Losses in Ferroelectric Materials.
Ferroelectric materials are the best dielectric and piezoelectric materials known today. Since the discovery of barium titanate in the 1940s, lead zirconate titanate ceramics in the 1950s and relaxor-PT single crystals (such as lead magnesium niobate-lead titanate and lead zinc niobate-lead titanate) in the 1980s and 1990s, perovskite ferroelectric materials have been the dominating piezoelectric materials for electromechanical devices, and are widely used in sensors, actuators and ultrasonic transducers. Energy losses (or energy dissipation) in ferroelectrics are one of the most critical issues for high power devices, such as therapeutic ultrasonic transducers, large displacement actuators, SONAR projectors, and high frequency medical imaging transducers. The losses of ferroelectric materials have three distinct types, i.e., elastic, piezoelectric and dielectric losses. People have been investigating the mechanisms of these losses and are trying hard to control and minimize them so as to reduce performance degradation in electromechanical devices. There are impressive progresses made in the past several decades on this topic, but some confusions still exist. Therefore, a systematic review to define related concepts and clear up confusions is urgently in need. With this objective in mind, we provide here a comprehensive review on the energy losses in ferroelectrics, including related mechanisms, characterization techniques and collections of published data on many ferroelectric materials to provide a useful resource for interested scientists and engineers to design electromechanical devices and to gain a global perspective on the complex physical phenomena involved. More importantly, based on the analysis of available information, we proposed a general theoretical model to describe the inherent relationships among elastic, dielectric, piezoelectric and mechanical losses. For multi-domain ferroelectric single crystals and ceramics, intrinsic and extrinsic energy loss mechanisms are discussed in terms of compositions, crystal structures, temperature, domain configurations, domain sizes and grain boundaries. The intrinsic and extrinsic contributions to the total energy dissipation are quantified. In domain engineered ferroelectric single crystals and ceramics, polarization rotations, domain wall motions and mechanical wave scatterings at grain boundaries are believed to control the mechanical quality factors of piezoelectric resonators. We show that a thorough understanding on the kinetic processes is critical in analyzing energy loss behavior and other time-dependent properties in ferroelectric materials. At the end of the review, existing challenges in the study and control of losses in ferroelectric materials are analyzed, and future perspective in resolving these issues is discussed.


A systematic review of task- shifting for HIV treatment and care in Africa.
Shortages of human resources for health (HRH) have severely hampered the rollout of antiretroviral therapy (ART) in sub-Saharan Africa. Current rollout models are hospital- and physician-intensive. Task shifting, or delegating tasks performed by physicians to staff with lower-level qualifications, is considered a means of expanding rollout in resource-poor or HRH-limited settings. We conducted a systematic literature review. Medline, the Cochrane library, the Social Science Citation Index, and the South African National Health Research Database were searched with the following terms: task shift*, balance of care, non-physician clinicians, substitute health care worker, community care givers, primary healthcare teams, cadres, and nurs* HIV. We mined bibliographies and corresponded with authors for further results. Grey literature was searched online, and conference proceedings searched for abstracts. We found 2960 articles, of which 84 were included in the core review. 51 reported outcomes, including research from 10 countries in sub-Saharan Africa. The most common intervention studied was the delegation of tasks (especially initiating and monitoring HAART) from doctors to nurses and other non-physician clinicians. Five studies showed increased access to HAART through expanded clinical capacity; two concluded task shifting is cost effective; 9 showed staff equal or better quality of care; studies on non-physician clinician agreement with physician decisions was mixed, with the majority showing good agreement. Task shifting is an effective strategy for addressing shortages of HRH in HIV treatment and care. Task shifting offers high-quality, cost-effective care to more patients than a physician-centered model. The main challenges to implementation include adequate and sustainable training, support and pay for staff in new roles, the integration of new members into healthcare teams, and the compliance of regulatory bodies. Task shifting should be considered for careful implementation where HRH shortages threaten rollout programmes.


Bacterial infections in patients with liver cirrhosis: clinical characteristics and the role of C-reactive protein.
The diagnosis of bacterial infection in cirrhotic patients may be difficult, because of the absence of classical signs such as fever and raised white blood cell count. The role of C-reactive protein (CRP) in this context has not been clearly defined. Clinical and laboratory characteristics of 210 consecutive cirrhotic patients with (n=100) or without (n=110) bacterial infection were compared with a control group of non-cirrhotic patients with infection (n=106). Significantly fewer patients with cirrhosis had a body temperature ≥37°C when presenting with bacterial infection (56% cirrhotic vs. 85.5% non-cirrhotic patients, P=0.01). Mean leukocyte count was 6.92 × 103/mm3 in patients with cirrhosis and infection, 5.75 × 103/mm3 (P=0.02) in cirrhotic patients without infection, and 11.28 × 103/mm3 in non-cirrhotic patients with infection (P<0.001). Multivariate analysis revealed that CRP level and model for end-stage liver disease score were significantly associated with the presence of infection in patients with cirrhosis. A cutoff level of CRP>10 mg/L indicated the presence of infection with a sensitivity of 68%, a specificity of 84.5% and an area under the receiver operating characteristic curve of 0.8197. CRP cutoff level differed according to the severity of the liver disease: Child-Pugh score (CPS) A: 21.3 mg/L, B: 17 mg/L, and C: 5.78 mg/L. CRP at admission could help diagnose infection in cirrhotic patients. Since the severity of liver disease seems to affect the CRP values, lower CRP levels might indicate infection. Clinical suspicion is necessary to avoid delay in diagnosis and initiate antibiotic treatment.


Physiological and transcriptional responses of Saccharomyces cerevisiae to d-limonene show changes to the cell wall but not to the plasma membrane.
Monoterpenes can, upon hydrogenation, be used as light-fraction components of sustainable aviation fuels. Fermentative production of monoterpenes in engineered microorganisms, such as Saccharomyces cerevisiae, has gained attention as a potential route to deliver these next-generation fuels from renewable biomass. However, end product toxicity presents a formidable problem for microbial synthesis. Due to their hydrophobicity, monoterpene inhibition has long been attributed to membrane interference, but the molecular mechanism remains largely unsolved. In order to gain a better understanding of the mode of action, we analyzed the composition and structural integrity of the cell envelope as well as the transcriptional response of yeast cells treated with an inhibitory amount of d-limonene (107 mg/liter). We found no alterations in membrane fluidity, structural membrane integrity, or fatty acid composition after the solvent challenge. A 4-fold increase in the mean fluorescence intensity per cell (using calcofluor white stain) and increased sensitivity to cell wall-degrading enzymes demonstrated that limonene disrupts cell wall properties. Global transcript measurements confirmed the membrane integrity observations by showing no upregulation of ergosterol or fatty acid biosynthesis pathways, which are commonly overexpressed in yeast to reinforce membrane rigidity during ethanol exposure. Limonene shock did cause a compensatory response to cell wall damage through overexpression of several genes (ROM1, RLM1, PIR3, CTT1, YGP1, MLP1, PST1, and CWP1) involved with the cell wall integrity signaling pathway. This is the first report demonstrating that cell wall, rather than plasma membrane, deterioration is the main source of monoterpene inhibition. We show that limonene can alter the structure and function of the cell wall, which has a clear effect on cytokinesis.


Responses of human endothelial cells to pathogenic and non-pathogenic Leptospira species.
Leptospirosis is a widespread zoonotic infection that primarily affects residents of tropical regions, but causes infections in animals and humans in temperate regions as well. The agents of leptospirosis comprise several members of the genus Leptospira, which also includes non-pathogenic, saprophytic species. Leptospirosis can vary in severity from a mild, non-specific illness to severe disease that includes multi-organ failure and widespread endothelial damage and hemorrhage. To begin to investigate how pathogenic leptospires affect endothelial cells, we compared the responses of two endothelial cell lines to infection by pathogenic versus non-pathogenic leptospires. Microarray analyses suggested that pathogenic L. interrogans and non-pathogenic L. biflexa triggered changes in expression of genes whose products are involved in cellular architecture and interactions with the matrix, but that the changes were in opposite directions, with infection by L. biflexa primarily predicted to increase or maintain cell layer integrity, while L. interrogans lead primarily to changes predicted to disrupt cell layer integrity. Neither bacterial strain caused necrosis or apoptosis of the cells even after prolonged incubation. The pathogenic L. interrogans, however, did result in significant disruption of endothelial cell layers as assessed by microscopy and the ability of the bacteria to cross the cell layers. This disruption of endothelial layer integrity was abrogated by addition of the endothelial protective drug lisinopril at physiologically relevant concentrations. These results suggest that, through adhesion of L. interrogans to endothelial cells, the bacteria may disrupt endothelial barrier function, promoting dissemination of the bacteria and contributing to severe disease manifestations. In addition, supplementing antibiotic therapy with lisinopril or derivatives with endothelial protective activities may decrease the severity of leptospirosis.


Genetic studies of body mass index yield new insights for obesity biology.
Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.


Thermometry, calorimetry, and mean body temperature during heat stress.
Heat balance in humans is maintained at near constant levels through the adjustment of physiological mechanisms that attain a balance between the heat produced within the body and the heat lost to the environment. Heat balance is easily disturbed during changes in metabolic heat production due to physical activity and/or exposure to a warmer environment. Under such conditions, elevations of skin blood flow and sweating occur via a hypothalamic negative feedback loop to maintain an enhanced rate of dry and evaporative heat loss. Body heat storage and changes in core temperature are a direct result of a thermal imbalance between the rate of heat production and the rate of total heat dissipation to the surrounding environment. The derivation of the change in body heat content is of fundamental importance to the physiologist assessing the exposure of the human body to environmental conditions that result in thermal imbalance. It is generally accepted that the concurrent measurement of the total heat generated by the body and the total heat dissipated to the ambient environment is the most accurate means whereby the change in body heat content can be attained. However, in the absence of calorimetric methods, thermometry is often used to estimate the change in body heat content. This review examines heat exchange during challenges to heat balance associated with progressive elevations in environmental heat load and metabolic rate during exercise. Further, we evaluate the physiological responses associated with heat stress and discuss the thermal and nonthermal influences on the body's ability to dissipate heat from a heat balance perspective.


