Occupational allergy to locusts: an investigation of the sources of the allergen.
Allergic symptoms occur commonly in subjects working closely with locusts and are associated with specific IgE antibody. Extracts of intact locusts (Schistocerca gregaria and Locusta migratoria) were used to identify specific IgE antibody, to define the major allergens of the locust and their sources, and to estimate aeroallergen concentration in the working environment. With questionnaire, skin prick tests, and specific IgE measurements, 35 individuals, working in a research center, were surveyed. Of the 15 currently exposed individuals, contact with locusts provoked asthma, rhinitis, and contact urticaria in five, rhinitis and urticaria in three, and rhinitis alone in one individual. Symptoms provoked by locusts and skin test reactions to locust extracts were associated with specific IgE antibody in the serum. The "immunoblot" technique demonstrated the presence of multiple allergens in the locust extracts of approximately 68, 66, 54, 43, 37, 29, and 18 K daltons molecular weight. Locust antigen was identified in the atmosphere by means of an immunochemical method involving elution of high-volume air-sampler filters exposed in the locust breeding room and analysis of eluate allergen content by RAST-inhibition assays. Logit transformation of RAST-inhibition lines demonstrated that the filter extract shared a common slope with the locust extract and with an extract of locust gut. This gut extract also shared a common slope with extracts of locust feces and peritrophic membrane. The major source of allergen appears to be the peritrophic membrane that is present in the gut and is excreted surrounding the feces.


[Health care and mortality of very-low-birth-weight neonates].
To assess inpatient mortality rate of very-low-birth-weight neonates, their clinical progression and factors associated with mortality. Longitudinal study including 360 neonates weighing 500-1500 g who were born in Londrina, Southern Brazil, from January 1, 2002 to June 30, 2004. Data were collected through interviews with the mothers and from medical records and follow-up of neonates during hospitalization. Chi-square test was used to determine the association between variables. Statistically significant variables were selected to the logistic regression model and the level of significance adopted was 5%. Mortality rate was 32.5%. In bivariate analysis, the following variables were associated with death: no prenatal use of corticosteroids; no hypertension/preeclampsia; labor; vaginal delivery; non-cephalic presentation; Apgar scores <or= 3 at the first and fifth minutes; Clinical Risk Index for Babies score > 5; male sex; weight < or=750 g; gestational age < 28 weeks; resuscitation procedures in the delivery room; respiratory distress syndrome; pneumothorax; intracranial hemorrhage; and mechanical ventilation. In the logistic regression, the following variables were still considered risk factors: low income; no prenatal use of corticosteroids; no use of continuous positive airway pressure. Despite technology advances, very-low-birth-weight neonates mortality is high in Brazil compared with developed countries. Prenatal use of corticosteroids should be encouraged to reduce morbidity and mortality of very-low-birth-weight neonates.


Management of postchemotherapy residual mass in patients with advanced seminoma: Indiana University experience.
Thirty-six patients with advanced seminoma treated with cisplatin combination chemotherapy were evaluated to assess the significance of postchemotherapy residual radiographic mass. All patients had a minimum follow-up of 2 years. Of the 36 patients 21 had an evaluable residual radiographic mass after completion of chemotherapy. Twelve of these patients had a less than 3 cm maximal transverse diameter residual mass, and nine had a greater than 3 cm persistent mass postchemotherapy. Only three of these 21 patients underwent postchemotherapy retroperitoneal lymph node dissection, and the histopathology revealed only necrotic fibrous tissue. The remaining patients were followed by close observation including repeat abdominal computed tomography (CT) every 3 months the first year and every 6 months the second year (or until normal); further therapeutic intervention was given only on evidence of progressive disease. Nineteen of these 21 patients have no evidence of disease, including eight of nine with greater than 3 cm persistent radiographic abnormality. The optimal management for advanced seminoma patients with a persistent radiographic mass postchemotherapy remains unresolved. However, based on this small series, we feel that observation is a viable option, reserving radiotherapy or chemotherapy for those patients who subsequently develop progressive disease.


Using small-area estimation method to calculate county-level prevalence of obesity in Mississippi, 2007-2009.
Obesity is one of Mississippi's pressing public health problems. Since 2005, the state has ranked first in the nation in adult obesity prevalence. For authorities to take targeted action against the obesity epidemic, counties, regions, and subpopulations that are most affected by obesity need to be identified. The objective of this study was to assess the scope, socioeconomic and geographic characteristics, and temporal trends of the obesity epidemic in Mississippi. Using 2007-2009 Mississippi Behavioral Risk Factor Surveillance System data and auxiliary data, we applied a small-area estimation method to estimate county-level obesity prevalence in 2007 through 2009, to assess the association between obesity and socioeconomic factors and to evaluate temporal trends. We determined geographic patterns by mapping obesity prevalence. We appraised the precision of estimates by the width of 95% confidence intervals, and we validated our small-area estimates by comparing them with direct estimates. In 2009, the county prevalence of obesity ranged from 30.5% to 44.2%. Counties with the highest prevalence of obesity were in the Delta region and along the Mississippi River. The obesity prevalence increased from 2007 through 2009. Age, sex, race, education, and employment status were associated with obesity. The 2009 obesity prevalence in all Mississippi counties was substantially higher than the national average and differed by geography and race. Although urgent intervention measures are needed in the entire state, policies and programs giving higher priority to higher-risk areas and subpopulations identified by this study may be better strategies.


Understanding men's networks and perceptions of leadership to promote HIV testing and treatment in Agincourt, South Africa.
Understanding informal leadership in high HIV prevalence settings is important for the success of popular opinion leader (POL) and other HIV testing and treatment promotion strategies which aim to leverage the influence of these leaders. We conducted a study in Mpumalanga province, South Africa, in which we aimed to: (1) describe men's personal networks and key social relationships; and (2) describe the types of individuals men identify as leaders. We administered a structured questionnaire with 45 men (15 HIV-positive and 30 HIV-negative) in which men enumerated and described characteristics of individuals they share personal matters with, and people they considered as leaders. We further conducted in-depth interviews with 25 of these men to better understand men's conceptualisation of leadership in their community. Family members were prominent in men's personal networks and among the leaders they nominated. Men living with HIV were much more likely to know others living with HIV, and described friendships on the basis of the shared experience of HIV treatment. Future POL interventions aiming to promote HIV testing and care among men in rural South Africa should consider the importance of family in community leadership, and seek to leverage the influence of connections between men living with HIV.


Prostate Health Index density improves detection of clinically significant prostate cancer.
To explore the utility of Prostate Health Index (PHI) density for the detection of clinically significant prostate cancer (PCa) in a contemporary cohort of men presenting for diagnostic evaluation of PCa. The study cohort included patients with elevated prostate-specific antigen (PSA; >2 ng/mL) and negative digital rectal examination who underwent PHI testing and prostate biopsy at our institution in 2015. Serum markers were prospectively measured per standard clinical pathway. PHI was calculated as ([{-2}proPSA/free PSA] × [PSA]½ ), and density calculations were performed using prostate volume as determined by transrectal ultrasonography. Logistic regression was used to assess the ability of serum markers to predict clinically significant PCa, defined as any Gleason score ≥7 cancer or Gleason score 6 cancer in >2 cores or >50% of any positive core. Of 118 men with PHI testing who underwent biopsy, 47 (39.8%) were found to have clinically significant PCa on biopsy. The median (interquartile range [IQR]) PHI density was 0.70 (0.43-1.21), and was 0.53 (0.36-0.75) in men with negative biopsy or clinically insignificant PCa and 1.21 (0.74-1.88) in men with clinically significant PCa (P < 0.001). Clinically significant PCa was detected in 3.6% of men in the first quartile of PHI density (<0.43), 36.7% of men in the IQR of PHI density (0.43-1.21), and 80.0% of men with PHI density >1.21 (P < 0.001). Using a threshold of 0.43, PHI density was 97.9% sensitive and 38.0% specific for clinically significant PCa, and 100% sensitive for Gleason score ≥7 disease. Compared with PSA (area under the curve [AUC] 0.52), PSA density (AUC 0.70), %free PSA (AUC 0.75), the product of %free PSA and prostate volume (AUC 0.79), and PHI (AUC 0.76), PHI density had the highest discriminative ability for clinically significant PCa (AUC 0.84). Based on the present prospective single-centre experience, PHI density could be used to avoid 38% of unnecessary biopsies, while failing to detect only 2% of clinically significant cancers.


