Dairy products, calcium, and prostate cancer risk: a systematic review and meta-analysis of cohort studies.
Dairy product and calcium intakes have been associated with increased prostate cancer risk, but whether specific dairy products or calcium sources are associated with risk is unclear. In the Continuous Update Project, we conducted a meta-analysis of prospective studies on intakes of dairy products and calcium and prostate cancer risk. PubMed and several other databases were searched up to April 2013. Summary RRs were estimated by using a random-effects model. Thirty-two studies were included. Intakes of total dairy products [summary RR: 1.07 (95% CI: 1.02, 1.12; n = 15) per 400 g/d], total milk [summary RR: 1.03 (95% CI: 1.00, 1.07; n = 14) per 200 g/d], low-fat milk [summary RR: 1.06 (95% CI: 1.01, 1.11; n = 6) per 200 g/d], cheese [summary RR: 1.09 (95% CI: 1.02, 1.18; n = 11) per 50 g/d], and dietary calcium [summary RR: 1.05 (95% CI: 1.02, 1.09; n = 15) per 400 mg/d] were associated with increased total prostate cancer risk. Total calcium and dairy calcium intakes, but not nondairy calcium or supplemental calcium intakes, were also positively associated with total prostate cancer risk. Supplemental calcium was associated with increased risk of fatal prostate cancer. High intakes of dairy products, milk, low-fat milk, cheese, and total, dietary, and dairy calcium, but not supplemental or nondairy calcium, may increase total prostate cancer risk. The diverging results for types of dairy products and sources of calcium suggest that other components of dairy rather than fat and calcium may increase prostate cancer risk. Any additional studies should report detailed results for subtypes of prostate cancer.


Neural bases of eye and gaze processing: the core of social cognition.
Eyes and gaze are very important stimuli for human social interactions. Recent studies suggest that impairments in recognizing face identity, facial emotions or in inferring attention and intentions of others could be linked to difficulties in extracting the relevant information from the eye region including gaze direction. In this review, we address the central role of eyes and gaze in social cognition. We start with behavioral data demonstrating the importance of the eye region and the impact of gaze on the most significant aspects of face processing. We review neuropsychological cases and data from various imaging techniques such as fMRI/PET and ERP/MEG, in an attempt to best describe the spatio-temporal networks underlying these processes. The existence of a neuronal eye detector mechanism is discussed as well as the links between eye gaze and social cognition impairments in autism. We suggest impairments in processing eyes and gaze may represent a core deficiency in several other brain pathologies and may be central to abnormal social cognition.


Etiologies and resistance profiles of bacterial community-acquired pneumonia in Cambodian and neighboring countries' health care settings: a systematic review (1995 to 2012).
Community-acquired pneumonia (CAP) is one of the most important causes of morbidity and mortality worldwide. Etiological data for Cambodia is scarce. We aimed to describe the main etiological agents causing CAP, and their resistance patterns in Cambodia and the greater Mekong region. A review of bacterial etiologies of CAP and antimicrobial resistance in Cambodia and neighboring countries was conducted via: (1) a systematic review of published literature in all NCBI databases using Pubmed, Google scholar, EMBASE, the World Health Organization and the Cambodian Ministry of Health libraries; (2) a review of unpublished data from Cambodia provided by national and international stakeholders working at different tiers of the healthcare system. Twenty three articles and five data sources reported etiologies for 5919 CAP patients diagnosed between May 1995 and December 2012, including 1421 (24.0%), 3571 (60.3%) and 927 (15.7%) from Cambodia, Thailand and Vietnam, respectively. Streptococcus pneumoniae and Haemophilus influenzae were the most common pathogens ranking among the five most prevalent in 12 and 10 studies, respectively. Gram-negative bacteria such as Burkholderia pseudomallei and Klebsiella pneumoniae were also frequently diagnosed, particularly in bacteremic CAP in Thai adults and Cambodian children. In Thailand and Vietnam, Mycoplasma pneumoniae and Chlamydia pneumoniae were frequently identified in settings using indirect laboratory testing. Based on this analysis, CAP data in Cambodia seems to present etiological and resistance profiles comparable to those of neighboring countries. Findings have been shared with the national authorities upon the revision of the national therapeutic guidelines and were disseminated using a specially created website.


The impact of a fast track area on quality and effectiveness outcomes: a Middle Eastern emergency department perspective.
Emergency department (ED) overcrowding is a ubiquitous problem with serious public health implications. The fast track area is a novel method which aims to reduce waiting time, patient dissatisfaction and morbidity. |The study objective was to determine the impact of a fast track area (FTA) on both effectiveness measures (i.e. waiting times [WT] and length of stay [LOS]) and quality measures (i.e. LWBS rates and mortality rates) in non-urgent patients. The secondary objective was to assess if a FTA negatively impacted on urgent patients entering the ED. The study took place in a 500 bed, urban, tertiary care hospital in Abu Dhabi, United Arab Emirates. This was a quasi-experimental, which examined the impact of a FTA on a pre-intervention control group (January 2005) (n = 4,779) versus a post-intervention study group (January 2006) (n = 5,706). Mean WTs of Canadian Triage Acuity Scale (CTAS) 4 patients decreased by 22 min (95% CI 21 min to 24 min, P < 0.001). Similarly, mean WTs of CTAS 5 patients decreased by 28 min (95% CI 19 min to 37 min, P < 0.001) post FTA. The mean WTs of urgent patients (CTAS 2/3) were also significantly reduced after the FTA was opened (P < 0.001). The LWBS rate was reduced from 4.7% to 0.7% (95% CI 3.37 to 4.64; P < 0.001). Opening a FTA had no significant impact on mortality rates (P = 0.88). The FTA improved ED effectiveness (WTs and LOS) and quality measures (LWBS rates) whereas mortality rate remained unchanged.


Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy.
Neocortical epilepsy is frequently drug-resistant. Surgery to remove the epileptogenic zone is only feasible in a minority of cases, leaving many patients without an effective treatment. We report the potential efficacy of gene therapy in focal neocortical epilepsy using a rodent model in which epilepsy is induced by tetanus toxin injection in the motor cortex. By applying several complementary methods that use continuous wireless electroencephalographic monitoring to quantify epileptic activity, we observed increases in high frequency activity and in the occurrence of epileptiform events. Pyramidal neurons in the epileptic focus showed enhanced intrinsic excitability consistent with seizure generation. Optogenetic inhibition of a subset of principal neurons transduced with halorhodopsin targeted to the epileptic focus by lentiviral delivery was sufficient to attenuate electroencephalographic seizures. Local lentiviral overexpression of the potassium channel Kv1.1 reduced the intrinsic excitability of transduced pyramidal neurons. Coinjection of this Kv1.1 lentivirus with tetanus toxin fully prevented the occurrence of electroencephalographic seizures. Finally, administration of the Kv1.1 lentivirus to an established epileptic focus progressively suppressed epileptic activity over several weeks without detectable behavioral side effects. Thus, gene therapy in a rodent model can be used to suppress seizures acutely, prevent their occurrence after an epileptogenic stimulus, and successfully treat established focal epilepsy.


A medium throughput device to study the effects of combinations of surface strains and fluid-flow shear stresses on cells.
We report a medium throughput device to study the effects of combinations of two mechanical stimuli - surface strains and fluid flow shear stresses, on cells. The first generation prototype can screen combinations of five strain and five shear stress levels. Computational modeling and empirical measurements were used to determine the generated strains and flows. Uniform equibiaxial strains up to 20% and shear stresses up to 0.3 Pa can be generated. Compatibility of the device with cell culture and end point fixation, staining and imaging is shown using C2C12 mouse myoblast cells.


Progression of coronary artery calcification in conventional hemodialysis, nocturnal hemodialysis, and kidney transplantation.
Cardiovascular disease is the leading cause of death in end-stage renal disease (ESRD) and is strongly associated with vascular calcification. An important driver of vascular calcification is high phosphate levels, but these become lower when patients initiate nocturnal hemodialysis or receive a kidney transplant. However, it is unknown whether nocturnal hemodialysis or kidney transplantation mitigate vascular calcification. Therefore, we compared progression of coronary artery calcification (CAC) between patients treated with conventional hemodialysis, nocturnal hemodialysis, and kidney transplant recipients. We measured CAC annually up to 3 years in 114 patients with ESRD that were transplantation candidates: 32 that continued conventional hemodialysis, 34 that initiated nocturnal hemodialysis (≥4x 8 hours/week), and 48 that received a kidney transplant. We compared CAC progression between groups as the difference in square root transformed volume scores per year (ΔCAC SQRV) using linear mixed models. Reference category was conventional hemodialysis. The mean age of the study population was 53 ±13 years, 75 (66%) were male, and median dialysis duration was 28 (IQR 12-56) months. Median CAC score at enrollment was 171 (IQR 10-647), which did not differ significantly between treatment groups (P = 0.83). Compared to conventional hemodialysis, CAC progression was non-significantly different in nocturnal hemodialysis -0.10 (95% CI -0.77 to 0.57) and kidney transplantation -0.33 (95% CI -0.96 to 0.29) in adjusted models. Nocturnal hemodialysis and kidney transplantation are not associated with significantly less CAC progression compared to conventional hemodialysis during up to 3 years follow-up. Further studies are needed to confirm these findings, to determine which type of calcification is measured with CAC in end-stage renal disease, and whether that reflects cardiovascular risk.


Managing adverse birth outcomes: helping parents and families cope.
Unexpected adverse fetal and neonatal outcomes (e.g., stillbirth, birth trauma, congenital anomalies) present a crisis for the family and the medical care team. In cases of stillbirth, the family physician should be flexible in supporting the parents' choices, validate the loss, and work as a team with the nursing staff. Psychosocial support includes offering counseling services, assessing women for postpartum depression and anxiety, and considering the effect of the loss on the entire family. Although infants with birth asphyxia or major anomalies may require transfer to facilities with a neonatal intensive care unit, the physician will usually provide ongoing care for the mother in the postpartum period. A comprehensive assessment can determine the etiology of fetal demise in most cases, which may guide future preconception and maternity care. Women with a previous adverse pregnancy outcome may have increased psychological stress in a subsequent pregnancy. Knowledge of community resources will facilitate care for the mother and her partner or family. Physicians may need to seek peer support to cope with their own feelings of loss.