Australian mycophagous species of the genus Deplorothrips (Thysanoptera, Phlaeothripinae).
The genus Deplorothrips Mound & Walker is recorded from Australia for the first time. The genus is found widely across the continent, and descriptions and an illustrated identification key are provided to 14 new species. These have been found living on dead twigs and branches, particularly of Eucalyptus trees. Typical members of this genus have short maxillary stylets that are scarcely retracted into the head capsule, but some of the species have more deeply retracted stylets. Structural polymorphism is recorded in several species, associated both with sex and with body size. Remarkable variation is recorded for some species in the number of sense cones on the antennal segments.


Food allergy: review, classification and diagnosis.
Food allergies, defined as an immune response to food proteins, affect as many as 8% of young children and 2% of adults in westernized countries, and their prevalence appears to be rising like all allergic diseases. In addition to well-recognized urticaria and anaphylaxis triggered by IgE antibody-mediated immune responses, there is an increasing recognition of cell-mediated disorders such as eosinophilic esophagitis and food protein-induced enterocolitis. New knowledge is being developed on the pathogenesis of both IgE and non-IgE mediated disease. Currently, management of food allergies consists of educating the patient to avoid ingesting the responsible allergen and initiating therapy if ingestion occurs. However, novel strategies are being studied, including sublingual/oral immunotherapy and others with a hope for future.


Model-based attenuation of movement artifacts in fMRI.
Behavioral analysis of multi-joint arm reaching has allowed important advances in understanding the control of voluntary movements. Complementing this analysis with functional magnetic resonance imaging (fMRI) would give insight into the neural mechanisms behind this control. However, fMRI is very sensitive to artifacts created by head motion and magnetic field deformation caused by the moving limbs. It is thus necessary to attenuate these motion artifacts in order to obtain correct activation patterns. Most algorithms in literature were designed for slow changes of head position over several brain scans and are not very effective on data when the movement is of duration below the resolution of a brain scan. This paper introduces a simple model-based method to remove motion artifacts during short duration movements. The proposed algorithm can account for head movement and field deformations due to movements within and outside of the scanner's field of view. It uses information from the experimental design and subject kinematics to focus the artifact attenuation in time and space and minimize the loss of uncorrupted data. Applications of the algorithm on arm reaching experimental data obtained with blocked and event-related designs demonstrate attenuation of motion artifacts with minimal effect on the brain activations.


Developmental neurotoxicity study of styrene by inhalation in Crl-CD rats.
This study was conducted to assess potential adverse functional and/or morphological effects of styrene on the neurological system in the F2 offspring following F0 and F1 generation whole-body inhalation exposures. Four groups of male and female Crl:CD (SD)IGS BR rats (25/sex/group) were exposed to 0, 50, 150, and 500 ppm styrene for 6 hr daily for at least 70 consecutive days prior to mating for the F0 and F1 generations. Inhalation exposure continued for the F0 and F1 females throughout mating and through gestation day 20. On lactation days 1 through 4, the F0 and F1 females received styrene in virgin olive oil via oral gavage at dose levels of 66, 117, and 300 mg/kg/day (divided into three equal doses, approximately 2 hr apart). Inhalation exposure of the F0 and F1 females was re-initiated on lactation day 5 and continued through weaning of the F1 or F2 pups on postnatal day (PND) 21. Developmental landmarks were assessed in F1 and F2 offspring. The neurological development of randomly selected pups from the F2 generation was assessed by functional observational battery, locomotor activity, acoustic startle response, learning and memory evaluations, brain weights and dimension measurements, and brain morphometric and histologic evaluation. Styrene exposure did not affect survival or the clinical condition of the animals. As expected from previous studies, slight body weight and histopathologic effects on the nasal olfactory epithelium were found in F0 and F1 rats exposed to 500 ppm and, to a lesser extent, 150 ppm. There were no indications of adverse effects on reproductive performance in either the F0 or F1 generation. There were exposure-related reductions in mean body weights of the F1 and F2 offspring from the mid and high-exposure groups and an overall pattern of slightly delayed development evident in the F2 offspring only from the 500-ppm group. This developmental delay included reduced body weight (which continued through day 70) and slightly delayed acquisition of some physical landmarks of development. Styrene exposure of the F0 and F1 animals had no effect on survival, the clinical condition or necropsy findings of the F2 animals. Functional observational battery evaluations conducted for all F1 dams during the gestation and lactation periods and for the F2 offspring were unaffected by styrene exposure. Swimming ability as determined by straight channel escape times measured on PND 24 were increased, and reduced grip strength values were evident for both sexes on PND 45 and 60 in the 500-ppm group compared to controls. There were no other parental exposure-related findings in the F2 pre-weaning and post-weaning functional observational battery assessments, the PND 20 and PND 60 auditory startle habituation parameters, in endpoints of learning and memory performance (escape times and errors) in the Biel water maze task at either testing age, or in activity levels measured on PND 61 in the 500-ppm group. Taken together, the exposure-related developmental and neuromotor changes identified in F2 pups from dams exposed to 500 ppm occurred in endpoints known to be both age- and weight-sensitive parameters, and were observed in the absence of any other remarkable indicators of neurobehavioral toxicity. Based on the results of this study, an exposure level of 50 ppm was considered to be the NOAEL for growth of F2 offspring; an exposure level of 500 ppm was considered to be the NOAEL for F2 developmental neurotoxicity.


Acute Inactivation of Primary Auditory Cortex Causes a Sound Localisation Deficit in Ferrets.
The objective of this study was to demonstrate the efficacy of acute inactivation of brain areas by cooling in the behaving ferret and to demonstrate that cooling auditory cortex produced a localisation deficit that was specific to auditory stimuli. The effect of cooling on neural activity was measured in anesthetized ferret cortex. The behavioural effect of cooling was determined in a benchmark sound localisation task in which inactivation of primary auditory cortex (A1) is known to impair performance. Cooling strongly suppressed the spontaneous and stimulus-evoked firing rates of cortical neurons when the cooling loop was held at temperatures below 10°C, and this suppression was reversed when the cortical temperature recovered. Cooling of ferret auditory cortex during behavioural testing impaired sound localisation performance, with unilateral cooling producing selective deficits in the hemifield contralateral to cooling, and bilateral cooling producing deficits on both sides of space. The deficit in sound localisation induced by inactivation of A1 was not caused by motivational or locomotor changes since inactivation of A1 did not affect localisation of visual stimuli in the same context.


Affinity maturation and fine functional mapping of an antibody fragment against a novel neutralizing epitope on human vascular endothelial growth factor.
We have previously reported the isolation of a novel single-chain variable fragment (scFv) against vascular endothelial growth factor (VEGF), from a phage-displayed human antibody repertoire. This scFv, denominated 2H1, was shown to block the binding of VEGF to its receptor but exhibited a moderate binding affinity. Here, we describe the affinity maturation of the 2H1 scFv. Two phage-displayed libraries were constructed by diversification of the third complementarity-determining regions (CDRs) of the light (VL) and heavy (VH) chain variable domains of 2H1 using parsimonious mutagenesis. A competitive phage-selection strategy in the presence of the parental scFv as a competitor was used to eliminate low affinity binders. High affinity variants were retrieved from both libraries. An optimized VL variant was designed and constructed by combining recurrent replacements found among selected variants in a single molecule, resulting in an additional affinity increase. Further affinity improvements were achieved by combining this optimized VL with the best VH variants. The final variant obtained here, L3H6, showed an overall affinity improvement of 18-fold over the parental scFv and exhibited an enhanced potency to block the binding of VEGF to its receptor. Using phage display and extensive mutagenesis of VEGF, we determined the fine specificity of L3H6. This functional mapping revealed a novel neutralizing epitope on human VEGF defined by the residues Y25, T71, E72, N100, K101, E103 and R105. The conformational epitope recognized by L3H6 was recapitulated by grafting human VEGF residues into the mouse molecule, providing further confirmation of the nature of the identified epitope.


Racial variations in processes of care for patients with community-acquired pneumonia.
Patients hospitalized with community acquired pneumonia (CAP) have a substantial risk of death, but there is evidence that adherence to certain processes of care, including antibiotic administration within 8 hours, can decrease this risk. Although national mortality data shows blacks have a substantially increased odds of death due to pneumonia as compared to whites previous studies of short-term mortality have found decreased mortality for blacks. Therefore we examined pneumonia-related processes of care and short-term mortality in a population of patients hospitalized with CAP. We reviewed the records of all identified Medicare beneficiaries hospitalized for pneumonia between 10/1/1998 and 9/30/1999 at one of 101 Pennsylvania hospitals, and randomly selected 60 patients at each hospital for inclusion. We reviewed the medical records to gather process measures of quality, pneumonia severity and demographics. We used Medicare administrative data to identify 30-day mortality. Because only a small proportion of the study population was black, we included all 240 black patients and randomly selected 720 white patients matched on age and gender. We performed a resampling of the white patients 10 times. Males were 43% of the cohort, and the median age was 76 years. After controlling for potential confounders, blacks were less likely to receive antibiotics within 8 hours (odds ratio with 95% confidence interval 0.6, 0.4-0.97), but were as likely as whites to have blood cultures obtained prior to receiving antibiotics (0.7, 0.3-1.5), to have oxygenation assessed within 24 hours of presentation (1.6, 0.9-3.0), and to receive guideline concordant antibiotics (OR 0.9, 0.6-1.7). Black patients had a trend towards decreased 30-day mortality (0.4, 0.2 to 1.0). Although blacks were less likely to receive optimal care, our findings are consistent with other studies that suggest better risk-adjusted survival among blacks than among whites. Further study is needed to determine why this is the case.


