CHD7 gene polymorphisms are associated with susceptibility to idiopathic scoliosis.
Idiopathic scoliosis (IS) is the most common spinal deformity in children, and its etiology is unknown. To refine the search for genes underlying IS susceptibility, we ascertained a new cohort of 52 families and conducted a follow-up study of genomewide scans that produced evidence of linkage and association with 8q12 loci (multipoint LOD 2.77; P=.0028). Further fine mapping in the region revealed significant evidence of disease-associated haplotypes (P<1.0 x 10-4) centering over exons 2-4 of the CHD7 gene associated with the CHARGE (coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness) syndrome of multiple developmental anomalies. Resequencing CHD7 exons and conserved intronic sequence blocks excluded coding changes but revealed at least one potentially functional polymorphism that is overtransmitted (P=.005) to affected offspring and predicts disruption of a caudal-type (cdx) transcription-factor binding site. Our results identify the first gene associated with IS susceptibility and suggest etiological overlap between the rare, early-onset CHARGE syndrome and common, later-onset IS.


An electrode array that minimizes blood loss for radiofrequency-assisted hepatic resection.
Hepatic resection is currently the standard treatment for liver cancer. During hepatic resection part of the liver containing the tumor is surgically removed. This type of surgery is accompanied by high blood loss of approximately 0.6-1.35 L. Blood loss is associated with increased complication rates, prolonged hospital stay, and reduced patient survival, especially when transfusion is required. Other researchers have suggested using radiofrequency (rf) or microwave ablation to coagulate a tissue slice before resection to reduce blood loss, but conventional devices typically take several hours. We developed a device consisting of a linear array of blade-shaped, 1 cm wide radiofrequency (rf) electrodes 1.5 cm apart. Bipolar rf power is applied between pairs of adjacent electrodes, leading to high tissue temperatures between the electrodes that promote coagulation of large vessels (>3 mm) in the resection plane. Rapid switching of applied power between pairs of adjacent electrodes allows simultaneous heating and coagulation of the entire resection plane within 3-6 min. In seven in vivo trials in a porcine model, resection along a plane pre-coagulated with the device resulted in little (<20 mL) to no blood loss, while coagulating all vessels (up to 4.5 mm diameter in this study). Average treatment time (from placement of the device to transection) was 6.8+/-0.5 min when four electrodes were used, and 11.3+/-1.2 min when 5-7 electrodes were used. This device may reduce blood loss related morbidity during resection and reduce treatment time by coagulating all vessels in the resection plane.


Systematic development of a self-regulation weight-management intervention for overweight adults.
This paper describes the systematic development of an intervention for the prevention of obesity among overweight adults. Its development was guided by the six steps of Intervention Mapping (IM), in which the establishment of program needs, objectives and methods is followed by development of the intervention and an implementation and evaluation plan. Weight gain prevention can be achieved by making small changes in dietary intake (DI) or physical activity (PA). The intervention objectives, derived from self-regulation theory, were to establish goal-oriented behaviour. They were translated into a computer-tailored Internet-delivered intervention consisting of four modules. The intervention includes strategies to target the main determinants of self-regulation, such as feedback and action planning.The first module is intended to ensure adults' commitment to preventing weight gain, choosing behaviour change and action initiation. The second and third modules are intended to evaluate behaviour change, and to adapt action and coping plans. The fourth module is intended to maintain self-regulation of body weight without use of the program.The intervention is being evaluated for its efficacy in an RCT, whose protocol is described in this paper. Primary outcomes are weight, waist circumference and skin-fold thickness. Other outcomes are DI, PA, cognitive mediators and self-regulation skills. The IM protocol helped us integrating insights from various theories. The performance objectives and methods were guided by self-regulation theory but empirical evidence with regard to the effectiveness of theoretical methods was limited. Sometimes, feasibility issues made it necessary to deviate from the original, theory-based plans. With this paper, we provide transparency with regard to intervention development and evaluation. NTR1862.


Committee Opinion No 672 Summary Clinical Challenges of Long-Acting Reversible Contraceptive Methods.
Long-acting reversible contraceptive methods are the most effective reversible contraceptives and have an excellent safety record. Although uncommon, possible long-acting reversible contraceptive complications should be included in the informed consent process. Obstetrician-gynecologists and other gynecologic care providers should understand the diagnosis and management of common clinical challenges. The American College of Obstetricians and Gynecologists recommends the algorithms included in this document for management of the most common clinical challenges.


Cdc42 regulates polarized growth and cell integrity in fission yeast.
Polarized cell growth requires a well-orchestrated number of events, namely selection of growth site, organization of cytoskeleton elements and delivery of new material to the growth region. The small Rho GTPase Cdc42 has emerged as a major organizer of polarized growth through its participation in many of these events. In the present short review, we focus on the regulation of Cdc42 activity and localization as well as how it controls downstream events necessary for polarized cell growth in Schizosaccharomyces pombe. Owing to the high level of similarity of the polarity pathways, analogies between fission yeast and other model systems can be useful to decipher how cells can actively define their shape by polarized growth.


Musculoskeletal injuries in Homer's Iliad: the War of Troy revisited.
Homer's Iliad--the most famous and influential epic poem--has been previously reviewed with respect to head, craniomaxillofacial, neck, thoracic, and hand injuries in the literature. However, to the best of the authors' knowledge, there are no data regarding musculoskeletal injuries. This article describes the musculoskeletal injuries that had ensued during the war of Troy. The Turkish translation of the original epic poem Iliad was reviewed for musculoskeletal injuries, that is, their descriptions, outcome, the weapons used, and the engaged warriors. Extremity injuries were evaluated as regards the affected bones. The pertinent treatment methods were also recorded. In total, 103 musculoskeletal injuries were detected during 81 combats. The most commonly involved areas were the shoulder (15.5%), the head (14.5%), the cervical vertebrae (14.5%), and the thoracic vertebrae (8.7%). The weapons used were spear (n = 52); sword (n = 9); arrow (n = 9); stone (n = 8); and cane, animal, the hand, Chariot race, and broken yoke (n = 1 for each). Fifty-four combats (66.6%) resulted in death. Therapeutic herbs, compound of milk, and essence of fig were used as treatment alternatives. While providing a historic snapshot on the war of Troy, in this article, the authors have reviewed the musculoskeletal injuries and their management in those ancient times. Despite the long period in between, unfortunately, physicians/surgeons are still faced with war injuries in current medical practice. The authors strongly hope that, at least in the near future, physicians will be left with only natural health problems and without those artificially generated by human beings.


Hippocampal differentiation without recognition: an fMRI analysis of the contextual cueing task.
A central role of the hippocampus is to consolidate conscious forms of learning and memory, while performance on implicit tasks appears to depend upon other structures. Recently, considerable debate has emerged about whether hippocampal-dependent tasks necessarily entail task awareness. In the contextual cueing task, repetition facilitation is implicit, but impaired in patients with amnesia. Whether the hippocampus alone or other MTL structures are required is unclear. Event-related functional magnetic resonance imaging revealed hippocampal activity that differentiates novel from repeated arrays. This pattern of results was observed without recognition of the repeating arrays. This finding provides support for the claim that the hippocampus is involved in processes outside the domain of conscious learning and memory.


Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population.
To determine the prevalence of focal lesions of the pituitary gland that suggest the presence of a pituitary adenoma in asymptomatic persons. 100 normal volunteers (70 women, 30 men; age range, 18 to 60 years old) were studied by high-resolution magnetic resonance imaging (MRI) of the pituitary gland before and after administration of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA). Occult pituitary adenomas are identified at autopsy in 3% to 27% of unselected asymptomatic patients. The frequency of incidental pituitary adenomas detected by MRI in normal persons is unknown. The MRI scans from volunteers were randomly mixed with scans of 57 patients with Cushing disease and interpreted independently by three blinded reviewers. Seven women (10%) and three men (10%) had focal areas of decreased signal intensity in the pituitary gland after administration of Gd-DTPA. The lesions ranged from 3 to 6 mm in greatest diameter and were diagnosed as pituitary adenomas by at least two of the three reviewers. When similar lesions were detected on MRI scans in patients with Cushing disease, the positive predictive value for identification of an adenoma at that site was 86%. About 10% of the normal adult population have pituitary abnormalities on MRI scans that are compatible with the diagnosis of asymptomatic pituitary adenomas. Most pituitary adenomas remain asymptomatic and do not require treatment.


A ring-polymer model shows how macromolecular crowding controls chromosome-arm organization in Escherichia coli.
Macromolecular crowding influences various cellular processes such as macromolecular association and transcription, and is a key determinant of chromosome organization in bacteria. The entropy of crowders favors compaction of long chain molecules such as chromosomes. To what extent is the circular bacterial chromosome, often viewed as consisting of "two arms", organized entropically by crowding? Using computer simulations, we examine how a ring polymer is organized in a crowded and cylindrically-confined space, as a coarse-grained bacterial chromosome. Our results suggest that in a wide parameter range of biological relevance crowding is essential for separating the two arms in the way observed with Escherichia coli chromosomes at fast-growth rates, in addition to maintaining the chromosome in an organized collapsed state. Under different conditions, however, the ring polymer is centrally condensed or adsorbed onto the cylindrical wall with the two arms laterally collapsed onto each other. We discuss the relevance of our results to chromosome-membrane interactions.


Use of Preprocedural MDCT for Cardiac Implantable Electric Device Lead Extraction: Frequency of Findings That Change Management.
Five percent of cardiac implantable electric devices (CIEDs) are removed each year. Percutaneous extraction is preferred but can be complicated if the leads adhere to the vasculature or perforate. The goal of this study is to assess the frequency of findings on dedicated MDCT that alter preprocedural planning for percutaneous CIED extraction. One hundred patients with CIEDs who underwent MDCT before percutaneous lead extraction were analyzed. Major findings that could preclude percutaneous removal, including lead course and termination, were distinguished from moderately significant findings that could alter but not preclude percutaneous removal, including endofibrosis of leads to the vasculature, lead termination abnormalities, central vein stenosis, or thrombus. Incidental findings were characterized separately. Findings were correlated with preprocedural decisions, the extraction procedure performed, and procedural outcomes. Twenty-six women and 74 men with 125 right ventricular leads, 84 right atrial leads, and 26 coronary venous leads were evaluated. Major findings were present in 7% of patients, including six patients with lead perforation and one with a lead coursing outside a tricuspid annuloplasty ring. Moderately significant findings of endothelial fibrosis were found in 78% of patients. The central veins were narrowed or occluded in 42% of patients, and thrombus was present in 2% of patients. Thirty-six percent of patients had incidental findings, and 4% of patients had unexpected findings requiring immediate inpatient attention. MDCT performed before CIED lead extraction is able to identify major and moderately significant findings that can alter either percutaneous extraction or preprocedural planning. The use of dedicated preprocedural MDCT can help to stratify patient risk, guide decision making by the proceduralist, and identify non-catheter-related findings that affect patient management.


