Acanthamoeba keratitis: a 12-year experience covering a wide spectrum of presentations, diagnoses, and outcomes.
Purpose. To review characteristics of confocal microscopy, clinical presentation, and clinical outcome in 372 cases of Acanthamoeba keratitis (AK) from 1999 to 2011. Methods. A retrospective case review was performed on 372 cases of AK diagnosed by confocal microscopy (CFM) at a single institution in Portland, Oregon, from 1999 to 2011. A numbered grading system was devised for describing the relative microscopic severity of the AK infections detected. Results. "grade 1," 94 as "grade 2," 40 as "grade 3," and 62 as "grade 4." Peak incidences occurred during 2000-2002 and 2005-2007. Seasonal variation was noted, with a peak during summer months. For the 231 cases with complete records, 64% indicated a history of soft contact lens use. Nine progressed to multiple failed penetrating keratoplasties (PKPs) or enucleation. Conclusion. We report an average of 31 new cases of AK per year from 1999 to 2011. This figure equates to 10.3 new cases/1,000,000/year for the Portland metropolitan area. Patients diagnosed with AK exhibited a wide spectrum of clinical and microscopic characteristics. Soft contact lens use remained the single largest risk factor.


Analysis of the Kenyan distance-running phenomenon.
To investigate the ethnicity of Kenya's most successful international runners, tracking their evolution over the period of their international emergence and current dominance. The authors analyzed male track distance events from 800m upwards from all the major global athletics championships from 1964 to 2013, and the annual Top-25 world marathon performances since 1990. The percentage of top-25 marathon performances and medals won by Kenyan and Kalenjin runners have increased over time with Nandi subtribe outperforming the rest of the world outside Africa (r > .70, large effect). However, Europe, North America, Oceania, Asia, and South America decreased over time in top marathon performances and track medals won (r > .70, large effect). The tribe and subtribe distribution was different in the marathon than in the track: Maasais were more likely to feature in medals won in shorter track events than in the top 25 of the world marathon rankings (risk ratio [RR] = 9.67, very large effect). This was also the case for Marakwets (RR = 6.44, very large effect) and Pokots (RR = 4.83, large effect). On the other hand, Keiyos, Kikuyus, Kipsigis, Sabaots, and Tugens were more likely to succeed in the marathon than in shorter track events (RR > 2.0, moderate effect). These data emphasize that the previously documented emergence of African distance runners is primarily a Kenyan phenomenon, driven by the Kalenjin tribe and in particular the Nandi subtribe. This supports the complex interaction between genotype, phenotype, and socioeconomic factors driving the remarkable dominance of Kenyan distance runners.


Organic compounds inhibiting S. epidermidis adhesion and biofilm formation.
The formation of biofilms on surfaces of indwelling medical devices is a serious medical problem. Staphylococcus epidermidis is a common pathogen found to colonize implanted devices and as a biofilm is more resistant to the host immune system as well as to antibiotic treatments. Combating S. epidermidis infections by preventing or eradicating biofilm formation of the bacterium is therefore a medically important challenge. We report here a study of biofilm formation of S. epidermidis on solid surfaces using a combination of confocal laser scanning (CLSM) and atomic force microscopy (AFM) in both air and aqueous environments. We have investigated the inhibitory effects of surfaces treated with four organic compounds, two benzoate derivatives denoted as compound 59 and 75 and two carboxamide derivatives denoted as compound 47 and 73, on S. epidermidis adhesion and biofilm formation. All four compounds evoke significant inhibitory effects on the formation of S. epidermidis biofilms with compounds 47 and 73 being most effective. None of the compounds were found to inhibit growth of S. epidermidis in liquid cultures. Bacteria attached to the substrate when exposed to the compounds were not affected indicating that these compounds inhibit initial adhesion. These results suggest a pretreatment for medically implanted surfaces that can prevent the biofilm formation and reduce infection.


A test of the hypothesis that oxalate secretion produces proximal tubule crystallization in primary hyperoxaluria type I.
The sequence of events by which primary hyperoxaluria type 1 (PH1) causes renal failure is unclear. We hypothesize that proximal tubule (PT) is vulnerable because oxalate secretion raises calcium oxalate (CaOx) supersaturation (SS) there, leading to crystal formation and cellular injury. We studied cortical and papillary biopsies from two PH1 patients with preserved renal function, and seven native kidneys removed from four patients at the time of transplant, after short-term (2) or longer term (2) dialysis. In these patients, and another five PH1 patients without renal failure, we calculated oxalate secretion, and estimated PT CaOx SS. Plasma oxalate was elevated in all PH1 patients and inverse to creatinine clearance. Renal secretion of oxalate was present in all PH1 but rare in controls. PT CaOx SS was >1 in all nonpyridoxine-responsive PH1 before transplant and most marked in patients who developed end stage renal disease (ESRD). PT from PH1 with preserved renal function had birefringent crystals, confirming the presence of CaOx SS, but had no evidence of cortical inflammation or scarring by histopathology or hyaluronan staining. PH1 with short ESRD showed CaOx deposition and hyaluronan staining particularly at the corticomedullary junction in distal PT while cortical collecting ducts were spared. Longer ESRD showed widespread cortical CaOx, and in both groups papillary tissue had marked intratubular CaOx deposits and fibrosis. CaOx SS in PT causes CaOx crystal formation, and CaOx deposition in distal PT appears to be associated with ESRD. Minimizing PT CaOx SS may be important for preserving renal function in PH1.


The effects of α-cellulose extraction and blue-stain fungus on retrospective studies of carbon and oxygen isotope variation in live and dead trees.
Tree-ring carbon and oxygen isotope ratios from live and recently dead trees may reveal important mechanisms of tree mortality. However, wood decay in dead trees may alter the δ(13)C and δ(18)O values of whole wood obscuring the isotopic signal associated with factors leading up to and including physiological death. We examined whole sapwood and α-cellulose from live and dead specimens of ponderosa pine (Pinus ponderosa), one-seed juniper (Juniperous monosperma), piñon pine (Pinus edulis) and white fir (Abies concolor), including those with fungal growth and beetle frass in the wood, to determine if α-cellulose extraction is necessary for the accurate interpretation of isotopic compositions in the dead trees. We found that the offset between the δ(13)C or δ(18)O values of α-cellulose and whole wood was the same for both live and dead trees across a large range of inter-annual and regional climate differences. The method of α-cellulose extraction, whether Leavitt-Danzer or Standard Brendel modified for small samples, imparts significant differences in the δ(13)C (up to 0.4‰) and δ(18) O (up to 1.2‰) of α-cellulose, as reported by other studies. There was no effect of beetle frass or blue-stain fungus (Ophiostoma) on the δ(13)C and δ(18)O of whole wood or α-cellulose. The relationships between whole wood and α-cellulose δ(13)C for ponderosa, piñon and juniper yielded slopes of ~1, while the relationship between δ(18)O of whole wood and α-cellulose was less clear. We conclude that there are few analytical or sampling obstacles to retrospective studies of isotopic patterns of tree mortality in forests of the western United States.


Expression of cytochrome p450 and other biotransformation genes in fetal and adult human nasal mucosa.
Despite recent progress in the identification and characterization of numerous nasal biotransformation enzymes in laboratory animals, the expression of biotransformation genes in human nasal mucosa remains difficult to study. Given the potential role of nasal biotransformation enzymes in the metabolism of airborne chemicals, including fragrance compounds and therapeutic agents, as well as the potential interspecies differences between laboratory animals and humans, it would be highly desirable to identify those biotransformation genes that are expressed in human nasal mucosa. In this study, a global gene expression analysis was performed to compare biotransformation enzymes expressed in human fetal and adult nasal mucosa to those expressed in liver. The identities of a list of biotransformation genes with apparently nasal mucosa-selective expression were subsequently confirmed by RNA-polymerase chain reaction (PCR) and DNA sequencing of the PCR products. Further quantitative RNA-PCR experiments indicated that, in the fetus, aldehyde dehydrogenase 6 (ALDH6), CYP1B1, CYP2F1, CYP4B1, and UDP glucuronosyltransferase 2A1 are expressed preferentially in the nasal mucosa and that ALDH7, flavin-containing monooxygenase 1, and glutathione S-transferase P1 are at least as abundant in the nasal mucosa as in the liver. The nasal mucosal expression of CYP2E1 was also detected. These findings provide a basis for further explorations of the metabolic capacity of the human nasal mucosa for xenobiotic compounds.


Neuropeptide Y activity in the nucleus accumbens modulates feeding behavior and neuronal activity.
Neuropeptide Y (NPY) is a hypothalamic neuropeptide that plays a prominent role in feeding and energy homeostasis. Expression of the NPY Y1 receptor (Y1R) is highly concentrated in the nucleus accumbens (Acb), a region important in the regulation of palatable feeding. In this study, we performed a number of experiments to investigate the actions of NPY in the Acb. First, we determined caloric intake and food choice after bilateral administration of NPY in the Acb in rats on a free-choice diet of saturated fat, 30% sucrose solution, and standard chow and whether this was mediated by the Y1R. Second, we measured the effect of intra-Acb NPY on neuronal activity using in vivo electrophysiology. Third, we examined co-localization of Y1R with enkephalin and dynorphin neurons and the effect of NPY on preproenkephalin messenger RNA levels in the striatum using fluorescent and radioactive in situ hybridization. Finally, using retrograde tracing, we examined whether NPY neurons in the arcuate nucleus projected to the Acb. In rats on the free-choice, high-fat, high-sugar diet, intra-Acb NPY increased intake of fat, but not sugar or chow, and this was mediated by the Y1R. Intra-Acb NPY reduced neuronal firing, as well as preproenkephalin messenger RNA expression in the striatum. Moreover, Acb enkephalin neurons expressed Y1R and arcuate nucleus NPY neurons projected to the Acb. NPY reduces neuronal firing in the Acb resulting in increased palatable food intake. Together, our neuroanatomical, pharmacologic, and neuronal activity data support a role and mechanism for intra-Acb NPY-induced fat intake.