Sclerosing hemangioma of the lung: an analysis of 44 cases.
Sclerosing hemangioma is a rare benign lung tumor. Preoperative diagnosis of this tumor is difficult, and sometimes even intraoperative frozen sections cannot differentiate it from malignant tumors. Herein, we present our experiences in investigating its characteristics. The medical records and pathological examinations of patients diagnosed with sclerosing hemangioma from 1982 to 2001 at the Division of Thoracic Surgery in Taipei-VGH were retrospectively reviewed. The incidence of sclerosing hemangioma in benign lung tumors resected during that period was 32.8%. There were 44 patients (7 male and 37 female) aged from 16 to 72 years, with a peak at fifth decade, and 72.7% of them were asymptomatic. Accurate preoperative diagnosis by chest CT could be achieved in only 20% (4/20) of patients, and malignancy could not be ruled out in 40% (8/20) of tumors. Histologically, this tumor exhibits four major patterns: solid, sclerotic, papillary and hemorrhagic. Five patients in this series had predominantly one pattern. At least two patterns existed in the remaining 39 patients, including eight patients who had tumors with all four patterns. There was no operative mortality or tumor recurrence despite that different operative methods were undertaken. Although rare, sclerosing hemangioma still accounts for the second common benign lung tumor in the current series. Chest CT and bronchoscopic examinations could not make accurate diagnosis preoperatively, and thoracotomy is usually indicated for definite diagnosis and treatment. Limited resection is warranted in view of uncommon tumor recurrence. In addition, multiple nodular lesions could not exclude the possibility of sclerosing hemangioma.


High-Definition Analysis of Host Protein Stability during Human Cytomegalovirus Infection Reveals Antiviral Factors and Viral Evasion Mechanisms.
Human cytomegalovirus (HCMV) is an important pathogen with multiple immune evasion strategies, including virally facilitated degradation of host antiviral restriction factors. Here, we describe a multiplexed approach to discover proteins with innate immune function on the basis of active degradation by the proteasome or lysosome during early-phase HCMV infection. Using three orthogonal proteomic/transcriptomic screens to quantify protein degradation, with high confidence we identified 35 proteins enriched in antiviral restriction factors. A final screen employed a comprehensive panel of viral mutants to predict viral genes that target >250 human proteins. This approach revealed that helicase-like transcription factor (HLTF), a DNA helicase important in DNA repair, potently inhibits early viral gene expression but is rapidly degraded during infection. The functionally unknown HCMV protein UL145 facilitates HLTF degradation by recruiting the Cullin4 E3 ligase complex. Our approach and data will enable further identifications of innate pathways targeted by HCMV and other viruses.


[Occupational complexity and late-life memory and reasoning abilities].
This study examined the associations between the complexity of an individual's primary lifetime occupation and his or her late-life memory and reasoning performance, using data from 824 community-dwelling participants aged 69-72 years. The complexity of work with data, people, and things was evaluated based on the Japanese job complexity score. The associations between occupational complexity and participant's memory and reasoning abilities were examined in multiple regression analyses. An association was found between more comple work with people and higher memory performance, as well as between more complex work with data and higher reasoning performance, after having controlled for gender, school records, and education. Further, an interaction effect was observed between gender and complexity of work with data in relation to reasoning performance: work involving a high degree of complexity with data was associated with high reasoning performance in men. These findings suggest the need to consider late-life cognitive functioning within the context of adulthood experiences, specifically those related to occupation and gender.


Urinary albumin concentration and long-term cardiovascular risk in acute coronary syndrome patients: a PROVE IT-TIMI 22 substudy.
Albuminuria has been shown to be associated with mortality and cardiovascular events, independent of traditional cardiovascular risk factors. This suggests that albuminuria may not just represent glomerular damage, but may be a marker of more diffuse endothelial dysfunction. We investigated the relationship between urinary albumin levels after an acute coronary syndrome and cardiovascular outcomes in statin treated subjects after acute coronary syndromes (ACS). Furthermore we assessed the effect of intensive statin treatment on albuminuria among patients in the PROVE IT-TIMI 22 trial, in which patients who had been hospitalized with ACS were randomized to pravastatin 40 mg (standard therapy) or atorvastatin 80 mg daily (intensive therapy). In univariate analyses, increasing urine albumin concentration was associated with increased risk of myocardial infarction, stroke, heart failure, and composite of death, myocardial infarction and stroke at 2 years. However, in a multivariable model containing traditional cardiovascular risk factors, albuminuria was not an independent predictor of the primary PROVE IT endpoint of death, myocardial infarction, unstable angina, revascularization and stroke, and was only an independent predictor of all-cause mortality at urinary albumin concentration >300 mcg/ml. There was no significant change in urinary albumin concentration from enrolment to end of study in either the standard or intensive statin therapy groups, and no significant difference between treatment groups. Our results suggest that after an acute coronary syndrome in statin treated patients, microalbuminuria may reflect traditional cardiovascular risk factor burden and offer little prognostic information independent of those factors.


Liver and biliary problems in cystic fibrosis.
Liver disease associated with cystic fibrosis has been increasingly diagnosed during recent years probably due to the combined effect of systematic hepatic assessment and reduced death from extra-hepatic causes of CF patients. In a group of 173 CF patients regularly followed at our Center, cumulative incidence of liver disease was 17% over a mean period of 10 years. Although it generally runs a mild course, it is considered a major complication of CF which may limit survival and quality of life of affected patients. CF-associated liver disease should be considered as the first inherited liver disorder in which the primary defect affects cholangiocyte transport systems. Although data assessing the effects of defective CFTR on cholangiocyte pathobiology are not yet available, the impaired secretory function of the biliary epithelium is considered responsible for reduced biliary fluidity and alkalinity and for subsequent bile duct damage by cytotoxic compounds or infectious agents. No clear association with specific CFTR mutations has been observed. Treatment with ursodeoxycholic acid, aimed at improving biliary secretion in terms of bile viscosity and bile acid composition, is currently the most useful therapeutic approach in CF-associated liver disease. Beneficial effects on liver biochemistry, hepatic excretory function, liver histology, and essential fatty acid status have been reported, but no long-term data exist on its effectiveness on clinically relevant outcomes, such as death or need for transplantation. The effectiveness of bile acid therapy may be higher if started in patients with early stage liver disease, before symptoms have become clinically evident. Early diagnosis and identification of CF patients who are more liable to develop liver disease should be actively pursued.


Setting apart the affected: the use of behavioral criteria in animal models of post traumatic stress disorder.
Post-traumatic stress disorder (PTSD) affects about 20-30% of exposed individuals. Clinical studies of PTSD generally employ stringent criteria for inclusion in study populations, and yet in animal studies the data collection and analysis are generally expressed as a function of exposed vs nonexposed populations, regardless of individual variation in response. Prior data support an approach to animal models analogous to inclusion criteria in clinical studies. This series of studies sought to assess prevalence rates of maladaptive vs adaptive responses determined according to a more stringent approach to the concept of inclusion/exclusion criteria (cutoff behavioral criteria-CBC), consisting of two successive behavioral tests (elevated plus maze and acoustic startle response tests). The rats were exposed to stressors in two different paradigms; exposure to a predator and underwater trauma. The prevalence rates of maladaptive responses to stress in these two distinct models dropped over time from 90% in the acute phase to 25% enduring/maladaptive response at 7 days, to remain constant over 30 days. As setting the affected individuals apart from the unaffected approximates clinical studies, it might also help to clarify some of the pending issues in PTSD research.


"That never would have occurred to me": a qualitative study of medical students' views of a cultural competence curriculum.
The evidence is mixed regarding the efficacy of cultural competence curricula in developing learners' knowledge, attitudes and skills. More research is needed to better understand both the strengths and shortcomings of existing curricula from the perspective of learners in order to improve training. We conducted three focus groups with medical students in their first year of clinical training to assess their perceptions of the cultural competence curriculum at a public university school of medicine. Students evaluated the informal curriculum as a more important source of learning about cultural competence than the formal curriculum. In terms of bias in both self and others, the cultural competence curriculum increased awareness, but was less effective in teaching specific interventional skills. Students also noted that the cultural competence curriculum did not always sufficiently help them find a balance between group-specific knowledge and respect for individual differences. Despite some concerns as to whether political correctness characterized the cultural competence curriculum, it was also seen as a way to rehumanize the medical education experience. Future research needs to pay attention to issues such as perceived relevance, stereotyping, and political correctness in developing cross-cultural training programs.


Do the posterior midline cortices belong to the electrophysiological default-mode network?
The default-mode network (DMN) and its principal core hubs in the posterior midline cortices (PMC), i.e., the precuneus and the posterior cingulate cortex, play a critical role in the human brain structural and functional architecture. Because of their centrality, they are affected by a wide spectrum of brain disorders, e.g., Alzheimer's disease. Non-invasive electrophysiological techniques such as magnetoencephalography (MEG) are crucial to the investigation of the neurophysiology of the DMN and its alteration by brain disorders. However, MEG studies relying on band-limited power envelope correlation diverge in their ability to identify the PMC as a part of the DMN in healthy subjects at rest. Since these works were based on different MEG recording systems and different source reconstruction pipelines, we compared DMN functional connectivity estimated with two distinct MEG systems (Elekta, now MEGIN, and CTF) and two widely used reconstruction algorithms (Minimum Norm Estimation and linearly constrained minimum variance Beamformer). Our results identified the reconstruction method as the critical factor influencing PMC functional connectivity, which was significantly dampened by the Beamformer. On this basis, we recommend that future electrophysiological studies on the DMN should rely on Minimum Norm Estimation (or close variants) rather than on the classical Beamformer. Crucially, based on analytic knowledge about these two reconstruction algorithms, we demonstrated with simulations that this empirical observation could be explained by the existence of a spontaneous linear, approximately zero-lag synchronization structure between areas of the DMN or among multiple sources within the PMC. This finding highlights a novel property of the neural dynamics and functional architecture of a core human brain network at rest.