Blood pressure in young adults.
Hypertension (HT) is a major cardiovascular risk factor. Elevated blood pressure (BP) in childhood predisposes to HT in adulthood. Epidemiological studies in young age-groups are scarce. The aim of this study was to determine the prevalence of HT in a population of university students aged between 18 and 25 years; to analyze the profile of HT in the presence of other risk factors; and to alert patients and physicians to the need to assess and control cardiovascular risk factors in young adults. We performed an observational, descriptive and cross-sectional study of a convenience sample of 402 university students, born between June 1, 1980 and May 24, 1988. Through a self-administered questionnaire and biometric measurements we recorded the following variables: BP, age, gender, smoking, regular medication, family history of HT, stress and body mass index. BP was determined by the mean of two measurements and classified according to the European Society of Cardiology guidelines. In the study population 229 (57%) individuals were female and 173 (42%) male, mean age 21 +/- 2 years. The prevalence of HT was 24.9% (20.4% with isolated systolic HT) and 27.4% had high normal BP. Among males 43.9% had HT, while among females only 10.5% were hypertensive. There was a high prevalence of HT in overweight (50.8%) and obese (50.0%) subjects. Among those exposed to stress, 27.2% had isolated systolic HT. A trend for HT was also found in young women taking oral contraceptives and in students with hypertensive first-degree relatives. The prevalence of HT and high normal BP in the study population of young adults was high. There was a statistically significant correlation between HT and male gender, HT and overweight and between isolated systolic HT and stress, confirming the existence of clusters of cardiovascular risk factors. Patients and their primary care physicians were alerted to the importance of assessing and controlling overall cardiovascular risk in young subjects.


Cyclic Feedback Systems with Quorum Sensing Coupling.
Synchronization and desynchronization is of great interest in the study of circadian rhythms, metabolic oscillations and time-dependent cell aggregate behaviors. Several recent studies examine synchronization and other dynamics in models of repressilators coupled by a quorum sensing mechanism that uses a diffusive signal. Their numerical simulations have shown the complexity of the collective behavior depends sensitively on which protein upregulates diffusive signal. In this paper, we rigorously prove that the collective dynamics indeed strongly depends on how the signaling network integrates into the repressilator network. In fact we prove a general result for a class of negative cyclic feedback systems with signaling of which the repressilator is but one example. We show that if the feedback along the signaling loop is also negative, the resulting negative feedback, negative signaling (Nf-Ns) system admits either unique stable equilibrium, or a stable oscillation. When a positive signaling feedback is included, the system is no longer (Nf-Ns) and numerically exhibits multistable dynamics (Ullner et al. in Phys Rev Lett 99:148103, 2007; Phys Rev E 78:031904, 2008). We demonstrate that this multistability emerges through saddle node bifurcations of a sole cubic curve-as in generic bistable models.


Cannabis Vapor Exposure Alters Neural Circuit Oscillatory Activity in a Neurodevelopmental Model of Schizophrenia: Exploring the Differential Impact of Cannabis Constituents.
Cannabis use is highly prevalent in patients with schizophrenia and worsens the course of the disorder. To understand how exposure to cannabis changes schizophrenia-related oscillatory disruptions, we investigated the impact of administering cannabis vapor containing either Δ9-tetrahydrocannabinol (THC) or balanced THC/cannabidiol (CBD) on oscillatory activity in the neonatal ventral hippocampal lesion (NVHL) rat model of schizophrenia. Male Sprague Dawley rats underwent lesion or sham surgeries on postnatal day 7. In adulthood, electrodes were implanted targeting the cingulate cortex (Cg), the prelimbic cortex (PrLC), the hippocampus (HIP), and the nucleus accumbens (NAc). Local field potential recordings were obtained after rats were administered either the "THC-only" cannabis vapor (8-18% THC/0% CBD) or the "Balanced THC:CBD" cannabis vapor (4-11% THC/8.5-15.5% CBD) in a cross-over design with a 2-week wash-out period between exposures. Compared to controls, NVHL rats had reduced baseline gamma power in the Cg, HIP, and NAc, and reduced HIP-Cg high-gamma coherence. THC-only vapor exposure broadly suppressed oscillatory power and coherence, even beyond the baseline reductions observed in NHVL rats. Balanced THC:CBD vapor, however, did not suppress oscillatory power and coherence, and in some instances enhanced power. For NVHL rats, THC-only vapor normalized the baseline HIP-Cg high-gamma coherence deficits. NHVL rats demonstrated a 20 ms delay in HIP theta to high-gamma phase coupling, which was not apparent in the PrLC and NAc after both exposures. In conclusion, cannabis vapor exposure has varying impacts on oscillatory activity in NVHL rats, and the relative composition of naturally occurring cannabinoids may contribute to this variability.


Distraction, restrained eating and disinhibition: An experimental study of food intake and the impact of 'eating on the go'.
To assess the impact of distraction on subsequent eating, 60 females consumed a cereal bar while watching TV, walking or talking, and their subsequent desire to eat and food intake were assessed. No effects were found for desire to eat. But while those higher in restrained eating consumed less overall and fewer calories after watching TV or talking, they consumed more overall and more calories (specifically five times more chocolate) if the cereal bar was eaten while walking. 'Eating on the go' may disinhibit restrained eaters either as a form of distraction or by offering a justification to overeat.


Postpartum screening for diabetes among women with a history of gestational diabetes mellitus.
To make recommendations for future clinical, public health, and research practices for women with abnormal glucose tolerance during pregnancy, we reviewed the latest evidence regarding rates of postpartum diabetes screening and types of screening tests. We searched PubMed for journal articles published from January 2008 through December 2010 that reported on postpartum screening and studies designed to prevent progression to type 2 diabetes among women with gestational diabetes mellitus (GDM). Two authors independently reviewed titles and abstracts from 265 articles. From 34% to 73% of women with GDM completed postpartum glucose screening. Predictors of higher screening rates included older age, nulliparity, and higher income or education. Screening rates varied by race/ethnicity; Asian women were more likely to be screened than were other racial/ethnic minorities. Women who received prenatal care, who were treated with insulin during pregnancy, or who completed a 6-week postpartum visit were also more likely to receive screening. A moderate proportion of women screened had type 2 diabetes (1.2%-4.5%) or prediabetes (12.2%-36.0%). Rates of postpartum screening among women with a history of GDM are low; only half of women in most populations are screened. Our findings can inform future screening initiatives designed to overcome barriers to screening for both providers and patients. Well-designed lifestyle interventions specific to women with a history of abnormal glucose tolerance during pregnancy and also studies to determine the efficacy and safety of pharmacological interventions will be important to help prevent progression to diabetes among these high-risk women.