PSD502 improves ejaculatory latency, control and sexual satisfaction when applied topically 5 min before intercourse in men with premature ejaculation: results of a phase III, multicentre, double-blind, placebo-controlled study.
To determine the effect of PSD502 applied topically 5 min before intercourse on the Index of Premature Ejaculation (IPE) and intravaginal ejaculatory latency time (IELT) of men with lifelong premature ejaculation (PE) defined according to the International Society of Sexual Medicine (ISSM) definition; secondary objectives were to evaluate the safety and tolerability of PSD502 in patients with PE, and their sexual partners. Men aged >18 years, in stable heterosexual, monogamous relationships, and with lifelong PE diagnosed according to both the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (text revision) criteria and the ISSM definition, consented (together with their partners) to enter the baseline period of the study. Patients who documented an IELT of <or=1 min with two or more of the first three sexual encounters during the 4-week baseline period were randomized, in a 2:1 ratio, to receive double-blind treatment with PSD502 (three actuations of spray each containing 7.5 mg lidocaine and 2.5 mg prilocaine applied 5 min before intercourse) or placebo for 3 months. Patients completed IPE and Premature Ejaculation Profile (PEP) questionnaires at entry and at monthly clinic visits, and recorded stopwatch-timed IELT during each sexual encounter. Patients rated the quality of their orgasms on a 5-point scale at baseline and at the end of the treatment period, and rated the study medication on a 4-point scale. Safety was assessed by collecting adverse event data. In all, 300 men with PE were randomized from 31 centres in Europe. The geometric mean (range) IELT over the 3-month treatment period increased from a baseline of 0.6 min in both groups to 3.8 (0.3-57.8) and 1.1 (0-15.0) min in the PSD502 and placebo groups, respectively. Adjusting for treatment-group imbalances, this represents a 6.3-fold and 1.7-fold increase in adjusted geometric means. There were significantly greater increases in the scores for the IPE domains of ejaculatory control and sexual satisfaction in the PSD502 group than in the placebo group, with a mean (sem) 7.0 (0.59)-point difference between treatments in change from baseline in the IPE domain for ejaculatory control and a 5.9 (0.57)- point difference in change from baseline in the IPE domain for sexual satisfaction (both P < 0.001). This was supported by improvements in all secondary endpoints. At the end of the treatment period 66% of patients rated PSD502 as 'good' or 'excellent'. PSD502 was well tolerated and no systemic adverse events were reported. Localized treatment-related adverse events were reported by 2.6% and 3.1% of patients and partners, respectively. PSD502 applied topically 5 min before intercourse improved ejaculatory latency and significantly improved ejaculatory control and sexual satisfaction, factors relevant for acceptance of a PE treatment by both patient/physician and regulatory authorities. PSD502 was well tolerated by both patients and partners, with no systemic side-effects and a low incidence of localized effects, and was rated favourably by most users. PSD502 therefore appears to offer significant advantages over other therapies in development for the treatment of PE.


Design and expression of organophosphorus acid anhydride hydrolase activity in human butyrylcholinesterase.
Serine esterases and proteases are rapidly and irreversibly inhibited by organophosphorus (OP) nerve agents. To overcome this limitation, we selected several residues that were predicted to be within 3-10 A of both the active site Ser O gamma and the oxyanion hole of human butyrylcholinesterase for mutation to His (G115H, G117H, Q119H, and G121H). In remarkable contrast with wild-type (WT) and all other His mutants tested, G117H underwent spontaneous reactivation following OP inhibition to regain 100% of original esterase activity with maximum k3 values of approximately 6.8 x 10(-5) and 16 x 10(-5) s-1 for GB (sarin) and VX, respectively, in 0.1 M Bis-Tris, 25 degrees C. The free energy of activation for k3 was 19 kcal mol-1, and measurement of pH dependence suggested that reactivation resulted from an acidic group with pKa 6.2. To evaluate further the importance of His in achieving this result, we changed the same Gly to Lys (G117K) and compared its substrate and inhibitor kinetics with those of G117H. Both mutants retained esterase activity with Km values similar to those of WT for neutral ester hydrolysis, but G117K did not reactivate. Complete reactivation proves that G117H is not irreversibly inhibited but instead functions as a catalyst for OP hydrolysis. Dephosphonylation is the rate-limiting step, and G117H effects overall rate constant enhancements of approximately 100- and 2000-fold above the uncatalyzed hydrolysis of GB and VX, respectively, at pH 6.0, 25.0 degrees C. We conclude that an appropriately positioned imidazolium ion in the oxyanion hole catalyzes dephosphonylation and, thereby, confers a novel organophosphorus acid anhydride hydrolase activity upon butyrylcholinesterase.


A tryptophan derivative, ITE, enhances liver cell metabolic functions in vitro.
Cell encapsulation provides a three-dimensional support by incorporating isolated cells into microcapsules with the goal of simultaneously maintaining cell survival and function, as well as providing active transport for a bioreactor in vitro similarly to that observed in vivo. However, the biotra-nsformation and metabolic functions of the encapsulated cells are not satisfactory for clinical applications. For this purpose, in this study, hepatoma-derived Huh7 cells/C3A cells were treated with 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), an endogenous non-toxic ligand for aryl hydrocarbon receptor, in monolayer cultures and on microspheres. The mRNA and protein levels, as well as the metabolic activities of drug metabolizing enzymes, albumin secretion and urea synthesis were determined. When the Huh7 and C3A cells cultured in a monolayer on two‑dimensional surfaces, ITE enhanced the protein levels and the metabolic activities of the major cytochrome P450 (CYP450) enzymes, CYP1A1, CYP1A2, CYP3A4 and CYP1B1, and slightly increased albumin secretion and urea synthesis. Moreover, when cultured on microspheres, ITE also substantially increased the protein levels and metabolic activities of CYP1A1, CYP1A2, CYP3A4 and CYP1B1 in both liver cell lines. On the whole, our findings indicate that ITE enhances the enzymatic activities of major CYP450 enzymes and the metabolic functions of liver cells cultured in monolayer or on microspheres, indicating that it may be utilized to improve the functions of hepatocytes. Thus, it may be used in the future for the treatment of liver diseases.


Persistent infection with neurotropic herpes viruses and cognitive impairment.
Herpes virus infections can cause cognitive impairment during and after acute encephalitis. Although chronic, latent/persistent infection is considered to be relatively benign, some studies have documented cognitive impairment in exposed persons that is untraceable to encephalitis. These studies were conducted among schizophrenia (SZ) patients or older community dwellers, among whom it is difficult to control for the effects of co-morbid illness and medications. To determine whether the associations can be generalized to other groups, we examined a large sample of younger control individuals, SZ patients and their non-psychotic relatives (n=1852). Method Using multivariate models, cognitive performance was evaluated in relation to exposures to herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and cytomegalovirus (CMV), controlling for familial and diagnostic status and sociodemographic variables, including occupation and educational status. Composite cognitive measures were derived from nine cognitive domains using principal components of heritability (PCH). Exposure was indexed by antibodies to viral antigens. PCH1, the most heritable component of cognitive performance, declines with exposure to CMV or HSV-1 regardless of case/relative/control group status (p = 1.09 × 10-5 and 0.01 respectively), with stronger association with exposure to multiple herpes viruses (β = -0.25, p = 7.28 × 10-10). There were no significant interactions between exposure and group status. Latent/persistent herpes virus infections can be associated with cognitive impairments regardless of other health status.


Microbial ecology in the age of genomics and metagenomics: concepts, tools, and recent advances.
Microbial ecology examines the diversity and activity of micro-organisms in Earth's biosphere. In the last 20 years, the application of genomics tools have revolutionized microbial ecological studies and drastically expanded our view on the previously underappreciated microbial world. This review first introduces the basic concepts in microbial ecology and the main genomics methods that have been used to examine natural microbial populations and communities. In the ensuing three specific sections, the applications of the genomics in microbial ecological research are highlighted. The first describes the widespread application of multilocus sequence typing and representational difference analysis in studying genetic variation within microbial species. Such investigations have identified that migration, horizontal gene transfer and recombination are common in natural microbial populations and that microbial strains can be highly variable in genome size and gene content. The second section highlights and summarizes the use of four specific genomics methods (phylogenetic analysis of ribosomal RNA, DNA-DNA re-association kinetics, metagenomics, and micro-arrays) in analysing the diversity and potential activity of microbial populations and communities from a variety of terrestrial and aquatic environments. Such analyses have identified many unexpected phylogenetic lineages in viruses, bacteria, archaea, and microbial eukaryotes. Functional analyses of environmental DNA also revealed highly prevalent, but previously unknown, metabolic processes in natural microbial communities. In the third section, the ecological implications of sequenced microbial genomes are briefly discussed. Comparative analyses of prokaryotic genomic sequences suggest the importance of ecology in determining microbial genome size and gene content. The significant variability in genome size and gene content among strains and species of prokaryotes indicate the highly fluid nature of prokaryotic genomes, a result consistent with those from multilocus sequence typing and representational difference analyses. The integration of various levels of ecological analyses coupled to the application and further development of high throughput technologies are accelerating the pace of discovery in microbial ecology.


Understanding heterogeneity in conduct disorder: A review of psychophysiological studies.
The present review is concerned with the role of different physiological systems (e.g., skin conductance, heart rate, electromyography, and the eye-bling startle reflex) in understanding heterogeneity in conduct disorder (CD). Four subtyping approaches are considered: age of onset, comorbid psychopathology, callous-unemotional traits, and proactive/reactive aggression. Empirical findings are discussed in terms of distinct theoretical perspectives that aim to explain CD behaviors based on physiological over-arousal, under-arousal, and empathy deficits. According to the studies reviewed, the callous-unemotional (CD+CU) and internalizing (CD+Internalizing) sub-types can best inform CD heterogeneity. Findings indicated that children in the CD+CU and CD+Internalizing subtypes score on opposite extremes on heart rate, skin conductance and startle reactivity measures. Heart rate variability and respiratory sinus arrhythmia dysfunctions, associated with emotional dysregulation, were more evident among children in the CD+Internalizing group, while dysfunctional facial electromyography activity, which has been linked with reduced empathy, with the CD+CU group. In conclusion, it might be important to redefine CD diagnostic criteria based on physiological heterogeneity to enable the identification of distinct subtypes of CD.