Long-term follow-up of remission duration, mortality, and second malignancies in hairy cell leukemia patients treated with pentostatin.
The nucleoside analogue, pentostatin, has demonstrated high complete response rates and long relapse-free survival times in patients with hairy cell leukemia, a disease that historically had been unresponsive to treatment. Long-term data on duration of overall survival and relapse-free survival and incidence of subsequent malignancies with this agent are lacking. Patients completing the treatment phase of a randomized, intergroup study who received pentostatin as an initial treatment or who crossed over after failure of interferon alpha were followed for survival, relapse, and diagnosis of subsequent malignancies. Two hundred forty-one patients treated with pentostatin as initial therapy (n = 154) or who crossed over after failure of interferon alpha (n = 87) were followed for a median duration of 9.3 years. Estimated 5- and 10-year survival rates (95% confidence interval) for all patients combined were 90% (87%-94%) and 81% (75%-86%), respectively. In the 173 patients with a confirmed complete response to pentostatin treatment, 5- and 10-year relapse-free survival rates were 85% (80%-91%) and 67% (58%-76%), respectively. Survival curves for patients initially treated with pentostatin and those crossed over were similar. Only 2 of 40 deaths were attributed to hairy cell leukemia. The mortality rate and incidence of subsequent malignancies were not higher than expected in the general population. Pentostatin is a highly effective regimen for hairy cell leukemia that produces durable complete responses. Subsequent malignancies do not appear to be increased with pentostatin treatment.


Targeted advertising, promotion, and price for menthol cigarettes in California high school neighborhoods.
To describe advertising, promotions, and pack prices for the leading brands of menthol and nonmenthol cigarettes near California high schools and to examine their associations with school and neighborhood demographics. In stores (n = 407) within walking distance (0.8 km [1/2 mile]) of California high schools (n = 91), trained observers counted ads for menthol and nonmenthol cigarettes and collected data about promotions and prices for Newport and Marlboro, the leading brand in each category. Multilevel modeling examined the proportion of all cigarette advertising for any menthol brand, the proportion of stores with sales promotions, and the lowest advertised pack price in relation to store types and school/neighborhood demographics. For each 10 percentage point increase in the proportion of Black students, the proportion of menthol advertising increased by 5.9 percentage points (e.g., from an average of 25.7%-31.6%), the odds of a Newport promotion were 50% higher (95% CI = 1.01, 2.22), and the cost of Newport was 12 cents lower (95% CI = -0.18, -0.06). By comparison, the odds of a promotion and the price for Marlboro, the leading brand of nonmenthol cigarettes, were unrelated to any school or neighborhood demographics. In high school neighborhoods, targeted advertising exposes Blacks to more promotions and lower prices for the leading brand of menthol cigarettes. This evidence contradicts the manufacturer's claims that the availability of its promotions is not based on race/ethnicity. It also highlights the need for tobacco control policies that would limit disparities in exposure to retail marketing for cigarettes.


Enhanced visualization of weak colloidal iron signals with Bodian's protein silver for demonstration of perineuronal nets of proteoglycans in the central nervous system.
The present study aimed for a clear visualization of faintly deposited colloidal iron in tissue sections for light microscopy. Paraffin blocks containing paraformaldehyde-fixed brain tissue from healthy adult mice were cut into sections 10-15 microm thick. After deparaffinization, the sections were stained with fine cationic iron colloid at a pH value of 1.0-1.5, and treated with a mixture of potassium ferrocyanide and hydrochloride for Prussian blue reaction. Some sections were further treated with Bodian's protein silver after the Prussian blue reaction. This sensitized development of Prussian blue reaction with Bodian's protein silver more clearly visualized the faintly deposited cationic colloidal irons than the demonstration by Prussian blue reaction alone, and allowed an enhanced visualization of the perineuronal nets of sulfated proteoglycans in the brain. Thus, such fine perineuronal sulfated proteoglycans as those in the CA3 field of the hippocampus, which are weakly stained with cationic iron colloid and usually overlooked by a demonstration with only a Prussian blue reaction, could be clearly visualized with striking contrast by the sensitized development with Bodian's protein silver after the Prussian blue reaction. Preliminary hyaluronidase digestion erased Bodian's protein silver development of perineuronal sulfated proteoglycans. Though some axonal fibers were also additionally stained with Bodian's protein silver itself, this sensitized development is useful to enhance such weak colloidal iron signals as are hardly detectable by only Prussian blue reaction.


The Effect of Flow-Related Aneurysms on Hemorrhagic Risk of Intracranial Arteriovenous Malformations.
Previous reports indicated an association between hemorrhagic presentation and flow-related aneurysms in arteriovenous malformation (AVM) patients. However, it remains unclear whether these flow-related aneurysms result in the hemorrhage of AVM. To characterize this hemorrhage risk using our institutional experience over 25 yr. We retrospectively reviewed records of patients at our institution diagnosed with AVM from 1990 to 2015. Patients without associated aneurysms (AVM only) and those with flow-related aneurysms (AVM-FA) were compared. Those with intranidal or unrelated aneurysms were excluded. Annual risk of AVM-related hemorrhage was calculated using the birth-to-treatment approach and compared using Poisson rate ratio test. Among 526 patients, there were 457 AVM only patients and 69 with flow-related aneurysms. AVM-FA patients were older (P = .005). AVMs with flow-related aneurysms were more likely located in the cerebellar vermis and hemispheres (P = .023 and .001, respectively). Presence of flow-related aneurysms increased the risk of presentation with subarachnoid hemorrhage (P < .001). Interestingly, no significant differences in presenting hemorrhage due to AVM rupture were found (P > .356). The majority of aneurysms were untreated (69.5%), and only 8 (9.8%) had ruptured presentation. At follow-up (mean = 5.3 yr), patients with flow-related aneurysms were less likely to develop seizures (P = .004). The annual risk of AVM hemorrhage was 1.33% and 1.05% for AVM only patients and AVM-FA patients, respectively (P = .248). Despite increased risk of subarachnoid hemorrhage at presentation, there was no increased likelihood of rupture in AVMs with flow-related aneurysms. More studies are warranted, as clarifying the competing risks of AVM vs aneurysm rupture may be critical in determining optimal treatment strategy.


Evaluation of reproductive endocrine status in hornyhead turbot sampled from Southern California's urbanized coastal environments.
As part of a regionwide collaboration to determine the occurrence of contaminants and biological effects in coastal ecosystems offshore of urban southern California, the present study characterized the reproductive endocrinology of an indigenous flatfish, the hornyhead turbot (Pleuronichthys verticalis), and compared groups sampled from different study sites representing varying degrees of pollution to screen for potential endocrine disruptive effects. Turbot were sampled from locations near the coastal discharge sites of four large municipal wastewater treatment plants (WWTPs) located between Los Angeles and San Diego, California, USA, and were compared with fish sampled from three far-field reference locations in the region. Despite environmental presence of both legacy contaminants and contaminants of emerging concern and evidence for fish exposure to several classes of contaminants, both males and females generally exhibited coordinated seasonal reproductive cycles at all study sites. Patterns observed included peaks in sex steroids (17β-estradiol, testosterone, 11-ketotestosterone) in the spring and low levels in the fall, changes corresponding to similarly timed gonadal changes and plasma vitellogenin concentrations in females. Comparisons between fish captured at the different study sites demonstrated some regional differences in plasma levels of estrogens and androgens, indicative of location-associated effects on the endocrine system. The observed differences, however, could not be linked to the ocean discharge locations of four of the largest WWTPs in the world.


Use of Biologic Agents to Promote Bone Formation in Implant Dentistry: A Critical Assessment of Systematic Reviews.
The use of biologic agents is emerging in bone regeneration procedures due to their ability to increase cellular events in wound healing and therefore to obtain more predictable outcomes. Hence, the aim of the present study was to critically evaluate the methodology of systematic reviews investigating biologic agents in promoting bone formation and implant site development. A literature search for systematic reviews with and without meta-analyses was performed in Medline, Embase, and the Cochrane database, as well as in journals with high impact factors in periodontics and implant dentistry. Titles, abstracts, and full-text articles were analyzed for potential inclusion. Three guidelines--AMSTAR, R-AMSTAR, and the checklist proposed by Glenny et al--were utilized to analyze their methodologic quality. Two calibrated reviewers performed all data extraction and appraisal. Cohen's kappa coefficients were calculated to appraise the interexaminer agreement. A total of 12 systematic reviews, 3 with meta-analyses, were evaluated. Platelet-rich derivatives and BMP-2 were the most widely studied biologic agents and sinus augmentation was the most common procedure evaluated. The R-AMSTAR mean score was 28 (range 14-38) and none of the systematic reviews analyzed met all of the items. In the AMSTAR checklist, the mean score was 5.75 (range 2-9) and the only item met by all the systematic reviews was the a priori design. The Glenny et al checklist mean score was 8.6 (range 4-13) and two items, "focused question" and "to identify all relevant studies," were met by all systematic reviews. Systematic reviews on biologic agents demonstrate substantial methodologic variability. Therefore, caution must be exercised when interpreting their findings.