Expression of kinase interacting with stathmin (KIS, UHMK1) in human brain and lymphoblasts: Effects of schizophrenia and genotype.
Single nucleotide polymorphisms (SNPs) within the gene encoding the serine/threonine kinase KIS (Kinase Interacting with Stathmin, also known as UHMK1) have recently been associated with schizophrenia. As none of the disease associated SNPs are coding, they may confer susceptibility by altering some facet of KIS expression. Here we have characterised the cellular distribution of KIS in human brain using in situ hybridisation and immunohistochemistry, and quantified KIS protein and mRNA in two large brain series to determine if KIS expression is altered in schizophrenia or bipolar disorder or in relation to a schizophrenia-associated SNP (rs7513662). Post-mortem tissue from the superior temporal gyrus of schizophrenia and control subjects, and also dorsolateral prefrontal cortex, anterior cingulate cortex, and cerebellum from schizophrenia, bipolar disorder, and control subjects were used. KIS expression was measured by quantitative PCR (mRNA) and immunoautoradiography (protein), and was also quantified by immunoblot in lymphoblast cell lines derived from schizophrenia and control subjects. Our results demonstrate that KIS is expressed in neurons, and its encoded protein is localised to the nucleus and cytoplasm. No difference in KIS expression was found between diagnostic groups, or in the lymphoblast cell lines, and no effect of rs7513662 genotype on KIS expression was found. Hence, these data do not provide support for the hypothesis that altered expression is the mechanism by which genetic variation of KIS may increase susceptibility to schizophrenia, nor evidence that KIS expression is altered in the disease itself, at least in terms of the parameters studied here.


Dendritic polyglycerolsulfate-SS-poly(ester amide) micelles for the systemic delivery of docetaxel: pushing the limits of stability through the insertion of π-π interactions.
Insufficient stability of micellar drug delivery systems is still the major limitation to their systematic application in chemotherapy. This work demonstrates novel π-electron stabilized polyelectrolyte block copolymer micelles based on dendritic polyglycerolsulfate-cystamine-block-poly(4-benzoyl-1,4-oxazepan-7-one)-pyrene (dPGS-SS-POxPPh-Py) presenting a very low critical micelle concentration (CMC) of 0.3 mg L-1 (18 nM), 55-fold lower than that of conventional amphiphilic block copolymer micelles. The drug loading capacities of up to 13 wt% allow the efficient encapsulation of the chemotherapeutic Docetaxel (DTX). The spherical morphology of the micelles was proven by cryogenic electron microscopy (cryo-EM). Gaussian Analysis revealed well-defined sizes of 57 nm and 80 nm in the unloaded/loaded state, respectively. Experiments by dynamic light scattering (DLS), ultraviolet-visible spectroscopy (UV-VIS), fluorescence spectroscopy, and cross-polarization solid-state 13C NMR studied the π-π interactions between the core-forming block segment of dPGS-SS-POxPPh-Py and DTX. The findings point to a substantial contribution of these noncovalent interactions to the system's high stability. By confocal laser scanning microscopy (CLSM), the cellular uptake of fluorescein-labelled FITC-dPGS-SS-POxPPh-Py micelles was monitored after one day displaying the successful cell insertion of the cargo-loaded systems. To ensure the drug release in cancerous cells, the disassembly of the micellar DTX-formulations was achieved by reductive and enzymatic degradation studied by light scattering and GPC experiments. Further, no size increase nor disassembly in the presence of human serum proteins after four days was detected. The precise in vitro drug release was also given by the high potency of inhibiting cancer cell growth, finding half-maximal inhibitory concentrations (IC50) efficiently reduced to 68 nM coming along with high viabilities of the empty polymer materials tested on tumor-derived HeLa, A549, and McF-7 cell lines after two days. This study highlights the substantial potential of micelles tailored through the combination of π-electron stabilization with dendritic polyglycerolsulfate for targeted drug delivery systems, enabling them to have a significant foothold in the clinical treatment of cancer.


Frequent hypoglycemic episodes in the treatment of patients with diabetic ketoacidosis.
Previous studies of the management of diabetic ketoacidosis have noted a wide range of incidence of hypoglycemia but have not studied the risk factors associated with it. To describe the incidence of hypoglycemia in patients hospitalized with diabetic ketoacidosis, we retrospectively reviewed the charts of all adult patients with the diagnosis of diabetic ketoacidosis at three private, community hospitals in Milwaukee, Wis, between January 1, 1987, and May 31, 1990. Two hundred twenty admissions in 150 patients met our inclusion criteria. In 30% (66/220) of cases of diabetic ketoacidosis, a serum glucose level or Accu-Chek (Boehringer-Mannheim, Indianapolis, Ind) finding was 2.7 mmol/L or less during the first 14 days of hospitalization. No factors could be identified that were associated with a significantly increased risk of early hypoglycemia (within the first 48 hours of admission). The risk of a "late" occurrence of hypoglycemia (after 48 hours of hospitalization) was increased by fever (relative risk, 2.05; 95% confidence interval [CI], 1.16 to 3.63), "nothing orally" status (relative risk, 3.01; 95% CI, 1.88 to 4.83), hepatic disease (relative risk, 2.56; 95% CI, 1.39 to 4.70), and renal disease (relative risk, 2.07; 95% CI, 1.26 to 3.39). A logistic regression analysis showed "nothing orally" status to be associated with an increased risk of any hypoglycemia occurring during the hospitalization (relative risk, 2.39; 95% CI, 1.63 to 3.51). Physicians and nurses documented the first episode of hypoglycemia in their notes 45.5% and 80.3% of the time, respectively. Hypoglycemia is still a common complication of diabetic ketoacidosis, is associated with hepatic and renal disease as well as fever and "nothing orally" status, and is not documented well in physician notes.


Resident physicians' knowledge of breastfeeding and infant growth.
It is well documented that breastfed infants grow differently from formula-fed infants. The purpose of this study was to assess resident physicians' knowledge of breastfeeding and infant growth. A cross-sectional, self-administered survey was administered to family medicine and pediatric resident physicians from three large, hospital-based public and private programs in North Carolina. One hundred and seven (46%) of 235 residents completed the study, representing 55 percent of family medicine residents and 39 percent of pediatric residents. Ninety-nine percent of participants reported frequently or always plotting infant growth at well-child visits. None reported plotting breastfed babies on a chart specific to breastfeeding. Only 5 percent of participants knew that breastfed infants grew at a slower velocity than formula-fed infants after 4 months of age. This knowledge was not significantly related to specialty, year of training, or gender; it was significantly related to breastfeeding experience (p < 0.04). Of the residents who did not have personal experience with breastfeeding, 99 percent answered incorrectly compared with 88 percent of those who had some personal experience in breastfeeding. In this sample of family medicine and pediatric residents, almost all were unaware that breastfed infants grow at slower rates after 4 months of age. Since the frequency of breastfeeding is increasing in the United States, it is important that physicians be able to monitor the growth of breastfed infants accurately and provide expert counseling for breastfeeding mothers.


Use of polyvinyl alcohol for chimeric antigen receptor T-cell expansion.
Serum albumin has long been an essential supplement for ex vivo hematopoietic and immune cell cultures. However, serum albumin medium supplements represent a major source of biological contamination in cell cultures and often cause loss of cellular function. As serum albumin exhibits significant batch-to-batch variability, it has also been blamed for causing major issues in experimental reproducibility. We recently discovered the synthetic polymer polyvinyl alcohol (PVA) as an inexpensive, Good Manufacturing Practice-compatible, and biologically inert serum albumin replacement for ex vivo hematopoietic stem cell cultures. Importantly, PVA is free of the biological contaminants that have plagued serum albumin-based media. Here, we describe that PVA can replace serum albumin in a range of blood and immune cell cultures including cell lines, primary leukemia samples, and human T lymphocytes. PVA can even replace human serum in the generation and expansion of functional chimeric antigen receptor (CAR) T cells, offering a potentially safer and more cost-efficient approach for this clinical cell therapy. In summary, PVA represents a chemically defined, biologically inert, and inexpensive alternative to serum albumin for a range of cell cultures in hematology and immunology.


