Fewer hernia recurrences were reported after mesh repair (Peto OR: 0.37, 95% CI: 0.26 to 0.51). There were too few data to reliably address differential effects for patients with recurrent, bilateral or femoral hernias. Two trials comparing flat mesh with plug and mesh were identified. There was no clear evidence of differences between the groups. REVIEWER'S CONCLUSIONS: There is evidence that the use of open mesh repair is associated with a reduction in the risk of recurrence of between 50% and 75%. Although the trials were heterogeneous there is also some evidence of quicker return to work and of lower rates of persisting pain following mesh repair.

Development of an injectable sustained-release formulation of morphine: antinociceptive properties in rats.

The antinociceptive actions of morphine incorporated into an injectable chitosan-based gel were investigated in rats. Subcutaneous administration of 4.8 mg/kg morphine sulphate in a gel composed of N,O-carboxymethylchitosan (NOCC) and chitosan resulted in significant antinociception within 10 min that was maximal at 60 min and persisted for 6 h. In contrast, the same dose of morphine sulphate injected in sterile saline produced maximal responses at 30 min but only persisted for 2 h. NOCC/chitosan gel was easily injectable using a 22 guage needle and appears stable in long-term storage. No local or systemic adverse effects other than morphine-induced sedation were observed either at the time of injection or during the subsequent 48 h. We conclude that gels composed of chitosan and chitosan derivatives are effective matrices for sustained-release formulations of opioid analgesics capable of providing long-lasting antinociception.

Canine and feline nephrolithiasis. Epidemiology, detection, and management.

Calcium oxalate (39%) and struvite (33%) were the predominant mineral types in canine nephroliths submitted to the Minnesota Urolith Center. Urate salts (12%) and calcium phosphate (2%) occurred less frequently. Provided they are not causing obstruction, struvite nephroliths may be dissolved with medical protocols. Although there are no dissolution protocols for nephroliths containing calcium, risk-benefit ratios should be considered before proceeding with surgery.

Reducing hospital admission through computer supported education for asthma patients. Grampian Asthma Study of Integrated Care (GRASSIC).

OBJECTIVE: To evaluate a personalised computer supported education programme for asthma patients. DESIGN: Pragmatic randomised trial comparing outcomes over 12 months between patients taking part in an enhanced education programme (four personalised booklets, sent by post) and patients receiving conventional oral education at outpatient or surgery visits. SETTING: Hospital outpatient clinics and general practices in north east Scotland. SUBJECTS: 801 adults attending hospital outpatient clinics, with a diagnosis of asthma confirmed by a chest physician and pulmonary function reversibility of at least 20%. MAIN OUTCOME MEASURES: Numbers of hospital admissions, consultations with general practitioner for asthma, steroid courses used, bronchodilators and inhaled steroids prescribed, days of restricted activity, and disturbed nights. RESULTS: Patients with asthma judged too severe for randomisation between clinic care and integrated care and thus retained in clinic care had 54% fewer hospital admissions after receiving enhanced education than did the control group (95% confidence interval 30% to 97%; P < 0.05) over the study year. Patients had not all spent a full year as "educated" patients within the study year: when "educated days" were controlled for, annual admission rates for the entire enhanced education group were 49% (31% to 78%) of those in the control group. Among patients with sleep variation, sleep disturbance in the education group in the week before a regular review was 80% (65% to 97%) of that in the control group. There was no significant difference in days of restricted activity, prescription of bronchodilators or inhaled steroids, use of oral steroids, or number of general practitioner consultations for asthma, and no significant interaction between ownership of a peak flow meter and education. CONCLUSIONS: An asthma education programme based on computerised booklets can reduce hospital admissions and improve morbidity among hospital outpatients.

A human monoclonal antibody 264RAD targeting αvß6 integrin reduces tumour growth and metastasis, and modulates key biomarkers in vivo.

αvß6 integrin expression is upregulated on a wide range of epithelial tumours, and is thought to play a role in modulating tumour growth. Here we describe a human therapeutic antibody 264RAD, which binds and inhibits αvß6 integrin function. 264RAD cross-reacts with human, mouse and cynomolgus monkey αvß6, and inhibits binding to all ligands including the latency-associated peptide of TGF-ß. Screening across a range of integrins revealed that 264RAD also binds and inhibits the related integrin αvß8, but not the integrins α5ß1, αvß3, αvß5 and α4ß1. In vitro 264RAD inhibited invasion of VB6 and Detroit 562 cells in a Matrigel invasion assay and αvß6 mediated production of matrix metalloproteinase-9 in Calu-3 cells. It inhibited TGF-ß-mediated activation of dermal skin fibroblasts by preventing local activation of TGF-ß by NCI-H358 tumour cells in a tumour cell-fibroblast co-culture assay. In vivo 264RAD showed dose-dependent inhibition of Detroit 562 tumour growth, regressing established tumours when dosed at 20 mg/kg once weekly. The reduction in growth associated with 264RAD was related to a dose-dependent inhibition of Ki67 and phospho-ERK and a reduction of αvß6 expression in the tumour cells, coupled to a reduction in fibronectin and alpha smooth muscle actin expression in stromal fibroblasts. 264RAD also reduced the growth and metastasis of orthotopic 4T1 tumours. At 20 mg/kg growth of both the primary tumour and the number of metastatic deposits in lung were reduced. The data support the conclusion that 264RAD is a potent inhibitor of αvß6 integrin, with some activity against αvß8 integrin, that reduces both tumour growth and metastasis.