Factors influencing development of pain after gastric endoscopic submucosal dissection: a randomized controlled trial.
Endoscopic submucosal dissection (ESD) is widely used for local treatment of gastric neoplasms. Although ESD-related complications such as bleeding and perforation have been reported, data are currently lacking on the development of pain, which is one of the most common adverse events after ESD. The aim of the current study was to investigate the incidence and clinicopathologic risk factors of pain after ESD. A prospective randomized controlled study was conducted to evaluate 156 patients with gastric neoplasms treated by ESD at Gangnam Severance Hospital between April 2011 and August 2013. All patients were randomly assigned to treatment with intravenous proton pump inhibitor (PPI) either before or after ESD. Acid infusion tests were performed in a subgroup of 21 patients to investigate the mechanism of pain after ESD. The incidence of moderate-to-severe pain after ESD was significantly lower in the group that received preprocedure PPI (44.9%) compared to those who did not (62.8%). Female sex, tumors of the distal stomach (I.e. lower third), baseline dyspeptic symptoms, and positive acid infusion testing were variables that correlated significantly with the development of pain after ESD, although female sex was not significant in multivariate analysis. Patients with tumors of the distal stomach and baseline dyspeptic symptoms were more likely to develop pain after gastric ESD. Hypersensitivity to acid was one mechanism fueling post-ESD pain. Prophylactic PPI treatment was effective at reducing post-ESD pain.Trial registered at Clinicaltrials.gov (NCT02254889).


Update in vitamin D.
The past decade, particularly the last 18 months, witnessed a vigorous increase in interest in vitamin D from both the lay and biomedical worlds. Much of the growing interest in vitamin D is powered by new data being extracted from the National Health and Nutrition Examination Survey (NHANES). The newest statistics demonstrate that more than 90% of the pigmented populace of the United States (Blacks, Hispanics, and Asians) now suffer from vitamin D insufficiency (25-hydroxyvitamin D <30 ng/ml), with nearly three fourths of the white population in this country also being vitamin D insufficient. This represents a near doubling of the prevalence of vitamin D insufficiency seen just 10 yr ago in the same population. This review attempts to provide some explanation for: 1) the rapid decline in vitamin D status in the United States; 2) the adverse impact of vitamin D insufficiency on skeletal, infectious/inflammatory, and metabolic health in humans; and 3) the therapeutic rationale and reliable means for vigorous supplementation of our diets with vitamin D.


Continuous expression in tobacco leaves of a Brassica napus PEND homologue blocks differentiation of plastids and development of palisade cells.
Brassica napus complementary deoxyribonucleic acid (cDNA) clones encoding a DNA-binding protein, BnPEND, were isolated by Southwestern screening. A distinctive feature of the protein was a bZIP-like sequence in the amino-terminal portion, which, after expression in Escherichia coli, bound DNA. BnPEND transcripts were present in B. napus roots and flower buds, and to a lesser extent in stems, flowers and young leaves. Treatment in the dark for 72 h markedly increased the amount of BnPEND transcript in leaves of all ages. Sequence comparison showed that BnPEND was similar to a presumed transcription factor from B. napus, GSBF1, a protein deduced from an Arabidopsis thaliana cDNA (BX825084) and the PEND protein from Pisum sativum, believed to anchor the plastid DNA to the envelope early during plastid development. Homology to expressed sequence tag (EST) sequences from additional species suggested that BnPEND homologues are widespread among the angiosperms. Transient expression of BnPEND fused with green fluorescent protein (GFP) in Nicotiana benthamiana epidermal cells showed that BnPEND is a plastid protein, and that the 15 amino acids at the amino-terminal contain information about plastid targeting. Expression of BnPEND in Nicotiana tabacum from the Cauliflower Mosaic Virus 35S promoter gave stable transformants with different extents of white to light-green areas in the leaves, and even albino plants. In the white areas, but not in adjacent green tissue, the development of palisade cells and chloroplasts was disrupted. Our data demonstrate that the BnPEND protein, when over-expressed at an inappropriate stage, functionally blocks the development of plastids and leads to altered leaf anatomy, possibly by preventing the release of plastid DNA from the envelope.


Evacuation behaviors and emergency communications: An analysis of real-world incident videos.
Emergencies such as fires and terrorist attacks pose risks of injuries and fatalities, which can be exacerbated by delayed, ill-informed, or unmanaged responses. Effective emergency communication strategies could be used to better inform people and reduce these risks. This research analyzes videos of real-world emergencies to: (a) identify people's observed behaviors that increase risk during evacuations, and (b) examine which emergency communication strategies might reduce risk behaviors. We analyzed 126 publicly available videos of emergency evacuations in different emergencies (e.g., fire, terror attack, evacuation alarm, perceived threat). We found evidence of three types of risk behaviors (delayed response, filming, running) and four emergency communication strategies (evacuation alarm, staff guiding people to exits, general prerecorded message, live announcement). Our analyses suggest that having staff guide people to exits is the most effective strategy for promoting faster and more effective responses. However, neither live announcements nor pre-recorded messages were associated with delayed responses, while evacuation alarms were associated with more delayed responses than other communication strategies. Although people filming the incident was unrelated to staff interactions, it occurred more with alarms sounding and prerecorded messages, suggesting that these emergency communications might not prevent filming. Compared to no communications, all emergency communication strategies reduced running during evacuations. We discuss the implications of this research for identifying effective emergency communication strategies and reducing risk-increasing evacuation behaviors.


Genetic context and biochemical characterization of the IMP-18 metallo-beta-lactamase identified in a Pseudomonas aeruginosa isolate from the United States.
The production of metallo-β-lactamase (MBL) is an important mechanism of resistance to β-lactam antibiotics, including carbapenems. Despite the discovery and emergence of many acquired metallo-β-lactamases, IMP-type determinants (now counting at least 27 variants) remain the most prevalent in some geographical areas. In Asian countries, and notably Japan, IMP-1 and its closely related variants are most widespread. Some other variants have been detected in other countries and show either an endemic (e.g., IMP-13 in Italy) or sporadic (e.g., IMP-12 in Italy or IMP-18 in the United States) occurrence. The IMP-18-producing Pseudomonas aeruginosa strain PS 297 from the southwestern United States carried at least two class 1 integrons. One was identical to In51, while the other, named In133 and carrying the bla(IMP-18) gene cassette in the third position, showed an original array of five gene cassettes, including aacA7, qacF, aadA1, and an unknown open reading frame (ORF). Interestingly. In133 differed significantly from In96, the bla(IMP-18)-carrying integron identified in a P. aeruginosa isolate from Mexico. The meropenem and ertapenem MIC values were much lower for Escherichia coli strains producing IMP-18 (0.06 and 0.12 μg/ml, respectively) than for strains producing IMP-1 (2 μg/ml for each). Kinetic data obtained with the purified enzyme revealed lower turnover rates of IMP-18 than of other IMP-type enzymes with most substrates.


Evidence to inform education, training and supportive work environments for midwives involved in the care of women with female genital mutilation: a review of global experience.
to identify how midwives in low and middle income countries (LMIC) and high income countries (HIC) care for women with female genital mutilation (FGM), their perceived challenges and what professional development and workplace strategies might better support midwives to provide appropriate quality care. an integrative review involving a narrative synthesis of the literature was undertaken to include peer reviewed research literature published between 2004 and 2014. 10 papers were included in the review, two from LMIC and eight from HIC. A lack of technical knowledge and limited cultural competency was identified, as well as socio-cultural challenges in the abandonment process of the practice, particularly in LMIC settings. Training in the area of FGM was limited. One study reported the outcomes of an education initiative that was found to be beneficial. professional education and training, a working environment supported by guidelines and responsive policy and community education, are necessary to enable midwives to improve the care of women with FGM and advocate against the practice. improved opportunities for midwives to learn about FGM and receive advice and support, alongside opportunities for collaborative practice in contexts that enable the effective reporting of FGM to authorities, may be beneficial and require further investigation.


Antimicrobial activity of copper surfaces against suspensions of Salmonella enterica and Campylobacter jejuni.
Salmonella enterica and Campylobacter jejuni are amongst the more prevalent bacterial pathogens that cause foodborne diseases. These microorganisms are common contaminants of poultry and poultry products. This study was aimed to evaluate the antibacterial activity of metallic copper surfaces on these important enteropathogens, and to determine the potential acquisition of copper by food exposed to this metal. The antibacterial activity of copper surfaces was evaluated overlying them with suspensions of 10(6) CFU/ml of S. enterica and C. jejuni. Bacterial counts obtained after 0, 2, 4 and 8 hours at 10 degrees C and 25 degrees C were compared with those obtained in stainless steel and a synthetic polymer as control surfaces. The results showed that when these enteropathogens were kept in contact with copper a significant antibacterial activity was noted, on the contrary when the same load of pathogen suspensions were tested over the control surfaces it was found that the bacterial counts remained unchanged or even increased with time. The potential acquisition of copper by food exposed to this surface was also evaluated. Meat exposed for one hour to a copper surface adsorbed residual copper in a time dependent manner. These results shows that metallic copper surfaces have an antibacterial activity against S. enterica and C. jejuni and suggest its potential application as an inhibitory agent in the various stages of the food processing operations.