Cell-penetrating peptide conjugates to enhance the antitumor effect of paclitaxel on drug-resistant lung cancer.
To conquer the drug resistance of tumors and the poor solubility of paclitaxel (PTX), two PTX-cell-penetrating peptide conjugates (PTX-CPPs), PTX-TAT and PTX-LMWP, were synthesized and evaluated for the first time. Compared with free PTX, PTX-CPPs displayed significantly enhanced cellular uptake, elevated cell toxicity, increased cell apoptosis, and decreased mitochondrial membrane potential (Δψm) in both A549 and A549T cells. PTX-LMWP exhibited a stronger inhibitory effect than PTX-TAT in A549T cells. Analysis of cell-cycle distribution showed that PTX-LMWP influenced mitosis in drug-resistant A549T tumor cells via a different mechanism than PTX. PTX-CPPs were more efficient in inhibiting tumor growth in tumor-bearing mice than free PTX, which suggested their better in vivo antitumor efficacy. Hence, this study demonstrates that PTX-CPPs, particularly PTX-LMWP, have outstanding potential for inhibiting the growth of tumors and are a promising approach for treating lung cancer, especially drug-resistant lung cancer.


Synthesis, biological evaluation and molecular modeling of 4,6-diarylpyrimidines and diarylbenzenes as novel non-nucleosides HIV-1 reverse transcriptase inhibitors.
A series of novel 4,6-diarylpyrimidines (4,6-DAPY) and diarylbenzenes (DABE) compounds were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Among them, the most potent HIV-1 inhibitors were 8b, 8d, 14b and 18 (EC(50) = 0.049, 0.381, 0.599 and 0.398 μM, respectively), with HIV-1 inhibitory activity improved or similar to nevirapine (NVP, EC(50) = 0.097 μM) and delavirdine (DEV, EC(50) = 0.55 μM). The other compounds displayed moderate activity (8c, EC(50) = 5.25 μM) or were inactive (8a and 14a) against HIV-1 replication. Molecular modeling studies were performed with the synthesized compounds in complex with the wild-type reverse transcriptase (RT). A correlation was found between the anti-HIV activity and the electrostatic energy of interaction with Lys101 residue. These findings enrich the SAR of these Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) families.


Transcriptional profile of hippocampal dentate granule cells in four rat epilepsy models.
Global expression profiling of neurologic or psychiatric disorders has been confounded by variability among laboratories, animal models, tissues sampled, and experimental platforms, with the result being that few genes demonstrate consistent expression changes. We attempted to minimize these confounds by pooling dentate granule cell transcriptional profiles from 164 rats in seven laboratories, using three status epilepticus (SE) epilepsy models (pilocarpine, kainate, self-sustained SE), plus amygdala kindling. In each epilepsy model, RNA was harvested from laser-captured dentate granule cells from six rats at four time points early in the process of developing epilepsy, and data were collected from two independent laboratories in each rodent model except SSSE. Hierarchical clustering of differentially-expressed transcripts in the three SE models revealed complete separation between controls and SE rats isolated 1 day after SE. However, concordance of gene expression changes in the SE models was only 26-38% between laboratories, and 4.5% among models, validating the consortium approach. Transcripts with unusually highly variable control expression across laboratories provide a 'red herring' list for low-powered studies.


Verification of predicted knee replacement kinematics during simulated gait in the Kansas knee simulator.
Evaluating total knee replacement kinematics and contact pressure distributions is an important element of preclinical assessment of implant designs. Although physical testing is essential in the evaluation process, validated computational models can augment these experiments and efficiently evaluate perturbations of the design or surgical variables. The objective of the present study was to perform an initial kinematic verification of a dynamic finite element model of the Kansas knee simulator by comparing predicted tibio- and patellofemoral kinematics with experimental measurements during force-controlled gait simulation. A current semiconstrained, cruciate-retaining, fixed-bearing implant mounted in aluminum fixtures was utilized. An explicit finite element model of the simulator was developed from measured physical properties of the machine, and loading conditions were created from the measured experimental feedback data. The explicit finite element model allows both rigid body and fully deformable solutions to be chosen based on the application of interest. Six degrees-of-freedom kinematics were compared for both tibio- and patellofemoral joints during gait loading, with an average root mean square (rms) translational error of 1.1 mm and rotational rms error of 1.3 deg. Model sensitivity to interface friction and damping present in the experimental joints was also evaluated and served as a secondary goal of this paper. Modifying the metal-polyethylene coefficient of friction from 0.1 to 0.01 varied the patellar flexion-extension and tibiofemoral anterior-posterior predictions by 7 deg and 2 mm, respectively, while other kinematic outputs were largely insensitive.


HAGE, a cancer/testis antigen expressed at the protein level in a variety of cancers.
The search for novel tumour antigens that are either uniquely expressed or over-expressed in a wide variety of tumours is still ongoing. Because of their expression in a broad spectrum of cancers and limited expression in normal tissues, cancer/testis antigens are considered to be potentially reliable targets for immunotherapy of cancer in general. The helicase antigen HAGE has been identified as a cancer/testis antigen. However, little is known about its expression in normal and cancer tissues. Using a newly developed antibody against HAGE, specific staining of its expression by immunohistochemistry was validated and optimised on murine tumours transfected to express the HAGE protein. The antibody was subsequently used to determine HAGE expression in normal human and cancer tissue microarrays. HAGE protein expression was confirmed in 75% (12/16) of carcinomas as compared to normal tissues, which either did not express HAGE at all or expressed HAGE at very low levels with the exception of testis. Interestingly, discrepancies were also found between mRNA analysis by real time quantitative PCR (RT-qPCR) and protein analysis by immunohistochemistry, emphasising the need to validate the expression of cancer/testis antigens at the protein level prior to the development of new vaccine strategies. HAGE is therefore proposed to be a valid candidate for designing a broad spectrum vaccine against cancer.


Delivery of a secreted soluble protein to the vacuole via a membrane anchor.
To further understand how membrane proteins are sorted in the secretory system, we devised a strategy that involves the expression of a membrane-anchored yeast invertase in transgenic plants. The construct consisted of a signal peptide followed by the coding region of yeast invertase and the transmembrane domain and cytoplasmic tail of calnexin. The substitution of a lysine near the C terminus of calnexin with a glutamic acid residue ensured progression through the secretory system rather than retention in or return to the endoplasmic reticulum. In the transformed plants, invertase activity and a 70-kD cross-reacting protein were found in the vacuoles. This yeast invertase had plant-specific complex glycans, indicating that transport to the vacuole was mediated by the Golgi apparatus. The microsomal fraction contained a membrane-anchored 90-kD cross-reacting polypeptide, but was devoid of invertase activity. Our results indicate that this membrane-anchored protein proceeds in the secretory system beyond the point where soluble proteins are sorted for secretion, and is detached from its membrane anchor either just before or just after delivery to the vacuole.


Are non-monetary rewards effective in attracting peer reviewers? A natural experiment.
Editors of scientific journals meet increasing challenges to find peer reviewers. Rewarding reviewers has been proposed as a solution to incentives peer review, and journals have already started to offer different kinds of rewards, particularly non-monetary ones. However, research so far has mainly explored the efficacy of monetary rewards, while research on non-monetary rewards is barely absent. The goal of this article is to fill this gap by exploring whether and under what conditions a rather common non-monetary reward employed by journals, i.e., to recognize reviewers work by publishing their names on a yearly issue, is effective in increasing the willingness of scientists to become peer reviewers. We test the efficacy of three different reward settings identified in the literature: (1) engagement contingent, (2) task-completion contingent, and (3) performance contingent, through a natural experiment involving 1865 scientists in faculties of business and economics of Romanian universities. We explore whether reward efficacy varies across scientists depending on their gender, academic rank, research productivity, and type of institution to which they are affiliated. The results show that the performance contingency strongly reduces the number of respondents willing to become reviewers (- 60 % compared to a no-reward setting), particularly males and research productive scientists. Scientists affiliated with private universities are strongly discouraged by the reward. In sum, the results suggest that non-monetary rewards are not necessarily effective, as in some cases they may actually discourage the most intrinsically motivated and competent reviewers.


CDK phosphorylation of a novel NLS-NES module distributed between two subunits of the Mcm2-7 complex prevents chromosomal rereplication.
Cyclin-dependent kinases (CDKs) use multiple mechanisms to block reassembly of prereplicative complexes (pre-RCs) at replication origins to prevent inappropriate rereplication. In Saccharomyces cerevisiae, one of these mechanisms promotes the net nuclear export of a pre-RC component, the Mcm2-7 complex, during S, G2, and M phases. Here we identify two partial nuclear localization signals (NLSs) on Mcm2 and Mcm3 that are each necessary, but not sufficient, for nuclear localization of the Mcm2-7 complex. When brought together in cis, however, the two partial signals constitute a potent NLS, sufficient for robust nuclear localization when fused to an otherwise cytoplasmic protein. We also identify a Crm1-dependent nuclear export signal (NES) adjacent to the Mcm3 NLS. Remarkably, the Mcm2-Mcm3 NLS and the Mcm3 NES are sufficient to form a transport module that recapitulates the cell cycle-regulated localization of the entire Mcm2-7 complex. Moreover, we show that CDK regulation promotes net export by phosphorylation of the Mcm3 portion of this module and that nuclear export of the Mcm2-7 complex is sufficient to disrupt replication initiation. We speculate that the distribution of partial transport signals among distinct subunits of a complex may enhance the specificity of protein localization and raises the possibility that previously undetected distributed transport signals are used by other multiprotein complexes.


Alloreactive cloned T cell lines. V. Differential kinetics of IL 2, CSF, and BCSF release by a cloned T amplifier cell and its variant.
A noncytolytic, Thy-1+, MIs-responsive cloned T amplifier cell, designated L2, derived from secondary C57BL/6 anti-DBA/2 mixed leukocyte culture was found to produce IL 2 (Interleukin 2), granulocyte/macrophage colony-stimulating factor (CSF), and a polyclonal B cell-stimulating factor (BCSF) after alloantigenic stimulation. IL 2 activity was present transiently, with maximal levels observed 12 to 24 hr after exposure to alloantigen. Only trace amounts were present 96 hr after initiation of culture. CSF and BCSF activities were present at high levels by 24 hr and remained elevated throughout an 8-day culture period. Further evidence that the lymphokine(s) having IL 2 activity is different from those having CSF and BCSF activities was provided by L2V, a variant of L2 that did not produce IL 2. The time course of CSF and BCSF production by L2V after stimulation with alloantigen was similar to that found with L2, although IL 2 activity was not detected at any time. Since the release of lymphokines from both L2 and L2V cells could be induced by Con A in the absence of stimulating alloantigen, it is likely that the biologically active factors were produced by the cloned T cell.