Folate-vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency.
Previous reports on pernicious anemia treatment suggested that high folic acid intake adversely influences the natural history of vitamin B-12 deficiency, which affects many elderly individuals. However, experimental investigation of this hypothesis is unethical, and the few existing observational data are inconclusive. With the use of data from the 1999-2002 National Health and Nutrition Examination Survey (NHANES), we evaluated the interaction between high serum folate and low vitamin B-12 status [ie, plasma vitamin B-12 < 148 pmol/L or methylmalonic acid (MMA) > 210 nmol/L] with respect to anemia and cognitive impairment. With subjects having both plasma folate < or = 59 nmol/L and normal vitamin B-12 status as the referent category, odds ratios for the prevalence of anemia compared with normal hemoglobin concentration and impaired compared with unimpaired cognitive function were 2.1 (95% CI: 1.1, 3.7) and 1.7 (95% CI: 1.01, 2.9), respectively, for those with low vitamin B-12 status but normal serum folate and 4.9 (95% CI: 2.3, 10.6) and 5.0 (95% CI: 2.7, 9.5), respectively, for those with low vitamin B-12 status and plasma folate >59 nmol/L. Among subjects with low vitamin B-12 status, mean circulating vitamin B-12 was 228 pmol/L for the normal-folate subgroup and 354 pmol/L for the high-folate subgroup. We subsequently showed increases in circulating homocysteine and MMA concentrations with increasing serum folate among NHANES participants with serum vitamin B-12 < 148 pmol/L, whereas the opposite trends occurred among subjects with serum vitamin B-12 > or = 148 pmol/L. These interactions, which were not seen in NHANES III before fortification, imply that, in vitamin B-12 deficiency, high folate status is associated with impaired activity of the 2 vitamin B-12-dependent enzymes, methionine synthase and MMA-coenzyme A mutase.


The consequences of Ireland's culture of medical migration.
In recent years, Ireland has experienced a large-scale, outward migration of doctors. This presents a challenge for national policy makers and workforce planners seeking to build a self-sufficient medical workforce that trains and retains enough doctors to meet demand. Although, traditionally, medical migration has been considered beneficial to the Irish health system, austerity has brought a greater level of uncertainty to the health system and, with it, a need to reappraise the professional culture of migration and its impact on the Irish health system. This paper illustrates how a culture of migration informs career and migration plans. It draws on quantitative data-registration and migration data from source and destination countries-and qualitative data-in-depth interviews with 50 doctors who had undertaken postgraduate medical training in Ireland. Of 50 respondents, 42 highlighted the importance of migration. The culture of medical migration rests on two assumptions-that international training/experience is beneficial to all doctors and that those who emigrate will return to Ireland with additional skills and experience. This assumption of return is challenged by a new generation of doctors whose professional lives have been shaped by globalisation and by austerity. Global comparisons reveal the comparatively poor working conditions, training and career opportunities in Ireland and the relative attractiveness of a permanent career abroad. In light of these changes, there is a need to critically appraise the culture of medical migration to determine if and in what circumstances migration is appropriate to the needs of the Irish health system. The paper considers the need to reappraise the culture of medical migration and the widespread emigration that it promotes.


"Is there an Association Between Self-Reported Sleep Duration, Body Mass Index and Waist-Hip Ratio in Young Adults? A Cross-Sectional Pilot Study".
Sleep is vital for mental and physical health of an individual. Duration of sleep influences the metabolism and regulates body weight. To assess the cross-sectional association of sleep duration with body mass index (BMI) and waist-hip ratio in Malaysian students. Eighty-nine Malaysian students of both genders, and with a mean (standard deviation) age of 21.2 (0.9) years were included. Institutional Ethics Committee clearance was obtained prior to the start of study. The subjects were interviewed regarding the average hours of sleep/day, their self-reported sleep duration was categorized as < 6hour/day (short sleep duration), 6-7hour/day and > 7hour/day. Their height (in meters), weight (in kilograms), waist and hip circumference (in centimetre) were measured. BMI and waist-hip ratio were calculated using appropriate formulas and expressed as mean (standard deviation). The duration of sleep was compared with BMI and waist-hip ratio using one way ANOVA. No statistical significance was observed when sleep duration was associated with BMI (p=0.65) and waist-hip ratio (p=0.95). Duration of sleep did not affect BMI and waist hip ratio in the Malaysian students in our study. The age and healthy lifestyle of the subjects in this study may have been a reason for no significant influence of short sleep duration on the BMI and waist-hip ratio. No association was found between sleep duration with BMI and waist hip ratio in the Malaysian students.


Prospective trial of different antimicrobial treatment durations for presumptive canine urinary tract infections.
Avoidance of unnecessary antimicrobial administration is a key tenet of antimicrobial stewardship; knowing the optimal duration of therapy obviates over-treatment. However, little research has been performed to establish course lengths for common canine infections. In clinical practice, antimicrobial therapy is frequently prescribed in dogs presenting lower urinary tract signs (haematuria, pollakiuria and dysuria/stranguria). The proposed length of treatment in International Consensus guidelines has decreased with each iteration, but these recommendations remain arbitrary and largely extrapolated from experience in people. The objective of this prospective, multi-centre study is to find the shortest course duration that is non-inferior to the standard duration of 7 days of amoxicillin/clavulanate in terms of clinical outcomes for female dogs with lower urinary tract signs consistent with a urinary tract infection. An electronic data capture platform will be used by participating veterinarians working in clinical practice in the United Kingdom. Eligible dogs must be female, aged between 6 months and 10 years and have lower urinary tract signs of up to seven days' duration. Enrolment will be offered in cases where the case clinician intends to prescribe antimicrobial therapy. Automatic pseudo-randomisation to treatment group will be based on the day of presentation (Monday-Friday); all antimicrobial courses will be completed on the Sunday after presentation generating different treatment durations. Follow-up data will be collected 1, 8 and 22-26 days after completion of the antimicrobial course to ensure effective safety netting, and to monitor short-term outcome and recurrence rates. Informed owner consent will be obtained in all cases. The study is approved by the Ethical Review Board of the University of Nottingham and has an Animal Test Certificate from the Veterinary Medicine's Directorate. This study has been designed to mirror current standards of clinical management; conclusions should therefore, be widely applicable and guide practising veterinarians in their antimicrobial decision-making process. A duration-response curve will be created allowing determination of the optimal treatment duration for the management of female dogs with lower urinary tract signs. It is hoped that these results will contribute valuable information to improve future antimicrobial stewardship as part of a wider one-health perspective.


Percutaneous balloon fenestration and stenting for life-threatening ischemic complications in patients with acute aortic dissection.
Acute aortic dissection frequently causes life-threatening ischemia of end-organs, historically associated with mortality exceeding 60%. Reperfusion with the use of interventional radiologic methods has evolved as a promising treatment. We report results of our initial 6 years of experience with percutaneous balloon fenestration of the intimal flap and endovascular stenting. Forty patients (32 male and 8 female) with a median age of 53 years (range 16-86 years) underwent percutaneous treatment for peripheral ischemic complications of 10 type A and 30 type B acute aortic dissections since 1991. Twenty patients had ischemia of multiple organ systems. Thirty patients had renal, 22 had leg, 18 had mesenteric, and 1 had arm ischemia. Fourteen patients were treated with stenting of either the true or false lumen combined with balloon fenestration of the intimal flap, 24 with stenting alone, and 2 with fenestration alone. Successful revascularization was achieved in 93% +/- 4% (+/-70% confidence levels) of patients (37/40). Nine patients had procedure-related complications. The 30-day mortality rate was 25% +/- 7% (10/40), often related to irreversible ischemia of intra-abdominal organs that was present before the procedure. Of the remaining 30 patients, 5 have died and the remaining 25 continue to have relief of ischemic symptoms at a mean follow-up of 29 months. Percutaneous balloon fenestration of the intimal flap and endovascular stenting is an effective treatment for life-threatening ischemic complications of acute aortic dissection.


The reform of health care funding.
It is argued that the history of health care in Hong Kong has been characterised by the lack of a coherent government policy concerning who should provide, use, and pay for services. This has led to the present fragmented funding and delivery system. Past reforms have been piecemeal and have failed to address fundamental issues. The Harvard Report offered a comprehensive solution, but its insurance-based approach to funding was politically unacceptable. Since funding determines patterns of service delivery, reform in that area is the necessary precondition for any substantive improvement in the quality and quantity of health care. Integrated funding mixes public and private money to overcome compartmentalisation between sectors. Without this, it is doubtful that a primary-led health care system could operate. Whether Government has the political will to implement its current proposals in the face of opposition, and whether these will provide a sufficient foundation for the development of primary-led health care, remains to be seen.


CCoAOMT Down-Regulation Activates Anthocyanin Biosynthesis in Petunia.
Anthocyanins and volatile phenylpropenes (isoeugenol and eugenol) in petunia (Petunia hybrida) flowers have the precursor 4-coumaryl coenzyme A (CoA) in common. These phenolics are produced at different stages during flower development. Anthocyanins are synthesized during early stages of flower development and sequestered in vacuoles during the lifespan of the flowers. The production of isoeugenol and eugenol starts when flowers open and peaks after anthesis. To elucidate additional biochemical steps toward (iso)eugenol production, we cloned and characterized a caffeoyl-coenzyme A O-methyltransferase (PhCCoAOMT1) from the petals of the fragrant petunia 'Mitchell'. Recombinant PhCCoAOMT1 indeed catalyzed the methylation of caffeoyl-CoA to produce feruloyl CoA. Silencing of PhCCoAOMT1 resulted in a reduction of eugenol production but not of isoeugenol. Unexpectedly, the transgenic plants had purple-colored leaves and pink flowers, despite the fact that cv Mitchell lacks the functional R2R3-MYB master regulator ANTHOCYANIN2 and has normally white flowers. Our results indicate that down-regulation of PhCCoAOMT1 activated the anthocyanin pathway through the R2R3-MYBs PURPLE HAZE (PHZ) and DEEP PURPLE, with predominantly petunidin accumulating. Feeding cv Mitchell flowers with caffeic acid induced PHZ expression, suggesting that the metabolic perturbation of the phenylpropanoid pathway underlies the activation of the anthocyanin pathway. Our results demonstrate a role for PhCCoAOMT1 in phenylpropene production and reveal a link between PhCCoAOMT1 and anthocyanin production.


A Novel Medical Device for Early Detection of Melanoma.
Melanoma is the deadliest form of skin cancer. Early detection of melanoma is vital, as it helps in decreasing the death rate as well as treatment costs. Dermatologists are using image-based diagnostic tools to assist them in decision-making and detecting melanoma at an early stage. We aim to develop a novel handheld medical scanning device dedicated to early detection of melanoma at the primary healthcare with low cost and high performance. However, developing this particular device is very challenging due to the complicated computations required by the embedded diagnosis system. In this paper, we propose a hardware-friendly design for implementing an embedded system by exploiting the recent hardware advances in reconfigurable computing. The developed embedded system achieved optimized implementation results for the hardware resource utilization, power consumption, detection speed and processing time with high classification accuracy rate using real data for melanoma detection. Consequently, the proposed embedded diagnosis system meets the critical embedded systems constraints, which is capable for integration towards a cost- and energy-efficient medical device for early detection of melanoma.