Molecular cytogenetic identification of nullisomy 5B induced homoeologous recombination between wheat chromosome 5D and barley chromosome 5H.
Chromosome 5H of Hordeum vulgare 'New Golden' (NG) carries a gene(s) that accelerates heading in a wheat background. To introduce the early heading gene(s) of NG barley into the wheat genome, we attempted to induce homoeologous recombination between wheat and NG 5H chromosomes by 5B nullisomy. A nullisomic 5B, trisomic 5A, monosomic 5H plant (2n = 42) was produced from systematic crosses between aneuploid stocks of wheat group 5 chromosomes. A total of 656 F2 plants produced by self-fertilization were screened for recombinants by a PCR assay with 3 5H-specific amplicon markers. Twelve plants (1.8%) were selected as putative wheat-barley 5H recombinants. Five of them were inviable or sterile and the remaining 7 were fertile and subjected to the progeny test. Cytological analyses using fluorescence in situ hybridization and C-banding revealed that 6 of the 7 progeny lines are true homoeologous recombinants between the long arms of chromosomes 5D and 5H, but that the other one was not a recombinant having an aberrant barley telosome. The 6 cytologically confirmed recombinant lines included only 2 types (3 lines each), which were reciprocal products derived from exchanges at the same distal interval defined by two flanking markers. One type had a small 5HL segment translocated to the 5DL terminal, and the other type had a small terminal 5DL segment translocated to the 5HL terminal. In the latter type, the physical length of translocated barley segments slightly differed among lines. Homoeologous recombinants obtained in this study should be useful for further chromosome manipulation to introgress a small interstitial 5HL chromosome segment with the early heading gene(s) to wheat. Preferential occurrence of restricted types of recombinants is discussed in relation to homoeologous relationships between wheat and barley chromosomes.


Assessing the Use of a Feedback Module to Model EQ-5D-5L Health States Values in Hong Kong.
An international valuation protocol exists for obtaining societal values for each of the 3125 health states of the five-level EuroQol-five dimensions (EQ-5D-5L) questionnaire. A feedback module (FM) that can be related to theoretical models used in behavioral economics was recently included in this protocol. Our objective was to assess the impact of using an FM to estimate an EQ-5D-5L value set in Hong Kong. EQ-5D-5L health states were elicited using a composite time trade-off (C-TTO) and a discrete-choice (DC) experiment. Use of the FM according to participant characteristics and the impact of the FM on the number of inconsistent C-TTO responses were assessed. We employed a main-effects hybrid model that combined data from both elicitation techniques. In total, 1014 individuals completed the survey. The sample was representative of the general Chinese Hong Kong population in terms of sex, educational attainment, marital status, and most age groups but not for employment status. The use of the FM reduced the number of C-TTO inconsistencies. Participant characteristics differed significantly between those who used and did not use the FM. The model without a constant resulted in logical consistent coefficients and was therefore selected as the model to produce the value set. The predicted EQ-5D-5L values ranged from -0.864 to 1. The use of an FM to allow participants to exclude C-TTO responses reduced the number of inconsistent responses and improved the quality of the data when estimating an EQ-5D-5L value set in Hong Kong.


Balancing Fistula First with Catheters Last.
The success of Fistula First nationwide has been accompanied by an unplanned increase in hemodialysis catheters. Complications related to prolonged hemodialysis catheter use include increased morbidity, mortality, and cost. We hypothesize that the national focus on increasing fistulas may have inadvertently diverted attention away from initiatives to decrease dependence on hemodialysis catheters. Based on a synthesis of guidelines, reviews, published evidence, and the authors' opinions, we propose that the national vascular access initiative be revised to have a dual goal of Fistula First and "Catheters Last." These goals are not mutually exclusive, but rather complementary. We recommend a systematic refocus on interventions that not only increase fistulas, but help avoid extended catheter use. Clearly, the ideal practice for hemodialysis vascular access remains early placement of fistulas with enough maturation time such that they can be used for initiating long-term hemodialysis therapy when the need arises. To effect this change, a reimbursement policy covering the costs associated with permanent access placement before the need for dialysis is essential. Individualized patient management strategies may consider such innovative approaches as initiating patients on peritoneal dialysis therapy or using nonautogenous grafts as bridge accesses in lieu of catheters. For patients who are dialyzing using catheters, immediate active planning for permanent access placement and removal of the catheter is necessary. In the same vein as Fistula First, the renal community should once again be galvanized in working together toward controlling the catheter epidemic in our dialysis population.


Objective assessment of keloid scars with three-dimensional imaging: quantifying response to intralesional steroid therapy.
Treatment of keloid scars poses a significant challenge. Assessment of treatment response and research in this area depend on the availability of objective, accurate, and reproducible outcome measures. At present, scars are assessed using subjective grading systems, or with cumbersome investigations such as direct casting. The authors assessed the feasibility of objectively monitoring response to intralesional steroid treatment in routine clinical practice with quantitative three-dimensional imaging. Scar volume was quantified using a validated three-dimensional speckle-pattern stereophotogrammetry before and for a minimum of 8 weeks after intralesional steroid therapy in 12 patients with keloid scars. Mean scar volume at the start of treatment was 0.73 +/- 0.701 cc (range, 0.12 to 2.15 cc); this was reduced to 0.14 +/- 0.302 cc (range, 0.007 to 1.08 cc) after monthly intralesional injections of triamcinolone acetate (p < 0.001; analysis of variance). The majority of patients achieved a greater than 50 percent response within 8 weeks of the start of therapy, but poor treatment response was noted and quantified in a minority of patients. Three-dimensional stereophotogrammetry is a rapid and noninvasive method of scar volume assessment that could allow accurate and objective monitoring of treatment response to be incorporated into clinical practice. Therefore, it can be of considerable value in assessing treatment efficacy and evaluating new therapeutic strategies.


How ideology shapes the evidence and the policy: what do we know about cannabis use and what should we do?
In the United Kingdom, as in many places, cannabis use is considered substantially within a criminal justice rather than a public health paradigm with prevention policy embodied in the Misuse of Drugs Act. In 2002 the maximum custodial sentence tariff for cannabis possession under the Act was reduced from 5 to 2 years. Vigorous and vociferous public debate followed this decision, centred principally on the question of whether cannabis use caused schizophrenia. It was suggested that new and compelling evidence supporting this hypothesis had emerged since the re-classification decision was made, meaning that the decision should be reconsidered. The re-classification decision was reversed in 2008. We consider whether the strength of evidence on the psychological harms of cannabis has changed substantially and discuss the factors that may have influenced recent public discourse and policy decisions. We also consider evidence for other harms of cannabis use and public health implications of preventing cannabis use. We conclude that the strongest evidence of a possible causal relation between cannabis use and schizophrenia emerged more than 20 years ago and that the strength of more recent evidence may have been overstated--for a number of possible reasons. We also conclude that cannabis use is almost certainly harmful, mainly because of its intimate relation to tobacco use. The most rational policy on cannabis from a public health perspective would seem to be one able to achieve the benefit of reduced use in the population while minimizing social and other costs of the policy itself. Prohibition, whatever the sentence tariff associated with it, seems unlikely to fulfil these criteria.


Optical correlation algorithm for reconstructing phase skeleton of complex optical fields for solving the phase problem.
We propose an optical correlation algorithm illustrating a new general method for reconstructing the phase skeleton of complex optical fields from the measured two-dimensional intensity distribution. The core of the algorithm consists in locating the saddle points of the intensity distribution and connecting such points into nets by the lines of intensity gradient that are closely associated with the equi-phase lines of the field. This algorithm provides a new partial solution to the inverse problem in optics commonly referred to as the phase problem.


Streptococcus equi subspecies zooepidemicus meningitis--a case report and review of the literature.
A case is described of a 79-year-old man, trampled by his horses, who subsequently developed a wound infection and, later, meningitis. Streptococcus equi subsp. zooepidemicus was isolated as the causative organism. S. equi subsp. zooepidemicus, which carries the Lancefield Group C antigen, is an uncommon human pathogen but is commonly isolated from bacterial infections in animals, particularly horses. It is most commonly acquired by humans following animal contact. A review of the literature identified 20 previously described cases of S. equi subsp. zooepidemicus meningitis. Crude mortality following infection was 24%. All of the patients who died were over 70 years of age and the ingestion of unpasteurised dairy products was associated with all but one of the fatal cases. Hearing loss was a frequent complication, occurring in 19% of cases. Only 38% of patients made a complete recovery. Treatment regimes commonly included benzylpenicillin or a third-generation cephalosporin, with a mean treatment duration in survivors of 23 days.


Surface phonon polariton characteristics of In(0.04)Al(0.06)Ga(0.90)N/AlN/Al(2)O(3) heterostructure.
Surface phonon polariton (SPP) characteristics of In(0.04)Al(0.06)Ga(0.90)N/AlN/Al(2)O(3) heterostructure are investigated by means of p-polarized infrared (IR) attenuated total reflection spectroscopy. Two absorption dips corresponding to In(0.04)Al(0.06)Ga(0.90)N SPP modes are observed. In addition, two prominent dips and one relatively weak and broad dip corresponding to the Al(2)O(3) SPP mode, In(0.04)Al(0.06)Ga(0.90)N/Al(2)O(3) interface mode, and Al(2)O(3) bulk polariton mode, respectively, are clearly seen. No surface mode feature originating from the AlN layer is observed because it is too thin. Overall, the observations are in good agreement with the theoretical predictions.