Nursing shortages and international nurse migration.

BACKGROUND: The United Kingdom and the United States are among several developed countries currently experiencing nursing shortages. While the USA has not yet implemented policies to encourage nurse immigration, nursing shortages will likely result in the growth of foreign nurse immigration to the USA. Understanding the factors that drive the migration of nurses is critical as the USA exerts more pull on the foreign nurse workforce. AIM: To predict the international migration of nurses to the UK using widely available data on country characteristics. METHOD: The Nursing and Midwifery Council serves as the source of data on foreign nurse registrations in the UK between 1998 and 2002. We develop and test a regression model that predicts the number of foreign nurse registrants in the UK based on source country characteristics. We collect country-level data from sources such as the World Bank and the World Health Organization. RESULTS: The shortage of nurses in the UK has been accompanied by massive and disproportionate growth in the number of foreign nurses from poor countries. Low-income, English-speaking countries that engage in high levels of bilateral trade experience greater losses of nurses to the UK. CONCLUSION: Poor countries seeking economic growth through international trade expose themselves to the emigration of skilled labour. This tendency is currently exacerbated by nursing shortages in developed countries. Countries at risk for nurse emigration should adjust health sector planning to account for expected losses in personnel. Moreover, policy makers in host countries should address the impact of recruitment on source country health service delivery.

Body fat distribution predicts cardiac risk factors in older female coronary patients.

BACKGROUND: After myocardial infarction, women have higher rates of recurrent coronary events than men. This is caused, at least in part, by a higher prevalence of obesity-related coronary risk factors such as hyperlipidemia, hypertension, sedentary lifestyle, insulin resistance, and diabetes. We studied the relationship between measures of body fat distribution, body composition, aerobic fitness, and dietary intake and several coronary risk factors including lipids, glucose, and insulin levels. METHODS: The study population included 20 women > 60 years of age with recently diagnosed coronary heart disease and a comparison group of 50 healthy women with low-risk coronary risk profiles. Dependent variables included lipid subfractions (fasting, triglycerides, high-density lipoprotein [HDL] cholesterol, and low-density lipoprotein [LDL] cholesterol), glucose levels, and serum insulin levels. RESULTS: Waist-to-hip ratio (WHR) was the best predictor of serum triglyceride levels (r = .65, P = .002), HDL cholesterol level (r = .46, P = .05), and fasting serum insulin levels (r = .76, P < .001) whereas peak oxygen consumption (Peak VO2) was the best predictor of LDL cholesterol (r = .73, P < .001). In a combined population of the 20 coronary patients and 50 healthy age-matched controls, WHR remained the best predictor of serum triglyceride levels (r = .57, P < .001) and insulin levels (r = .63, P < .001) and Peak V02 was the best predictor of HDL (r = .40, P < .001) and LDL cholesterol (r = .57, P = .004). CONCLUSIONS: Body fat distribution and peak aerobic fitness, both modifiable factors, are significant predictors of risk factors for second coronary events in older female coronary patients.

Complete reversions of a gypsy retrotransposon-induced cut locus mutation in Drosophila melanogaster involving jockey transposon insertions and flanking gypsy sequence deletions.

We have analysed the structures of three phenotypic revertant alleles of a gypsy retrotransposon-induced mutation at the cut locus of Drosophila melanogaster. All three revertants are associated with the insertion of jockey transposons into a common region of gypsy. Two of these alleles are complete reversions to wild type. One complete revertant (ct+D) is derived from a third allele, a partial revertant (ctMRpD) by a deletion of part of the gypsy sequence flanking the jockey transposon. Sequence differences between the jockey elements in ctMRpD and ct+D suggest that this deletion may have been created by the insertion of a second jockey near to the first, followed by recombinational excision of a composite jockey and the region between the two genetic elements. The other complete revertant also carries a deletion of gypsy DNA flanking the jockey insertion. The deleted regions of both complete revertants and the target region for all the jockey insertions contain a repeated sequence that resembles a transcriptional enhancer. The strength of the cut phenotype in these mutants correlates with the proportion of this region remaining near the gypsy transcriptional start site, suggesting that the jockey insertions relieve the gypsy-induced mutation at cut by interfering with a region which is required for the transcriptional competence of gypsy.

Pharmacokinetics of an injectable sustained-release formulation of morphine for use in dogs.