Meta- and pooled analyses of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and colorectal cancer: a HuGE-GSEC review.
Worldwide, over 1 million cases of colorectal cancer (CRC) were reported in 2002, with a 50% mortality rate, making CRC the second most common cancer in adults. Certain racial/ethnic populations continue to experience a disproportionate burden of CRC. A common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been associated with a lower risk of CRC. The authors performed both a meta-analysis (29 studies; 11,936 cases, 18,714 controls) and a pooled analysis (14 studies; 5,068 cases, 7,876 controls) of the C677T MTHFR polymorphism and CRC, with stratification by racial/ethnic population and behavioral risk factors. There were few studies on different racial/ethnic populations. The overall meta-analysis odds ratio for CRC for persons with the TT genotype was 0.83 (95% confidence interval (CI): 0.77, 0.90). An inverse association was observed in whites (odds ratio = 0.83, 95% CI: 0.74, 0.94) and Asians (odds ratio = 0.80, 95% CI: 0.67, 0.96) but not in Latinos or blacks. Similar results were observed for Asians, Latinos, and blacks in the pooled analysis. The inverse association between the MTHFR 677TT polymorphism and CRC was not significantly modified by smoking status or body mass index; however, it was present in regular alcohol users only. The MTHFR 677TT polymorphism seems to be associated with a reduced risk of CRC, but this may not hold true for all populations.


Minimal Energy Requirements in Communication
The literature describing the energy needs for a communications channel has been dominated by analyses of linear electromagnetic transmission, often without awareness that this is a special case. This case leads to the conclusion that an amount of energy equal to kTln 2, where kT is the thermal noise per unit bandwidth, is needed to transmit a bit, and more if quantized channels are used with photon energies hnu > kT. Alternative communication methods are proposed to show that there is no unavoidable minimal energy requirement per transmitted bit. These methods are invoked as part of an analysis of ultimate limits and not as practical procedures.


Common structures of CO2 on structurally different coin metal surfaces.
We investigate superstructures formed by CO2 on Ag(100) and Cu(111) from small clusters forming at 21 K up to multilayers grown at 43 K by low temperature scanning tunneling microscopy. On both surfaces, CO2 nucleates only at defects, here at co-adsorbed CO. At the lower adsorption temperature, superstructures of different symmetry coexist on both surfaces at submonolayer coverage, while the superstructures formed at the higher adsorption temperature differ largely for the two surfaces. On Ag(100), the CO2 monolayer exhibits a long-range order interrupted by antiphase domain boundaries. On Cu(111), a random distribution of domain structures of different symmetry leads to a monolayer without long-range order. Surprisingly, the degree of ordering is inverted for the 2nd layer of CO2. On Ag(100), the coexistence of different superstructures in the 2nd layer leads to reduced long-range order. On Cu(111), a hexagonal 2nd layer exhibits long-range order. A layer of a similar superstructure, hexagonal with long-range order, exists as the 3rd layer of Ag(100). Despite the different substrates, a multitude of common structural features of CO2 exist. Hexagonal layers grow with a long-range order on less ordered layers on both surfaces. Our results suggest that the preferred structure of a CO2 layer is hexagonal.


Treatment with a new benzimidazole derivative bearing a pyrrolidine side chain overcomes sorafenib resistance in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. Currently, sorafenib is the standard first-line drug for patients with advanced HCC. However, long-term exposure to sorafenib often results in reduced sensitivity of tumour cells to the drug, leading to acquired resistance. Therefore, developing new compounds to treat sorafenib resistance is urgently needed. Although benzimidazole and its derivatives have been reported to exert antimicrobial and antitumour effects, the anti-drug resistance potential of these molecules is still unknown. In this study, we established sorafenib-resistant (SR) cell lines and an acquired sorafenib resistance xenograft model. We showed that treatment with a benzimidazole derivative bearing a pyrrolidine side chain (compound 9a) inhibited the proliferation of SR cells by blocking the phosphorylation of AKT, p70S6 and the downstream molecule RPS6. In addition, caspase 3/PARP-dependent apoptotic signals were induced in 9a-treated cells. Regarding epithelial-mesenchymal transition (EMT) activities, 9a treatment significantly suppressed the migration of SR cells. In particular, the levels of EMT-related transcription factors (snail, slug and twist) and mesenchymal markers (vimentin and N-cadherin) were downregulated. In the acquired sorafenib resistance xenograft model, compound 9a administration decreased the growth of tumours with acquired sorafenib resistance and the expression of the HCC markers α-fetoprotein, glypican 3 and survivin. In conclusion, treatment with this compound may be a novel therapeutic strategy for patients with sorafenib resistance.


Sauna as a valuable clinical tool for cardiovascular, autoimmune, toxicant- induced and other chronic health problems.
Sauna therapy has been used for hundreds of years in the Scandinavian region as a standard health activity. Studies document the effectiveness of sauna therapy for persons with hypertension, congestive heart failure, and for post-myocardial infarction care. Some individuals with chronic obstructive pulmonary disease (COPD), chronic fatigue, chronic pain, or addictions also find benefit. Existing evidence supports the use of saunas as a component of depuration (purification or cleansing) protocols for environmentally-induced illness. While far-infrared saunas have been used in many cardiovascular studies, all studies applying sauna for depuration have utilized saunas with radiant heating units. Overall, regular sauna therapy (either radiant heat or far-infrared units) appears to be safe and offers multiple health benefits to regular users. One potential area of concern is sauna use in early pregnancy because of evidence suggesting that hyperthermia might be teratogenic.


Age-specific risk of breast cancer in women with neurofibromatosis type 1.
Young women with neurofibromatosis type 1 (NF1) are reported to have a higher risk of breast cancer than others, and this might have implications for screening programmes. Our aim was to calculate this risk. An all-England linked data set of hospital admissions and deaths was analysed to determine age-specific rates of breast cancer in women with NF1 and controls. The age-specific excess risk of breast cancer, comparing the NF1 cohort with the control cohort, was elevated 6.5-fold (95% confidence interval 2.6-13.5) in women aged 30-39 years. There was a 4.4 (2.5-7.0) times higher risk among women aged 40-49. Women with NF1 develop breast cancer at younger ages than the general population.


Immunosuppression Has Long-Lasting Effects on Circulating Follicular Regulatory T Cells in Kidney Transplant Recipients.
Background: FoxP3+ follicular regulatory T cells (Tfr) have been identified as the cell population controlling T follicular helper (Tfh) cells and B cells which, are both involved in effector immune responses against transplanted tissue. Methods: To understand the biology of Tfr cells in kidney transplant patients treated with tacrolimus and mycophenolate mofetil (MMF) combination immunosuppression, we measured circulating (c)Tfh and cTfr cells in peripheral blood by flow cytometry in n = 211 kidney transplant recipients. At the time of measurement patients were 5-7 years after transplantation. Of this cohort of patients, 23.2% (49/211) had been previously treated for rejection. Median time after anti-rejection therapy was 4.9 years (range 0.4-7 years). Age and gender matched healthy individuals served as controls. Results: While the absolute numbers of cTfh cells were comparable between kidney transplant recipients and healthy controls, the numbers of cTfr cells were 46% lower in immunosuppressed recipients (p < 0.001). More importantly, in transplanted patients, the ratio of cTfr to cTfh was decreased (median; 0.10 vs. 0.06), indicating a disruption of the balance between cTfr and cTfh cells. This shifted balance was observed for both non-rejectors and rejectors. Previous pulse methylprednisolone or combined pulse methylprednisolone + intravenous immunoglobulin anti-rejection therapy led to a non-significant 30.6% (median) and 51.2% (median) drop in cTfr cells, respectively when compared to cTfr cell numbers in transplant patients who did not receive anti-rejection therapy. A history of alemtuzumab therapy did lead to a significant decrease in cTfr cells of 85.8% (median) compared with patients not treated with anti-rejection therapy (p < 0.0001). No association with tacrolimus or MMF pre-dose concentrations was found. Conclusion: This cross-sectional study reveals that anti-rejection therapy with alemtuzumab significantly lowers the number of cTfr cells in kidney transplant recipients. The observed profound effects by these agents might dysregulate cTfr functions.


A Fast and Robust Extrinsic Calibration for RGB-D Camera Networks.
From object tracking to 3D reconstruction, RGB-Depth (RGB-D) camera networks play an increasingly important role in many vision and graphics applications. Practical applications often use sparsely-placed cameras to maximize visibility, while using as few cameras as possible to minimize cost. In general, it is challenging to calibrate sparse camera networks due to the lack of shared scene features across different camera views. In this paper, we propose a novel algorithm that can accurately and rapidly calibrate the geometric relationships across an arbitrary number of RGB-D cameras on a network. Our work has a number of novel features. First, to cope with the wide separation between different cameras, we establish view correspondences by using a spherical calibration object. We show that this approach outperforms other techniques based on planar calibration objects. Second, instead of modeling camera extrinsic calibration using rigid transformation, which is optimal only for pinhole cameras, we systematically test different view transformation functions including rigid transformation, polynomial transformation and manifold regression to determine the most robust mapping that generalizes well to unseen data. Third, we reformulate the celebrated bundle adjustment procedure to minimize the global 3D reprojection error so as to fine-tune the initial estimates. Finally, our scalable client-server architecture is computationally efficient: the calibration of a five-camera system, including data capture, can be done in minutes using only commodity PCs. Our proposed framework is compared with other state-of-the-arts systems using both quantitative measurements and visual alignment results of the merged point clouds.