Comparative analytics of infusion pump data across multiple hospital systems.
A Web-based analytics system for conducting inhouse evaluations and cross-facility comparisons of alert data generated by smart infusion pumps is described. The Infusion Pump Informatics (IPI) project, a collaborative effort led by research scientists at Purdue University, was launched in 2009 to provide advanced analytics and tools for workflow analyses to assist hospitals in determining the significance of smart-pump alerts and reducing nuisance alerts. The IPI system allows facility-specific analyses of alert patterns and trends, as well as cross-facility comparisons of alert data uploaded by more than 55 participating institutions using different types of smart pumps. Tools accessible through the IPI portal include (1) charts displaying aggregated or breakout data on the top drugs associated with alerts, numbers of alerts per device or care area, and override-to-alert ratios, (2) investigative reports that can be used to characterize and analyze pump-programming errors in a variety of ways (e.g., by drug, by infusion type, by time of day), and (3) "drill-down" workflow analytics enabling users to evaluate alert patterns—both internally and in relation to patterns at other hospitals—in a quick and efficient stepwise fashion. The formation of the IPI analytics system to support a community of hospitals has been successful in providing sophisticated tools for member facilities to review, investigate, and efficiently analyze smart-pump alert data, not only within a member facility but also across other member facilities, to further enhance smart pump drug library design.


The dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016), cooperates with tamoxifen to inhibit both cell proliferation- and estrogen-dependent gene expression in antiestrogen-resistant breast cancer.
Effective treatment of estrogen receptor (ER)-positive breast cancers with tamoxifen is often curtailed by the development of drug resistance. Antiestrogen-resistant breast cancers often show increased expression of the epidermal growth factor receptor family members, ErbB1 and ErbB2. Tamoxifen activates the cyclin-dependent kinase inhibitor, p27 to mediate G(1) arrest. ErbB2 or ErbB1 overexpression can abrogate tamoxifen sensitivity in breast cancer lines through both reduction in p27 levels and inhibition of its function. Here we show that the dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016), can restore tamoxifen sensitivity in ER-positive, tamoxifen-resistant breast cancer models. Treatment of MCF-7(pr), T-47D, and ZR-75 cells with lapatinib or tamoxifen alone caused an incomplete cell cycle arrest. Treatment with both drugs led to a more rapid and profound cell cycle arrest in all three lines. Mitogen-activated protein kinase and protein kinase B were inhibited by lapatinib. The two drugs together caused a greater reduction of cyclin D1 and a greater p27 increase and cyclin E-cdk2 inhibition than observed with either drug alone. In addition to inhibiting mitogenic signaling and cell cycle progression, lapatinib inhibited estrogen-stimulated ER transcriptional activity and cooperated with tamoxifen to further reduce ER-dependent transcription. Lapatinib in combination with tamoxifen effectively inhibited the growth of tamoxifen-resistant ErbB2 overexpressing MCF-7 mammary tumor xenografts. These data provide strong preclinical data to support clinical trials of ErbB1/ErbB2 inhibitors in combination with tamoxifen in the treatment of human breast cancer.


Maternal nutrition among women from Sub-Saharan Africa, with a focus on Nigeria, and potential implications for pregnancy outcomes among immigrant populations in developed countries.
Pregnant women in countries of Sub-Saharan Africa (SSA) are at risk of poor nutritional status and adverse outcomes as a result of poverty, food insecurity, sub-optimal healthcare facilities, frequent infections and frequent pregnancies. Studies from Nigeria, for example, have revealed a high prevalence of both under- and over-nutrition, as well as nutrient deficiencies, including iron, folate, vitamin D and vitamin A. Subsequently, obstetric complications, including hypertension, anaemia, neural tube defects, night-blindness, low birth weight and maternal and perinatal mortality, are common. Migration patterns from SSA to the Western world are on the rise in recent years, with Nigerians now representing the most prevalent immigrant African population in many developed countries. However, the effect of immigration, if any, on the nutritional status and pregnancy outcomes of these women in their host countries has not yet been studied. Consequently, it is unknown to what extent the nutritional deficiencies and pregnancy complications occurring in Nigeria, and other countries of SSA, present in these women post-emigration. This may result in missed opportunities for appropriate antenatal care of a potential high-risk group in pregnancy. The present review discusses the literature regarding nutrition in pregnancy among SSA women, using Nigeria as an example, the common nutrition-related complications that arise and the subsequent obstetric outcomes. The concept of dietary acculturation among immigrant groups is also discussed and deficiencies in the literature regarding studies on the diets of pregnant immigrant women are highlighted.


Discovery Genome-Wide Association Study of Body Composition in 4,386 Adults From the UK Biobank's Pilot Imaging Enhancement Study.
Body composition (fat, skeletal muscle and bone mass) is an important determinant of overall health and risk of endocrine disorders such as type 2 diabetes and osteoporosis. Although diet and physical activity are strongly implicated, body composition is also heritable. We conducted a discovery genome-wide association study on 31 phenotypes from the three-compartment body composition model (fat, lean and bone mass) in a set of 4 386 individuals (n = 2 109 males, n = 2 294 females) from the UK Biobank pilot imaging enhancement program that underwent a dual energy X-ray absorptiometry (DXA) scan for assessment of body composition and genetic screening. From 6 137 607 imputed single nucleotide polymorphisms (SNPs) we identified 17 body composition loci (P<5.0 x 10-8). GWAS from the combined dataset identified four statistically significant SNPs (rs7592270, rs145972737, rs13212044, rs77772562). In sex-stratified GWAS, 10 male specific SNPs across all traits were identified and five female specific SNPs. Of the 17 SNPs, six were in or close to a gene where there was a plausible functional connection. Three SNPs (rs7592270, rs77772562 and rs7552312) were correlated with obesity phenotypes, one SNP (rs2236705) with lean phenotypes and two with bone mass phenotypes (rs112098641 and rs113380185). These results highlight candidate genes and biological pathways related to body composition, including glucose metabolism and estrogen regulation, that are of interest to replicate in future studies.


Muscle Activity in Upper-Body Single-Joint Resistance Exercises with Elastic Resistance Bands vs. Free Weights.
Elastic resistance bands require little space, are light and portable, but their efficacy has not yet been established for several resistance exercises. The main objective of this study was to compare the muscle activation levels induced by elastic resistance bands versus conventional resistance training equipment (dumbbells) in the upper-body resistance exercises flyes and reverse flyes. The level of muscle activation was measured with surface electromyography in 29 men and women in a cross-over design where resistance loadings with elastic resistance bands and dumbbells were matched using 10-repetition maximum loadings. Elastic resistance bands induced slightly lower muscle activity in the muscles most people aim to activate during flyes and reverse flies, namely pectoralis major and deltoideus posterior, respectively. However, elastic resistance bands increased the muscle activation level substantially in perceived ancillary muscles, that is deltoideus anterior in flyes, and deltoideus medius and trapezius descendens in reverse flyes, possibly due to elastic bands being a more unstable resistance modality. Overall, the results show that elastic resistance bands can be considered a feasible alternative to dumbbells in flyes and reverse flyes.


The Relation Between Intellectual Functioning and Adaptive Behavior in the Diagnosis of Intellectual Disability.
Intellectual disability originates during the developmental period and is characterized by significant limitations both in intellectual functioning and in adaptive behavior as expressed in conceptual, social, and practical adaptive skills. In this article, we present a brief history of the diagnostic criteria of intellectual disability for both the DSM-5 and AAIDD. The article also (a) provides an update of the understanding of adaptive behavior, (b) dispels two thinking errors regarding mistaken temporal or causal link between intellectual functioning and adaptive behavior, (c) explains that there is a strong correlational, but no causative, relation between intellectual functioning and adaptive behavior, and (d) asserts that once a question of determining intellectual disability is raised, both intellectual functioning and adaptive behavior are assessed and considered jointly and weighed equally in the diagnosis of intellectual disability. We discuss the problems created by an inaccurate statement that appears in the DSM-5 regarding a causal link between deficits in intellectual functioning and adaptive behavior and propose an immediate revision to remove this erroneous and confounding statement.


Supracondylar dome osteotomy for cubitus valgus deformity associated with a lateral condylar nonunion in children.
Open reduction, autogenous bone-grafting, and internal fixation for the treatment of established nonunion of the lateral condyle associated with a cubitus valgus deformity has a high rate of complications. As a consequence, we developed a new technique that includes in situ compression fixation of the lateral condylar nonunion and a dome-shaped supracondylar osteotomy of the distal aspect of the humerus through a single posterior incision. Eight consecutive patients were treated with the new surgical technique between 1994 and 2000. The mean age at the time of surgery was 8.6 years. The mean interval between the lateral condylar fracture and surgery was 4.9 years. The mean preoperative radiographic humerus-ulna angle was 31 degrees of valgus. The postoperative results were classified with a modification of the scoring system described by Dhillon et al., which assesses pain, weakness, range of motion, the humerus-ulna angle, and prominence of the medial epicondyle on a 12-point scale. All eight lateral condylar nonunions achieved union within three months postoperatively. The mean postoperative humerus-ulna angle was 5.5 degrees of valgus. All of the supracondylar dome osteotomies healed uneventfully, and there was no loss of correction postoperatively. The mean duration of follow-up was 4.5 years. The overall results were excellent in two patients, good in four patients, and fair in two patients. With better exposure of the lateral condylar nonunion through a posterior approach, we can effectively stabilize the lateral condylar nonunion and avoid postoperative loss of motion and osteonecrosis of the condyle. With a dome-shaped supracondylar osteotomy, we can correct the cubitus valgus deformity and avoid the development of a medial epicondylar prominence. With careful selection of patients, this new technique can be an effective method to treat this clinically challenging problem.