Automated psychological therapy using immersive virtual reality for treatment of fear of heights: a single-blind, parallel-group, randomised controlled trial.
Engaging, interactive, and automated virtual reality (VR) treatments might help solve the unmet needs of individuals with mental health disorders. We tested the efficacy of an automated cognitive intervention for fear of heights guided by an avatar virtual coach (animated using motion and voice capture of an actor) in VR and delivered with the latest consumer equipment. We did a randomised trial of automated VR versus usual care. We recruited adults aged older than 18 years with a fear of heights by radio advertisements in Oxfordshire, UK. We diagnosed fear of heights if participants scored more than 29 on the Heights Interpretation Questionnaire (HIQ). We randomly allocated participants by computer in a 1:1 ratio to either automated VR delivered in roughly six 30-min sessions administered about two to three times a week over a 2-week period (intervention group) or to usual care (control group). Randomisation was stratified by severity of fear of heights. The research team, who were unaware of the random allocation, administered three fear-of-height assessments, at baseline (0 weeks), at the end of treatment (2 weeks), and at follow-up (4 weeks). The primary outcome measure was HIQ score (range 16-80, with higher scores indicating greater severity). This trial is registered with the ISRCTN registry, number ISRCTN11898283. Between Nov 25, 2017, and Feb 27, 2018, 100 individuals were enrolled and underwent randomisation, of whom 49 were assigned to the VR treatment group and 51 to the control group. All participants completed the 4-week follow-up. The mean total treatment time in VR was 124·43 min (SD 34·23). Compared with participants in the control group, the VR treatment reduced fear of heights at the end of treatment (mean change score -24·5 [SD 13·1] in the VR group vs -1·2 [7·3] in the control group; adjusted difference -24·0, 95% CI -27·7 to -20·3; Cohen's d=2·0; p<0·0001). The benefit was maintained at follow-up (mean change score -25·1 [SD 13·9] in the VR group vs -1·5 [7·8] in the control group; adjusted difference -24·3, 95% CI -27·9 to -20·6; Cohen's d=2·0; p<0·0001). The number needed to treat to at least halve the fear of heights was 1·3. No adverse events were reported. Psychological therapy delivered automatically by a VR coach can produce large clinical benefits. Evidence-based VR treatments have the potential to greatly increase treatment provision for mental health disorders. Oxford VR, and the National Institute of Health Research Oxford Health Biomedical Research Centre.


Why glucocorticosteroids should remain in the list of prohibited substances: a sports medicine viewpoint.
In addition to their therapeutic applications, glucocorticosteroids have been widely used and abused in the belief that these substances may enhance athletic performance. Analysis of athlete urine samples by antidoping laboratories around the world support this conclusion. It is commonly accepted in medical practice to use local glucocorticosteroid injections in the treatment of non-infectious local musculotendinous inflammatory conditions conveying symptom relief and often a speedier return to sporting activity. This practice is not to be considered illicit, but sports physicians must accept that such an intervention is not in itself an immediate cure and that an athlete will still require a period of recuperation before continuing sporting activity. How long such a period of recuperation should last is a matter of conjecture and there is little concrete data to support what is, or what is not, an acceptable period of inactivity. In the interest of athlete safety, we would propose to maintain systemic glucocorticosteroids on the World Anti-Doping Agency's (WADA) list of prohibited substances, both in and out-of-competition as well as a mandatory period of 48 hours of rest from play after receiving a local glucocorticosteroid injection.


A decade of studying implicit racial/ethnic bias in healthcare providers using the implicit association test.
Disparities in the care and outcomes of US racial/ethnic minorities are well documented. Research suggests that provider bias plays a role in these disparities. The implicit association test enables measurement of implicit bias via tests of automatic associations between concepts. Hundreds of studies have examined implicit bias in various settings, but relatively few have been conducted in healthcare. The aim of this systematic review is to synthesize the current knowledge on the role of implicit bias in healthcare disparities. A comprehensive literature search of several databases between May 2015 and September 2016 identified 37 qualifying studies. Of these, 31 found evidence of pro-White or light-skin/anti-Black, Hispanic, American Indian or dark-skin bias among a variety of HCPs across multiple levels of training and disciplines. Fourteen studies examined the association between implicit bias and healthcare outcomes using clinical vignettes or simulated patients. Eight found no statistically significant association between implicit bias and patient care while six studies found that higher implicit bias was associated with disparities in treatment recommendations, expectations of therapeutic bonds, pain management, and empathy. All seven studies that examined the impact of implicit provider bias on real-world patient-provider interaction found that providers with stronger implicit bias demonstrated poorer patient-provider communication. Two studies examined the effect of implicit bias on real-world clinical outcomes. One found an association and the other did not. Two studies tested interventions aimed at reducing bias, but only one found a post-intervention reduction in implicit bias. This review reveals a need for more research exploring implicit bias in real-world patient care, potential modifiers and confounders of the effect of implicit bias on care, and strategies aimed at reducing implicit bias and improving patient-provider communication. Future studies have the opportunity to build on this current body of research, and in doing so will enable us to achieve equity in healthcare and outcomes.


Observing degradation of visual representations over short intervals when medial temporal lobe is damaged.
Medial temporal lobe (MTL) contributions to the brief maintenance of visual representations were evaluated by studying a group of patients with MTL damage. Eye movements of patients and healthy comparison subjects were tracked while performing a visual search for a target among complex stimuli of varying similarity to that target. Despite the task having no imposed delays, patients were impaired behaviorally, and eye movement measures showed abnormally rapid degradation of target representations in the patients. Eye movement data showed a modulation of the duration of fixations as a function of the similarity of fixated array lures to the target, but the effect was attenuated in patients during long fixation paths away from the sample target. This effect manifested despite patients' shorter searches and more frequent fixations of the sample target. Novel techniques provided unique insight into visual representation without healthy MTL, which may support maintenance of information through hippocampal-dependent relational binding.


A sulphite respiration system in the chemoheterotrophic human pathogen Campylobacter jejuni.
The ability to use sulphite as a respiratory electron donor is usually associated with free-living chemolithotrophic sulphur-oxidizing bacteria. However, this paper shows that the chemoheterotrophic human pathogen Campylobacter jejuni has the ability to respire sulphite, with oxygen uptake rates of 23 +/- 8 and 28 +/- 15 nmol O(2) min(-1) (mg cell protein)(-1) after the addition of 0.5 mM sodium sulphite or metabisulphite, respectively, to intact cells. The C. jejuni NCTC 11168 Cj0004c and Cj0005c genes encode a monohaem cytochrome c and molybdopterin oxidoreductase, respectively, homologous to the sulphite : cytochrome c oxidoreductase (SOR) of Starkeya novella. Western blots of C. jejuni periplasm probed with a SorA antibody demonstrated cross-reaction of a 45 kDa band, consistent with the size of Cj0005. The Cj0004c gene was inactivated by insertion of a kanamycin-resistance cassette. The resulting mutant showed wild-type rates of formate-dependent respiration but was unable to respire with sulphite or metabisulphite as electron donors. 2-Heptyl-4-hydroxyquinoline-N-oxide (HQNO), a cytochrome bc(1) complex inhibitor, did not affect sulphite respiration at concentrations up to 25 microM, whereas formate respiration (which occurs partly via a bc(1) dependent route) was inhibited 50%, thus suggesting that electrons from sulphite enter the respiratory chain after the bc(1) complex at the level of cytochrome c. Periplasmic extracts of wild-type C. jejuni 11168 showed a symmetrical absorption peak at 552 nm after the addition of sulphite, demonstrating the reduction of cytochrome c. No cytochrome c reduction was observed after addition of sulphite to periplasmic extracts of the Cj0004c mutant. A fractionation study confirmed that the majority of the SOR activity is located in the periplasm in C. jejuni, and this activity was partially purified by ion-exchange chromatography. The presence of a sulphite respiration system in C. jejuni is another example of the surprising diversity of the electron-transport chain in this small-genome pathogen. Sulphite respiration may be of importance for survival in environmental microaerobic niches and some foods, and may also provide a detoxification mechanism for this normally growth-inhibitory compound.


Zinc stable isotopes in urine as diagnostic for cancer of secretory organs.
Breast, prostate, and pancreatic cancers alter the zinc (Zn) metabolism. Combined analyses of urinary Zn concentrations [Zn] and Zn stable isotope compositions (δ66Zn) may provide a non-invasive approach for tracing malignancy-induced Zn dyshomeostasis. In this study, we measured [Zn] and δ66Zn in urine from prostate (n = 22), breast (n = 16), and from women with benign breast disease (n = 14) and compared those with age-matched healthy controls (22-49 years or 50+ years) and published data for pancreatic cancer (n = 17). Our results show that cancer-induced changes are reflected in higher urinary [Zn] and lower urinary δ66Zn for pancreatic and prostate cancer and benign breast disease when compared with healthy controls. For prostate cancer, the progression of low [Zn] and high δ66Zn for patients of low-risk disease toward high [Zn] and low δ66Zn for the higher risk patients demonstrates that [Zn] and δ66Zn in urine could serve as a reliable prognostic tool. Urinary excretion of isotopically light Zn by patients with prostatic and pancreatic cancer is probably the result of increased reactive oxygen species in cancerous cells, which limits the scavenging of hydroxyl radicals and thus facilitates the oxidation of metalloproteins with sulfur-rich ligands. Urine from breast cancer patients shows undistinguishable δ66Zn to healthy controls, implying that the expression of metalloproteins with sulfur-rich ligands is stronger in breast cancer tissues. In conclusion, urinary δ66Zn may provide a non-invasive diagnostic tool for pancreatic cancer and support disease prognosis for prostate cancer. These findings should translate to comprehensive transverse and longitudinal cohort studies in future.


YAMAT-seq: an efficient method for high-throughput sequencing of mature transfer RNAs.
Besides translation, transfer RNAs (tRNAs) play many non-canonical roles in various biological pathways and exhibit highly variable expression profiles. To unravel the emerging complexities of tRNA biology and molecular mechanisms underlying them, an efficient tRNA sequencing method is required. However, the rigid structure of tRNA has been presenting a challenge to the development of such methods. We report the development of Y-shaped Adapter-ligated MAture TRNA sequencing (YAMAT-seq), an efficient and convenient method for high-throughput sequencing of mature tRNAs. YAMAT-seq circumvents the issue of inefficient adapter ligation, a characteristic of conventional RNA sequencing methods for mature tRNAs, by employing the efficient and specific ligation of Y-shaped adapter to mature tRNAs using T4 RNA Ligase 2. Subsequent cDNA amplification and next-generation sequencing successfully yield numerous mature tRNA sequences. YAMAT-seq has high specificity for mature tRNAs and high sensitivity to detect most isoacceptors from minute amount of total RNA. Moreover, YAMAT-seq shows quantitative capability to estimate expression levels of mature tRNAs, and has high reproducibility and broad applicability for various cell lines. YAMAT-seq thus provides high-throughput technique for identifying tRNA profiles and their regulations in various transcriptomes, which could play important regulatory roles in translation and other biological processes.