Nerve growth factor and neural oncology.
The precise role of the nerve growth factor protein (NGF) during the growth and development of the human nervous system is not determined. Although it appears to influence a number of neural functions, its mechanism of action is poorly understood. A number of researchers have proposed that NGF may be involved in several pathological conditions including cancer. It has been shown that NGF is secreted by certain sarcoma (23), neuroblastoma (113), and glioma (7,102,136) cell lines and can bind to neuroblastoma and metastatic melanoma cell lines (42). Neuroblastoma (136,181) and pheochromocytoma (165) cells in vitro can be induced by NGF to differentiate toward a morphologically "more benign" state and appropriate NGF treatment of rats can reduce the number of chemically induced gliomas and neurinomas (174,178). NGF can also reduce the growth of intracerebrally inoculated anaplastic glioma cells (172). Anti-NGF treatment of rats (178) and mice (179) can alter the tumor distribution observed following ethylnitrosourea or benzo(a)pyrene treatment (10). In humans, it has been reported that serum levels of NGF are usually elevated in persons "at risk" for neurofibromatosis (156). The precise nature of the NGF role is not known in these instances. Further understanding of the action of NGF could be of clinical importance.


The endocannabinoid system as a potential therapeutic target for pain modulation.
Although cannabis has been used for pain management for millennia, very few approved cannabinoids are indicated for the treatment of pain and other medical symptoms. Cannabinoid therapy re-gained attention only after the discovery of endocannabinoids and fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the enzymes playing a role in endocannabinoid metabolism. Nowadays, research has focused on the inhibition of these degradative enzymes and the elevation of endocannabinoid tonus locally; special emphasis is given on multi-target analgesia compounds, where one of the targets is the endocannabinoid degrading enzyme. In this review, I provide an overview of the current understanding about the processes accounting for the biosynthesis, transport and metabolism of endocannabinoids, and pharmacological approaches and potential therapeutic applications in this area, regarding the use of drugs elevating endocannabinoid levels in pain conditions.


Tunable Low Loss 1D Surface Plasmons in InAs Nanowires.
Due to the ability to manipulate photons at nanoscale, plasmonics has become one of the most important branches in nanophotonics. The prerequisites for the technological application of plasmons include high confining ability (λ0 /λp ), low damping, and easy tunability. However, plasmons in typical plasmonic materials, i.e., noble metals, cannot satisfy these three requirements simultaneously and cause a disconnection to modern electronics. Here, the indium arsenide (InAs) nanowire is identified as a material that satisfies all the three prerequisites, providing a natural analogy with modern electronics. The dispersion relation of InAs plasmons is determined using the nanoinfrared imaging technique, and show that their associated wavelengths and damping ratio can be tuned by altering the nanowire diameter and dielectric environment. The InAs plasmons possess advantages such as high confining ability, low loss, and ease of fabrication. The observation of InAs plasmons could enable novel plasmonic circuits for future subwavelength applications.


Measurement of cytochrome oxidase and mitochondrial energetics by near-infrared spectroscopy.
Cytochrome oxidase is the terminal electron acceptor of the mitochondrial respiratory chain. It is responsible for the vast majority of oxygen consumption in the body and essential for the efficient generation of cellular ATP. The enzyme contains four redox active metal centres; one of these, the binuclear CuA centre, has a strong absorbance in the near-infrared that enables it to be detectable in vivo by near-infrared spectroscopy. However, the fact that the concentration of this centre is less than 10% of that of haemoglobin means that its detection is not a trivial matter. Unlike the case with deoxyhaemoglobin and oxyhaemoglobin, concentration changes of the total cytochrome oxidase protein occur very slowly (over days) and are therefore not easily detectable by near-infrared spectroscopy. However, the copper centre rapidly accepts and donates an electron, and can thus change its redox state quickly; this redox change is detectable by near-infrared spectroscopy. Many factors can affect the CuA redox state in vivo (Cooper et al. 1994), but most significant is likely to be the molecular oxygen concentration (at low oxygen tensions, electrons build up on CuA as reduction of oxygen by the enzyme starts to limit the steady-state rate of electron transfer). The factors underlying haemoglobin oxygenation, deoxygenation and blood volume changes are, in general, well understood by the clinicians and physiologists who perform near-infrared spectroscopy measurements. In contrast, the factors that control the steady-state redox level of CuA in cytochrome oxidase are still a matter of active debate, even amongst biochemists studying the isolated enzyme and mitochondria. Coupled with the difficulties of accurate in vivo measurements it is perhaps not surprising that the field of cytochrome oxidase near-infrared spectroscopy has a somewhat chequered past. Too often papers have been written with insufficient information to enable the measurements to be repeated and few attempts have been made to test the algorithms in vivo. In recent years a number of research groups and commercial spectrometer manufacturers have made a concerted attempt to not only say how they are attempting to measure cytochrome oxidase by near-infrared spectroscopy but also to demonstrate that they are really doing so. We applaud these attempts, which in general fall into three areas: first, modelling of data can be performed to determine what problems are likely to derail cytochrome oxidase detection algorithms (Matcher et al. 1995); secondly haemoglobin concentration changes can be made by haemodilution (using saline or artificial blood substitutes) in animals (Tamura 1993) or patients (Skov & Greisen 1994); and thirdly, the cytochrome oxidase redox state can be fixed by the use of mitochondrial inhibitors and then attempts make to cause spurious cytochrome changes by dramatically varying haemoglobin oxygenation, haemoglobin concentration and light scattering (Cooper et al. 1997). We have previously written reviews covering the difficulties of measuring the cytochrome near-infrared spectroscopy signal in vivo (Cooper et al. 1997) and the factors affecting the oxidation state of cytochrome oxidase CuA (Cooper et al. 1994). In this article we would like to strike a somewhat more optimistic note--we will stress the usefulness this measurement may have in the clinical environment, as well as describing conditions under which we can have confidence that we are measuring real changes in the CuA redox state.


The judgement process in evidence-based medicine and health technology assessment.
This article describes the judgements used to interpret evidence in evidence-based medicine (EBM) and health technology assessment (HTA). It outlines the methods and processes of EBM and HTA. Respectively, EBM and HTA are approaches to medical clinical decision making and efficient allocation of scarce health resources. At the heart of both is a concern to review and synthesise evidence, especially evidence derived from randomised controlled trials (RCTs) of clinical effectiveness. The driver of the approach of both is a desire to eliminate, or at least reduce, bias. The hierarchy of evidence, which is used as an indicator of the likelihood of bias, features heavily in the process and methods of EBM and HTA. The epistemological underpinnings of EBM and HTA are explored with particular reference to the distinction between rationalism and empiricism, developed by the philosopher David Hume and elaborated by Immanuel Kant in the Critique of Pure Reason. The importance of Humian and Kantian principles for understanding the projects of EBM and HTA is considered and the ways in which decisions are made in both, within a judgemental framework originally outlined by Kant, are explored.