Wildland fire as a self-regulating mechanism: the role of previous burns and weather in limiting fire progression.
Theory suggests that natural fire regimes can result in landscapes that are both self-regulating and resilient to fire. For example, because fires consume fuel, they may create barriers to the spread of future fires, thereby regulating fire size. Top-down controls such as weather, however, can weaken this effect. While empirical examples demonstrating this pattern-process feedback between vegetation and fire exist, they have been geographically limited or did not consider the influence of time between fires and weather. The availability of remotely sensed data identifying fire activity over the last four decades provides an opportunity to explicitly quantify-the ability of wildland fire to limit the progression of subsequent fire. Furthermore, advances in fire progression mapping now allow an evaluation of how daily weather as a top-down control modifies this effect. In this study, we evaluated the ability of wildland fire to create barriers that limit the spread of subsequent fire along a gradient representing time between fires in four large study areas in the western United States. Using fire progression maps in conjunction with weather station data, we also evaluated the influence of daily weather. Results indicate that wildland fire does limit subsequent fire spread in all four study areas, but this effect decays over time; wildland fire no longer limits subsequent fire spread 6-18 years after fire, depending on the study area. We also found that the ability of fire to regulate, subsequent fire progression was substantially reduced under extreme conditions compared to moderate weather conditions in all four study areas. This study increases understanding of the spatial feedbacks that can lead to self-regulating landscapes as well as the effects of top-down controls, such as weather, on these feedbacks. Our results will be useful to managers who seek to restore natural fire regimes or to exploit recent burns when managing fire.


Evaluation of missed diagnoses for patients admitted from the emergency department.
To define a quality assurance instrument to evaluate errors in diagnostic processes made by physicians in the emergency department (ED). This was a retrospective clinical investigation of inpatient ED records. Over a six-year period, 5,000 medical records of admitted patients were randomly selected for evaluation. Each record was initially examined by one of five physician evaluators. If the primary ED diagnosis differed from the primary discharge diagnosis, the ED record was inspected to determine reasons for the misdiagnosis. The authors considered several aspects of the diagnostic process, including patient history, tests ordered, interpretation of clinical data, choice and performance of procedures, injury pattern recognition, reasoning, and evaluation. Records that demonstrated errors in the diagnostic process were reevaluated for the same diagnostic process errors by a sixth physician. Disagreements regarding suspected errors in the diagnostic process were settled by discussion. Finally, to determine potential medical consequences of the misdiagnosis, one individual reviewed the complete medical records of patients whose ED medical records were scored with errors by both evaluators. Interevaluator reliability was assessed using Cochran's Q-test with a selected series of medical records. Twenty-eight records (0.6%) were found to contain one or more errors in the diagnostic process that contributed to misdiagnosis. For these patients appropriate diagnosis was not made until one to 16 days after admission. Three patients of 18 whose records were available for detailed review may have suffered complications that resulted, in part, from the delay in diagnosis and subsequent treatment. Significant interevaluator reliability for identification of errors in the diagnostic process was obtained (p > 0.1). A two-tiered evaluation of ED records selected by inconsistent initial and final diagnoses can be used reliably to screen for errors in the diagnostic process made by emergency physicians (EPs). The rate of physician error contributing to a misdiagnosis is very low, suggesting that EPs are delivering quality patient care.


Classification and Assessment of Medication Risk in the Elderly (CARE): Use of a Medication Risk Score to Inform Patients' Readmission Likelihood after Hospital Discharge.
Existing risk tools that identify patients at high risk of medication-related iatrogenesis are not sufficient to holistically evaluate a patient's entire medication regimen. This study used a novel medication risk score (MRS) which holistically evaluates medication regimens and provides actionable solutions. The main purpose of this study was to quantify adults ≥ 65 years with a high medication risk burden using the MRS and secondarily, appraise MRS association with hospital readmission. This retrospective cohort study included all consecutive patients in a 6-month period aged 65 years and older, admitted for at least 48 h, and prescribed at least five medications upon discharge. Out of 3017 patients screened, 1386 met all criteria. The primary outcome was the proportion of patients with a score of ≥20 and the secondary outcome was the 30-day readmission rate. In the overall population, 17% of patients had an MRS ≥ 20. For patients discharged home, there was a 19% readmission rate for a score ≥ 20 and 11% for <20 (p = 0.009). A score of ;≥20 was associated with a 1.8-fold increased risk of readmission in patients discharged home. Only 7% of patients met these criteria, which can help direct future use of the MRS at patients with the highest risk of medication-related iatrogenesis.


Private sector contributions and their effect on physician emigration in the developing world.
The contribution made by the private sector to health care in a low- or middle-income country may affect levels of physician emigration from that country. The increasing importance of the private sector in health care in the developing world has resulted in newfound academic interest in that sector's influences on many aspects of national health systems. The growth in physician emigration from the developing world has led to several attempts to identify both the factors that cause physicians to emigrate and the effects of physician emigration on primary care and population health in the countries that the physicians leave. When the relevant data on the emerging economies of Ghana, India and Peru were investigated, it appeared that the proportion of physicians participating in private health-care delivery, the percentage of health-care costs financed publicly and the amount of private health-care financing per capita were each inversely related to the level of physician expatriation. It therefore appears that private health-care delivery and financing may decrease physician emigration. There is clearly a need for similar research in other low- and middle-income countries, and for studies to see if, at the country level, temporal trends in the contribution made to health care by the private sector can be related to the corresponding trends in physician emigration. The ways in which private health care may be associated with access problems for the poor and therefore reduced equity also merit further investigation. The results should be of interest to policy-makers who aim to improve health systems worldwide.


Reduced expression of SKCa and IKCa channel proteins in rat small mesenteric arteries during angiotensin II-induced hypertension.
Ca(2+)-activated K(+) channels (K(Ca)), in particular, the small and intermediate K(Ca) (SK(Ca) and IK(Ca), respectively) channels, are key players in endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation in small arteries. Hypertension is characterized by an endothelial dysfunction, possibly via reduced EDHF release and/or function. We hypothesize that during angiotensin II (14 days)-induced hypertension (ANG II-14d), the contribution of SK(Ca) and IK(Ca) channels in ACh-induced relaxations is reduced due to decreased expression of SK(Ca) and IK(Ca) channel proteins in rat small mesenteric arteries (MAs). Nitric oxide- and prostacyclin-independent vasorelaxation to ACh was similar in small MAs of sham-operated and ANG II-14d rats. Catalase had no inhibitory effects on these relaxations. The highly selective SK(Ca) channel blocker UCL-1684 almost completely blocked these responses in MAs of sham-operated rats but partially in MAs of ANG II-14d rats. These changes were pressure dependent since UCL-1684 caused a greater inhibition in MAs of 1-day ANG II-treated normotensive rats compared with ANG II-14d rats. Expression levels of both mRNA and protein SK3 were significantly reduced in MAs of ANG II-14d rats. The IK(Ca) channel blocker 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34) resulted in comparable reductions in the relaxation responses to ACh in MAs of sham-operated and ANG II-14d rats. Relative mRNA expression levels of IK1 were significantly reduced in MAs of ANG II-14d rats, whereas protein levels of IK1 were not but tended to be lower in MAs of ANG II-14d rats. The findings demonstrate that EDHF-like responses are not compromised in a situation of reduced functional activity and expression of SK3 channels in small MAs of ANG II-induced hypertensive rats. The role of IK1 channels is less clear but might compensate for reduced SK3 activity.


Role of a conserved glutamate residue in the Escherichia coli SecA ATPase mechanism.
Escherichia coli SecA uses ATP to drive the transport of proteins across cell membranes. Glutamate 210 in the "DEVD" Walker B motif of the SecA ATP-binding site has been proposed as the catalytic base for ATP hydrolysis (Hunt, J. F., Weinkauf, S., Henry, L., Fak, J. J., McNicholas, P., Oliver, D. B., and Deisenhofer, J. (2002) Science 297, 2018-2026). Consistent with this hypothesis, we find that mutation of glutamate 210 to aspartate results in a 90-fold reduction of the ATP hydrolysis rate compared with wild type SecA, 0.3 s(-1) versus 27 s(-1), respectively. SecA-E210D also releases ADP at a slower rate compared with wild type SecA, suggesting that in addition to serving as the catalytic base, glutamate 210 might aid turnover as well. Our results contradict an earlier report that proposed aspartate 133 as the catalytic base (Sato, K., Mori, H., Yoshida, M., and Mizushima, S. (1996) J. Biol. Chem. 271, 17439-17444). Re-evaluation of the SecA-D133N mutant used in that study confirms its loss of ATPase and membrane translocation activities, but surprisingly, the analogous SecA-D133A mutant retains full activity, revealing that this residue does not play a key role in catalysis.


Incidence of chyloabdomen diagnosis in dogs and cats and corresponding clinical signs, clinicopathologic test results, and outcomes: 53 cases (1984-2014).
OBJECTIVE To determine the incidence of chyloabdomen diagnosis in cats and dogs and characterize and compare between species the corresponding clinical signs, clinicopathologic test results, and outcomes. DESIGN Retrospective case series. ANIMALS 36 cats and 17 dogs in which chyloabdomen was diagnosed at a veterinary teaching hospital between 1984 and 2014. PROCEDURES Medical records were reviewed, and data retrieved included patient signalment; clinical signs at initial evaluation; results of physical examination, diagnostic tests, and imaging studies; and outcomes. Survival analyses, descriptive statistics, and comparisons between species were completed. RESULTS The incidence of chyloabdomen at the veterinary teaching hospital during the study period was 2.0 cases/100,000 admissions for cats and 2.8 cases/100,000 admissions for dogs. The mean age at diagnosis of chyloabdomen in cats was 11.3 years, compared with 6.9 years in dogs. The most common clinical signs in dogs and cats combined were lethargy (39/51 [76%]) and anorexia (37/51 [73%]), but fewer (23/53 [43%]) had abdominal distention. Chylothorax was a common comorbidity (25/53 [47%]), with malignant neoplasia being the most common underlying diagnosis (24/53 [45%]). Survival analyses included 44 patients; median survival time from diagnosis of chyloabdomen was 31 days overall, 8 days for patients with malignant neoplasia, and 73 days for patients without neoplasia. CONCLUSIONS AND CLINICAL RELEVANCE There were multiple causes of chyloabdomen in dogs and cats of the study, and outcome depended on underlying cause. Because of this and the rarity of chyloabdomen, a multicenter prospective study of disease progression, treatment response, and clinical outcome for dogs and cats with chyloabdomen is needed.