Flow cytometric analysis of lectin binding to human peripheral blood lymphocytes.
The binding of fluorescein-conjugated lentil lectin and concanavalin A to the surface membrane of human peripheral blood lymphocytes was studied by flow cytometry. The lymphocytes bound 3-fold more lentil lectin molecules compared with concanavalin A molecules and lentil lectin binding approached saturation at a much lower concentration than did that of concanavalin A. Lentil lectin identified two groups of lymphocytes: a low-binding T-cell fraction and a high-binding B-cell-enriched fraction. Concanavalin A did not discriminate between these populations in unseparated lymphocytes. Competition studies indicated that lentil lectin and concanavalin A were bound to different sites on the lymphocyte surface, although about 50% of lentil lectin sites were in close proximity to concanavalin A sites.


Vascular endothelial growth factor promotes brain tissue regeneration with a novel biomaterial polydimethylsiloxane-tetraethoxysilane.
In the brain after infarction or trauma, the tissue eventually becomes pannecrotic and forms a cavity. In such situations, a scaffold is necessary for the implanted or migrated cells to produce new tissue. In this present study, therefore, we attempted to restore brain tissue using a novel biomaterial, polydimethylsiloxane-tetraethoxysilane (PDMS-TEOS) hybrid with or without vascular endothelial growth factor (VEGF), which is crucial for new vessel formation. When PDMS-TEOS scaffold was implanted into the artificial brain defect, it remained at the implanted site and kept the integrity of the brain shape. At 30 days after the implantation, the marginal territory of PDMS-TEOS scaffold became occupied by newly formed tissue. Immunohistochemical analysis revealed that the new tissue was constituted by astrocytes and endothelial cells. Addition of VEGF increased the newly produced tissue volume, and the immunohistochemical analysis showed that the numbers of astrocytes and endothelial cells were increased. Double staining with proliferation maker Ki67 demonstrated that VEGF significantly increased newly formed astrocytes and endothelial cells, indicating that addition of VEGF accelerated tissue restoration and angiogenesis. These findings show that implantation of PDMS-TEOS scaffold with VEGF might be effective for treating old brain infarction or trauma.


Is there a link between subjective daytime somnolence and sickness absenteeism? A study in a working population.
A number of studies have highlighted the increasing incidence and financial cost of sleep-related disorders in the general population, but little research has been carried out on the impact of subjective daytime somnolence on health status. The existence of a survey of the health of employees of the French National Gas and Electricity Board has allowed us to investigate this question and measure the link between subjective daytime somnolence and sickness absenteeism, used here as a general health indicator. In order to evaluate the quality of sleep over the previous 3 months, a questionnaire was given to each participant. The association between subjective daytime somnolence and absence as a result of sickness was explored using the data of sickness absenteeism provided by the company's social security department during a 12-month follow-up period. Of our 1105 subjects, 6.7% reported severe subjective daytime somnolence of 3 days or more a week and 30% of our study population had at least one spell of sickness absence during the 12-month period of follow-up. A strong association was observed between subjective daytime somnolence and sickness absence, which remained significant even after adjustment for potential confounding variables (age, sex, employment grade, sleep symptoms and self-reported diseases). The odds-ratio for absence as a result of sickness during the follow-up period associated with subjective daytime somnolence of 3 days or more a week was 2.2 (95% CI: 1.3--3.8). Employees suffering from severe subjective daytime somnolence lose more working days for health reasons than their more alert colleagues. This may have long-term implications for employees' health.


Factors associated with unfavourable birth outcomes in Kenya.
Studies addressing factors associated with adverse birth outcomes have almost exclusively been based on hospital statistics. This is a serious limitation in developing countries where the majority of births do not occur within health facilities. This paper examines factors associated with premature deliveries, small baby's size at birth and Caesarean section deliveries in Kenya based on the 1993 Kenya Demographic and Health Survey data. Due to the hierarchical nature of the data, the analysis uses multilevel logistic regression models to take into account the family and community effects. The results show that the odds of unfavourable birth outcomes are significantly higher for first births than for higher order births. Furthermore, antenatal care (measured by frequency of antenatal care visits and tetanus toxoid injection) is observed to have a negative association with the incidence of premature births. For the baby's size at birth, maternal nutritional status is observed to be a predominant factor. Short maternal stature is confirmed as a significant risk factor for Caesarean section deliveries. The observed higher odds of Caesarean section deliveries among women from households of high socioeconomic status are attributed to the expected association between socioeconomic status and the use of appropriate maternal health care services. The odds of unfavourable birth outcomes vary significantly between women. In addition, the odds of Caesarean section deliveries vary between districts, after taking into account the individual-level characteristics of the woman.


Stigmatization in the context of the COVID-19 pandemic: a survey experiment using attribution theory and the familiarity hypothesis.
The COVID-19 pandemic has created a global health crisis, leading to stigmatization and discriminatory behaviors against people who have contracted or are suspected of having contracted the virus. Yet the causes of stigmatization in the context of COVID-19 remain only partially understood. Using attribution theory, we examine to what extent attributes of a fictitious person affect the formation of stigmatizing attitudes towards this person, and whether suspected COVID-19 infection (vs. flu) intensifies such attitudes. We also use the familiarity hypothesis to explore whether familiarity with COVID-19 reduces stigma and whether it moderates the effect of a COVID-19 infection on stigmatization. We conducted a multifactorial vignette survey experiment (28-design, i.e., NVignettes = 256) in Germany (NRespondents = 4,059) in which we experimentally varied signals and signaling events (i.e., information that may trigger stigma) concerning a fictitious person in the context of COVID-19. We assessed respondents' cognitive (e.g., blameworthiness) and affective (e.g., anger) responses as well as their discriminatory inclinations (e.g., avoidance) towards the character. Furthermore, we measured different indicators of respondents' familiarity with COVID-19. Results revealed higher levels of stigma towards people who were diagnosed with COVID-19 versus a regular flu. In addition, stigma was higher towards those who were considered responsible for their infection due to irresponsible behavior. Knowing someone who died from a COVID infection increased stigma. While higher self-reported knowledge about COVID-19 was associated with more stigma, higher factual knowledge was associated with less. Attribution theory and to a lesser extent the familiarity hypothesis can help better understand stigma in the context of COVID-19. This study provides insights about who is at risk of stigmatization and stigmatizing others in this context. It thereby allows identifying the groups that require more support in accessing healthcare services and suggests that basic, factually oriented public health interventions would be promising for reducing stigma.


Sellar and parasellar tumor removal without discontinuing antithrombotic therapy.
Treatment with dual antiplatelet agents associated with coronary stenting procedures and long-term anticoagulant therapy is increasingly common, but the treatment carries risks during surgical procedures. Evidence-based recommendations have proposed discontinuation of antithrombotic treatment or introduction of bridging therapy in some procedures less invasive and with lower risk of bleeding. However, neurosurgical procedures without discontinuation of antithrombotic treatment and perioperative management have received little investigation. Between October 2008 and January 2014, 15 consecutive patients (11 males and 4 females; age range 51-75 years [mean 68.2 years]), with sellar and parasellar tumors were treated through the transsphenoidal approach without discontinuation of antithrombotic therapy. Clinical data were compared with another 15 patients, who underwent transsphenoidal surgeries without preoperative antithrombotic therapy. Gross-total removal of the tumor or total aspiration of the content of Rathke's cleft cyst was achieved in 13 patients, and subtotal removal was achieved in 1 patient with a small remnant in the cavernous sinus. No difference was found in intraoperative bleeding between the antithrombotic agent group and the control group (mean 255 ml vs 215 ml, Mann-Whitney U-test, p = 0.547), and no patient required transfusion. No difference was found in operation time between the antithrombotic agent group and the control group (167.8 minutes vs 150.0 minutes, Mann-Whitney U-test, p = 0.262). All patients were discharged on postoperative Day 12 without neurological deficits. The present study suggests that discontinuation of antithrombotic therapy may be unnecessary before the typical transsphenoidal surgery. Large randomized clinical trials at multiple centers are needed to confirm these findings.


Metabolic, Mental and Immunological Effects of Normoxic and Hypoxic Training in Multiple Sclerosis Patients: A Pilot Study.
Background: Physical activity might attenuate inflammation and neurodegeneration in multiple sclerosis (MS). Erythropoietin, which is produced upon exposure to hypoxia, is thought to act as a neuroprotective agent in MS. Therefore, we studied the effects of intermittent hypoxic training on activity energy expenditure, maximal workload, serum erythropoietin, and immunophenotype focusing on regulatory and IL-17A-producing T cells. Methods: We assigned 34 relapsing-remitting MS patients within a randomized, single blind, parallel-group study to either normoxic (NO) or hypoxic (HO) treadmill training, both 3 times/week for 1 h over 4 weeks (Clinicaltrials.gov identifier: NCT02509897). Before and after training, activity energy expenditure (metabolic chamber), maximal workload (incremental treadmill test), walking ability, depressive symptoms (Beck Depression Inventory I), serum erythropoietin concentrations, and immunophenotype of peripheral blood mononuclear cells (PBMCs) were assessed. Results: Energy expenditure did not change due to training in both groups, but was rather fueled by fat than by carbohydrate oxidation after HO training (P = 0.002). Maximal workload increased by 40 Watt and 42 Watt in the NO and HO group, respectively (both P < 0.0001). Distance patients walked in 6 min increased by 25 m and 27 m in the NO and HO group, respectively (NO P = 0.02; HO P = 0.01). Beck Depression Inventory score markedly decreased in both groups (NO P = 0.03; HO P = 0.0003). NO training shifted Treg subpopulations by increasing and decreasing the frequency of CD39+ and CD31+ Tregs, respectively, and decreased IL-17A-producing CD4+ cells. HO training provoked none of these immunological changes. Erythropoietin concentrations were within normal range and did not significantly change in either group. Conclusion: 4 weeks of moderate treadmill training had considerable effects on fitness level and mood in MS patients, both under normoxic and hypoxic conditions. Additionally, NO training improved Th17/Treg profile and HO training improved fatty acid oxidation during exercise. These effects could not be attributed to an increase of erythropoietin. Clinical Trial Registration: ClinicalTrials.gov; NCT02509897; http://www.clinicaltrials.gov.