Effect of linker and spacer on the design of a fibronectin-mimetic peptide evaluated via cell studies and AFM adhesion forces.
The design of a fibronectin-mimetic peptide that specifically binds to the alpha 5beta 1 integrin has been widely studied because of this integrin's participation in many physiological and pathological processes. A promising design for such a peptide includes both the primary binding site RGD and the synergy site PHSRN connected by a linker and extended off of a surface by a spacer. Our original hypothesis was that the degree of hydrophobicity/hydrophilicity between the two sequences (RGD and PHSRN) in fibronectin is an important parameter in designing a fibronectin-mimetic peptide (Mardilovich, A.; Kokkoli, E. Biomacromolecules 2004, 5, 950-957). A peptide-amphiphile, PR_b, that was previously designed in our laboratory employed a hydrophobic tail connected to the N terminus of a peptide headgroup that was composed of a spacer, the synergy site sequence, a linker mimicking both the distance and hydrophobicity/hydrophilicity present in the native protein fibronectin (thus presenting an overall "neutral" linker), and finally the primary binding sequence. Even though our previous work (Mardilovich, A.; Craig, J. A.; McCammon, M. Q.; Garg, A.; Kokkoli, E. Langmuir 2006, 22, 3259-3264) demonstrated that PR_b is a promising sequence compared to fibronectin, this is the first study that tests our hypothesis by comparing PR_b to other peptides with hydrophobic or hydrophilic linkers. Furthermore, different peptide-amphiphiles were designed that could be used to study the effect of building blocks systematically, such as the peptide headgroup linker length and hydrophobicity/hydrophilicity as well as the headgroup spacer length on integrin adhesion. Circular dichroism spectroscopy was first employed, and the collected spectra demonstrated that only one peptide-amphiphile exhibited a secondary structure. Their surface topography was evaluated by taking atomic force microscopy (AFM) images of Langmuir-Blodgett peptide-amphiphile membranes supported on mica. Their adhesion was first evaluated with AFM force measurements between the different sequences and an AFM tip functionalized with purified integrins. The amphiphiles were further characterized via 1-12 h cell studies that examined human umbilical vein endothelial cell adhesion and extracellular matrix fibronectin production. The AFM studies were in good agreement with the cell studies. Overall, the adhesion studies validated our hypothesis and demonstrated for the first time that a "neutral" linker, which more closely mimics the cell adhesion domain of fibronectin, supports higher levels of adhesion compared to other peptide designs with a hydrophobic or hydrophilic linker or even fibronectin. Neutral linker lengths that were within the distance found between PHSRN and RGD in fibronectin performed equally well. However, the 10 amino acid neutral linker gave slightly better cell adhesion than did the control fibronectin at all times. Also, a short spacer was shown to give higher adhesion than other sequences with no spacer or a longer spacer, suggesting that a short spacer is necessary to extend the sequence further away from the interface. In conclusion, this work outlines a logical approach that can be applied for the rational design of any protein-mimetic peptide with two binding sites.


Ionizing radiation exposure to patients admitted with acute myocardial infarction in the United States.
Invasive and noninvasive cardiovascular imaging is beneficial in the care of patients admitted with acute myocardial infarction. Little is known about patients' cumulative radiation exposure. All patients admitted with an acute myocardial infarction to any of 49 University HealthSystem Consortium member hospitals from 2006 to 2009 were reviewed for inpatient procedures involving ionizing radiation that included chest radiograph, computed tomogram scans, radionuclide imaging, diagnostic cardiac catheterization, and percutaneous coronary intervention. The average cumulative effective radiation dose per patient was estimated on the basis of published typical effective radiation doses for imaging procedures. Patients (n=64 071) admitted for acute myocardial infarction had a median age of 64.9 years. A total of 276 651 procedures involving ionizing radiation were performed during the study period, a median of 4.3 procedures per patient per admission. The majority of patients had invasive catheterization (77%), followed by computed tomogram scans (52%), mostly body examinations. The median cumulative effective radiation dose delivered was 15.02 mSv per patient per acute myocardial infarction admission. Postprocedural bleeding was a significant predictor of radiation exposure (odds ratio, 2.01; 95% confidence interval, 1.85 to 2.18), together with postprocedural mechanical complications resulting from device implantation (odds ratio, 2.86; 95% confidence interval, 2.61 to 3.13). Patients with higher underlying clinical complexity (defined by severity of illness scores) had higher radiation exposure and higher mortality (P<0.0001). There was also significant geographic variation in radiation exposure; patients in New England received the lowest cumulative exposure (odds ratio, 0.78; 95% confidence interval, 0.74 to 0.81). Acute myocardial infarction inpatients are exposed to an approximate median radiation dose of 15 mSv. This exposure is a result of multiple cardiovascular and noncardiovascular procedures. Efforts should be made to understand the risks and benefits of radiation exposure per episode of care for acute myocardial infarction.


Role of lysosome rupture in controlling Nlrp3 signaling and necrotic cell death.
The Nod-like receptor, Nlrp3, has been linked to inflammatory diseases and adjuvant-mediated immune responses. A wide array of structurally diverse agents does not interact directly with Nlrp3, but is thought to activate the Nlrp3 inflammasome by inducing a common upstream signal, such as lysosome rupture. To test the connection between lysosome integrity and Nlrp3 signaling, we analyzed inflammasome activation following stimulation of murine macrophages with lysosome-destabilizing agents and pyroptosis inducers. Here we provide evidence that lysosomal rupture and the corresponding release of lysosomal hydrolases is an early event in macrophages exposed to the lysosome-destabilizing adjuvants LLOMe and alum. Lysosome rupture preceded cell death induction mediated by these agents and was associated with the degradation of low-molecular weight proteins, including the inflammasome component caspase-1. Proteolysis of caspase-1 was controlled by specific cathepsins, but was independent of autocatalytic processes and Nlrp3 signaling. Consistent with these findings, lysosome-disrupting agents triggered only minimal caspase-1 activation and failed to cause caspase-1-dependent cell death (pyroptosis), generally associated with Nlrp3 signaling. In contrast, lysosome rupture was a late event in macrophages exposed to prototypical pyroptosis inducers. These agents triggered extensive Nlrp3 signaling prior to lysosome rupture with only minimal impact on the cellular proteome. Taken together, our findings suggest that lysosome impairment triggers a cascade of events culminating in cell death but is not crucial for Nlrp3 signaling. The significant differences observed between lysosome-disrupting agents and pyroptosis inducers might explain the distinct immunologic responses associated with these compounds.


Therapeutic potential of n-3 polyunsaturated fatty acids in disease.
The potential therapeutic benefits of supplementation with n-3 polyunsaturated fatty acids (PUFAs) in various diseases are reviewed, and the antiinflammatory actions, activity, and potential drug interactions and adverse effects of n-3 PUFAs are discussed. Fish oils are an excellent source of long-chain n-3 PUFAs, such as eicosapentaenoic acid and docosahexaenoic acid. After consumption, n-3 PUFAs can be incorporated into cell membranes and reduce the amount of arachidonic acid available for the synthesis of proinflammatory eicosanoids (e.g., prostaglandins, leukotrienes). Likewise, n-3 PUFAs can also reduce the production of inflammatory cytokines, such as tumor necrosis factor alpha, interleukin-1, and interleukin-6. Considerable research has been conducted to evaluate the potential therapeutic effects of fish oils in numerous conditions, including arthritis, coronary artery disease, inflammatory bowel disease, asthma, and sepsis, all of which have inflammation as a key component of their pathology. Additional investigations into the use of supplementation with fish oils in patients with neural injury, cancer, ocular diseases, and critical illness have recently been conducted. The most commonly reported adverse effects of fish oil supplements are a fishy aftertaste and gastrointestinal upset. When recommending an n-3 PUFA, clinicians should be aware of any possible adverse effect or drug interaction that, although not necessarily clinically significant, may occur, especially for patients who may be susceptible to increased bleeding (e.g., patients taking warfarin). The n-3 PUFAs have been shown to be efficacious in treating and preventing various diseases. The wide variation in dosages and formulations used in studies makes it difficult to recommend dosages for specific treatment goals.


In situ synthesis of uniform Fe2O3/BiOCl p/n heterojunctions and improved photodegradation properties for mixture dyes.
The xFe2O3/yBiOCl composites (xFe/yBi, x/y = 0/100, 5/100, 10/100, 20/100, 30/100 and 40/100 molar ratios) are prepared for the first time through an in situ hydrolysis method under hydrothermal conditions. The samples are characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), selected area electron diffraction (SAED) and UV-visible diffuse reflectance spectroscopy (UV-DRS). The photodegradation performances of the xFe/yBi samples are investigated using a simulated industrial wastewater mixture containing both rhodamine B (RhB) and methyl orange (MO). The uniform Fe2O3 nanocubes are found to be well distributed on the BiOCl nanosheets. Moreover, the xFe/yBi photocatalysts exhibit unexpectedly higher efficiencies than bare BiOCl or Fe2O3 under ultraviolet light irradiation (λ ≤ 420 nm). Specifically, the degradation rates of the xFe/yBi samples at x/y = 5/100 and 10/100 are four times higher than that of bare BiOCl for MO-RhB mixed dye solutions. Their high photocatalytic activities are mainly attributed to the formation of stable p/n heterojunctions between Fe2O3 and BiOCl, which greatly improve the separation of photogenerated carriers. Importantly, the highly efficient and inexpensive xFe/yBi p/n heterojunctions are expected to be useful in practical industrial wastewater applications involving complicated toxic components.