A comparison of justice frameworks for international research.
Justice frameworks have been developed for international research that provide guidance on the selection of research targets, ancillary care, research capacity strengthening, and post-trial benefits. Yet there has been limited comparison of the different frameworks. This paper examines the underlying aims and theoretical bases of three such frameworks--the fair benefits framework, the human development approach and research for health justice--and considers how their aims impact their guidance on the aforementioned four ethical issues. It shows that the frameworks' underlying objectives vary across two dimensions. First, whether they seek to prevent harmful or exploitative international research or to promote international research with health benefits for low and middle-income countries. Second, whether they address justice at the micro level or the macro level. The fair benefits framework focuses on reforming contractual elements in individual international research collaborations to ensure fairness, whereas the other two frameworks aim to connect international research with the reduction of global health inequities. The paper then highlights where there is overlap between the frameworks' requirements and where differences in the strength and content of the obligations they identify arise as a result of their varying objectives and theoretical bases. In doing so, it does not offer a critical comparison of the frameworks but rather seeks to add clarity to current debates on justice and international research by showing how they are positioned relative to one another.


Flow and hydrodynamic shear stress inside a printing needle during biofabrication.
We present a simple but accurate algorithm to calculate the flow and shear rate profile of shear thinning fluids, as typically used in biofabrication applications, with an arbitrary viscosity-shear rate relationship in a cylindrical nozzle. By interpolating the viscosity with a set of power-law functions, we obtain a mathematically exact piecewise solution to the incompressible Navier-Stokes equation. The algorithm is validated with known solutions for a simplified Carreau-Yasuda fluid, full numerical simulations for a realistic chitosan hydrogel as well as experimental velocity profiles of alginate and chitosan solutions in a microfluidic channel. We implement the algorithm in an easy-to-use Python tool, included as Supplementary Material, to calculate the velocity and shear rate profile during the printing process, depending on the shear thinning behavior of the bioink and printing parameters such as pressure and nozzle size. We confirm that the shear stress varies in an exactly linear fashion, starting from zero at the nozzle center to the maximum shear stress at the wall, independent of the shear thinning properties of the bioink. Finally, we demonstrate how our method can be inverted to obtain rheological bioink parameters in-situ directly before or even during printing from experimentally measured flow rate versus pressure data.


A Gift or a Waste? Quintavalle, Surplus Embryos and the Abortion Act 1967.
The destruction of an embryo must be justified in law. This is to prevent frivolous wastage and to show the respect afforded by the Warnock Report (1984). For example, embryonic destruction during pregnancy is underpinned by the Abortion Act 1967, and embryonic destruction during fertility treatment is regulated by the Human Fertilisation and Embryology Act 1990. However, following the appeal decision in R (Quintavalle) v Human Fertilisation and Embryology Authority (and Secretary of State for Health) [2005] 2 A.C. 561, embryos can now be created for a bone marrow tissue match to a sick sibling under the Human Fertility and Embryology Act 1990 according to the subjective desires of the mother. This opens the door to the first example of embryonic destruction on unique social-eugenic grounds with no clear lawful justification. It is argued that these embryos should be afforded a unique destruction provision under an amended version of section 1(1)(a) of the Abortion Act 1967 in light of their 'social-eugenic' nature. This would protect the Human Fertilisation and Embryology Authority from accusations of undercover eugenic practices and reinstate the respect shown towards embryos in law.


Association between Change in Alcohol Consumption and Metabolic Syndrome: Analysis from the Health Examinees Study.
The association between change in alcohol intake and metabolic syndrome is unclear. This retrospective cohort consisted of 41,368 males and females from the Health Examinees-GEM study. Participants were divided into non-drinkers (0.0 g/day), light drinkers (male: 0.1 to 19.9 g/day; female: 0.1 to 9.9 g/day), moderate drinkers (male: 20.0 to 39.9 g/day; female: 10.0 to 19.9 g/day), and heavy drinkers (male: ≥40.0 g/day; female: ≥20.0 g/day) for each of the initial and follow-up health examinations. Logistic regression analysis was used to determine the adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for developing metabolic syndrome according to the change in alcohol consumption between the initial and follow-up health examinations. Adjusted mean values for the change in waist circumference, fasting serum glucose (FSG), blood pressure, triglycerides, and high density lipoprotein cholesterol (HDL-C) levels were determined according to the change in alcohol consumption by linear regression analysis. Compared to persistent light drinkers, those who increased alcohol intake to heavy levels had elevated risk of metabolic syndrome (aOR, 1.45; 95% CI, 1.09 to 1.92). In contrast, heavy drinkers who became light drinkers had reduced risk of metabolic syndrome (aOR, 0.61; 95% CI, 0.44 to 0.84) compared to persistent heavy drinkers. Increased alcohol consumption was associated with elevated adjusted mean values for waist circumference, FSG, blood pressure, triglycerides, and HDL-C levels (all P<0.05). Reduction in alcohol intake was associated with decreased waist circumference, FSG, blood pressure, triglycerides, and HDL-C levels among initial heavy drinkers (all P<0.05). Heavy drinkers who reduce alcohol consumption could benefit from reduced risk of metabolic syndrome.


Public sector mental health systems in South Africa: inter-provincial comparisons and policy implications.
There is growing recognition that mental health is an important public health issue in South Africa. Yet mental health services remain chronically under-resourced. The aim of this study was to document levels of current public sector mental health service provision in South Africa and compare services across provinces, in relation to current national policy and legislation. A survey was conducted of public sector mental health service resources and utilisation in South Africa during the 2005 calendar year, using the World Health Organization's Assessment Instrument for Mental Health Systems (WHO-AIMS) Version 2.2. South African policy and legislation both advocate for community-based mental health service provision within a human rights framework. Structures are in place at national level and in all nine provinces to implement these provisions. However, there is wide variation between provinces in the level of mental health service resources and provision. Per 100,000 population, there are 2.8 beds (provincial range 0-7.0) in psychiatric inpatient units in general hospitals, 3.6 beds (0-6.4) in community residential facilities, 18 beds (7.1-39.1) in mental hospitals, and 3.5 beds (0-5.5) in forensic facilities. The total personnel working in mental health facilities are 11.95 per 100,000 population. Of these, 0.28 per 100,000 are psychiatrists, 0.45 other medical doctors (not specialised in psychiatry), 10.08 nurses, 0.32 psychologists, 0.40 social workers, 0.13 occupational therapists, and 0.28 other health or mental health workers. Although there have been important developments in South African mental health policy and legislation, there remains widespread inequality between provinces in the resources available for mental health care; a striking absence of reliable, routinely collected data that can be used to plan services and redress current inequalities; the continued dominance of mental hospitals as a mode of service provision; and evidence of substantial unmet need for mental health care. There is an urgent need to address weak policy implementation at provincial level in South Africa.


Neighborhood walkability and cardiometabolic risk factors in Australian adults: an observational study.
Studies repeatedly highlight associations between the built environment and physical activity, particularly walking. Fewer studies have examined associations with cardiometabolic risk factors, with associations with obesity inconsistent and scarce evidence examining associations with other cardiometabolic risk factors. We aim to investigate the association between neighborhood walkability and the prevalence of obesity, hypertension, hypercholesterolaemia, and type-2 diabetes mellitus. Cross-sectional study of 5,970 adults in Western Australia. Walkability was measured objectively for a 1,600 m and 800 m neighborhood buffer. Logistic regression was used to assess associations overall and by sex, adjusting for socio-demographic factors. Mediation by physical activity and sedentary behavior was investigated. Individuals living in high compared with less walkable areas were less likely to be obese (1,600 m OR: 0.84, 95% CI: 0.7 to 1; 800 m OR: 0.75, 95% CI: 0.62 to 0.9) and had lower odds of type-2 diabetes mellitus at the 800 m buffer (800 m OR: 0.69, 95% CI: 0.51 to 0.93). There was little evidence for an association between walkability and hypertension or hypercholesterolaemia. The only significant evidence of any difference in the associations in men and women was a stronger association with type-2 diabetes mellitus at the 800 m buffer in men. Associations with obesity and diabetes attenuated when additionally adjusting for physical activity and sedentary behavior but the overall association with obesity remained significant at the 800 m buffer (800 m OR: 0.78, 95% CI: 0.64 to 0.96). A protective association between neighborhood walkability and obesity was observed. Neighborhood walkability may also be protective of type-2 diabetes mellitus, particularly in men. No association with hypertension or hypercholesterolaemia was found. This warrants further investigation. Findings contribute towards the accumulating evidence that city planning and policy related strategies aimed at creating supportive environments could play an important role in the prevention of chronic diseases.


QT interval dispersion: a non-invasive marker of susceptibility to arrhythmia in patients with sustained ventricular arrhythmias?
To assess QT interval dispersion on the surface electrocardiogram in patients with sustained ventricular arrhythmias. A retrospective and prospective blinded controlled study of patients referred for investigation of ventricular arrhythmias at a tertiary cardiac centre. 89 consecutive patients with sustained ventricular arrhythmias due to chronic ischaemic heart disease, cardiomyopathy, or ventricular tachycardia (VT) in a normal heart. 32 patients did not meet the inclusion criteria; therefore 57 patients were compared with a control group of 40 patients with myocardial disease but no history of arrhythmias and 12 normal controls with no myocardial disease. Standard 12 lead electrocardiograms were enlarged, the QT intervals for each lead measured, and QT dispersion calculated. There was a significantly greater mean QT dispersion (77 ms) in patients with sustained ventricular arrhythmias compared with the control group (38 ms, p < 0.01). This held for all groups; after myocardial infarction VT (82 (22) ms v control 38 (10) ms; p < 0.01), dilated cardiomyopathy VT (76 (18) ms v control 40 (11) ms, p < 0.01), and normal heart VT (65 (7) ms v control 32 (8), p < 0.05). There was also a greater QT dispersion in patients with impaired left ventricular function and VT, with a correlation between left ventricular function and QT dispersion in patients with VT (r = 0.56, p < 0.01). QT interval dispersion may be a further non-invasive marker of susceptibility to ventricular arrhythmias.