REDESIGN: RDF-based Differential Signaling Framework for Precision Medicine Analytics.
Pathway-based analysis holds promise to be instrumental in precision and personalized medicine analytics. However, the majority of pathway-based analysis methods utilize "fixed" or "rigid" data sets that limit their ability to account for complex biological inter-dependencies. Here, we present REDESIGN: RDF-based Differential Signaling Pathway informatics framework. The distinctive feature of the REDESIGN is that it is designed to run on "flexible" ontology-enabled data sets of curated signal transduction pathway maps to uncover high explanatory differential pathway mechanisms on gene-to-gene level. The experiments on two morphoproteomic cases demonstrated REDESIGN's capability to generate actionable hypotheses in precision/personalized medicine analytics.


Frequency-domain wide-field laser Doppler in vivo imaging.
We present a new instrument, based on a low-frame-rate (8 Hz) CCD camera used in a heterodyne optical-mixing configuration, that can create wide-field laser Doppler maps. As an illustration, we show results obtained in a mouse brain, in vivo, showing the Doppler signature of blood flow. The instrument is based on a frequency-shifting digital holography scheme.


Proteomics imaging and the kidney.
Matrix-assisted laser desorption/ionization (MALDI) and mass spectrometry (MS) imaging are advanced technologies capable of revealing the spatial distribution of different molecules--e.g., drugs and their metabolites, endogenous lipids and complex peptides/proteins--directly in tissue specimens at the same time. Information obtained regarding tissues by MALDI profiling/imaging analysis can be correlated with other MS-based techniques, auxiliary imaging technologies and routine immunohistochemical stainings. In this review we describe the MALDI profiling/imaging technologies, providing examples of their application in kidney research.


Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels.
Plasma high density lipoprotein (HDL) levels are strongly genetically determined and show a general inverse relationship with coronary heart disease (CHD). The cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to other lipoproteins and is a key participant in the reverse transport of cholesterol from the periphery to the liver. A high prevalence of two different CETP gene mutations (D442G, 5.1%; intron 14G:A, 0.5%), was found in 3,469 men of Japanese ancestry in the Honolulu Heart Program and mutations were associated with decreased CETP (-35%) and increased HDL chol levels (+10% for D442G). However, the overall prevalence of definite CHD was 21% in men with mutations and 16% in men without mutations. The relative risk (RR) of CHD was 1.43 in men with mutations (P < .05); after adjustment for CHD risk factors, the RR was 1.55 (P = .02); after additional adjustment for HDL levels, the RR was 1.68 (P = .008). Similar RR values were obtained for the D442G mutation alone. Increased CHD in men with mutations was primarily observed for HDL chol 41-60 mg/dl; for HDL chol > 60 mg/dl men with and without mutations had low CHD prevalence. Thus, genetic CETP deficiency appears to be an independent risk factor for CHD, primarily due to increased CHD prevalence in men with the D442G mutation and HDL cholesterol between 41 and 60 mg/dl. The findings suggest that both HDL concentration and the dynamics of cholesterol transport through HDL (i.e., reverse cholesterol transport) determine the anti-atherogenicity of the HDL fraction.


Reversal of epigenetic silencing of MHC class I chain-related protein A and B improves immune recognition of Merkel cell carcinoma.
Merkel cell carcinoma (MCC) is a virally associated cancer characterized by its aggressive behavior and strong immunogenicity. Both viral infection and malignant transformation induce expression of MHC class I chain-related protein (MIC) A and B, which signal stress to cells of the immune system via Natural Killer group 2D (NKG2D) resulting in elimination of target cells. However, despite transformation and the continued presence of virally-encoded proteins, MICs are only expressed in a minority of MCC tumors in situ and are completely absent on MCC cell lines in vitro. This lack of MIC expression was due to epigenetic silencing via MIC promoter hypo-acetylation; indeed, MIC expression was re-induced by pharmacological inhibition of histone deacetylases (HDACs) both in vitro and in vivo. This re-induction of MICs rendered MCC cells more sensitive to immune-mediated lysis. Thus, epigenetic silencing of MICs is an important immune escape mechanism of MCCs.


On the parameters used in finite element modeling of compound peripheral nerves.
Computational modeling is an important tool for developing and optimizing implantable neural stimulation devices, but requires accurate electrical and geometrical parameter values to improve predictive value. We quantified the effects of perineurial (resistive sheath around each fascicle) and endoneurial (within each fascicle) parameter values for modeling peripheral nerve stimulation. We implemented 3D finite element models of compound peripheral nerves and cuff electrodes to quantify activation and block thresholds of model axons. We also implemented a 2D finite element model of a bundle of axons to estimate the bulk transverse endoneurial resistivity; we compared numerical estimates to an analytical solution. Since the perineurium is highly resistive, potentials were approximately constant over the cross section of a fascicle, and the perineurium resistivity, longitudinal endoneurial resistivity, and fascicle diameter had important effects on thresholds. Activation thresholds increased up to ~130% for higher perineurium resistivity (~400 versus 2200 Ω m) and by ~35%-250% for lower longitudinal endoneurial resistivity (3.5 versus 0.75 Ω m), with larger increases for smaller diameter axons and for axons in larger fascicles. Further, thresholds increased by ~30%-180% for larger fascicle radii, yielding a larger increase with higher perineurium resistivity. Thresholds were largely insensitive to the transverse endoneurial resistivity, but estimates of the bulk resistivity increased with extracellular resistivity and axonal area fraction; the numerical and analytical estimates were in strong agreement except at high axonal area fractions, where structured axon placements that achieved tighter packing produced electric field inhomogeneities. We performed a systematic investigation of the effects of values and methods for modeling the perineurium and endoneurium on thresholds for neural stimulation and block. These results provide guidance for future modeling studies, including parameter selection, data interpretation, and comparison to experimental results.


Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome.
Epigenetic regulation is important in hematopoiesis, but the involvement of histone variants is poorly understood. Myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic stem cell (HSC) disorders characterized by ineffective hematopoiesis. MacroH2A1.1 is a histone H2A variant that negatively correlates with the self-renewal capacity of embryonic, adult, and cancer stem cells. MacroH2A1.1 is a target of the frequent U2AF1 S34F mutation in MDS. The role of macroH2A1.1 in hematopoiesis is unclear. MacroH2A1.1 mRNA levels are significantly decreased in patients with low-risk MDS presenting with chromosomal 5q deletion and myeloid cytopenias and tend to be decreased in MDS patients carrying the U2AF1 S34F mutation. Using an innovative mouse allele lacking the macroH2A1.1 alternatively spliced exon, we investigated whether macroH2A1.1 regulates HSC homeostasis and differentiation. The lack of macroH2A1.1 decreased while macroH2A1.1 haploinsufficiency increased HSC frequency upon irradiation. Moreover, bone marrow transplantation experiments showed that both deficiency and haploinsufficiency of macroH2A1.1 resulted in enhanced HSC differentiation along the myeloid lineage. Finally, RNA-sequencing analysis implicated macroH2A1.1-mediated regulation of ribosomal gene expression in HSC homeostasis. Together, our findings suggest a new epigenetic process contributing to hematopoiesis regulation. By combining clinical data with a discrete mutant mouse model and in vitro studies of human and mouse cells, we identify macroH2A1.1 as a key player in the cellular and molecular features of MDS. These data justify the exploration of macroH2A1.1 and associated proteins as therapeutic targets in hematological malignancies.