Effectiveness of Initial Transarterial Chemoembolization for Hepatocellular Carcinoma Among Medicare Beneficiaries.
Optimal administration of transarterial chemoembolization (TACE), the standard approach for intermediate-stage hepatocellular carcinoma (HCC), requires clinical and technical expertise. We sought to evaluate whether TACE retains its effectiveness when administered across a broad range of health care settings. Furthermore, as the use of yttrium(90) (Y(90)) radioembolization has been increasing, we explored the comparative effectiveness of Y(90) as an alternative to TACE. Patients with HCC diagnosed from 2004 through 2009 treated initially with TACE or Y(90) were identified from the SEER-Medicare linkage. Key covariates included prediagnosis α-fetoprotein (AFP) screening, complications of cirrhosis, and tumor extent. Effect of treatment, patient, and health care system factors on overall survival (OS) was evaluated using multivariable Cox proportional hazards. Stratified OS estimates are provided. Propensity score (PS) weighting was used to compare effectiveness of Y(90) with TACE. Of 1528 patients who underwent intra-arterial embolization, 577 received concurrent chemotherapy (eg, TACE). Median OS was 21 months (95% CI, 18-23) following TACE and 9 months (95% CI, 1-41) following Y(90). Refined survival estimates stratified by stage, AFP screening, and liver comorbidity are presented. The 90-day mortality rate after TACE was 21% to 25% in patients with extrahepatic spread or vascular invasion. In the PS-weighted analysis, Y(90) was associated with inferior survival, with an adjusted hazard ratio of 1.39 (95% CI, 1.02-1.90). The effectiveness of TACE is generalizable to Medicare patients receiving care in a variety of treatment settings. However, early posttreatment mortality is high in patients with advanced disease. We found no evidence of improved outcomes with Y(90) compared with TACE. Survival estimates from this large cohort can be used to provide prognostic information to patients considering palliative TACE.


High-technology augmentative and alternative communication for individuals with intellectual and developmental disabilities and complex communication needs: a meta-analysis.
The use of mobile technology is ubiquitous in modern society and is rapidly increasing in novel use. The use of mobile devices and software applications ("apps") as augmentative and alternative communication (AAC) is rapidly expanding in the community, and this is also reflected in the research literature. This article reports the social-communication outcome results of a meta-analysis of single-case experimental research on the use of high-tech AAC, including mobile devices, by individuals with intellectual and developmental disabilities, including autism spectrum disorder. Following inclusion determination, and excluding studies with poor design quality, raw data from 24 publications were extracted and included 89 A-B phase contrasts. Tau-U nonparametric, non-overlap effect size was used to aggregate the results across all studies for an omnibus and moderator analyses. Kendall's S was calculated for confidence intervals, p-values, and standard error. The omnibus analysis indicated overall low to moderate positive effects on social-communication outcomes for high-tech AAC use by individuals with intellectual and developmental disabilities.


Basal breast cancer: a complex and deadly molecular subtype.
During the last decade, gene expression profiling of breast cancer has revealed the existence of five molecular subtypes and allowed the establishment of a new classification. The basal subtype, which represents 15-25% of cases, is characterized by an expression profile similar to that of myoepithelial normal mammary cells. Basal tumors are frequently assimilated to triple-negative (TN) breast cancers. They display epidemiological and clinico-pathological features distinct from other subtypes. Their pattern of relapse is characterized by frequent and early relapses and visceral locations. Despite a relative sensitivity to chemotherapy, the prognosis is poor. Recent characterization of their molecular features, such as the dysfunction of the BRCA1 pathway or the frequent expression of EGFR, provides opportunities for optimizing the systemic treatment. Several clinical trials dedicated to basal or TN tumors are testing cytotoxic agents and/or molecularly targeted therapies. This review summarizes the current state of knowledge of this aggressive and hard-to-treat subtype of breast cancer.


Effects of Tartary Buckwheat Bran Flour on Dough Properties and Quality of Steamed Bread.
Steamed bread is a traditional staple food of China. Replacing wheat flour (WF) with Tartary buckwheat is expected to improve the nutritional value of steamed bread. In this study, Tartary buckwheat flour (TBF), Tartary buckwheat bran flour (TBBF), and Tartary buckwheat core flour (TBCF) were prepared, their composition and physicochemical properties were compared. It was found that TBBF had higher protein and rutin contents, so its antioxidant activity and dough rheological properties were obviously superior to those of TBF and TBCF. When TBBF was mixed with WF, its weight proportion in the blend (Wbran) had a significant effect on the dough rheological properties. When Wbran was 30%, the dough had the optimal mixing tolerance, and when Wbran exceeded 30%, it caused dilution effect, weakening the gluten network. With the increase of Wbran, the color of the steamed bread developed by the TBBF-WF blend gradually darkened and yellowed, the specific volume declined, and its hardness, gumminess, and chewiness ascended gradually. The appropriate addition of TBBF (Wbran = 10% and 30%) was beneficial to cell diameter and volume of steamed bread, but the further rise of Wbran would destroy its gas retention ability. The predicted glycemic index (pGI) of steamed bread declined significantly with the increasing Wbran.


Transovarial transmission of Borrelia spirochetes by Ixodes scapularis: a summary of the literature and recent observations.
Transovarial transmission (TOT) of Borrelia burgdorferi (sensu lato), the agent of Lyme disease, by the Ixodes persulcatus group of hard ticks (Ixodidae) has frequently been reported in the literature since the discovery of Lyme disease 1982. Evidence for and against TOT by B. burgdorferi has led to uncertainty and confusion in the literature, causing misconceptions that may have public health consequences. In this report, we review the published information implicating B. burgdorferi as a bacterium transovarially transmitted among ticks of the Ixodes persulcatus group and present new data indicating the transovarially transmitted agent is actually Borrelia miyamotoi. B. miyamotoi, first described in 1995, is antigenically and phylogenetically related to B. burgdorferi, although more closely related to the relapsing fever-group Borrelia typically transmitted by soft ticks (Argasidae). Borrelia infections of unfed larvae derived from egg clutches of wild-caught Ixodes scapularis are demonstrated to result from transovarial transmission of B. miyamotoi, not B. burgdorferi. The presence of this second Borrelia species, apparently sympatric with B. burgdorferi worldwide also may explain other confusing observations reported on Borrelia/Ixodes relationships.


Quantification of different water species in acetone using a NIR-triple-wavelength fiber laser.
A fiber laser using a thulium-doped ZBLAN gain medium was used to generate laser radiation simultaneously at 1461, 1505 and 1874 nm, with > 5 mW output power at each of the wavelengths. The laser was used to quantify the near-infrared absorption of liquid water in acetone. Additionally, near-infrared spectra were recorded using a broad band source and were interpreted using parallel factor (PARAFAC) analysis to rationalize the concentration-dependent peak shifts.


A fish-specific transposable element shapes the repertoire of p53 target genes in zebrafish.
Transposable elements, as major components of most eukaryotic organisms' genomes, define their structural organization and plasticity. They supply host genomes with functional elements, for example, binding sites of the pleiotropic master transcription factor p53 were identified in LINE1, Alu and LTR repeats in the human genome. Similarly, in this report we reveal the role of zebrafish (Danio rerio) EnSpmN6_DR non-autonomous DNA transposon in shaping the repertoire of the p53 target genes. The multiple copies of EnSpmN6_DR and their embedded p53 responsive elements drive in several instances p53-dependent transcriptional modulation of the adjacent gene, whose human orthologs were frequently previously annotated as p53 targets. These transposons define predominantly a set of target genes whose human orthologs contribute to neuronal morphogenesis, axonogenesis, synaptic transmission and the regulation of programmed cell death. Consistent with these biological functions the orthologs of the EnSpmN6_DR-colonized loci are enriched for genes expressed in the amygdala, the hippocampus and the brain cortex. Our data pinpoint a remarkable example of convergent evolution: the exaptation of lineage-specific transposons to shape p53-regulated neuronal morphogenesis-related pathways in both a hominid and a teleost fish.


Two distinct pathways can control expression of the gene encoding the Drosophila antimicrobial peptide metchnikowin.
Metchnikowin is a recently discovered proline-rich peptide from Drosophila with antibacterial and antifungal properties. Like most other antimicrobial peptides from insects, its expression is immune-inducible. Here we present evidence that induction of metchnikowin gene expression can be mediated either by the TOLL pathway or by the imd gene product. We show that the gene remains inducible in Toll-deficient mutants, in which the antifungal response is blocked, as well as in imd mutants, which fail to mount an antibacterial response. However, in Toll-deficient;imd double mutants, metchnikowin gene expression can no longer be detected after immune challenge. Our results suggest that expression of this peptide with dual activity can be triggered by signals generated by either bacterial or fungal infection. Cloning of the metchnikowin gene revealed the presence in the 5' flanking region of several putative cis-regulatory motifs characterized in the promoters of insect immune genes: namely, Rel sites, GATA motifs, interferon consensus response elements and NF-IL6 response elements. Establishment of transgenic fly lines in which the GFP reporter gene was placed under the control of 1.5 kb of metchnikowin gene upstream sequences indicates that this fragment is able to confer full immune inducibility and tissue specificity of expression on the transgene.


NAADP regulates human platelet function.
Platelets play a vital role in maintaining haemostasis. Human platelet activation depends on Ca2+ release, leading to cell activation, granule secretion and aggregation. NAADP (nicotinic acid-adenine dinucleotide phosphate) is a Ca2+-releasing second messenger that acts on acidic Ca2+ stores and is used by a number of mammalian systems. In human platelets, NAADP has been shown to release Ca2+ in permeabilized human platelets and contribute to thrombin-mediated platelet activation. In the present study, we have further characterized NAADP-mediated Ca2+ release in human platelets in response to both thrombin and the GPVI (glycoprotein VI)-specific agonist CRP (collagen-related peptide). Using a radioligand-binding assay, we reveal an NAADP-binding site in human platelets, indicative of a platelet NAADP receptor. We also found that NAADP releases loaded 45Ca2+ from intracellular stores and that total platelet Ca2+ release is inhibited by the proton ionophore nigericin. Ned-19, a novel cell-permeant NAADP receptor antagonist, competes for the NAADP-binding site in platelets and can inhibit both thrombin- and CRP-induced Ca2+ release in human platelets. Ned-19 has an inhibitory effect on platelet aggregation, secretion and spreading. In addition, Ned-19 extends the clotting time in whole-blood samples. We conclude that NAADP plays an important role in human platelet function. Furthermore, the development of Ned-19 as an NAADP receptor antagonist provides a potential avenue for platelet-targeted therapy and the regulation of thrombosis.