Utilization of an EMR-biorepository to identify the genetic predictors of calcineurin-inhibitor toxicity in heart transplant recipients.
Calcineurin-inhibitors CI are immunosuppressive agents prescribed to patients after solid organ transplant to prevent rejection. Although these drugs have been transformative for allograft survival, long-term use is complicated by side effects including nephrotoxicity. Given the narrow therapeutic index of CI, therapeutic drug monitoring is used to prevent acute rejection from underdosing and acute toxicity from overdosing, but drug monitoring does not alleviate long-term side effects. Patients on calcineurin-inhibitors for long periods almost universally experience declines in renal function, and a subpopulation of transplant recipients ultimately develop chronic kidney disease that may progress to end stage renal disease attributable to calcineurin inhibitor toxicity (CNIT). Pharmacogenomics has the potential to identify patients who are at high risk for developing advanced chronic kidney disease caused by CNIT and providing them with existing alternate immunosuppressive therapy. In this study we utilized BioVU, Vanderbilt University Medical Center's DNA biorepository linked to de-identified electronic medical records to identify a cohort of 115 heart transplant recipients prescribed calcineurin-inhibitors to identify genetic risk factors for CNIT We identified 37 cases of nephrotoxicity in our cohort, defining nephrotoxicity as a monthly median estimated glomerular filtration rate (eGFR)<30 mL/min/1.73 m2 at least six months post-transplant for at least three consecutive months. All heart transplant patients were genotyped on the Illumina ADME Core Panel, a pharmacogenomic genotyping platform that assays 184 variants across 34 genes. In Cox regression analysis adjusting for age at transplant, pre-transplant chronic kidney disease, pre-transplant diabetes, and the three most significant principal components (PCAs), we did not identify any markers that met our multiple-testing threshold. As a secondary analysis we also modeled post-transplant eGFR directly with linear mixed models adjusted for age at transplant, cyclosporine use, median BMI, and the three most significant principal components. While no SNPs met our threshold for significance, a SNP previously identified in genetic studies of the dosing of tacrolimus CYP34A rs776746, replicated in an adjusted analysis at an uncorrected p-value of 0.02 (coeff(S.E.)=14.60(6.41)). While larger independent studies will be required to further validate this finding, this study underscores the EMRs usefulness as a resource for longitudinal pharmacogenetic study designs.


Injectable vaccines for preventing pneumococcal infection in patients with chronic obstructive pulmonary disease.
As chronic obstructive pulmonary disease (COPD) progresses, exacerbations can occur with increasing frequency. One goal of therapy is to prevent these exacerbations, thereby reducing morbidity and associated healthcare costs. Pneumococcal vaccinations are one strategy for reducing the risk of infective exacerbations. To determine the safety and efficacy of pneumococcal vaccination in COPD. The primary outcomes assessed were episodes of pneumonia and acute exacerbations. Secondary outcomes of interest included hospital admissions, adverse events related to treatment, disability, change in lung function, mortality, and cost effectiveness. We searched the Cochrane Airways Group COPD trials register and the databases CENTRAL, MEDLINE and EMBASE using pre-specified terms. The latest searches were performed in March 2010. Randomised controlled trials assessing the effects of injectable pneumococcal vaccine in people with COPD were included. Two review authors independently extracted data and three review authors independently assessed trial quality. Seven studies were identified that met the inclusion criteria for this review and were included in the 2010 review update. Two older trials used a 14-valent vaccine and five more recent trials used a 23-valent injectable vaccine.In six studies involving 1372 people, the reduction in likelihood of developing pneumonia with pneumococcal vaccination compared to control did not achieve statistical significance, the odds ratio (OR) was 0.72 (95% confidence interval (CI) 0.51 to 1.01), with moderate heterogeneity present between studies. The reduction in likelihood of acute exacerbations of COPD from two studies involving 216 people was not statistically significant (Peto OR 0.58; 95% CI 0.30 to 1.13).Of the secondary outcomes for which data were available there was no statistically significant effect for reduction in hospital admissions (two studies) or emergency department visits (one study). There was no significant reduction in pooled results from three studies involving 888 people for odds of all-cause mortality for periods up to 48 months post-vaccination (OR 0.94; 95% CI 0.67 to 1.33), or for death from cardiorespiratory causes (OR 1.07; 95% CI 0.69 to 1.66). The limited evidence from randomised controlled trials (RCTs) included in this review suggests that, while it is possible that injectable polyvalent pneumococcal vaccines may provide some protection against morbidity in persons with COPD, no significant effect on any of the outcomes was shown. Further large RCTs in this population would be needed to confirm effectiveness of the vaccine suggested by results from longitudinal studies.


Outcome of scalp donor sites in 450 consecutive pediatric burn patients.
The scalp is a useful and reliable donor site in pediatric burn patients that can be multiply harvested with minimal morbidity. Healing complications, however, may include alopecia and chronic folliculitis. To investigate scalp donor-site morbidity, a consecutive series of 2478 pediatric burn patients treated over a 10-year period were reviewed. A total of 450 of these patients had scalp donor sites for wound closure. Percent of total body surface area burned was 46+/-23 percent (mean+/-standard deviation), and the mean number of sequential scalp donor-site harvests was 2.2+/-2 (range, 1 to 10) with mean intervals between harvesting of 6+/-0.6 days. Ten patients (2.2 percent) had related complications. Eight patients developed scalp folliculitis, with Staphylococcus sp as the predominant organism (80 percent). Two patients were managed successfully with wound care alone; the other six patients required surgical debridement and split-thickness skin grafting to achieve wound healing. These eight patients developed varying degrees of alopecia. Two patients developed alopecia without previous folliculitis. Six patients required reconstructive surgery, which consisted of primary closure (3), staged excision (1), and tissue expansion (2). A number of variables were examined to determine any differences in the group that had complications compared with the group of patients that did not. No differences in age, sex, race, burn type, burn size, septic episodes, time to wound closure, or number of times the scalp was harvested were detected. Healed second-degree burns to the scalp that were subsequently taken as donor sites seemed to be a risk factor (p < 0.05) for folliculitis and alopecia. Our study confirms that scalp donor sites are reliable with low morbidity. Complications include alopecia and chronic folliculitis that can be avoided by meticulous technique and avoidance of previously burned areas.


HIV genome transcription induced by polyoma virus middle T antigen through both enhancer- and promoter-dependent LTR activation.
In order to understand the regulation of HIV genome transcription induced by cell stimulation through transmembrane receptors, we have transfected cells with polyoma middle T antigen (PyMT) expression vectors, thus mimicking activated receptor-dependent cell stimulation. PyMT-expressing Cos7 cells provided an environment where transcription of an HIV provirus was activated. PyMT expression induced the activity of both enhancer- and promoter-dependent HIV-LTR luciferase vectors. Induction of the HIV promoter domain depended on Sp1-binding sites and could be blocked by Wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K). This indicates that PyMT-induced HIV transcription and replication are controlled by both the enhancer and promoter domains of the HIV-LTR. The latter, but not the former, was induced in a PI3K-dependent way. Thus at least 2 different transduction pathways appear to collaborate for induction of full HIV genome transcription in activated cells.


Cameo: A Python Library for Computer Aided Metabolic Engineering and Optimization of Cell Factories.
Computational systems biology methods enable rational design of cell factories on a genome-scale and thus accelerate the engineering of cells for the production of valuable chemicals and proteins. Unfortunately, the majority of these methods' implementations are either not published, rely on proprietary software, or do not provide documented interfaces, which has precluded their mainstream adoption in the field. In this work we present cameo, a platform-independent software that enables in silico design of cell factories and targets both experienced modelers as well as users new to the field. It is written in Python and implements state-of-the-art methods for enumerating and prioritizing knockout, knock-in, overexpression, and down-regulation strategies and combinations thereof. Cameo is an open source software project and is freely available under the Apache License 2.0. A dedicated Web site including documentation, examples, and installation instructions can be found at http://cameo.bio . Users can also give cameo a try at http://try.cameo.bio .


Acute and chronic effects of temperature, and of nutritional state, on ion homeostasis and energy metabolism in teleost hepatocytes.
Short- and long-term effects of temperature on ion flux and energy turnover were studied in hepatocytes from thermally acclimated trout and roach. In trout hepatocytes K+ efflux was insensitive towards acute exposure to low temperature but was downregulated during cold acclimation of the fish so as to balance the uncompensated decreased K+ (Rb+) uptake of the cells. In contrast, both K+ (Rb+) uptake and K+ efflux of roach hepatocytes were temperature sensitive in the short term. These acute effects, however, were offset during cold acclimation by a near perfect compensation of both fluxes leading to re-establishment of ion flux homeostasis at the original level. Our findings, based on a new method permitting the simultaneous monitoring of K+ efflux and uptake in the same cell population, provide experimental verification of two of the three possible strategies, recently discussed by Cossins et al. (1995), by which the ionic steady state of fish cells may adjust to acute and chronic temperature change. By comparing hepatocytes from two groups of trout, one kept on a maintenance diet (ration I), the other fed ad libitum (ration II), we discovered striking effects of nutritional state on the absolute levels as well as on the temperature relationships of K+ uptake and protein synthetic activity. Both of these functions in the hepatocytes increased in the ration II fed as compared to the ration I fed trouts, but the increase of protein synthetic activity was greater and more uniform at the three experimental temperatures than that of K+ uptake. Moreover, protein synthetic activity proved to be considerably more temperature sensitive than K+ uptake and, in contrast to the latter, showed a compensatory response after cold acclimation.