The Declaration of Istanbul on Organ Trafficking and Transplant Tourism.
Organ commercialism, which targets vulnerable populations (such as illiterate and impoverished persons, undocumented immigrants, prisoners, and political or economic refugees) in resource-poor countries, has been condemned by international bodies such as the World Health Organization for decades. Yet in recent years, as a consequence of the increasing ease of Internet communication and the willingness of patients in rich countries to travel and purchase organs, organ trafficking and transplant tourism have grown into global problems. For example, as of 2006, foreigners received two-thirds of the 2000 kidney transplants performed annually in Pakistan. The Istanbul Declaration proclaims that the poor who sell their organs are being exploited, whether by richer people within their own countries or by transplant tourists from abroad. Moreover, transplant tourists risk physical harm by unregulated and illegal transplantation. Participants in the Istanbul Summit concluded that transplant commercialism, which targets the vulnerable, transplant tourism, and organ trafficking should be prohibited. And they also urged their fellow transplant professionals, individually and through their organizations, to put an end to these unethical activities and foster safe, accountable practices that meet the needs of transplant recipients while protecting donors. Countries from which transplant tourists originate, as well as those to which they travel to obtain transplants, are just beginning to address their respective responsibilities to protect their people from exploitation and to develop national self-sufficiency in organ donation. The Declaration should reinforce the resolve of governments and international organizations to develop laws and guidelines to bring an end to wrongful practices. "The legacy of transplantation is threatened by organ trafficking and transplant tourism. The Declaration of Istanbul aims to combat these activities and to preserve the nobility of organ donation. The success of transplantation as a life-saving treatment does not require-nor justify-victimizing the world's poor as the source of organs for the rich" (Steering Committee of the Istanbul Summit).


Campylobacter hyointestinalis subsp. lawsonii subsp. nov., isolated from the porcine stomach, and an emended description of Campylobacter hyointestinalis.
The taxonomic relationships of seven isolates obtained from porcine stomachs (the "CHY" group), which resembled (but were distinct from) the type strain and other reference strains of Campylobacter hyointestinalis, were examined by using phenotypic and genomic methods. The phenotypic characteristics and ultrastructure of the new organisms were characteristic of Campylobacter species, although they could be distinguished from all previously described taxa. A numerical analysis of 38 phenotypic characters revealed that the new isolates formed a distinct group at a similarity level of 90.1% and could be clearly distinguished from reference strains representing 20 related taxa, principally species and subspecies belonging to the genera Campylobacter, Arcobacter, and Helicobacter. DNA-DNA hybridization studies revealed that the porcine stomach strains were genomically homogeneous (levels of relatedness, 84 to 90%), although the levels of DNA homology with type and reference strains of C. hyointestinalis were relatively high (56 to 71%). Differences in the DNA base compositions of the CHY group and C. hyointestinalis strains were also observed. Our data indicate that the new porcine isolates should be considered members of a subspecies of C. hyointestinalis, for which we propose the name Campylobacter hyointestinalis subsp. lawsonii subsp. nov. The type strain is strain CHY 5 (= LMG 14432 = NCTC 12901 = CCUG 34538). The description of C. hyointestinalis is emended accordingly, and a description of Campylobacter hyointestinalis subsp. hyointestinalis subsp. nov. is given.


Women as easy scapegoats: witchcraft accusations and women as targets in tea plantations of India.
This article revisits a much-debated question: Why are women popular targets during witch hunts? By using in-depth interviews this article provides an answer. Women are easy targets or scapegoats for two reasons. First, it is widely believed in the community that was studied that witches do, in fact, exist, and the images of witches are always female. Second, tribal women hold lower positions than men in all social, political, and ritual matters, and this contributes to their vulnerability during the hunt for scapegoats. This article also highlights the roles that rumors play during manipulation of witchcraft accusations to gather support for witch hunts.


Shyness versus social phobia in US youth.
Scholars and the popular press have suggested that the diagnostic entity of social phobia "medicalizes" normal human shyness. In this study we examined the plausibility of this hypothesis by (1) determining the frequency of shyness and its overlap with social phobia in a nationally representative adolescent sample, (2) investigating the degree to which shyness and social phobia differ with regard to sociodemographic characteristics, functional impairment, and psychiatric comorbidity, and (3) examining differences in rates of prescribed medication use among youth with shyness and/or social phobia. The National Comorbidity Survey-Adolescent Supplement is a nationally representative, face-to-face survey of 10,123 adolescents, aged 13 to 18 years, in the continental United States. Lifetime social phobia was assessed by using a modified version of the fully structured World Health Organization Composite International Diagnostic Interview. Adolescents and parents also provided information on youth shyness and prescribed medication use. Only 12% of the youth who identified themselves as shy also met the criteria for lifetime social phobia. Relative to adolescents who were characterized as shy, adolescents affected with social phobia displayed significantly greater role impairment and were more likely to experience a multitude of psychiatric disorders, including disorders of anxiety, mood, behavior, and substance use. However, those adolescents were no more likely than their same-age counterparts to be taking prescribed medications. The results of this study provide evidence that social phobia is an impairing psychiatric disorder, beyond normal human shyness. Such findings raise questions concerning the "medicalization" hypothesis of social phobia.


Superior episodic memory in inconsistent-handers: a replication and extension using fNIRS.
A large body of evidence supports the existence of a robust handedness difference in episodic memory retrieval, with inconsistent-handedness being associated with superior memory across a wide variety of paradigms, including superior retrieval of lab-based and real world memories. Despite superior episidoc memory in inconsistent-handers, and despite neuroanatomical and neurophysiological differences in cortical regions between inconsistent- and consistent-handers, we are aware of no studies to date that have examined physiological activity in the brains of inconsistent- versus consistent-handers while engaged in memory tasks. The purpose of this paper, therefore, is to present a first look at this issue, using functional near-infrared spectroscopy (fNIRS) as a simple, non-invasive measure of frontal lobe activity during encoding and recall of list words in inconsistent- and consistent-handers. Behaviourally, we replicated prior studies, finding a significant inconsistent-handed advantage in free recall. Using fNIRS-derived oxygenated haemoglobin (O2Hb) as a measure of frontal lobe activity, we found the first evidence for handedness differences in brain activity that are associated with the handedness differences in episodic retrieval. Specifically, the primary finding was that increased O2Hb in the right hemisphere during recall was associated with better retrieval, but for consistent-handers only.


Community-derived recommendations for healthcare systems and medical students to support people who are houseless in Portland, Oregon: a mixed-methods study.
People who are houseless (also referred to as homeless) perceive high stigma in healthcare settings, and face disproportionate disparities in morbidity and mortality versus people who are housed. Medical students and the training institutions they are a part of play important roles in advocating for the needs of this community. The objective of this study was to understand perceptions of how medical students and institutions can meet needs of the self-identified needs of the houseless community. Between February and May 2018, medical students conducted mixed-methods surveys with semi-structured qualitative interview guides at two community-based organizations that serve people who are houseless in Portland, Oregon. Medical students approach guests at both locations to ascertain interest in participating in the study. Qualitative data were analyzed using thematic analysis rooted in an inductive process. We enrolled 38 participants in this study. Most participants were male (73.7%), white (78.9%), and had been houseless for over a year at the time of interview (65.8%). Qualitative themes describe care experiences among people with mental health and substance use disorders, and roles for medical students and health-care institutions. Specifically, people who are houseless want medical students to 1) listen to and believe them, 2) work to destigmatize houselessness, 3) engage in diverse clinical experiences, and 4) advocate for change at the institutional level. Participants asked healthcare institutions to use their power to change laws that criminalize substance use and houselessness, and build healthcare systems that take better care of people with addiction and mental health conditions. Medical students, and the institutions they are a part of, should seek to reduce stigma against people who are houseless in medical systems. Additionally, institutions should change their approaches to healthcare delivery and advocacy to better support the health of people who are houseless.