Mooren's ulcer in children.
To describe the epidemiology, clinical features, management and outcomes of paediatric Mooren's peripheral ulcerative keratitis. All patients with Mooren's ulcer aged < 18 years presenting at a single centre from 1987 to 2010 were enrolled. Epidemiological features, symptomatology, clinical signs, disease severity, investigations, treatment, outcomes and complications were studied. Main outcome measures were anatomical and functional outcomes, disease activity and complications. 14 eyes of 11 children (seven males and four females with an average age of 12.45 ± 2.25 years at presentation) with Mooren's ulcer were included. Eight cases were unilateral and three bilateral. Symptoms at presentation were more severe than in adults. Trauma was the commonest predisposing factor. Eight eyes had severe corneal involvement. Medical management included intensive topical steroid therapy, oral steroid therapy and immunosuppressant agents. Surgical therapy included tissue adhesive and bandage contact lens application, amniotic membrane transplantation, optical penetrating keratoplasty and limbal stem cell transplantation and was performed in most eyes as part of primary management or later during the disease course. Patients were followed up for a mean of 69.1 weeks. Ten eyes healed successfully and one developed descemetocele. Three eyes developed secondary infections, one of which ultimately became phthisical. In most eyes, final vision either remained stable or was better than at presentation. Our data suggest demographic and clinical features of Mooren's ulcer in children differ from those in adults. Good anatomical results and stable visual results can be achieved with appropriate medical and surgical therapies. Systemic steroids and immunosuppression should be used judiciously with close monitoring.


Do Australian desert frogs co-accumulate counteracting solutes with urea during aestivation?
Australian desert frogs of the genera Neobatrachus, Cyclorana and Heleioporus experience significant dehydration, and iono- and osmoconcentration, during aestivation in the laboratory and accumulate substantial amounts of urea (100-200 mmol)(l-1). We expected a priori that aestivating frogs probably would not need to accumulate balancing osmolytes but would accumulate trimethylamine oxide (TMAO) or betaine as counteracting solutes to urea. These aestivating frogs did not co-accumulate a substantial quantity of any particular balancing osmolyte or counteracting solute, such as a methylamine [TMAO, trimethylamine amine (TMA), betaine, sarcosine, glycerophosphorylcholine (GPC)] or polyol (inositol, mannitol, sorbitol) in plasma or muscle relative to urea accumulation. However, for aestivating frogs, the total concentration of all measured methylamines and polyols (TMAO + TMA + betaine + sarcosine + GPC + inositol) in muscle was approximately 35-45 mmol kg-1, and so it is possible that all of these solutes have a combined counteracting osmolyte role in aestivating frogs at a ratio to urea of approximately 1:2.5, as has been described for elasmobranch fishes. Alternatively, the absence of substantial co-accumulation with urea of any particular solute suggests that aestivating frogs might not require any major extracellular or intracellular counteracting solutes (TMAO, betaine, GPC). The enzyme systems of these aestivating frogs may be insensitive to the perturbing effects of urea, or the perturbing effects of accumulated urea may be a mechanism for metabolic depression, during aestivation.


Designing a prosthesis to simulate the elastic properties of skin.
The materials which are currently used to make maxillofacial prostheses are far from ideal and require considerable improvement with respect to their ability to mimic the properties of skin. To this aim, a novel three-layered maxillofacial prosthesis has been designed consisting of a silicone rubber base layer, an inner gel layer and an outer polymeric coating (to simulate the elastic properties of skin). The aim of the work in this study was to develop the inner silicone gel layer which displays similar properties to facial skin. Through the use of unique linear extensometry testing, in vivo measurements for the Area under the Curve (AUC), Hysteresis (viscoelastic behaviour), Fmax (maximum force), F30 and F60 (force after 30 and 60 seconds) were obtained from the facial skin of 15 volunteers. The results were used as a basis for developing silicone gel formulations for the inner layer, to closely resemble those of facial skin. Gels were made by the addition of both low and high molecular weight unreactive silicone fluids and were further tested for compression, water absorption and dehydration. Testing showed that a gel has been produced that closely simulates the elastic properties of skin when bonded to a base silicone rubber layer. Further testing will need to deduce whether these properties will be affected by the addition of the outer polymeric layer.


Evaluation of silica-coating techniques for zirconia bonding.
To evaluate silica-coating/silane treatment techniques for zirconia bonding. 19 groups of zirconia disks were subjected to different surface treatments: polished or sandblasted by CoJet or alumina, and treatment with silane or zirconia primers (containing phosphate- or phosphonate-monomer). After surface treatments, the zirconia disks were cemented with resin cements and stored in deionized water for 2 hours at 370 degrees C prior to shear bond strength testing. Zirconia surface (polished and unpolished), CoJet sand, Cojet-treated zirconia surface (before and after water rinsing) and representative debonded surfaces were examined by scanning electron microscopy (SEM). The zirconia surface after silica-coating was examined by Fourier Transform Infrared-Attenuated Total Reflectance (FTIR-ATR) spectroscopy. A non-phosphate-containing resin cement (Choice 2) had almost no bond strength on polished zirconia, while MDP-containing cements (Panavia F2.0) had mild bond strength. After zirconia was sandblasted with CoJet or alumina, bond strengths were slightly increased. Silane treatment did not increase bond strength, while phosphate/carboxylate-based primer (i.e. Exp Z-Prime) doubled the bond strengths. Silica nanoparticles identified by FTIR-ATR spectra, were observed by SEM on the zirconia surface after CoJet treatment. However, these nanoparticles were removed by forceful water stream.


Baseline tumour necrosis factor alpha levels predict the necessity for dose escalation of infliximab therapy in patients with rheumatoid arthritis.
To investigate the possible role of baseline plasma tumour necrosis factor alpha levels (baseline-TNF) on the clinical response to infliximab in patients with rheumatoid arthritis (RA). Patients with RA refractory to methotrexate received 3, 6, or 10 mg/kg of infliximab every 8 weeks, in a randomised, double-blind manner: the RISING study. Clinical response (disease activity score in 28 joints based on C-reactive protein or American College of Rheumatology core set) at week 54 and serum infliximab levels were compared in three patient groups with low, intermediate, or high baseline-TNF (TNF-low, TNF-int, or TNF-high). In TNF-low patients, the clinical response to different doses of infliximab was comparable, whereas TNF-int patients exhibited a dose-dependent trend. In contrast, TNF-high patients (approximately 13% of the total patients) had a clinical response to 10 mg/kg significantly better than the response to 3 and 6 mg/kg of infliximab. In TNF-high patients, the median trough serum levels of infliximab were below the detection limit (<0.1 μg/ml) at 3 and 6 mg/kg but were greater than 2 μg/ml at 10 mg/kg, whereas the levels were approximately 1 μg/ml for each dosage group in TNF-low patients. In patients with RA, baseline-TNF is significantly associated with the clinical response to infliximab in patients with a high baseline-TNF. A higher dose of infliximab may be necessary in these patients, whereas lower doses of infliximab are sufficient for those with a low baseline-TNF. Baseline-TNF may be a useful measure for personalising the treatment of RA using infliximab.


Recognition of a natural WT1 epitope by a modified WT1 peptide-specific T-cell receptor.
Wilms' tumor gene WT1 is highly expressed in leukemia and in various types of solid tumors and exerts an oncogenic function. Thus, WT1 protein is a most promising tumor-associated antigen. We have been successfully performing WT1 vaccination with a 9-mer modified WT1(235) peptide, which has one amino acid substitution (M→Y) at position 2 of 9-mer natural WT1(235) peptide (235-243 a.a.), for close to 700 HLA-A*24:02-positive patients with leukemia or solid tumors. Although vaccination of modified WT1(235) peptide induced natural WT1(235) peptide-recognizing cytotoxic T-lymphocytes (CTLs) and exerted cytotoxic activity towards leukemia and solid tumor cells that expressed the natural WT1(235) peptide (epitope) but not the vaccinated modified WT1(235) peptide (epitope), the molecular basis has remained unclear. In this study, we established a modified WT1(235) peptide-specific CTL clone, we isolated T-cell receptor (TCR) genes from it and transduced the TCR genes into CD8(+) T-cells. The TCR-transduced CD8(+) T-cells produced interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα) in response to stimulation not only with the modified WT1(235) peptide but also with the natural WT1(235) peptide and lysed modified or natural WT1(235) peptide-pulsed target cells and endogenously WT1-expressing leukemia cells in a HLA-A*24:02-restriction manner. These results provided us, for the first time at molecular basis, with a proof-of-concept of modified WT1(235) peptide-based immunotherapy for natural WT1(235) peptide-expressing malignancies.


The Moral Reasoning of Genetic Dilemmas Amongst Jewish Israeli Undergraduate Students with Different Religious Affiliations and Scientific Backgrounds.
The main objective of this study was to shed light on the moral reasoning of undergraduate Israeli students towards genetic dilemmas, and on how these are affected by their religious affiliation, by the field they study and by their gender. An open ended questionnaire was distributed among 449 undergraduate students in institutions of higher education in Israel, and their answers were analyzed according to the framework described by Sadler and Zeidler (Science Education, 88(1), 4-27, 2004). They were divided into two major categories: those whose reasoning was based on the consideration of moral consequences (MC), and those who supported their opinion by citing non-consequentialist moral principles (MP). Students' elaborations to questions dealing with values towards genetic testing showed a correlation between the students' religious affiliation and their reasoning, with religious students' elaborations tending to be more principle based than those of secular ones. Overall, the students' elaborations indicate that their main concern is the possibility that their personal genetic information will be exposed, and that their body's personal rights will be violated. We conclude the paper by offering several practical recommendations based on our findings for genetic counseling that is specifically tailored to fit different patients according to their background.