New records and modelling the impacts of climate change on the black-tailed marmosets.
Climate change represents an unprecedented threat to global biodiversity and, for many species, gaps in our knowledge of their biology remain acute. Gaps in baseline knowledge, such as confirmed identifications (Linnean shortfalls) and adequate collections (Wallacean shortfalls), need to be minimized with new studies, since this is often critical for effective conservation. Despite the increase in scientific research on primates in the southwest of the Brazilian Amazon, little is known about the species Mico nigriceps (Ferrari & Lopes, 1992) Primates, Platirryni. In the current study, we sought to reduce the extent of the Wallacean shortfall for M. nigriceps, understand whether climate change represents a threat to the distribution of the species, and identify priority areas for its conservation. Accordingly, we provide 121 new records in 14 locations, obtained directly from the field, and five from the literature. Using this, we carried out ecological niche modeling, to better understand how environmental suitability might limit the area occupied by the species. We then projected a distribution for 2070 with the SSP2-4.5 (more optimistic) and SSP5-8.5 (more pessimistic) scenarios. Our data confirmed the geographic distribution of the species as being restricted to headwaters of the Ji-Paraná/Machado river, but with a 400 km extension to the south. Under the modeled climate change scenarios, the area suitable for the species declines by 21% under the most optimistic, and by 27% in the pessimistic, scenario across the projected 50-year period. Although we have expanded the area of known occurrence for this species, we point out that climate change threatens the stability of this newly-discovered population strongly, and that this danger is intensified by deforestation, fire and hunting. We recommend that further studies be carried out to confirm the presence of the species in adjacent areas, those indicated by generated models as being potential environmentally suitable. In addition, we recommend intensifying forest restoration in currently pastured areas, and protection of the areas forming the current and future habitat of this species through such measures as protected area creation.


The JNK-interacting protein-1 scaffold protein targets MAPK phosphatase-7 to dephosphorylate JNK.
The c-Jun N-terminal kinase (JNK) group of mitogen-activated protein kinases (MAPKs) are activated by pleiotropic signals including environmental stresses, growth factors, and hormones. A subset of JNK can bind to distinct scaffold proteins that also bind upstream kinases of the JNK pathway, allowing sequential kinase activation within a signaling module. The JNK-interacting protein-1 (JIP-1) scaffold protein specifically binds JNK, MAP kinase kinase 7, and members of the MLK family and is essential for stress-mediated JNK activation in neurones. Here we report that JIP-1 also binds the dual-specificity phosphatases MKP7 and M3/6 via a region independent of its JNK binding domain. The C-terminal region of MKP7, homologous to that of M3/6 but not other DSPs, is required for interaction with JIP-1. When MKP7 is bound to JIP-1 it reduces JNK activation leading to reduced phosphorylation of the JNK target c-Jun. These results indicate that the JIP-1 scaffold protein modulates JNK signaling via association with both protein kinases and protein phosphatases that target JNK.


First Report of Powdery Mildew Caused by an Oidium sp. on Papaver nudicaule in Italy.
Iceland poppy (Papaver nudicaule L.) is grown on the Italian Riviera for export as a cut flower and its importance in the industry is increasing. During the spring of 2003, severe outbreaks of powdery mildew that had not been reported previously, occurred in several commercial plantings grown outdoors in containers near Imperia in northern Italy. Mycelium was observed on all green organs of the plant (leaves, stems, and petioles). Both surfaces on the leaves were affected, and heavily colonized leaves were distorted. As the disease progressed, diseased leaves turned yellow and died. The disease did not affect the flowers. Conidia were hyaline, cylindric, and measured 10.8 to 29.8 × 16.8 to 48.0 μm (average 13.7 × 37.3 μm). Foot cells were cylindric and appressoria unlobed. Fibrosin bodies were not present, and cleistothecia were not observed. The pathogen was identified as Oidium sp. subgenus Pseudoidium (1,2). Pathogenicity was confirmed by gently pressing leaves with visible sporulation onto the leaves of five 90-day-old P. nudicaule plants that were healthy and free of symptoms. Five noninoculated healthy plants served as controls. Inoculated and noninoculated plants were maintained in a growth chamber at 15°C with a 12-h photoperiod. After 7 to 10 days, typical symptoms of powdery mildew developed on inoculated plants but not on noninoculated plants. Previously, Erysiphe cruciferarum Opiz ex L. Junell has been reported on P. nudicaule in all continents, and E. cichoracearum DC. and E. polygoni DC. have been reported in several countries, including Italy, as a causal agent of powdery mildew on other species of Papaver including P. rhoeas and P. strigosum. To our knowledge, this is the first report of powdery mildew caused by an Oidium sp. on P. nudicaule in Italy. The voucher specimen is kept in the department collection at the University of Torino. References: (1) R. Belanger et al., eds. The Powdery Mildew A Comprehensive Treatise. The American Phytopathological Society, St Paul, MN, 2002. (2) U. Braun. Nova Hedwigia. 89:700, 1987.


PDX1-engineered embryonic stem cell-derived insulin producing cells regulate hyperglycemia in diabetic mice.
Type 1 diabetes can be treated by the transplantation of cadaveric whole pancreata or isolated pancreatic islets. However, this form of treatment is hampered by the chronic shortage of cadaveric donors. Embryonic stem (ES) cell-derived insulin producing cells (IPCs) offer a potentially novel source of unlimited cells for transplantation to treat type 1 and possibly type 2 diabetes. However, thus far, the lack of a reliable protocol for efficient differentiation of ES cells into IPCs has hindered the clinical exploitation of these cells. To efficiently generate IPCs using ES cells, we have developed a double transgenic ES cell line R1Pdx1AcGFP/RIP-Luc that constitutively expresses pancreatic β-cell-specific transcription factor pancreatic and duodenal homeobox gene 1 (Pdx1) as well as rat insulin promoter (RIP) driven luciferase reporter. We have established several protocols for the reproducible differentiation of ES cells into IPCs. The differentiation of ES cells into IPCs was monitored by immunostaining as well as real-time quantitative RT-PCR for pancreatic β-cell-specific markers. Pancreatic β-cell specific RIP became transcriptionally active following the differentiation of ES cells into IPCs and induced the expression of the luciferase reporter. Glucose stimulated insulin secretion by the ES cell-derived IPCs was measured by ELISA. Further, we have investigated the therapeutic efficacy of ES cell-derived IPCs to correct hyperglycemia in syngeneic streptozotocin (STZ)-treated diabetic mice. The long term fate of the transplanted IPCs co-expressing luciferase in syngeneic STZ-induced diabetic mice was monitored by real time noninvasive in vivo bioluminescence imaging (BLI). We have recently demonstrated that spontaneous in vivo differentiation of R1Pdx1AcGFP/RIP-Luc ES cell-derived pancreatic endoderm-like cells (PELCs) into IPCs corrects hyperglycemia in diabetic mice. Here, we investigated whether R1Pdx1AcGFP/RIP-Luc ES cells can be efficiently differentiated in vitro into IPCs. Our new data suggest that R1Pdx1AcGFP/RIP-Luc ES cells efficiently differentiate into glucose responsive IPCs. The ES cell differentiation led to pancreatic lineage commitment and expression of pancreatic β cell-specific genes, including Pax4, Pax6, Ngn3, Isl1, insulin 1, insulin 2 and PC2/3. Transplantation of the IPCs under the kidney capsule led to sustained long-term correction of hyperglycemia in diabetic mice. Although these newly generated IPCs effectively rescued hyperglycemic mice, an unexpected result was teratoma formation in 1 out of 12 mice. We attribute the development of the teratoma to the presence of either non-differentiated or partially differentiated stem cells. Our data show the potential of Pdx1-engineered ES cells to enhance pancreatic lineage commitment and to robustly drive the differentiation of ES cells into glucose responsive IPCs. However, there is an unmet need for eliminating the partially differentiated stem cells.


Evolved cellular automata for protein secondary structure prediction imitate the determinants for folding observed in nature.
We demonstrate the first application of cellular automata to the secondary structure predictions of proteins. Cellular automata use localized interactions to simulate global phenomena, which resembles the protein folding problem where individual residues interact locally to define the global protein conformation. The protein's amino acid sequence was input into the cellular automaton and rules for updating states were evolved using a genetic algorithm. An optimized accuracy (Q3) for the RS126 and CB513 dataset of 58.21% and 56.51%, respectively, could be obtained. Thus, the current work demonstrates the applicability of a rather simple algorithm on a problem as complex as protein secondary structure prediction.


Argonaute2, a link between genetic and biochemical analyses of RNAi.
Double-stranded RNA induces potent and specific gene silencing through a process referred to as RNA interference (RNAi) or posttranscriptional gene silencing (PTGS). RNAi is mediated by RNA-induced silencing complex (RISC), a sequence-specific, multicomponent nuclease that destroys messenger RNAs homologous to the silencing trigger. RISC is known to contain short RNAs ( approximately 22 nucleotides) derived from the double-stranded RNA trigger, but the protein components of this activity are unknown. Here, we report the biochemical purification of the RNAi effector nuclease from cultured Drosophila cells. The active fraction contains a ribonucleoprotein complex of approximately 500 kilodaltons. Protein microsequencing reveals that one constituent of this complex is a member of the Argonaute family of proteins, which are essential for gene silencing in Caenorhabditis elegans, Neurospora, and Arabidopsis. This observation begins the process of forging links between genetic analysis of RNAi from diverse organisms and the biochemical model of RNAi that is emerging from Drosophila in vitro systems.


Constraints to the potential efficiency of converting solar radiation into phytoenergy in annual crops: from leaf biochemistry to canopy physiology and crop ecology.
A new simple framework was proposed to quantify the efficiency of converting incoming solar radiation into phytoenergy in annual crops. It emphasizes the need to account for (i) efficiency gain when scaling up from the leaf level to the canopy level, and (ii) efficiency loss due to incomplete canopy closure during early and late phases of the crop cycle. Equations are given to estimate losses due to the constraints in various biochemical or physiological steps. For a given amount of daily radiation, a longer daytime was shown to increase energy use efficiency, because of the convex shape of the photosynthetic light response. Due to the higher cyclic electron transport, C4 leaves were found to have a lower energy loss via non-photochemical quenching, compared with C3 leaves. This contributes to the more linear light response in C4 than in C3 photosynthesis. Because of this difference in the curvature of the light response, canopy-to-leaf photosynthesis ratio, benefit from the optimum acclimation of the leaf nitrogen profile in the canopy, and productivity gain from future improvements in leaf photosynthetic parameters and canopy architecture were all shown to be higher in C3 than in C4 species. The indicative efficiency of converting incoming solar radiation into phytoenergy is ~2.2 and 3.0% in present C3 and C4 crops, respectively, when grown under well-managed conditions. An achievable efficiency via future genetic improvement was estimated to be as high as 3.6 and 4.1% for C3 and C4 crops, respectively.