This study investigated the pharmacokinetics of morphine sulphate in an injectable chitosan-based gel. Gels were made from a combination of N-O-carboxymethylchitosan (NOCC) and chitosan and were easily injectable via a 22 gauge needle and appeared stable during long-term storage. Groups of six beagles were injected subcutaneously (s.c.) with 1.2 mg/kg morphine sulphate, either in sterile saline or in sterilized gels, and serial blood samples were withdrawn via a jugular catheter and later analysed for morphine concentrations using radioimmunoassay. Data were analysed according to non-compartmental pharmacokinetics. NOCC-based gels resulted in significantly lower serum morphine concentrations at 10 and 30 min following injection but significantly higher concentrations at all points from 120 to 480 min post-injection. Dogs receiving morphine gel exhibited equivalent or lesser variability in serum morphine concentrations than dogs receiving conventional morphine sulphate. Pharmacokinetic analysis revealed that morphine release from the gel matrix was significantly prolonged but fully bioavailable. There were no significant differences in either distribution (Vd) or terminal elimination (t 1/2). Dogs experienced no adverse effects other than those normally associated with morphine administration at the time of injection but all dogs receiving the gel presented with an undefined stiffness the next day that resolved spontaneously within 48 h. We conclude that carboxymethylchitosan-based gels hold considerable promise for the development of injectable sustained-release formulations of opioid analgesics.

Progressive biparietal atrophy: an atypical presentation of Alzheimer's disease.

OBJECTIVES: To define the clinical, neuropsychological, and radiological features of bilateral parietal lobe atrophy. METHODS: Four patients underwent a comprehensive longitudinal neuropsychological assessment, as well as MRI and HMPAO-SPECT. RESULTS: The consistent findings in the patients were early visuospatial problems, agraphia of a predominantly peripheral (or apraxic) type, and difficulty with bimanual tasks, all of which outweighted deficits in memory and language until later in the course of the illness. As the disease progressed, impairments in the phonological aspects of language and in auditory-verbal short term memory were often striking, perhaps reflecting spread from the parietal lobe to perisylvian language areas. Three patients went on to develop a global dementia and fulfilled the criteria for a clinical diagnosis of probable Alzheimer's disease; the fourth patient has only recently been identified. Neuroimaging disclosed bilateral parietal lobe atrophy (MRI) and hypoperfusion (SPECT), which was out of proportion to that seen elsewhere in the brain. One patient has died and had pathologically confirmed Alzheimer's disease with particular concentration in both superior parietal lobes. CONCLUSIONS: Bilateral biparietal atrophy is a recognisable clinical syndrome which can be the presenting feature of Alzheimer's disease. Although the label "posterior cortical atrophy" has been applied to such cases, review of the medical literature suggests that this broad rubric actually consists of two main clinical syndromes with features reflecting involvement of the occipitotemporal (ventral) and biparietal (dorsal) cortical areas respectively.

Instability in the ctMR2 strain of Drosophila melanogaster: role of P element functions and structure of revertants.

Simultaneous multiple transpositions and long-term genetic instability have been described in the ctMR2 strain of Drosophila melanogaster and its derivatives. This strain originated from a cross that was dysgenic in the P-M system. While spontaneous instability declined over 2 years, instability has been reactivated by backcross to the progenitor P element bearing strain MRh12/Cy. We show here using germline transformation that active P factor alone cannot mimic the effect of this cross, suggesting that MRh12/Cy contains some other activator. In addition, we have observed that ct+ exceptional progeny arise in the F1 as well as the F2 generations. Molecular analysis of X chromosomes from some ct+ progeny indicates that phenotypic reversion of the ct mutation can arise through two unrelated mechanisms.

Outcome of children of parents with atopic asthma and transient childhood wheezy bronchitis.

BACKGROUND: Childhood asthma and wheeze only in the presence of respiratory infection (wheezy bronchitis) appear to have different prognoses and may differ in their aetiology and heritability. In particular, slight reductions in lung function may be associated with episodes of wheezing associated with intercurrent viral infection. METHODS: Outcomes for wheezing symptoms and lung function were studied in 133 offspring of three distinct groups of 69 middle aged probands with childhood histories of (1) atopic asthma (n = 18), (2) wheeze associated with upper respiratory tract infection (wheezy bronchitis, n = 24), and (3) no symptoms (n = 27). Probands were selected from a previously studied cohort in which outcomes of wheezy bronchitis and asthma had been shown to differ. RESULTS: Children of probands with wheezy bronchitis had a lower prevalence of current wheezing symptoms. Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) in boys of probands with a history of wheezy bronchitis were significantly reduced compared with either of the other two groups (p < 0.0001). In a multivariate analysis, grouping based on parent proband had a significant effect on lung function, independent of factors such as symptoms, atopy or smoking history. CONCLUSIONS: The different symptomatic and lung function outcome in children of probands with wheezy bronchitis and asthma provides further evidence that wheezy bronchitis and asthma differ in their natural history and heritability, and suggests that there may be familial factors specific to each wheezing syndrome.