Trace-level detection of atrazine using immuno-chemiluminescence: dipstick and automated flow injection analyses formats.
A sensitive chemiluminescence (CL)-based immunoassay technique based on both dipstick and flow injection analytical formats is reported for the detection of atrazine. In the dipstick-based immunoassay technique, antibody (anti-atrazine) was first immobilized on the nitrocellulose membranes. The dipstick was then treated with atrazine and atrazine-horseradish peroxidase conjugate (atra-HRP) to facilitate the competitive binding. The dipstick was further treated with urea-hydrogen peroxide (U-H202) and luminol to generate photons. The number of photons generated was inversely proportional to the atrazine concentration. In the flow injection analysis (FIA) format, the antibody was immobilized on protein-A sepharose matrix and packed in a glass capillary column, which functioned as an immunoreactor. Competitive binding of antigen and antibody occurred. The CL signals generated during the biochemical reactions were correlated with atrazine concentrations in the analytical samples. By using dipstick technique, it was possible to detect atrazine concentration down to 0.1 ng/mL; with the FIA format, the detection of atrazine was down to 0.01 ng/mL.


Variants in linkage disequilibrium with the late cornified envelope gene cluster deletion are associated with susceptibility to psoriatic arthritis.
A common deletion mapping to the psoriasis susceptibility locus 4 on chromosome 1q21, encompassing two genes of the late cornified envelope (LCE) gene cluster, has been associated with an increased risk of psoriasis vulgaris (PsV). One previous report found no association of the deletion with psoriatic arthritis (PsA), suggesting it may be a specific risk factor for PsV. Given the genetic overlap between PsA and PsV, a study was undertaken to investigate whether single nucleotide polymorphisms (SNPs) mapping to this locus are risk factors for PsA in a UK and Irish population. Three SNPs with prior evidence of association with susceptibility to PsV were genotyped in 1057 patients with PsA using Sequenom iPlex chemistry and genotype frequencies compared with data available for 5575 healthy controls. Two of the SNPs, rs4112788 and rs4085613, were reported to be highly correlated with the LCE deletion. The third SNP, rs6701216, was previously reported to be associated with PsV in a US population. Alleles tagging the deletion for both rs4112788 and rs4085613 were found to be enriched in cases compared with controls (69% vs 65%) and significantly associated with increased susceptibility to PsA (p(trend) = 0.001, OR 1.19 and p(trend) = 0.001, OR 1.18, respectively). No association was observed with rs6701216. The evidence presented here supports LCE deletion as a risk factor for PsA in a UK and Irish population. It suggests that this locus is a risk factor within a shared aetiological pathway that contributes to psoriatic skin disease in both PsV and PsA.


The coevolution of galaxies and supermassive black holes: a local perspective.
One of the most fascinating discoveries in the past decade was that galaxies typically contain a centrally located black hole with a mass that is millions or even billions of times that of the Sun. There is now compelling evidence that we cannot understand how galaxies formed and evolved without understanding the life cycles of these supermassive black holes (and vice versa). We summarize the current understanding of this coevolution of galaxies and supermassive black holes (based largely on observations of the local, present-day universe) and describe prospects for the future.


ATM and ATR as therapeutic targets in cancer.
In order to maintain genomic stability, cells have developed sophisticated signalling pathways to enable DNA damage or DNA replication stress to be resolved. Key mediators of this DNA damage response (DDR) are the ATM and ATR kinases, which induce cell cycle arrest and facilitate DNA repair via their downstream targets. Inhibiting the DDR has become an attractive therapeutic concept in cancer therapy, since (i) resistance to genotoxic therapies has been associated with increased DDR signalling, and (ii) many cancers have defects in certain components of the DDR rendering them highly dependent on the remaining DDR pathways for survival. ATM and ATR act as the apical regulators of the response to DNA double strand breaks and replication stress, respectively, with overlapping but non-redundant activities. Highly selective small molecule inhibitors of ATM and ATR are currently in preclinical and clinical development, respectively. Preclinical data have provided a strong rationale for clinical testing of these compounds both in combination with radio- or chemotherapy, and in synthetic lethal approaches to treat tumours with deficiencies in certain DDR components. Whole genome sequencing studies have reported that mutations in DDR genes occur with a high frequency in many common tumour types, suggesting that a synthetic lethal approach with ATM or ATR inhibitors could have widespread utility, providing that appropriate biomarkers are developed.


The effects of selective consonant amplification on sentence recognition in noise by hearing-impaired listeners.
Weak consonants (e.g., stops) are more susceptible to noise than vowels, owing partially to their lower intensity. This raises the question whether hearing-impaired (HI) listeners are able to perceive (and utilize effectively) the high-frequency cues present in consonants. To answer this question, HI listeners were presented with clean (noise absent) weak consonants in otherwise noise-corrupted sentences. Results indicated that HI listeners received significant benefit in intelligibility (4 dB decrease in speech reception threshold) when they had access to clean consonant information. At extremely low signal-to-noise ratio (SNR) levels, however, HI listeners received only 64% of the benefit obtained by normal-hearing listeners. This lack of equitable benefit was investigated in Experiment 2 by testing the hypothesis that the high-frequency cues present in consonants were not audible to HI listeners. This was tested by selectively amplifying the noisy consonants while leaving the noisy sonorant sounds (e.g., vowels) unaltered. Listening tests indicated small (∼10%), but statistically significant, improvements in intelligibility at low SNR conditions when the consonants were amplified in the high-frequency region. Selective consonant amplification provided reliable low-frequency acoustic landmarks that in turn facilitated a better lexical segmentation of the speech stream and contributed to the small improvement in intelligibility.


Job strain and alcohol intake: a collaborative meta-analysis of individual-participant data from 140,000 men and women.
The relationship between work-related stress and alcohol intake is uncertain. In order to add to the thus far inconsistent evidence from relatively small studies, we conducted individual-participant meta-analyses of the association between work-related stress (operationalised as self-reported job strain) and alcohol intake. We analysed cross-sectional data from 12 European studies (n = 142 140) and longitudinal data from four studies (n = 48 646). Job strain and alcohol intake were self-reported. Job strain was analysed as a binary variable (strain vs. no strain). Alcohol intake was harmonised into the following categories: none, moderate (women: 1-14, men: 1-21 drinks/week), intermediate (women: 15-20, men: 22-27 drinks/week) and heavy (women: >20, men: >27 drinks/week). Cross-sectional associations were modelled using logistic regression and the results pooled in random effects meta-analyses. Longitudinal associations were examined using mixed effects logistic and modified Poisson regression. Compared to moderate drinkers, non-drinkers and (random effects odds ratio (OR): 1.10, 95% CI: 1.05, 1.14) and heavy drinkers (OR: 1.12, 95% CI: 1.00, 1.26) had higher odds of job strain. Intermediate drinkers, on the other hand, had lower odds of job strain (OR: 0.92, 95% CI: 0.86, 0.99). We found no clear evidence for longitudinal associations between job strain and alcohol intake. Our findings suggest that compared to moderate drinkers, non-drinkers and heavy drinkers are more likely and intermediate drinkers less likely to report work-related stress.


Dupilumab reduces opacification across all sinuses and related symptoms in patients with CRSwNP.
Chronic rhinosinusitis with nasal polyposis (CRSwNP) is associated with substantial sinus opacification. In a phase 2a study (NCT01920893), dupilumab, a fully human anti-IL-4Rα monoclonal antibody, improved outcomes in CRSwNP refractory to intranasal corticosteroids. We evaluated dupilumab's effect on sinus opacification in relation to effects on nasal polyp burden, symptoms, and health-related quality of life (HRQoL) in patients with CRSwNP. 16-week randomized, double-blind, placebo-controlled, parallel-group study in 60 adults with CRSwNP. Patients received weekly subcutaneous dupilumab 300-mg or placebo and daily mometasone furoate nasal spray. Sinus opacification was assessed using standard and Zinreich-modified Lundâ€"Mackay (zLMK) scoring. Correlation was assessed between zLMK score and CRSwNP endpoints, including nasal polyp score (NPS), SNOT-22, daily symptom scores, and UPSIT smell-test score. Baseline characteristics were similar across treatment groups. Mean plus/minus SD baseline LMK scores of 18.7 plus/minus 5.5 (placebo) and 18.6 plus/minus 5.0 (dupilumab) indicated severe disease with extensive opacification involving all sinuses. Baseline LMK and LMK scores correlated with NPS severity and loss of sense of smell (daily symptoms; SNOT-22 smell/taste; loss of sense of smell [UPSIT]). At Week 16, dupilumab-treated patients had significantly improved sinus opacification measured by LMK in all individual sinuses vs placebo. Dupilumab also showed similar efficacy with zLMK, with only small differences from LMK, and correlated with SNOT22 smell/taste. The most common adverse events were nasopharyngitis, injection-site reactions, and headache. In patients with CRSwNP, baseline LMK showed extensive sinus opacification and correlated with symptoms, HRQoL, and hyposmia. Dupilumab treatment reduces opacification across all sinuses and related symptoms in patients with CRSwNP.


NEO: NEuro-Inspired Optimization-A Fractional Time Series Approach.
Solving optimization problems is a recurrent theme across different fields, including large-scale machine learning systems and deep learning. Often in practical applications, we encounter objective functions where the Hessian is ill-conditioned, which precludes us from using optimization algorithms utilizing second-order information. In this paper, we propose to use fractional time series analysis methods that have successfully been used to model neurophysiological processes in order to circumvent this issue. In particular, the long memory property of fractional time series exhibiting non-exponential power-law decay of trajectories seems to model behavior associated with the local curvature of the objective function at a given point. Specifically, we propose a NEuro-inspired Optimization (NEO) method that leverages this behavior, which contrasts with the short memory characteristics of currently used methods (e.g., gradient descent and heavy-ball). We provide evidence of the efficacy of the proposed method on a wide variety of settings implicitly found in practice.


A conflict-based model of color categorical perception: evidence from a priming study.
Categorical perception (CP) of color manifests as faster or more accurate discrimination of two shades of color that straddle a category boundary (e.g., one blue and one green) than of two shades from within the same category (e.g., two different shades of green), even when the differences between the pairs of colors are equated according to some objective metric. The results of two experiments provide new evidence for a conflict-based account of this effect, in which CP is caused by competition between visual and verbal/categorical codes on within-category trials. According to this view, conflict arises because the verbal code indicates that the two colors are the same, whereas the visual code indicates that they are different. In Experiment 1, two shades from the same color category were discriminated significantly faster when the previous trial also comprised a pair of within-category colors than when the previous trial comprised a pair from two different color categories. Under the former circumstances, the CP effect disappeared. According to the conflict-based model, response conflict between visual and categorical codes during discrimination of within-category pairs produced an adjustment of cognitive control that reduced the weight given to the categorical code relative to the visual code on the subsequent trial. Consequently, responses on within-category trials were facilitated, and CP effects were reduced. The effectiveness of this conflict-based account was evaluated in comparison with an alternative view that CP reflects temporary warping of perceptual space at the boundaries between color categories.