Functional test for the hemiparetic upper extremity.
A test, called the Functional Test, that evaluates the integrated function of the total upper extremity of an adult hemiparetic patient has been developed. It was used with 82 patients admitted to Rancho Los Amigos Hospital for stroke rehabilitation, together with a battery of six objective test measures. Sequential testing by two examiners demonstrated that the test had interrater reliability. The Functional Test score accounted for 87 percent of the variation in the scores achieved by the patients on the six separate objective measures. This tool integrates the information from these objective assessments and appears to be a valid measure of functional use of the hemiparetic upper extremity. The test can be administered in approximately 30 minutes, can be used in different treatment settings, and provides an accurate and immediate assessment of upper extremity capabilities.


Electric field-induced crossover from 3D to 2D topological defects in a nematic liquid crystal: experimental verification.
A substrate was patterned with two pairs of half-integer strength topological defects, (+1/2, +1/2) and (+1/2, -1/2). In a sufficiently thick cell, a disclination line runs in an arch above the substrate connecting the two half integer defects within each pair. The director around the disclination line for the like-sign pair must rotate in 3D, whereas for the opposite-sign defect pair the director lies in the xy-plane parallel to the substrate. For a negative dielectric anisotropy nematic, an electric field applied normal to the substrate drives the director into the xy-plane, forcing the arch of the disclination line of the like-sign pair to become extended along the z-axis. For sufficiently large field the arch splits, resulting in two nearly parallel disclination lines traversing the cell from one substrate to the other. The opposite-sign defect pair is largely unaffected by the electric field as the director already lies in the xy-plane. Experimental results are presented, which are consistent with numerical simulations.


Tilt-less 3-D electron imaging and reconstruction of complex curvilinear structures.
The ability to obtain three-dimensional (3-D) information about morphologies of nanostructures elucidates many interesting properties of materials in both physical and biological sciences. Here we demonstrate a novel method in scanning transmission electron microscopy (STEM) that gives a fast and reliable assessment of the 3-D configuration of curvilinear nanostructures, all without needing to tilt the sample through an arc. Using one-dimensional crystalline defects known as dislocations as a prototypical example of a complex curvilinear object, we demonstrate their 3-D reconstruction two orders of magnitude faster than by standard tilt-arc TEM tomographic techniques, from data recorded by selecting different ray paths of the convergent STEM probe. Due to its speed and immunity to problems associated with a tilt arc, the tilt-less 3-D imaging offers important advantages for investigations of radiation-sensitive, polycrystalline, or magnetic materials. Further, by using a segmented detector, the total electron dose is reduced to a single STEM raster scan acquisition; our tilt-less approach will therefore open new avenues for real-time 3-D electron imaging of dynamic processes.


Longitudinal Patterns of Electronic Teen Dating Violence Among Middle School Students.
We investigated rates and developmental trends of electronic teen dating violence (TDV) perpetration and victimization overall and by gender. Data were collected from a single cohort of seventh-grade students from four schools using paper-and-pencil surveys administered at 6-month intervals (N = 795). Data were analyzed with descriptive statistics and longitudinal growth models to estimate change over time in TDV. Overall, 32% of youth reported electronic TDV perpetration, and 51% reported electronic TDV victimization. Victimization was more prevalent for boys (42%) than for girls (31%) at baseline only (t = 2.55, p < .05). Perpetration did not differ at any wave. Perpetration and victimization each decreased significantly from the beginning of seventh grade to the end of eighth grade, β = -.129 (.058), p < .05, for perpetration, and β = -.138 (.048), p < .01, for victimization. Gender moderated the decrease in reported victimization, with simple slopes indicating girls showed almost no change in victimization, β = .006 (.066), ns, whereas boys decreased significantly over the 2 years, β = -.292 (.069), p < .001. Although moderation by gender of change in perpetration was not conventionally significant, the simple slopes revealed that girls again showed a nonsignificant change in TDV across seventh and eighth grades, β = -.067 (.078), ns, whereas boys showed a significant decline in reported electronic TDV perpetration, β = -.197 (.083), p < .05. The high prevalence of electronic TDV underscore the need for addressing these behaviors within TDV prevention interventions.


Kinematic Model-Based Pedestrian Dead Reckoning for Heading Correction and Lower Body Motion Tracking.
In this paper, we present a method for finding the enhanced heading and position of pedestrians by fusing the Zero velocity UPdaTe (ZUPT)-based pedestrian dead reckoning (PDR) and the kinematic constraints of the lower human body. ZUPT is a well known algorithm for PDR, and provides a sufficiently accurate position solution for short term periods, but it cannot guarantee a stable and reliable heading because it suffers from magnetic disturbance in determining heading angles, which degrades the overall position accuracy as time passes. The basic idea of the proposed algorithm is integrating the left and right foot positions obtained by ZUPTs with the heading and position information from an IMU mounted on the waist. To integrate this information, a kinematic model of the lower human body, which is calculated by using orientation sensors mounted on both thighs and calves, is adopted. We note that the position of the left and right feet cannot be apart because of the kinematic constraints of the body, so the kinematic model generates new measurements for the waist position. The Extended Kalman Filter (EKF) on the waist data that estimates and corrects error states uses these measurements and magnetic heading measurements, which enhances the heading accuracy. The updated position information is fed into the foot mounted sensors, and reupdate processes are performed to correct the position error of each foot. The proposed update-reupdate technique consequently ensures improved observability of error states and position accuracy. Moreover, the proposed method provides all the information about the lower human body, so that it can be applied more effectively to motion tracking. The effectiveness of the proposed algorithm is verified via experimental results, which show that a 1.25% Return Position Error (RPE) with respect to walking distance is achieved.


Effect of repetitive activity upon intracellular pH, sodium and contraction in sheep cardiac Purkinje fibres.
1. The influence of repetitive activity upon intracellular pH (pHi), intracellular Na+ activity (aNA(i)) and contraction was examined in isolated sheep cardiac Purkinje fibres. Ion-selective microelectrodes were used to measure intracellular Na+ and H+ ion activity. Twitch tension was elicited by field stimulation or by depolarizing pulses applied using a two-microelectrode voltage clamp. Experiments were performed in HEPES-buffered solution equilibrated either with air or 100% O2. 2. An increase in action potential frequency from a basal rate of 0.1 to 1-4 Hz induced a reversible fall in pHi and a reversible rise in aNa(i). These effects reached a steady state 3-10 min following an increase in stimulation frequency, and showed a linear dependence on frequency with a mean slope of 0.023 pH units Hz-1 and 0.57 mmol l-1 Hz-1, respectively. The rise in total intracellular acid and aNa(i) associated with a single action potential was estimated as 5.3 mu equiv l-1 of acid and 3.5 mu equiv l-1 of Na+. 3. At action potential frequencies greater than 1 Hz, the rate-dependent rise in aNa(i) was usually accompanied by a positive force staircase. 4. The fall in pHi following a rate increase also occurred when fibres were bathed in Tyrode solution equilibrated with 23 mM-HCO3- plus nominally 5% CO2/95% O2. In these cases, however, the fall in pHi was halved in magnitude. 5. In fibres exposed to strophanthidin (0.5 microM), the rate-dependent fall in pHi was doubled in magnitude and its time course was more variable than under drug-free conditions. The rate-dependent rise in aiNa was also usually larger in strophanthidin. 6. In order to examine the influence of the rate-dependent acidosis on developed tension, the acidosis was reversed experimentally by adding 2 mmol l-1 NH4Cl to the bathing solution. This produced a rise in pHi accompanied by a large increase in twitch tension. Such an effect of pHi upon tension was quantitatively similar to that observed in previous work on Purkinje fibres (Vaughan-Jones, Eisner & Lederer, 1987). 7. It is concluded that the rate dependence of pHi will influence both the magnitude and the time course of an inotropic response to a change in heart rate.


Visit-to-Visit Glucose Variability Predicts the Development of End-Stage Renal Disease in Type 2 Diabetes: 10-Year Follow-Up of Taiwan Diabetes Study.
The purpose of this study was to examine the association of glucose variability using coefficient of variation of fasting plasma glucose (FPG-CV) and coefficient of variation of glycated hemoglobin (HbA1c-CV) to end-stage renal disease (ESRD) in 31,841 Chinese patients with type 2 diabetes.Patients with type 2 diabetes enrolled in National Diabetes Care Management Program, aged ≧30 years, and free of ESRD (n = 31,841) in January 1, 2002 to December 31, 2004 were included. Extended Cox proportional hazards regression models with competing risk of all-cause mortality were used to evaluate risk factors on ESRD incidence. Patients were followed till 2012.After a median follow-up period of 8.23 years, 1642 patients developed ESRD, giving a crude incidence rate of 6.27/1000 person-years (6.36 for men, 6.19 for women). After the multivariate adjustment, both FPG-CV and HbA1c-CV were independent predictors of ESRD with corresponding hazard ratios of 1.20 (95% confidence interval [CI] 1.01, 1.41), 1.24 (95% CI 1.05, 1.46) in HbA1c-CV from fourth to fifth quintile and 1.23 (95% CI 1.03, 1.47) in FPG-CV from fifth quintile.One-year visit-to-visit glucose variability expressed by FPG-CV and HbA1c-CV predicted development of ESRD in patients with type 2 diabetes, suggesting therapeutic strategies toward a goal to minimize glucose fluctuation.


Visualizing and assessing discrimination in the logistic regression model.
Logistic regression models are widely used in medicine for predicting patient outcome (prognosis) and constructing diagnostic tests (diagnosis). Multivariable logistic models yield an (approximately) continuous risk score, a transformation of which gives the estimated event probability for an individual. A key aspect of model performance is discrimination, that is, the model's ability to distinguish between patients who have (or will have) an event of interest and those who do not (or will not). Graphical aids are important in understanding a logistic model. The receiver-operating characteristic (ROC) curve is familiar, but not necessarily easy to interpret. We advocate a simple graphic that provides further insight into discrimination, namely a histogram or dot plot of the risk score in the outcome groups. The most popular performance measure for the logistic model is the c-index, numerically equivalent to the area under the ROC curve. We discuss the comparative merits of the c-index and the (standardized) mean difference in risk score between the outcome groups. The latter statistic, sometimes known generically as the effect size, has been computed in slightly different ways by several different authors, including Glass, Cohen and Hedges. An alternative measure is the overlap between the distributions in the outcome groups, defined as the area under the minimum of the two density functions. The larger the overlap, the weaker the discrimination. Under certain assumptions about the distribution of the risk score, the c-index, effect size and overlap are functionally related. We illustrate the ideas with simulated and real data sets.