Two weeks of additional standing balance circuit classes during inpatient rehabilitation are cost saving and effective: an economic evaluation.
Among people admitted for inpatient rehabilitation, is usual care plus standing balance circuit classes more cost-effective than usual care alone? Cost-effectiveness study embedded within a randomised controlled trial with concealed allocation, assessor blinding and intention-to-treat analysis. 162 rehabilitation inpatients from a metropolitan hospital in Sydney, Australia. The experimental group received a 1-hour standing balance circuit class, delivered three times a week for 2 weeks, in addition to usual therapy. The circuit classes were supervised by one physiotherapist and one physiotherapy assistant for up to eight patients. The control group received usual therapy alone. Costs were estimated from routinely collected hospital use data in the 3 months after randomisation. The functional outcome measure was mobility measured at 3 months using the Short Physical Performance Battery administered by a blinded assessor. An incremental analysis was conducted and the joint probability distribution of costs and outcomes was examined using bootstrapping. The median cost savings for the intervention group was AUD4,741 (95% CI 137 to 9,372) per participant; 94% of bootstraps showed that the intervention was both effective and cost saving. Two weeks of additional standing balance circuit classes delivered in addition to usual therapy resulted in decreased healthcare costs at 3 months in hospital inpatients admitted for rehabilitation. There is a high probability that this intervention is both cost saving and effective. ACTRN12611000412932. [Treacy D, Howard K, Hayes A, Hassett L, Schurr K, Sherrington C (2018) Two weeks of additional standing balance circuit classes during inpatient rehabilitation are cost saving and effective: an economic evaluation. Journal of Physiotherapy 64: 41-47].


Adjuvant External Radiation Impacts Outcome of Pelvis-limited Stage III Endometrial Carcinoma: A Multi-institutional Study.
Adjuvant therapy choice for women with FIGO stage III endometrial carcinoma (EC) is controversial. We investigate the comparative benefit of adjuvant chemotherapy (CT) alone, radiation therapy alone (RT) or in combination (chemotherapy and radiation therapy [CRT]) with respect to recurrence-free survival (RFS) and overall survival (OS) in women with pelvis-limited (PL) EC (stage IIIA, IIIB, and IIIC1). A multi-institutional database of 270 surgically staged women with PLEC was analyzed. Univariate log-rank analyses and Cox regression multivariate analyses (MVA) were performed to identify factors associated with RFS and OS. Median RFS and OS were 112 and 130 months, respectively, for the full cohort. Adjuvant treatment was CT in 21%, RT in 27%, and CRT in 47%. Age, year of treatment, grade, histology, and adjuvant treatment were significantly associated with RFS and OS on univariate analysis. PLEC patients receiving CT alone fared worse in terms of RFS (P=0.07 relative to RT and <0.01 relative to CRT). On MVA, CRT retained significantly improved RFS relative to CT (hazard ratio for recurrence 0.38, P<0.01). PLEC patients receiving RT or CRT had improved OS compared with CT, P<0.01 and 0.03, respectively. On MVA, both RT only and CRT retained association with improved OS relative to CT alone (hazard ratio for death, 0.43, P=0.02 and 0.40, P<0.01, respectively). For surgically staged PL stage III EC, treatment regimens incorporating RT were associated with improved survival endpoints relative to CT alone. As such, RT should be considered an important component in the adjuvant management of stage III PLEC.


Lower genital tract lesions requiring surgical intervention in girls: perspective from a developing country.
To determine the spectrum, outcome of treatment and the challenges of managing surgical lesions of lower genital tract in girls in a low-resource setting. Retrospective study of 87 girls aged 13-years and younger, with lower genital tract lesions managed between February 2002 and January 2007 at the University of Nigeria Teaching Hospital, Enugu, southeastern Nigeria. Clinical charts were reviewed to determine the types, management, outcome of treatment and management difficulties. The median age at presentation was 1 year (range 2 days-13 years). Congenital lesions comprised 67.8% and acquired lesions 32.2%. The lesions included: masculinized external genitalia (24), vestibular fistula from anorectal malformation (23), post-circumcision labial fusion (12), post-circumcision vulval cyst (6), low vaginal malformations (6), labial adhesion (5), cloacal malformation (3), bifid clitoris (3) urethral prolapse (3), and acquired rectovaginal fistula (2). Seventy-eight (89.7%) had operative treatment. Procedure related complications occurred in 19 cases (24.4%) and consisted of surgical wound infection (13 cases), labial adhesion (4 cases) and urinary retention (2 cases). There was no mortality. Overall, 14 (16.1%) abandoned treatment at one stage or another. Challenges encountered in management were inadequate diagnostic facilities, poor multidisciplinary collaboration and poor patient follow up. There is a wide spectrum of lower genital lesion among girls in our setting. Treatment of these lesions may be challenging, but the outcome in most cases is good. High incidence of post-circumcision complications and poor treatment compliance may require more efforts at public enlightenment.


QuikClot Combat Gauze use for hemorrhage control in military trauma: January 2009 Israel Defense Force experience in the Gaza Strip--a preliminary report of 14 cases.
Standard gauze field dressings and direct pressure occasionally are inadequate for the control of hemorrhage. QuikClot® Combat Gauze™ (QCG) combines surgical gauze with an inorganic material and is approved by the Food and Drug Administration and by the Israeli Standards Institute for external hemorrhage control. The purpose of this article is to report clinical use of this dressing during Operation Cast Lead in the Gaza strip during January 2009. QuikClot Combat Gauze and the QCG guidelines were issued to advanced life support (ALS) providers during the preparations for the Operation. All cases of injuries involving hemorrhage were reviewed, as well as interviews with the ALS providers (physicians and paramedics) and injured soldiers. Fourteen uses of QCG were reported and reviewed (out of a total of 56 hemostatic interventions in 35 cases). Dressings were applied to injuries to the head, neck, axilla, buttocks, abdomen, back, and pelvis in 10 cases, and to extremities in four cases. In 13 cases (93%), injuries were caused by blast or gunshot mechanisms. The success rate was reported as 79% (11/14). Failure to control hemorrhage was reported in three cases in three different locations: neck, buttock, and thigh. All failures were attributed to severe soft tissue and vascular injuries. No complications or adverse events were reported. This report on the clinical field use of the QCG dressing by ALS providers suggests that it is an effective and safe product, and applicable for prehospital treatment of combat casualties. This report further suggests that QCG should be issued to medics as well as ALS providers. Larger clinical investigations are needed to confirm these findings.