Engraftment and survival after unrelated-donor bone marrow transplantation: a report from the national marrow donor program.
We analyzed engraftment of unrelated-donor (URD) bone marrow in 5246 patients who received transplants facilitated by the National Marrow Donor Program between August 1991 and June 1999. Among patients surviving at least 28 days, 4% had primary graft failure (failure to achieve an absolute neutrophil count > 5 x 10(8)/L before death or second stem-cell infusion). Multivariate logistic regression analysis showed that engraftment was associated with marrow matched at HLA-A, HLA-B, and DRB1; higher cell dose; younger recipient; male recipient; and recipient from a non-African American ethnic group. More rapid myeloid engraftment was associated with marrow serologically matched at HLA-A and HLA-B, DRB1 match, higher cell dose (in non-T-cell-depleted cases), younger recipient, recipient seronegativity for cytomegalovirus (CMV), male donor, no methotrexate for graft-versus-host disease prophylaxis, and transplantation done in more recent years. A platelet count higher than 50 x 10(9)/L was achieved by 47% of patients by day 100. Conditional on survival to day 100, survival at 3 years was 61% in those with platelet engraftment at day 30, 58% in those with engraftment between day 30 and day 100, and 33% in those without engraftment at day 100 (P <.0001). Factors favoring platelet engraftment were higher cell dose, DRB1 allele match, recipient seronegativity for CMV, HLA-A and HLA-B serologically matched donor, and male donor. Secondary graft failure occurred in 10% of patients achieving initial engraftment, and 18% of those patients are alive. These data demonstrate that quality of engraftment is an important predictor of survival after URD bone marrow transplantation.


A yeast GTPase-activating protein that interacts specifically with a member of the Ypt/Rab family.
Members of the Ras superfamily of GTP-binding proteins are involved in a variety of cellular processes, including signal transduction, cytoskeletal organization and protein transport. GTP-binding proteins of the Ypt/Rab family direct vesicular protein transport in the secretory and endocytic pathways in the yeast Saccharomyces cerevisiae (Ypt proteins) and in mammalian systems (Rab proteins). The cellular activity of monomeric GTP-binding proteins is influenced by proteins that regulate GDP/GTP exchange and GTP hydrolysis. GTPase-activating proteins (GAPs) can increase the slow intrinsic GTPase activity of GTP-binding proteins by several orders of magnitude. As GAPs modulate the activity of GTP-binding proteins, they are thought to give a biochemical handle on the functioning of Ypt/Rab proteins in transport vesicle budding and docking or fusion at donor and acceptor membranes. We report here the first cloned GTPase-activating protein for the Ypt/Rab protein family. The gene, GYP6 (GAP of Ypt6 protein), encodes a protein of 458 amino acids which is highly specific for the Ypt6 protein and shows little or no cross-reactivity with other Ypt/Rab family members or with H-Ras p21.


Using macromolecular-crystallography beamline and microfluidic platform for small-angle diffraction studies of lipidic matrices for membrane-protein crystallization.
Macromolecular-crystallography (MX) beamlines routinely provide a possibility to change X-ray beam energy, focus the beam to a size of tens of microns, align a sample on a microdiffractometer using on-axis video microscope, and collect data with an area-detector positioned in three dimensions. These capabilities allow for running complementary measurements of small-angle X-ray scattering and diffraction (SAXS) at the same beamline with such additions to the standard MX setup as a vacuum path between the sample and the detector, a modified beam stop, and a custom sample cell. On the 21-ID-D MX beamline at the Advanced Photon Source we attach a vacuum flight tube to the area detector support and use the support motion for aligning a beam stop built into the rear end of the flight tube. At 8 KeV energy and 1 m sample-to-detector distance we can achieve a small-angle resolution of 0.01A-1 in the reciprocal space. Measuring SAXS with this setup, we have studied phase diagrams of lipidic mesophases used as matrices for membrane-protein crystallization. The outcome of crystallization trials is significantly affected by the structure of the lipidic mesophases, which is determined by the composition of the crystallization mixture. We use a microfluidic chip for the mesophase formulation and in situ SAXS data collection. Using the MX beamline and the microfluidic platform we have demonstrated the viability of the high-throughput SAXS studies facilitating screening of lipidic matrices for membrane-protein crystallization.


Binocular vision with primary microstrabismus.
Patients with primary microstrabismus have a high degree of binocularity, which suggests that their ocular misalignment may have a sensory rather than an oculomotor origin, as in large-angle strabismus. The purpose of these experiments was to determine whether microstrabismic subjects have sensory abnormalities that could give rise to a small angle of strabismus. The binocular disparity response functions for sensory and motor processes were compared in seven orthotropic subjects and six strabismic subjects (four with primary microstrabismus and two with infantile esotropia). Binocularity was assessed by disparity vergence (central and peripheral stimuli) and depth discrimination (relative and absolute disparities) measures. Motor and sensory disparity response functions were both determined by psychophysical methods: vergence responses by dichoptic nonius alignment and sensory responses by forced-choice depth discrimination. All the strabismic subjects demonstrated normal retinal correspondence with peripheral binocular stimuli and anomalous retinal correspondence with central fusion stimuli. The microstrabismic subjects' disparity vergence responses with peripheral fusion stimuli were centered on disparities relative to their angle of strabismus. However, with central fusion stimuli, the disparity vergence responses were relative to the subjective angle of strabismus. The microstrabismic subjects' stereoacuities were substantially reduced, but their discrimination responses did not show an asymmetry indicative of an unrepresented population of disparity-selective mechanisms. The data do not support a sensory abnormality as the primary cause of microstrabismus. The results are not compatible with an oculomotor adaptation to an inherent anomalous correspondence or with a strabismus caused by an absence of a class of disparity-selective mechanisms. Thus, just as in large-angle strabismus, the anomalous retinal correspondence and defective stereopsis of microstrabismus appear to be consequences of abnormal visual experience caused by an interocular deviation.


Response to high osmotic conditions and elevated temperature in Saccharomyces cerevisiae is controlled by intracellular glycerol and involves coordinate activity of MAP kinase pathways.
In the yeast Saccharomyces cerevisiae, response to an increase in external osmolarity is mediated by the HOG (high osmolarity glycerol) MAP kinase pathway. HOG pathway mutant strains display osmosensitive phenotypes. Recently evidence has been obtained that the osmosensitivity of HOG pathway mutants is reduced during growth at elevated temperature (37 degrees C). A notable exception is the ste11ssk2ssk22 mutant, which displays hypersensitivity to osmotic stress at 37 degrees C. This paper reports that overexpression of FPS1 or GPD1 (encoding the glycerol transport facilitator and glycerol-3-phosphate dehydrogenase, respectively, and both affecting intracellular glycerol levels) reduces the hypersensitivity to osmotic stress of ste11ssk2ssk22 at 37 degrees C. Although in this particular HOG pathway mutant a correlation between suppression of the phenotype and glycerol content could be demonstrated, the absolute level of intracellular glycerol per se does not determine whether a strain is osmosensitive or not. Rather, evidence was obtained that the glycerol level may have an indirect effect, viz. by influencing signalling through the PKC (protein kinase C) MAP kinase pathway, which plays an important role in maintenance of cellular integrity. In order to validate the data obtained with a HOG pathway mutant strain for wild-type yeast cells, MAP kinase signalling under different growth conditions was examined in wild-type strains. PKC pathway signalling, which is manifest at elevated growth temperature by phosphorylation of MAP kinase Mpk1p, is rapidly lost when cells are shifted to high external osmolarity conditions. Expression of bck1-20 or overexpression of WSC3 in wild-type cells resulted in restoration of PKC signalling. Both PKC and HOG signalling, cell wall phenotypes and high osmotic stress responses in wild-type cells were found to be influenced by the growth temperature. The data taken together indicate the intricate interdependence of growth temperature, intracellular glycerol, cell wall structure and MAP kinase signalling in the hyperosmotic stress response of yeast.


Severe Pleuropulmonary Paragonimiasis Caused by Paragonimus mexicanus Treated as Tuberculosis in Ecuador.
A 30-year-old male, from a subtropical region of Ecuador, was hospitalized with a 5-year history of persistent cough with rusty brown sputum, chest pain, and progressive dyspnea. The patient underwent thoracic surgery 3 years ago for pleural effusion and subsequently received a 9-month regimen treatment of tuberculosis. However, there was no clinical resolution and symptoms became progressively worse. A chest radiograph and computerized tomography scan showed several small nodules in both lungs. Eggs of Paragonimus spp. were observed in sputum smears, but the smears were negative for acid-fast bacilli. Molecular characterization of eggs by the internal transcribed spacer-2 regions identified them as Paragonimus mexicanus The patient was treated with praziquantel and tested negative parasitologically for 12 months. There was clinical resolution of the cough and expectoration, but dyspnea and chest pain persisted.


Triple-wavelength, narrowband Mg/SiC multilayers with corrosion barriers and high peak reflectance in the 25-80 nm wavelength region.
We have developed new, Mg/SiC multilayer coatings with corrosion barriers which can be used to efficiently and simultaneously reflect extreme ultraviolet (EUV) radiation in single or multiple narrow bands centered at wavelengths in the spectral region from 25 to 80 nm. Corrosion mitigation was attempted through the use of Al-Mg or Al thin layers. Three different multilayer design concepts were developed and deposited by magnetron sputtering and the reflectance was measured at near-normal incidence in a broad spectral range. Standard Mg/SiC multilayers were also deposited and measured for comparison. They were shown to efficiently reflect radiation at a wavelength of 76.9 nm with a peak reflectance of 40.6% at near-normal incidence, the highest experimental reflectance reported at this wavelength for a narrowband coating. The demonstration of multilayer coatings with corrosion resistance and multiple-wavelength EUV performance is of great interest in the development of mirrors for space-borne solar physics telescopes and other applications requiring long-lasting coatings with narrowband response in multiple emission lines across the EUV range.