Assessment of deep vein thrombosis or pulmonary embolism by the combined use of clinical model and noninvasive diagnostic tests.
Deep vein thrombosis (DVT) and pulmonary embolism (PE) are relatively common diseases and are amenable to therapy but with a potentially fatal outcome if untreated. The diagnosis can be made in most patients with use of the noninvasive imaging tests, but limitations exist. The standard first choice of investigation in patients with suspected DVT is compression ultrasonography (CUS). As with all tests, there is a potential for false-positive and false-negative results. The latter are especially an issue for calf vein thrombi, and this in part has led to the concept of serial CUS testing of the proximal venous system and not imaging of the calf. The premise of the repeat (serial) CUS test is that only thrombi that extend to the proximal system are clinically relevant, and these thrombi will be detected during subsequent testing. However, despite the safety of the serial CUS testing concept, it is inconvenient and expensive. The standard first choice of investigation in patients with suspected PE, the ventilation-perfusion (V/Q) lung scan is nondiagnostic in most cases. In the past few years, the diagnostic process has improved because of the validation of clinical models that accurately categorize patients as having low (5%), moderate (20% to 30%), or high probability (>60%) for venous thromboembolic disease. Among the improvements this provides is the elimination of serial CUS testing if the ultrasound results are normal and the clinical probability is low in patients with suspected DVT. In patients with suspected PE in whom further testing is necessary, determination of clinical probability allows selection of invasive (angiography) or noninvasive testing (serial ultrasound) in patients with non-high-probability V/Q scans. The fibrin degradation product D-dimer has had a high negative predictive value; negative results with enzyme-linked immunosorbent assay (ELISA) tests effectively rule out DVT or PE. In addition, a negative result with less-sentive D-dimer testing and a low clinical probability excludes DVT or PE.


Can Electronic Health Records Databases Complement Spontaneous Reporting System Databases? A Historical-Reconstruction of the Association of Rofecoxib and Acute Myocardial Infarction.
Background: Several initiatives have assessed if mining electronic health records (EHRs) may accelerate the process of drug safety signal detection. In Europe, Exploring and Understanding Adverse Drug Reactions (EU-ADR) Project Focused on utilizing clinical data from EHRs of over 30 million patients from several European countries. Rofecoxib is a prescription COX-2 selective Non-Steroidal Anti-Inflammatory Drugs (NSAID) approved in 1999. In September 2004, the manufacturer withdrew rofecoxib from the market because of safety concerns. In this study, we investigated if the signal concerning rofecoxib and acute myocardial infarction (AMI) could have been identified in EHR database (EU-ADR project) earlier than spontaneous reporting system (SRS), and in advance of rofecoxib withdrawal. Methods: Data from the EU-ADR project and WHO-VigiBase (for SRS) were used for the analysis. Signals were identified when respective statistics exceeded defined thresholds. The SRS analyses was conducted two ways- based on the date the AMI events with rofecoxib as a suspect medication were entered into the database and also the date that the AMI event occurred with exposure to rofecoxib. Results: Within the databases participating in EU-ADR it was possible to identify a strong signal concerning rofecoxib and AMI since Q3 2000 [RR LGPS = 4.5 (95% CI: 2.84-6.72)] and peaked to 4.8 in Q4 2000. In WHO-VigiBase, for AMI term grouping, the EB05 threshold of 2 was crossed in the Q4 2004 (EB05 = 2.94). Since then, the EB05 value increased consistently and peaked in Q3 2006 (EB05 = 48.3) and then again in Q2 2008 (EB05 = 48.5). About 93% (2260 out of 2422) of AMIs reported in WHO-VigiBase database actually occurred prior to the product withdrawal, however, they were reported after the risk minimization/risk communication efforts. Conclusion: In this study, EU-EHR databases were able to detect the AMI signal 4 years prior to the SRS database. We believe that for events that are consistently documented in EHR databases, such as serious events or events requiring in-patient medical intervention or hospitalization, the signal detection exercise in EHR would be beneficial for newly introduced medicinal products on the market, in addition to the SRS data.


HGF/Met Signaling in Head and Neck Cancer: Impact on the Tumor Microenvironment.
Studies to date have revealed several major molecular alterations that contribute to head and neck squamous cell carcinoma (HNSCC) initiation, progression, metastatic spread, and therapeutic failure. The EGFR is the only FDA-approved therapeutic target, yet responses to cetuximab have been limited. Activation and cross-talk of cellular receptors and consequent activation of different signaling pathways contribute to limited activity of blockade of a single pathway. The hepatocyte growth factor (HGF) receptor, Met, has been implicated in HNSCC tumorigenesis and EGFR inhibitor resistance. HGF, the sole ligand of Met, is overexpressed in the tumor microenvironment. The role of HGF/Met signaling in proliferation, metastasis, and angiogenesis has been investigated in HNSCC, leading to clinical trials with various Met inhibitors and HGF antibodies. However, the role of the HGF/Met signaling axis in mediating the tumor microenvironment has been relatively understudied in HNSCC. In this review, we discuss the functional roles of Met and HGF in HNSCC with a focus on the tumor microenvironment and the immune system. Clin Cancer Res; 22(16); 4005-13. ©2016 AACR.


Medical students' perspectives on euthanasia and physician-assisted suicide and their views on legalising these practices in South Africa.
Euthanasia/physician-assisted suicide have been a controversial and sometimes taboo topic for a long time, not only in South Africa (SA) but also internationally. A recent (SA) judicial case has seen the topic debated again. Consensus on accepting or abolishing these practices in SA has yet to be reached. All relevant role players need to be adequately engaged before policy can be informed. To determine the views of future doctors (medical students) regarding euthanasia and physician-assisted suicide (PAS) and to ascertain their stance on its legalisation in South Africa (SA). A paper-based, semi-quantitative descriptive study design consisting of 16 questions, using convenience sampling of third- to fifth-year medical students at Stellenbosch University, was used. The overall response rate was 69.3% (N=277). In total, 52.7% of participants (n=146) felt that the practices of euthanasia/PAS should be legalised in SA. Responses varied depending on patient morbidities. If a patient had terminal disease with intractable suffering, 41.9% of participants would terminate the patient's life upon request. A further 36.1% of participants stated that they would have no part in ending a patient's life, while 35.0% said that they would be comfortable with providing the patient with the correct means to end their life (PAS). The majority (80.1%) of participants indicated that they would prefer a dedicated ethics committee to decide who receives euthanasia/PAS. Many factors influenced participants' responses, but differences in opinion between and within the various religious groups were particularly evident in the responses received. More than half the respondents in this study were open to legalising euthanasia/PAS, substantially more than in previous studies. However, only 41.9% of respondents would consider actually performing euthanasia/PAS, for certain patients. Views of other healthcare workers as well as the public are required before policy can be informed.


Development and characterization of cDNA resources for the common marmoset: one of the experimental primate models.
The common marmoset is a new world monkey, which has become a valuable experimental animal for biomedical research. This study developed cDNA libraries for the common marmoset from five different tissues. A total of 290 426 high-quality EST sequences were obtained, where 251 587 sequences (86.5%) had homology (1E(-100)) with the Refseqs of six different primate species, including human and marmoset. In parallel, 270 673 sequences (93.2%) were aligned to the human genome. When 247 090 sequences were assembled into 17 232 contigs, most of the sequences (218 857 or 15 089 contigs) were located in exonic regions, indicating that these genes are expressed in human and marmoset. The other 5578 sequences (or 808 contigs) mapping to the human genome were not located in exonic regions, suggesting that they are not expressed in human. Furthermore, a different set of 118 potential coding sequences were not similar to any Refseqs in any species, and, thus, may represent unknown genes. The cDNA libraries developed in this study are available through RIKEN Bio Resource Center. A Web server for the marmoset cDNAs is available at http://marmoset.nig.ac.jp/index.html, where each marmoset EST sequence has been annotated by reference to the human genome. These new libraries will be a useful genetic resource to facilitate research in the common marmoset.


Fingertip force control during bimanual object lifting in hemiplegic cerebral palsy.
In the present study we examined unimanual and bimanual fingertip force control during grasping in children with hemiplegic cerebral palsy (CP). Participants lifted, transported and released an object with one hand or both hands together in order to examine the effect on fingertip force control for each hand separately and to determine whether any benefit exists for the affected hand when it performed the task concurrently with the less-affected hand. Seven children with hemiplegic CP performed the task while their movement and fingertip force control were measured. In the bimanual conditions, the weight of the instrumented objects was equal or unequal. The durations of the all temporal phases for the less-affected hand were prolonged during bimanual control compared to unimanual control. We observed close synchrony of both hands when the task was performed with both hands, despite large differences in duration between both hands when they performed separately. There was a marginal benefit for two of the five force related variables for the affected hand (grip force at onset of load force, and peak grip force) when it transported the object simultaneously with the less-affected hand. Collectively, these results corroborate earlier findings of reaching studies that showed slowing down of the less-affected hand when it moved together with the affected hand. A new finding that extends these studies is that bimanual tasks may have the potential to facilitate force control of the affected hand. The implications of these findings for recent rehabilitative therapies in children with CP that make use of bimanual training are discussed.


Characterization of the carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline in cooking aerosols under domestic conditions.
Lung cancer in women is the leading cause of cancer death in Taiwan. Most Chinese women are non-smokers and 60% of female lung cancer patients have adenocarcinomas. Epidemiological data indicate that the incidence of lung cancer among Chinese women may be correlated with cooking fumes. However, the carcinogenic compound(s) in cooking fume aerosols is not defined. In the present study, the cooking aerosols from Chinese stir-frying of fish were prepared under domestic conditions. To determine the mutagenic compounds in the cooking aerosol, mutagens were purified by two steps of high-performance liquid chromatography (HPLC), and their mutagenicity was monitored with Salmonella typhimurium TA98. The mutagen was eluted as a single peak. The chemical structure of the mutagenic fraction of cooking aerosol from frying of fish was characterized by UV spectra and electrospray mass spectrometry. The bacterial indirect-acting mutagenic compound in the cooking aerosol extract was determined to be 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). An amount of 0.25 ng MeIQx/g of meat per min was estimated based on the mutagenic response. These data indicated that significant amounts of MeIQx (268.1 ng/Chinese dish of frying fish) were present in cooking aerosol in a short time. Chinese women spend approximately 1 h preparing meals everyday, thus, they may be exposed to significant amounts of MeIQx from cooking aerosols in the kitchen.