A contribution to the rational design of Ru(CO)3Cl2L complexes for in vivo delivery of CO.
A few ruthenium based metal carbonyl complexes, e.g. CORM-2 and CORM-3, have therapeutic activity attributed to their ability to deliver CO to biological targets. In this work, a series of related complexes with the formula [Ru(CO)3Cl2L] (L = DMSO (3), L-H3CSO(CH2)2CH(NH2)CO2H) (6a); D,L-H3CSO(CH2)2CH(NH2)CO2H (6b); 3-NC5H4(CH2)2SO3Na (7); 4-NC5H4(CH2)2SO3Na (8); PTA (9); DAPTA (10); H3CS(CH2)2CH(OH)CO2H (11); CNCMe2CO2Me (12); CNCMeEtCO2Me (13); CN(c-C3H4)CO2Et) (14)) were designed, synthesized and studied. The effects of L on their stability, CO release profile, cytotoxicity and anti-inflammatory properties are described. The stability in aqueous solution depends on the nature of L as shown using HPLC and LC-MS studies. The isocyanide derivatives are the least stable complexes, and the S-bound methionine oxide derivative is the more stable one. The complexes do not release CO gas to the headspace, but release CO2 instead. X-ray diffraction of crystals of the model protein Hen Egg White Lysozyme soaked with 6b (4UWN) and 8 (4UWN) shows the addition of Ru(II)(CO)(H2O)4 at the His15 binding site. Soakings with 7(4UWN) produced the metallacarboxylate [Ru(COOH)(CO)(H2O)3](+) bound to the His15 site. The aqueous chemistry of these complexes is governed by the water-gas shift reaction initiated with the nucleophilic attack of HO(-) on coordinated CO. DFT calculations show this addition to be essentially barrierless. The complexes have low cytotoxicity and low hemolytic indices. Following i.v. administration of CORM-3, the in vivo bio-distribution of CO differs from that obtained with CO inhalation or with heme oxygenase stimulation. A mechanism for CO transport and delivery from these complexes is proposed.


Plant community composition and biomass in Gulf Coast Chenier Plain marshes: responses to winter burning and structural marsh management.
Many marshes in the Gulf Coast Chenier Plain, USA, are managed through a combination of fall or winter burning and structural marsh management (i.e., levees and water control structures; hereafter SMM). The goals of winter burning and SMM include improvement of waterfowl and furbearer habitat, maintenance of historic isohaline lines, and creation and maintenance of emergent wetlands. Although management practices are intended to influence the plant community, effects of these practices on primary productivity have not been investigated. Marsh processes, such as vertical accretion and nutrient cycles, which depend on primary productivity may be affected directly or indirectly by winter burning or SMM. We compared Chenier Plain plant community characteristics (species composition and above- and belowground biomass) in experimentally burned and unburned control plots within impounded and unimpounded marshes at 7 months (1996), 19 months (1997), and 31 months (1998) after burning. Burning and SMM did not affect number of plant species or species composition in our experiment. For all three years combined, burned plots had higher live above-ground biomass than did unburned plots. Total above-ground and dead above-ground biomasses were reduced in burned plots for two and three years, respectively, compared to those in unburned control plots. During all three years, belowground biomass was lower in impounded than in unimpounded marshes but did not differ between burn treatments. Our results clearly indicate that current marsh management practices influence marsh primary productivity and may impact other marsh processes, such as vertical accretion, that are dependent on organic matter accumulation and decay.


Phylogenetic tests of distribution patterns in South Asia: towards an integrative approach.
The last four decades have seen an increasing integration of phylogenetics and biogeography. However, a dearth of phylogenetic studies has precluded such biogeographic analyses in South Asia until recently. Noting the increase in phylogenetic research and interest in phylogenetic biogeography in the region, we outline an integrative framework for studying taxon distribution patterns. While doing so, we pay particular attention to challenges posed by the complex geological and ecological history of the region, and the differences in distribution across taxonomic groups. We outline and compare three widely used phylogenetic biogeographic approaches: topology-based methods (TBMs), pattern-based methods (PBMs) and event-based methods (EBMs). TBMs lack a quantitative framework and utilize only part of the available phylogenetic information. Hence, they are mainly suited for preliminary enquiries. Both PBMs and EBMs have a quantitative framework, but we consider the latter to be particularly suited to the South Asian context since they consider multiple biogeographic processes explicitly, and can accommodate a reticulated history of areas. As an illustration, we present a biogeographic analysis of endemic Sri Lankan agamid lizards. The results provide insights into the relative importance of multiple processes and specific zones in the radiation of two speciose lizard clades.


Smear layer: overview of structure and function.
Smear layers are created on hard tissues whenever they are cut with hand or rotary instruments. This thin (1-2 microns) layer of denatured cutting debris is very tenacious and, in fact, is often the surface to which restorative materials are luted. The solubility characteristics, chemical reactivity and the structure-function relationships of this layer have not yet been well-defined. During creation of the smear layer, cutting debris is forced variable distances into dentinal tubules. These so-called smear plugs, together with the smear layer decrease dentin permeability, dentin sensitivity and surface wetness. Bonding adhesive resins to smear layers appears to limit the theoretical bond strength unless the smear layers are loosened or partially removed. Future research in this area will include the use of surface analytical techniques such as Auger electron spectroscopy and ESCA. These techniques are required because of the thinness of the smear layer. It is clear that the nature of this critical interface between dental materials and cut hard tissues remains largely unknown. This field will provide fertile ground for future research.


Home videophones improve direct observation in tuberculosis treatment: a mixed methods evaluation.
THE USE OF DIRECT OBSERVATION TO MONITOR TUBERCULOSIS TREATMENT IS CONTROVERSIAL: cost, practical difficulties, and lack of patient acceptability limit effectiveness. Telehealth is a promising alternative delivery method for improving implementation. This study aimed to evaluate the clinical and cost-effectiveness of a telehealth service delivering direct observation, compared to an in-person drive-around service. The study was conducted within a community nursing service in South Australia. Telehealth patients received daily video calls at home on a desktop videophone provided by the nursing call center. A retrospective cohort study assessed the effectiveness of the telehealth and traditional forms of observation, defined by the proportion of missed observations recorded in case notes. This data was inputted to a model, estimating the incremental cost-effectiveness ratio (ICER) of telehealth. Semi-structured interviews were conducted with current patients, community nursing and Chest Clinic staff, concerning service acceptability, usability and sustainability. The percentage of missed observations for the telehealth service was 12.1 (n = 58), compared to 31.1 for the in-person service (n = 70). Most of the difference of 18.9% (95% CI: 12.2 - 25.4) was due to fewer pre-arranged absences. The economic analysis calculated the ICER to be AUD$1.32 (95% CI: $0.51 - $2.26) per extra day of successful observation. The video service used less staff time, and became dominant if implemented on a larger scale and/or with decreased technology costs. Qualitative analysis found enabling factors of flexible timing, high patient acceptance, staff efficiency, and Chest Clinic support. Substantial technical problems were manageable, and improved liaison between the nursing service and Chest Clinic was an unexpected side-benefit. Home video observation is a patient-centered, resource efficient way of delivering direct observation for TB, and is cost-effective when compared with a drive-around service. Future research is recommended to determine applicability and effectiveness in other settings.


Repeatability of 18 F-FDG PET radiomic features: A phantom study to explore sensitivity to image reconstruction settings, noise, and delineation method.
18 F-fluoro-2-deoxy-D-Glucose positron emission tomography (18 F-FDG PET) radiomics has the potential to guide the clinical decision making in cancer patients, but validation is required before radiomics can be implemented in the clinical setting. The aim of this study was to explore how feature space reduction and repeatability of 18 F-FDG PET radiomic features are affected by various sources of variation such as underlying data (e.g., object size and uptake), image reconstruction methods and settings, noise, discretization method, and delineation method. The NEMA image quality phantom was scanned with various sphere-to-background ratios (SBR), simulating different activity uptakes, including spheres with low uptake, that is, SBR smaller than 1. Furthermore, images of a phantom containing 3D printed inserts reflecting realistic heterogeneity uptake patterns were acquired. Data were reconstructed using various matrix sizes, reconstruction algorithms, and scan durations (noise). For every specific reconstruction and noise level, ten statistically equal replicates were generated. The phantom inserts were delineated using CT and PET-based segmentation methods. A total of 246 radiomic features was extracted from each image dataset. Images were discretized with a fixed number of 64 bins (FBN) and a fixed bin width (FBW) of 0.25 for the high and a FBW of 0.05 for the low uptake data. In terms of feature reduction, we determined the impact of these factors on the composition of feature clusters, which were defined on the basis of Spearman's correlation matrices. To assess feature repeatability, the intraclass correlation coefficient was calculated over the ten replicates. In general, larger spheres with high uptake resulted in better repeatability compared to smaller low uptake spheres. In terms of repeatability, features extracted from heterogeneous phantom inserts were comparable to features extracted from bigger high uptake spheres. For example, for an EARL-compliant reconstruction, larger and smaller high uptake spheres yielded good repeatability for 32% and 30% of the features, while the heterogeneous inserts resulted in 34% repeatable features. For the low uptake spheres, this was the case for 22% and 20% of the features for bigger and smaller spheres, respectively. Images reconstructed with point-spread-function (PSF) resulted in the highest repeatability when compared with OSEM or time-of-flight, for example, 53%, 30%, and 32% of repeatable features, respectively (for unsmoothed data, discretized with FBN, 300 s scan duration). Reducing image noise (increasing scan duration and smoothing) and using CT-based segmentation for the low uptake spheres yielded improved repeatability. FBW discretization resulted in higher repeatability than FBN discretization, for example, 89% and 35% of the features, respectively (for the EARL-compliant reconstruction and larger high uptake spheres). Feature space reduction and repeatability of 18 F-FDG PET radiomic features depended on all studied factors. The high sensitivity of PET radiomic features to image quality suggests that a high level of image acquisition and preprocessing standardization is required to be used as clinical imaging biomarker.