SWOT analysis of program design and implementation: a case study on the reduction of maternal mortality in Afghanistan.
This case study analyzes the design and implementation of the Basic Package of Health Services (BPHS) in Afghanistan by synthesizing the literature with a focus on maternal health services. The authors are a group of graduate students in the Brandeis University International Health Policy and Management Program and Sustainable International Development Program who used the experience in Afghanistan to analyze an example of successfully implementing policy; two of the authors are Afghan physicians with direct experience in implementing the BPHS. Data is drawn from a literature review, and a unique aspect of the case study is the application of the business-oriented SWOT analysis to the design and implementation of the program that successfully targeted lowering maternal mortality in Afghanistan. It provides a useful example of how SWOT analysis can be used to consider the reasons for, or likelihood of, successful or unsuccessful design and implementation of a policy or program. Copyright © 2015 John Wiley & Sons, Ltd.


Changes in Choroidal Component Ratio and Circulation After Coffee Intake in Healthy Subjects.
The effects of coffee intake on the ratio of stromal and luminal components in the choroid and the underlying mechanism remain unclear. This prospective cross-sectional study aimed to explore how coffee intake affects the choroidal component ratio and circulation. Forty-nine right eyes of healthy adult volunteers were evaluated as the coffee intake group. Thirty-two right eyes of healthy volunteers served as the control group. The participants consumed 185 mL of coffee or water, respectively, and the systemic hemodynamics, enhanced-depth imaging optical coherence tomographic (EDI-OCT) images, and foveal mean blur rate (MBR), an indicator of blood flow velocity, were recorded at baseline and after coffee or water intake. The EDI-OCT images were binarized using ImageJ software, and subfoveal choroidal thickness (SCT) and whole, luminal, and stromal choroidal areas were calculated. In the coffee intake group, significant decreases in SCT and luminal area peaked at 60 minutes after intake (both P < 0.001), whereas a significant increase in MBR peaked at 30 minutes (P < 0.001). No significant stromal area fluctuations were observed. SCT and luminal area fluctuations exhibited a significant positive correlation (r = 0.978, P < 0.001). Significant negative correlations of luminal area fluctuations with MBR fluctuations were observed by stepwise regression analysis (r = -0.220, P < 0.001). The control group exhibited no significant fluctuations. Coffee-induced choroidal thinning may result mainly from a reduction in the choroidal vessel lumen, and this vessel lumen reduction correlated with an increased choroidal blood flow velocity after coffee intake. These coffee-induced changes in choroidal component ratio and circulation should be considered when evaluating choroids.


Heat shock protein 27 as a predictor of prognosis in patients admitted to hospital with acute COPD exacerbation.
Episodes of acute exacerbations are major drivers of hospitalisation and death from COPD. To date, there are no objective biomarkers of disease activity or biomarkers to predict patient outcome. In this study, 211 patients hospitalised for an acute exacerbation of COPD have been included. At the time of admission, routine blood tests have been performed including complete blood count, C-reactive protein, cardiac troponin T and NT-proBNP. Heat shock protein 27 (HSP27) serum concentrations were determined at time of admission, discharge and 180 days after discharge by ELISA. We were able to demonstrate significantly increased HSP27 serum concentrations in COPD patients at time of admission to hospital as compared to HSP27 concentrations obtained 180 days after discharge. In univariable Cox regression analyses, a HSP27 serum concentration ≥ 3098 pg/mL determined at admission was a predictor of all-cause mortality at 90 days, 180 days, 1 year and 3 years. In multivariable analyses, an increased HSP27 serum concentration at admission retained its prognostic ability with respect to all-cause mortality for up to 1-year follow-up. However, an increased HSP27 serum concentration at admission was not an independent predictor of long-term all-cause mortality at 3 years. Elevated serum HSP27 concentrations significantly predicted short-term mortality in patients admitted to hospital with acute exacerbation of COPD and could help to improve outcomes by identifying high-risk patients.


DNA recognition for virus assembly through multiple sequence-independent interactions with a helix-turn-helix motif.
The helix-turn-helix (HTH) motif features frequently in protein DNA-binding assemblies. Viral pac site-targeting small terminase proteins possess an unusual architecture in which the HTH motifs are displayed in a ring, distinct from the classical HTH dimer. Here we investigate how such a circular array of HTH motifs enables specific recognition of the viral genome for initiation of DNA packaging during virus assembly. We found, by surface plasmon resonance and analytical ultracentrifugation, that individual HTH motifs of the Bacillus phage SF6 small terminase bind the packaging regions of SF6 and related SPP1 genome weakly, with little local sequence specificity. Nuclear magnetic resonance chemical shift perturbation studies with an arbitrary single-site substrate suggest that the HTH motif contacts DNA similarly to how certain HTH proteins contact DNA non-specifically. Our observations support a model where specificity is generated through conformational selection of an intrinsically bent DNA segment by a ring of HTHs which bind weakly but cooperatively. Such a system would enable viral gene regulation and control of the viral life cycle, with a minimal genome, conferring a major evolutionary advantage for SPP1-like viruses.


Basal chordae sites on the mitral valve determine the severity of secondary mitral regurgitation.
To evaluate the variation between individuals in terms of basal chordae (BC) attachment sites on the mitral valve (MV) and the influence of this variation on secondary mitral regurgitation (MR) severity. BC-mediated MV tenting is the main cause of secondary MR. In this prospective cross-sectional study, 38 consecutive patients with dilated or ischaemic cardiomyopathy who were due for cardiac transplantation underwent preoperative 3D full volume/colour Doppler echocardiography in sinus rhythm, and MV apparatus geometry, LV volume and MR severity were assessed. The lengths and insertion sites of four BC in the explanted hearts were measured post-transplantation before fixation. Multiple linear regression analyses revealed that the anterior leaflet systolic tenting angle and bending angle associated with the distance between the medial and lateral BC insertion sites. By contrast, the posterior leaflet tenting angle associated largely with LV volume indices. The mean longitudinal distance of the four BC from the MV edge was the main determinant of the distal length of the anterior MV from the angulation point. Square root of effective regurgitant orifice area (√EROA) only associated significantly with the mean longitudinal distance of the outer two BC from the MV edge (r=0.509, p=0.001) among pathological parameters, and the central MV tenting area (r=0.524, p=0.001) among echocardiographical parameters. √EROA did not correlate with LV volume indices, LVEF or BC lengths. BC insertion sites were associated with systolic anterior MV configuration and secondary MR severity in dilated LV and severe systolic dysfunction.


Ultrasound evaluation of surgically repaired hand tendons during rehabilitation and its relation to clinical and functional assessment.
This study aimed to evaluate the contribution of musculoskeletal ultrasound to the follow-up of surgically repaired hand tendons during rehabilitation programs and correlate ultrasound findings with the clinical outcome. In the prospective observational study, 40 patients (29 males, 11 females; mean age: 27.4±10.7 years; range, 15 to 55 years) who presented with postoperative hand tendon repair between January 2019 and March 2020 were randomized into two groups: Group 1 included 15 subjects with 16 repaired flexor tendons, whereas Group 2 consisted of 25 subjects with repaired extensor tendons. Afterward, the assessment was performed at the four, eight, and 12 weeks of rehabilitation utilizing the total active motion of injured fingers, Visual Analog Scale (VAS), grip strength, ultrasound, and hand assessment tool (HAT). The study's findings revealed a substantial improvement in pain based on the evaluation of grip strength, total active motion, VAS, and the affected hand's HAT score in both groups (p<0.001). In both groups, ultrasonographic evaluation of healing tendons revealed considerable enhancement in margination, defect size, thickness, echogenicity, and vascularity. A positive correlation was detected between VAS and healing tendon margination as well as the HAT score and handgrip margination in Group 1. High-frequency ultrasound is an easily accessible modality in the follow-up and evaluation of tendon healing after surgical repair and during a rehabilitation program.


Planned to perfection? Use of the model repositioning instrument to plan maxillary movements for orthognathic surgery.
Previous studies have reported significant discrepancies between the surgical treatment objectives and final surgical results in orthognathic surgery patients. When dealing with complex asymmetrical maxillary movements in bimaxillary osteotomy patients, it can often be difficult to reposition the maxilla with a desirable degree of accuracy at the planning stage. Inaccurate placement of the maxilla can result in an unwanted repositioning of the mandible, which can lead to less than ideal functional and esthetic outcomes. The use of a model respositioning frame for orthognathic surgical planning is demonstrated. This can be utilized to position the maxilla at the model surgery stage with increased accuracy in both the vertical and horizontal plane. This frame can be used on semiadjustable articulators.


Temporal evolution of bacterial communities associated with the in situ wetland-based remediation of a marine shore porphyry copper tailings deposit.
Mine tailings are a serious threat to the environment and public health. Remediation of these residues can be carried out effectively by the activation of specific microbial processes. This article presents detailed information about temporal changes in bacterial community composition during the remediation of a section of porphyry copper tailings deposited on the Bahía de Ite shoreline (Peru). An experimental remediation cell was flooded and transformed into a wetland in order to prevent oxidation processes, immobilizing metals. Initially, the top oxidation zone of the tailings deposit displayed a low pH (3.1) and high concentrations of metals, sulfate, and chloride, in a sandy grain size geological matrix. This habitat was dominated by sulfur- and iron-oxidizing bacteria, such as Leptospirillum spp., Acidithiobacillus spp., and Sulfobacillus spp., in a microbial community which structure resembled acid mine drainage environments. After wetland implementation, the cell was water-saturated, the acidity was consumed and metals dropped to a fraction of their initial respective concentrations. Bacterial communities analyzed by massive sequencing showed time-dependent changes both in composition and cell numbers. The final remediation stage was characterized by the highest bacterial diversity and evenness. Aside from classical sulfate reducers from the phyla δ-Proteobacteria and Firmicutes, community structure comprised taxa derived from very diverse habitats. The community was also characterized by an elevated proportion of rare phyla and unaffiliated sequences. Numerical ecology analysis confirmed that the temporal population evolution was driven by pH, redox, and K. Results of this study demonstrated the usefulness of a detailed follow-up of the remediation process, not only for the elucidation of the communities gradually switching from autotrophic, oxidizing to heterotrophic and reducing living conditions, but also for the long term management of the remediation wetlands.


Plasma Exchange as a First Line Therapy in Acute Attacks of Neuromyelitis Optica Spectrum Disorders.
Neuromyelitis optica spectrum disorder (NMOSD) is a demyelinating disorder of central nervous system with deleterious effects. At present Intravenous corticosteroids are used for the relapse as the first line of treatment, but with only a class evidence III-IV. Having an underlying humoral immune mechanism in the pathogenesis of NMOSD and as it is rightly said that "Time is Cord and Eyes", delaying the time to start plasma exchange (PLEX) awaiting favorable outcome in response to corticosteroids is detrimental for the patient. Hence, PLEX may be a promising first line therapeutic approach in the management of severe attacks of NMOSD. The aim of this study is to evaluate the efficacy of PLEX as the first line of treatment for the acute attacks in patients with NMOSD that is being largely used as an add-on therapy for more than 10 years, and also to define the time opportunity window for the starting of PLEX. The study analysed the therapeutic efficacy and safety profile of PLEX as a first line therapy in 30 patients diagnosed with NMOSD over a period of 30 months. PLEX was performed using a Hemonetics Mobile Collection System plus machine with due written consent including the risks and benefits of the treatment that is being proposed to the patient/relative in their own language. A total of 30 patients were analysed, out of which 16 were females and rest males. 85% of the patients were in the age group of 25-35 years. All the patients had severe Expanded Disability Status Scale (EDSS) scores at the baseline, and 73.33% showed significant improvement following PLEX. The only predictor of good outcome was the time to PLEX i.e shorter delay betters the outcome. The study ascertained the importance of early PLEX as a therapeutic intervention in severe attacks of NMOSD irrespective of their Anti-Aquaporin 4 (AQP4) antibody status.


Complementary and alternative interventions for fatigue management after traumatic brain injury: a systematic review.
We systematically reviewed randomized controlled trials (RCTs) of complementary and alternative interventions for fatigue after traumatic brain injury (TBI). We searched multiple online sources including ClinicalTrials.gov, the Cochrane Library database, MEDLINE, CINAHL, Embase, the Web of Science, AMED, PsychINFO, Toxline, ProQuest Digital Dissertations, PEDro, PsycBite, and the World Health Organization (WHO) trial registry, in addition to hand searching of grey literature. The methodological quality of each included study was assessed using the Jadad scale, and the quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. A descriptive review was performed. Ten RCTs of interventions for post-TBI fatigue (PTBIF) that included 10 types of complementary and alternative interventions were assessed in our study. There were four types of physical interventions including aquatic physical activity, fitness-center-based exercise, Tai Chi, and aerobic training. The three types of cognitive and behavioral interventions (CBIs) were cognitive behavioral therapy (CBT), mindfulness-based stress reduction (MBSR), and computerized working-memory training. The Flexyx Neurotherapy System (FNS) and cranial electrotherapy were the two types of biofeedback therapy, and finally, one type of light therapy was included. Although the four types of intervention included aquatic physical activity, MBSR, computerized working-memory training and blue-light therapy showed unequivocally effective results, the quality of evidence was low/very low according to the GRADE system. The present systematic review of existing RCTs suggests that aquatic physical activity, MBSR, computerized working-memory training, and blue-light therapy may be beneficial treatments for PTBIF. Due to the many flaws and limitations in these studies, further controlled trials using these interventions for PTBIF are necessary.


Treatment modalities for peri-implant mucositis and peri-implantitis.
To review treatment modalities used for peri-implant mucositis and peri-implantitis. A literature search was performed in PubMed for articles published until May 2013 using peri-implantitis and peri-implant mucositis and different modalities of treatment as search terms. The search was limited to the English literature. Titles and abstracts were searched in order to find studies eligible for the review. The present review reported that treatment of peri-implant mucositis lesions using mechanical therapy is possible. The additional use of professionally delivered antimicrobials has commonly failed to show additional benefits as compared to mechanical debridement alone. The scientific evidence on the efficacy of non-surgical and surgical therapies in the treatment of peri-implantitis is limited. Complete resolution of peri-implantitis using mechanical, laser, or photodynamic therapy does not seem to result in a predictable outcome. Following surgical interventions around implants diagnosed with peri-implantitis, clinical improvements as judged by reductions of probing depths and bleeding on probing have been reported. Bone or bone substitutes have been used in attempts to regenerate bone loss around implants. When regenerative modalities have been employed, radiographic evidence of defect fill has been reported. Few long term follow up studies on the treatment of peri-implantitis are available. Positive treatment results can be maintained over a period of 3-5 years. Regardless of the treatment performed, adequate plaque control by the patient is fundamental to treatment success. If the patient cannot obtain an adequate level of oral hygiene, the infection around the implants will reoccur.


High cell-free virus load and robust autologous humoral immune responses in breast milk of simian immunodeficiency virus-infected african green monkeys.
The design of immunologic interventions to prevent postnatal transmission of human immunodeficiency virus (HIV) will require identification of protective immune responses in this setting. Simian immunodeficiency virus (SIV)-infected rhesus monkeys (RMs), a species that develops an AIDS-like illness following experimental infection, transmit the virus at a high rate during breastfeeding. In contrast, postnatal transmission of SIV occurs rarely or not at all in natural, asymptomatic primate hosts of SIV. These contrasting transmission patterns provide a unique opportunity to study mechanisms that evolved to protect suckling infants from SIV infection. We compared the virologic and immunologic properties of milk of SIV-infected and uninfected natural hosts of SIV, African green monkeys (AGMs), to that of RMs. Interestingly, despite a low number of milk CD4(+) T lymphocytes in uninfected AGMs, milk virus RNA load in SIV-infected AGMs was comparable to that of SIV-infected RMs and that in AGM plasma. This observation is in contrast to the relatively low virus load in milk compared to that in plasma of SIV-infected RMs and HIV-infected women. Milk of SIV-infected AGMs also displayed robust virus-specific cellular immune responses. Importantly, an autologous challenge virus-specific neutralization response was detected in milk of five of six SIV-infected AGMs that was comparable in magnitude to that in plasma. In contrast, autologous challenge virus neutralization was not detectable in milk of SIV-infected RMs. The autologous virus-specific adaptive immune responses in breast milk of AGMs may contribute to impedance of virus transmission in the infant oral/gastrointestinal tract and the rarity of postnatal virus transmission in natural hosts of SIV.


Association of coffee drinking with total and cause-specific mortality.
Coffee is one of the most widely consumed beverages, but the association between coffee consumption and the risk of death remains unclear. We examined the association of coffee drinking with subsequent total and cause-specific mortality among 229,119 men and 173,141 women in the National Institutes of Health-AARP Diet and Health Study who were 50 to 71 years of age at baseline. Participants with cancer, heart disease, and stroke were excluded. Coffee consumption was assessed once at baseline. During 5,148,760 person-years of follow-up between 1995 and 2008, a total of 33,731 men and 18,784 women died. In age-adjusted models, the risk of death was increased among coffee drinkers. However, coffee drinkers were also more likely to smoke, and, after adjustment for tobacco-smoking status and other potential confounders, there was a significant inverse association between coffee consumption and mortality. Adjusted hazard ratios for death among men who drank coffee as compared with those who did not were as follows: 0.99 (95% confidence interval [CI], 0.95 to 1.04) for drinking less than 1 cup per day, 0.94 (95% CI, 0.90 to 0.99) for 1 cup, 0.90 (95% CI, 0.86 to 0.93) for 2 or 3 cups, 0.88 (95% CI, 0.84 to 0.93) for 4 or 5 cups, and 0.90 (95% CI, 0.85 to 0.96) for 6 or more cups of coffee per day (P<0.001 for trend); the respective hazard ratios among women were 1.01 (95% CI, 0.96 to 1.07), 0.95 (95% CI, 0.90 to 1.01), 0.87 (95% CI, 0.83 to 0.92), 0.84 (95% CI, 0.79 to 0.90), and 0.85 (95% CI, 0.78 to 0.93) (P<0.001 for trend). Inverse associations were observed for deaths due to heart disease, respiratory disease, stroke, injuries and accidents, diabetes, and infections, but not for deaths due to cancer. Results were similar in subgroups, including persons who had never smoked and persons who reported very good to excellent health at baseline. In this large prospective study, coffee consumption was inversely associated with total and cause-specific mortality. Whether this was a causal or associational finding cannot be determined from our data. (Funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics.).


Screening over Speech in Unselected Populations for Clinical Trials in AD (PROSPECT-AD): Study Design and Protocol.
Speech impairments are an early feature of Alzheimer's disease (AD) and consequently, analysing speech performance is a promising new digital biomarker for AD screening. Future clinical AD trials on disease modifying drugs will require a shift to very early identification of individuals at risk of dementia. Hence, digital markers of language and speech may offer a method for screening of at-risk populations that are at the earliest stages of AD, eventually in combination with advanced machine learning. To this end, we developed a screening battery consisting of speech-based neurocognitive tests. The automated test performs a remote primary screening using a simple telephone. PROSPECT-AD aims to validate speech biomarkers for identification of individuals with early signs of AD and monitor their longitudinal course through access to well-phenotyped cohorts. PROSPECT-AD leverages ongoing cohorts such as EPAD (UK), DESCRIBE and DELCODE (Germany), and BioFINDER Primary Care (Sweden) and Beta-AARC (Spain) by adding a collection of speech data over the telephone to existing longitudinal follow-ups. Participants at risk of dementia are recruited from existing parent cohorts across Europe to form an AD 'probability-spectrum', i.e., individuals with a low risk to high risk of developing AD dementia. The characterization of cognition, biomarker and risk factor (genetic and environmental) status of each research participants over time combined with audio recordings of speech samples will provide a well-phenotyped population for comparing novel speech markers with current gold standard biomarkers and cognitive scores. N= 1000 participants aged 50 or older will be included in total, with a clinical dementia rating scale (CDR) score of 0 or 0.5. The study protocol is planned to run according to sites between 12 and 18 months. The speech protocol includes the following neurocognitive tests which will be administered remotely: Word List [Memory Function], Verbal Fluency [Executive Functions] and spontaneous free speech [Psychological and/ or behavioral symptoms]. Speech features on the linguistic and paralinguistic level will be extracted from the recordings and compared to data from CSF and blood biomarkers, neuroimaging, neuropsychological evaluations, genetic profiles, and family history. Primary candidate marker from speech will be a combination of most significant features in comparison to biomarkers as reference measure. Machine learning and computational techniques will be employed to identify the most significant speech biomarkers that could represent an early indicator of AD pathology. Furthermore, based on the analysis of speech performances, models will be trained to predict cognitive decline and disease progression across the AD continuum. The outcome of PROSPECT-AD may support AD drug development research as well as primary or tertiary prevention of dementia by providing a validated tool using a remote approach for identifying individuals at risk of dementia and monitoring individuals over time, either in a screening context or in clinical trials.