Chronic benzodiazepine administration. VIII. Receptor upregulation produced by chronic exposure to the inverse agonist FG-7142.
Treatment with benzodiazepine agonists is associated with the development of behavioral tolerance and receptor downregulation, whereas antagonist administration has been reported to lead to increased activity and receptor upregulation. To determine the effects of chronic inverse agonist administration, mice were treated with FG-7142 (20 mg/kg/day) by implanted s.c. osmotic pumps for 1 to 14 days. No seizures were observed in FG-7142-exposed animals. Open-field activity was unchanged as compared to controls at days 1 and 2, but was elevated significantly at days 4 and 7. Activity was reduced below control values at day 14. Benzodiazepine receptor binding determined in vivo was unchanged for days 1, 4 and 7 within the hippocampus but was elevated at day 14. Binding remained unchanged in the cortex, cerebellum, hypothalamus and pons-medulla for the duration of drug exposure. Cortical benzodiazepine binding assessed in vitro was unchanged at days 1 and 2 but increased at days 4, 7 and 14 vs. vehicle treated controls. Binding at the gamma-aminobutyric acid site was increased at day 7 whereas binding of t-[35S]butylbicyclophosphoro-thionate was increased at days 7 and 14 of FG-7142 exposure. Maximal muscimol-slimulated [36Cl-] uptake was elevated at days 4, 7 and 14 compared to day 1 of exposure. These results demonstrate that chronic continuous exposure to FG-7142 is associated with an absence of kindled seizures and with behavioral and neurochemical changes indicative of gamma-aminobutyric acidA receptor upregulation.


[Syncope due to giant goitre].
We present a case report of a 70-year-old male patient with a giant goitre. The patient experienced recurrent episodes of syncope/fainting, when he turned his head towards to the right, and he experienced discomfort when lying on his back. A CT scan showed compression of the right carotid artery and carotid sinus from a thyroid mass. After a mass of 1,473 g of thyroid tissue had been removed by a right thyroid lobectomy, the patient experienced no further episodes of syncope. It is well known, that giant goitres can bring a wide range of symptoms including compression of arteries, veins, nerves and related structures on the neck and in the thorax.


Unusual nucleotide-binding properties of the chloroplast protein import receptor, atToc33.
Arabidopsis Toc33 (atToc33) is a GTP-binding protein of the chloroplast outer envelope membrane. We studied its nucleotide-binding properties in vitro, and found that it binds GTP, GDP and XTP, with similar efficiencies, but not ATP. We further demonstrated that atToc33 has intrinsic GTPase activity. Mutations within the putative G4 motif of the atToc33 nucleotide-binding domain (D217N, D219N and E220Q) had no effect on nucleotide specificity or GTPase activity. Similarly, a mutation in the newly assigned G5 motif (E208Q) did not affect nucleotide specificity or GTPase activity. Furthermore, the D217N and D219N mutations did not affect atToc33 functionality in vivo. The data demonstrate that atToc33 belongs to a novel class of GTPases with unusual nucleotide-binding properties.


Contrasting responses of Kupffer cells and inflammatory mononuclear phagocytes to biliary obstruction in a mouse model of cholestatic liver injury.
Biliary obstruction and cholestasis are serious complications of many liver diseases. Although resident hepatic macrophages (Kupffer cells) are frequently implicated in disease progression, most studies fail to differentiate the contribution of Kupffer cells and inflammatory mononuclear phagocytes (iMNPs) that infiltrate the liver subsequent to obstruction. This study was undertaken to examine the roles and potential interactions of these two disparate mononuclear phagocyte populations in hepatic injury attending cholestasis. Female, C57Bl/6 mice were injected with magnetic beads on day 3 prior to sham operation or bile duct ligation (BDL) to facilitate subsequent Kupffer cell isolation. Three days post-surgery, animals were euthanized, and bead-containing Kupffer cells and iMNPs were separated, purified and analysed. To examine the ability of Kupffer cells to modulate iMNP activity, iMNPs were isolated from the livers of intact and Kupffer cell-depleted mice on day 3 post-surgery and compared. Purified Kupffer cells and iMNP populations obtained from BDL mice exhibited heterogeneous morphologies rendering them visually indistinguishable. iMNPs, however, were characterized by the increased expression of Ly-6C and CD11b and the elevated production of chemokines/cytokines characteristic of inflammatory cells. In the absence of Kupffer cells, iMNPs immigrating to the liver following BDL exhibited significant decreases in CD11b and Ly-6C expression, and in pro-inflammatory chemokine/cytokine production. Kupffer cells and iMNPs exhibit disparate biological responses to biliary obstruction and cholestasis. Kupffer cells play a key role in regulating iMNP influx and activity.


The Effect of Deep Versus Moderate Neuromuscular Block on Surgical Conditions and Postoperative Respiratory Function in Bariatric Laparoscopic Surgery: A Randomized, Double Blind Clinical Trial.
In recent literature, it has been suggested that deep neuromuscular block (NMB) improves surgical conditions during laparoscopy; however, the evidence supporting this statement is limited, and this was not investigated in laparoscopic bariatric surgery. Moreover, residual NMB could impair postoperative respiratory function. We tested the hypotheses that deep NMB could improve the quality of surgical conditions for laparoscopic bariatric surgery compared with moderate NMB and investigated whether deep NMB puts patients at risk for postoperative respiratory impairment compared with moderate NMB. Sixty patients were evenly randomized over a deep NMB group (rocuronium bolus and infusion maintaining a posttetanic count of 1-2) and a moderate NMB group (rocuronium bolus and top-ups maintaining a train-of-four count of 1-2). Anesthesia was induced and maintained with propofol and remifentanil. The primary outcome measures were the quality of surgical conditions assessed by a single surgeon using a 5-point rating scale (1 = extremely poor, 5 = optimal), the number of intra-abdominal pressure increases >18 cmH2O and the duration of surgery. Secondary outcome measure was the postoperative pulmonary function assessed by peak expiratory flow, forced expiratory volume in 1 second, and forced vital capacity, and by the need for postoperative respiratory support. Data are presented as mean ± standard deviation with estimated treatment effect (ETE: mean difference [95% confidence interval]) for group comparisons. There was no statistically significant difference in the surgeon's rating regarding the quality of the surgical field between the deep and moderate NMB group (4.2 ± 1.0 vs 3.9 ± 1.1; P = .16, respectively; ETE: 0.4 [-0.1, 0.9]). There was no difference in the proportional rating of surgical conditions over the 5-point rating scale between both groups (P = .91). The number of intra-abdominal pressure increases >18 cmH2O and the duration of surgery were not statistically different between the deep and moderate NMB group (0.2 ± 0.9 vs 0.3 ± 1.0; P = .69; ETE: -0.1 [-0.5, 0.4] and 61.3 ± 15.1 minutes vs 70.6 ± 20.8 minutes; P = .07, ETE: -9.3 [-18.8, 0.1], respectively). All the pulmonary function tests were considerably impaired in both groups when compared with baseline (P < .001). There was no statistically significant difference in the decrease in peak expiratory flow, forced expiratory volume in 1 second, and forced vital capacity (expressed as % change from baseline) between the deep and the moderate NMB group. Compared with a moderate NMB, there was insufficient evidence to conclude that deep NMB improves surgical conditions during laparoscopic bariatric surgery. Postoperative pulmonary function was substantially decreased after laparoscopic bariatric surgery independently of the NMB regime that was used. The study is limited by a small sample size.


Long-term physical impairment and functional outcomes after complex facial fractures.
To develop an understanding of the expected functional outcomes after facial trauma, a retrospective cohort study of patients with complex facial fractures was conducted. A cohort of adults aged 18 to 55 years who were admitted to the R. Adams Cowley Shock Trauma Center between July of 1986 and July of 1994 for treatment of a Le Fort midface fracture (resulting from blunt force) was retrospectively identified. Outcomes of interest included measures of general health status and psychosocial well being in addition to self-reported somatic symptoms. General health status was ascertained using the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). The Body Satisfaction Scale was used to define patient concerns about altered body image and shape. To determine whether complex maxillofacial trauma and facial fractures contributed to altered social interactions, the Social Avoidance and Distress scale was used. In addition, information about a patient, his or her injury, and its treatment were ascertained from the medical records. Using the methods described above, 265 patients with Le Fort fractures were identified. These individuals were matched to a similar group of 242 general injury patients. A total of 190 of the Le Fort patients (72 percent of those eligible for the study) and 144 (60 percent) general injury patients were successfully located, and long-term interview data were acquired.Le Fort fracture patients as a group had similar health status outcomes when compared with the group of general injury patients. However, when outcomes were examined by the complexity of the Le Fort fracture, the authors found that study subjects with severe, comminuted Le Fort injuries (group D) had significantly lower SF-36 scores (worse outcomes) for the two dimensions related to role limitations: role limitations due to physical problems and role limitations due to emotional problems (p < 0.05). SF-36 scores for all other dimensions except physical function were also lower for comminuted versus less complex Le Fort fractures, although differences were not statistically significant.Specifically, there was a direct relationship between severity of facial injury and patients reporting work disability. Of group C and D Le Fort patients (severely comminuted fractures) only 55 and 58 percent, respectively, had returned to work at the time of follow-up interview. These figures are significantly lower than the back-to-work percentage of patients with less severe facial injury (70 percent). When study participants were asked if they were experiencing specific somatic symptoms at the time of the interview that they had not experienced before the injury, a significantly larger percent of the Le Fort fracture patients (compared with the general injury patients) responded in the affirmative. Differences between the Le Fort fracture and general injury groups were statistically significant (p < 0.05) for all 11 symptoms. The percentage of patients reporting complaints increased with increasing complexity of facial fracture in the areas of visual problems, alterations in smell, difficulty with mastication, difficulty with breathing, and epiphora, and these differences reached statistical significance. Patients sustaining comminuted Le Fort facial fractures report poorer health outcomes than patients with less severe facial injury and substantially worse outcomes than population norms. It is also this severely injured population that reports the greatest percentage of injury-related disability, preventing employment at long-term follow-up. The long-term goal of centralized tertiary trauma treatment centers must be to return the patient to a productive, active lifestyle.