Use of videotaped consultations in summative assessment of trainees in general practice.
There are many different methods by which trainees may be assessed summatively. The objective of the study was to determine if videotaped consultations could be used to identify reliably those general practitioner trainees who have not yet reached acceptable levels of competence. Videotapes of 10 trainees carrying out normal consultations were assessed by 20 assessors for acceptable competence using a rating scale specifically developed for the purpose. A principal components analysis showed a strong correlation among the items in the rating scale used, indicating that a single underlying factor accounted for 76% of the overall scores. Agreement between assessors on the scoring of individual consultations was limited. There was much greater consistency with regard to the decision on overall competence, examined for the first consultation. A non-competent trainee would have a 95% probability of being identified by the process as described using two assessors for each videotape. The assessors had reached firm judgements on each trainee by the time four consultations had been viewed. The workload involved in producing and analysing the tapes is discussed. Considerations of patient consent are addressed. It is concluded that the use of videotaped consultations appears to offer a feasible and reliable method of summative assessment of general practitioner trainees.


The role of micromere signaling in Notch activation and mesoderm specification during sea urchin embryogenesis.
In the sea urchin embryo, the micromeres act as a vegetal signaling center. These cells have been shown to induce endoderm; however, their role in mesoderm development has been less clear. We demonstrate that the micromeres play an important role in the induction of secondary mesenchyme cells (SMCs), possibly by activating the Notch signaling pathway. After removing the micromeres, we observed a significant delay in the formation of all mesodermal cell types examined. In addition, there was a marked reduction in the numbers of pigment cells, blastocoelar cells and cells expressing the SMC1 antigen, a marker for prospective SMCs. The development of skeletogenic cells and muscle cells, however, was not severely affected. Transplantation of micromeres to animal cells resulted in the induction of SMC1-positive cells, pigment cells, blastocoelar cells and muscle cells. The numbers of these cell types were less than those found in sham transplantation control embryos, suggesting that animal cells are less responsive to the micromere-derived signal than vegetal cells. Previous studies have demonstrated a role for Notch signaling in the development of SMCs. We show that the micromere-derived signal is necessary for the downregulation of the Notch protein, which is correlated with its activation, in prospective SMCs. We propose that the micromeres induce adjacent cells to form SMCs, possibly by presenting a ligand for the Notch receptor.


The influence of smoking on reward responsiveness and cognitive functions: a natural experiment.
To investigate the effects of (a) nicotine abstinence and (b) cigarette smoking after abstinence, on reward responsiveness and cognitive functions which are putatively dependent on activity in the dopaminergic system implicated in smoking. During Ramadhan, Muslim smokers elected to abstain from smoking either for the whole month (RAMQUIT) or during daylight hours (DAYQUIT). These groups, and non-smokers (NOSMOKE), were assessed on two occasions 6 hours apart (TEST1 and TEST2). DAYQUIT participants had abstained for 6 hours at TEST1 and smoked a single cigarette immediately prior to TEST2. RAMQUIT participants had abstained for at least 10 days prior to TEST1 and remained abstinent at TEST2. NOSMOKE and RAMQUIT participants are a small snack prior to TEST2 to control for non-specific consummatory effects. TEST1 was conducted at the mosque and TEST2 in participants' homes. All were male; mean age was 26.7 years. Modal cigarette consumption prior to Ramadhan by both the 13 DAYQUIT and the 11 RAMQUIT smokers was 21-30 per day. DAYQUIT subjects rated themselves as more dependent. The Card Arranging Reward Responsivity Objective Test (CARROT), testing behavioural responsiveness to small financial incentive; digit span, measuring attention; verbal fluency, indexing frontal lobe function; and the two-choice guessing test (2CGT; at TEST1 only), measuring response stereotypy. At TEST1, compared with non-smokers, both smoking groups showed greater stereotypy (2CG) and lower reward responsiveness (CARROT). DAYQUIT participants improved on all measures after smoking a single cigarette. No marked changes were seen in the other groups. These data suggest that (i) abstaining smokers have impaired dopaminergic function and (ii) nicotine consumption may boost their dopaminergic activity.


Testing alternative models of climate-mediated extirpations.
Biotic responses to climate change will vary among taxa and across latitudes, elevational gradients, and degrees of insularity. However, due to factors such as phenotypic plasticity, ecotypic variation, and evolved tolerance to thermal stress, it remains poorly understood whether losses should be greatest in populations experiencing the greatest climatic change or living in places where the prevailing climate is closest to the edge of the species' bioclimatic envelope (e.g., at the hottest, driest sites). Research on American pikas (Ochotona princeps) in montane areas of the Great Basin during 1994-1999 suggested that 20th-century population extirpations were predicted by a combination of biogeographic, anthropogenic, and especially climatic factors. Surveys during 2005-2007 documented additional extirpations and within-site shifts of pika distributions at remaining sites. To evaluate the evidence in support of alternative hypotheses involving effects of thermal stress on pikas, we placed temperature sensors at 156 locations within pika habitats in the vicinity of 25 sites with historical records of pikas in the Basin. We related these time series of sensor data to data on ambient temperature from weather stations within the Historical Climate Network. We then used these highly correlated relationships, combined with long-term data from the same weather stations, to hindcast temperatures within pika habitats from 1945 through 2006. To explain patterns of loss, we posited three alternative classes of direct thermal stress: (1) acute cold stress (number of days below a threshold temperature); (2) acute heat stress (number of days above a threshold temperature); and (3) chronic heat stress (average summer temperature). Climate change was defined as change in our thermal metrics between two 31-yr periods: 1945-1975 and 1976-2006. We found that patterns of persistence were well predicted by metrics of climate. Our best models suggest some effects of climate change; however, recent and long-term metrics of chronic heat stress and acute cold stress, neither previously recognized as sources of stress for pikas, were some of the best predictors of pika persistence. Results illustrate that extremely rapid distributional shifts can be explained by climatic influences and have implications for conservation topics such as reintroductions and early-warning indicators.


Helicobacter pullorum sp. nov.-genotype and phenotype of a new species isolated from poultry and from human patients with gastroenteritis.
Campylobacter-like organisms were isolated from the liver, duodenum and caecum of broiler and layer chickens, and from humans with gastroenteritis. They formed a unique DNA homology group and a polyphasic taxonomic analysis was made of 16 strains. Analysis of the nucleotide sequence of the 16S rRNA gene from seven of the strains identified them as belonging to a single species, within the genus Helicobacter. This conclusion was supported by the studies of relative DNA homology and of total protein electrophoretic patterns. The new species could be biochemically differentiated from other helicobacters and its ultrastructure in the electron microscope was typical of the genus except that the flagellum was not sheathed. We propose the name Helicobacter pullorum sp. nov. for this group. Like H. fennelliae or H. cinaedi it represents another non-gastric urease-negative Helicobacter species colonizing the lower bowel. Its isolation from the livers of chickens with vibrionic hepatitis is significant. We describe a species-specific PCR assay for H. pullorum sp. nov. which will facilitate its identification and further studies of its epidemiology.


Identification and analysis of dihydrofolate reductase alleles from Plasmodium falciparum present at low frequency in polyclonal patient samples.
As resistance to chloroquine spreads in sub-Saharan Africa, pyrimethamine plus sulfadoxine (PSD) is increasingly used as a first-line treatment for falciparum malaria. Populations of Plasmodium falciparum (Pf) resistant to PSD have been selected quickly in other regions. The resistance is strongly correlated with point mutations in dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS), the two targets of the drug. It is critical to identify drug-resistant Pf-DHFR alleles that are present at a low frequency in these populations since alleles that confer drug resistance will be quickly selected by PSD use. It is difficult to identify these rare alleles by standard molecular techniques. We have designed a yeast expression system that facilitates the identification and rapid analysis of Pf-DHFR alleles that confer PSD resistance, even when they are present at very low frequency in polyclonal patient samples. We analyzed samples from patients in Kilifi, Kenya collected between 1992 and 1995. We determined the prevalence of the drug-sensitive and drug-resistant alleles in patient samples analyzed in parallel by an allele-specific enzyme digestion (ASED) assay. We identified a pyrimethamine-resistant allele (S108N) present at a frequency of < 1% in a sample that was scored as only S108 by ASED. In addition, a novel pyrimethamine-resistant allele (1164M) was isolated twice, once each from two different patient samples. This approach will allow determination of the prevalence of Pf-DHFR alleles that confer pyrimethamine resistance in particular regions, and the rapid identification of novel alleles that confer drug resistance.


Dose-dependency of theophylline clearance and protein binding.
Dose-dependency in theophylline pharmacokinetics and protein binding characteristics was examined in 10 healthy male volunteers. Theophylline disposition was determined after an intravenous infusion of both 1 mg/kg and 6 mg/kg aminophylline in a randomised crossover study. There was considerable intrasubject variability in theophylline clearance but no significant dose-dependency. Theophylline protein binding was assessed by equilibrium dialysis at varying theophylline concentrations. The percentage of free non-protein bound theophylline was significantly increased at high theophylline concentrations. This increase in free theophylline would lead to a non-linear increase in the risk of toxicity with increasing drug concentration.


Evolutionary stability and the rarity of grandmothering.
The provision of intergenerational care, via the Grandmother Hypothesis, has been implicated in the evolution of postfertile longevity, particularly in humans. However, if grandmothering does provide fitness benefits, a key question is why has it evolved so infrequently? We investigate this question with a combination of life-history and evolutionary game theory. We derive simple eligibility and stability thresholds, both of which must be satisfied if intergenerational care is first to evolve and then to persist in a population. As one threshold becomes easier to fulfill, the other becomes more difficult, revealing a conflict between the two. As such, we suggest that, in fact, we should expect the evolution of grandmothering to be rare.