Nationwide surveillance of antimicrobial resistance among clinically important Gram-negative bacteria, with an emphasis on carbapenems and colistin: Results from the Surveillance of Multicenter Antimicrobial Resistance in Taiwan (SMART) in 2018.
Multicentre surveillance of antimicrobial susceptibility of clinically important Gram-negative bacteria (GNB) from 16 Taiwanese hospitals was performed. Escherichia coli (n = 398), Klebsiella pneumoniae (n = 346), Pseudomonas aeruginosa (n = 252) and Acinetobacter baumannii complex (ABC) (n = 188) bloodstream isolates, non-typhoidal Salmonella (n = 230) and Shigella flexneri (n = 18) from various sources were collected. Antimicrobial MICs were determined using broth microdilution. Genes encoding K. pneumoniae carbapenemases (KPCs), New Delhi metallo-β-lactamases (NDMs), Verona integron-encoded metallo-β-lactamase (VIM), OXA-48-like carbapenemase (OXA-48) as well as mcr-1-5 genes were detected by molecular methods. Rates of carbapenem non-susceptibility were 2.8%, 9.0%, 0.4%, 0%, 10.3% and 48.8% for E. coli, K. pneumoniae, Salmonella, Shigella, P. aeruginosa and ABC, respectively. For carbapenemases, one (0.3%) E. coli harboured blaNDM-1. Fifteen (4.3%), two (0.6%) and two (0.6%) K. pneumoniae contained blaKPC, blaOXA-48 and blaVIM, respectively. Two (0.5%) E. coli and fourteen (4.0%) K. pneumoniae were non-wild-type according to the colistin MIC. Among Enterobacteriaceae with a colistin MIC ≥ 2 mg/L, mcr-1 was detected in one E. coli, two K. pneumoniae and three Salmonella spp. All three mcr-1-positive Salmonella isolates were collected from community-acquired infections; none of the six mcr-1-positive Enterobacteriaceae were carbapenem-resistant. Carbapenem resistance has increased among clinically important GNB, especially among hospital-acquired infections. blaKPC, especially the blaKPC-2 variant, was detected in approximately one-half of the carbapenem-resistant K. pneumoniae isolates in this study. Although resistance rates to colistin remained low among Enterobacteriaceae, the finding of mcr-1 from different species raises concern of potential dissemination.


Hypoxia-inducible factor-1 activation in nonhypoxic conditions: the essential role of mitochondrial-derived reactive oxygen species.
Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor for responses to low oxygen. Different nonhypoxic stimuli, including hormones and growth factors, are also important HIF-1 activators in the vasculature. Angiotensin II (Ang II), the main effecter hormone in the renin-angiotensin system, is a potent HIF-1 activator in vascular smooth muscle cells (VSMCs). HIF-1 activation by Ang II involves intricate mechanisms of HIF-1α transcription, translation, and protein stabilization. Additionally, the generation of reactive oxygen species (ROS) is essential for HIF-1 activation during Ang II treatment. However, the role of the different VSMC ROS generators in HIF-1 activation by Ang II remains unclear. This work aims at elucidating this question. Surprisingly, repression of NADPH oxidase-generated ROS, using Vas2870, a specific inhibitor or a p22(phox) siRNA had no significant effect on HIF-1 accumulation by Ang II. In contrast, repression of mitochondrial-generated ROS, by complex III inhibition, by Rieske Fe-S protein siRNA, or by the mitochondrial-targeted antioxidant SkQ1, strikingly blocked HIF-1 accumulation. Furthermore, inhibition of mitochondrial-generated ROS abolished HIF-1α protein stability, HIF-1-dependent transcription and VSMC migration by Ang II. A large number of studies implicate NADPH oxidase-generated ROS in Ang II-mediated signaling pathways in VSMCs. However, our work points to mitochondrial-generated ROS as essential intermediates for HIF-1 activation in nonhypoxic conditions.


Photodynamics of [26]- and [28]hexaphyrin-bodipy hybrids.
A set of hybrids having gradual variation in distances between hexaphyrin and bodipy moieties, given by uses of phenylene, biphenylene, and triphenyelene bridges was prepared. Efficient PET processes from bodipy (donor) to [26]- or [28]hexaphyrin (acceptor) were successfully observed, where the PET speed was controlled by intramolecular distances between the donor and the acceptor. UV irradiation at 515 nm raised a band corresponding to the bodipy absorption. As the time delayed, the bodipy bands decreased and new absorption bands at 615 and 580 nm corresponding to respective absorption bands of [28]- and [26]-hybrids gradually appeared. Whereas the femtosecond transient absorption spectra of [28]/[26]-hybrids having terphenylene bridges completely showed energy transfers from bodipy to hexaphyrin, irradiation of the hybrids using 615 and 580 nm pulses did not induce opposite ways of the PET process. On the basis of enlarged center-to-center-distances of [26]-hybrids than those of [28]-hybrids, the set of [26]-hybrids resulted in slow decay/rise processes. PET parameters obtained with the experiments were fairly consistent with the PET parameters calculated.


Melatonin promotes osteoblast differentiation and mineralization of MC3T3-E1 cells under hypoxic conditions through activation of PKD/p38 pathways.
Osteoblastic differentiation and bone-forming capacity are known to be suppressed under hypoxic conditions. Melatonin has been shown to influence cell differentiation. A number of in vitro and in vivo studies have suggested that melatonin also has an anabolic effect on bone, by promoting osteoblastic differentiation. However, the precise mechanisms and the signaling pathways involved in this process, particularly under hypoxic conditions, are unknown. This study investigated whether melatonin could promote osteoblastic differentiation and mineralization of preosteoblastic MC3T3-E1 cells under hypoxic conditions. Additionally, we examined the molecular signaling pathways by which melatonin mediates this process. We found that melatonin is capable of promoting differentiation and mineralization of MC3T3-E1 cells cultured under hypoxic conditions. Melatonin upregulated ALP activity and mRNA levels of Alp, Osx, Col1, and Ocn in a time- and concentration-dependent manner. Alizarin red S staining showed that the mineralized matrix in hypoxic MC3T3-E1 cells formed in a manner that was dependent on melatonin concentration. Moreover, melatonin stimulated phosphorylation of p38 Mapk and Prkd1 in these MC3T3-E1 cells. We concluded that melatonin promotes osteoblastic differentiation of MC3T3-E1 cells under hypoxic conditions via the p38 Mapk and Prkd1 signaling pathways.


Prenatal nicotine exposure impairs beta-adrenergic function: persistent chronotropic subsensitivity despite recovery from deficits in receptor binding.
Gestational exposure to nicotine has been shown to interfere with biochemical markers of development of central and peripheral noradrenergic activity. The current study examines the development and function of cardiac beta-adrenergic receptors in the offspring of pregnant rats given nicotine infusions of 6 mg/kg/day from gestational days 4 through 20, administered by subcutaneously implanted osmotic minipumps. Prenatal nicotine exposure delayed the development of beta-adrenergic receptor binding capabilities, as assessed with [125I]pindolol in membrane preparations from heart and kidney. The deficits in receptor binding were associated with marked subsensitivity of chronotropic responses to administration of a beta-adrenergic agonist, isoproterenol. Although the effects on receptor binding resolved after weaning, functional deficiencies in responsiveness to isoproterenol or to preganglionic electrical stimulation of sympathetic nerves to the heart persisted into adulthood. These results indicate that prenatal exposure to nicotine produces long-term alterations in adrenergic responsiveness of sympathetic target tissues.


Functional comparisons of the lysophosphatidic acid receptors, LP(A1)/VZG-1/EDG-2, LP(A2)/EDG-4, and LP(A3)/EDG-7 in neuronal cell lines using a retrovirus expression system.
Lysophosphatidic acid (LPA) is a potent lipid mediator with diverse physiological actions on a wide variety of cells and tissues. Three cognate G-protein-coupled receptors have been identified as mammalian LPA receptors: LP(A1)/VZG-1/EDG-2, LP(A2)/EDG-4, and LP(A3)/EDG-7. The mouse forms of these genes were analyzed in rodent cell lines derived from nervous system cells that can express these receptors functionally. An efficient retrovirus expression system was used, and each receptor was heterologously expressed in B103 rat neuroblastoma cells that neither express these receptors nor respond to LPA in all assays tested. Comparative analyses of signaling pathways that are activated within minutes of ligand delivery were carried out. LPA induced cell rounding in LP(A1)- and LP(A2)-expressing cells. By contrast, LP(A3) expression resulted in neurite elongation in B103 cells and inhibited LPA-dependent cell rounding in TR mouse neuroblast cells that endogenously express LP(A1) and LP(A2) but not LP(A3). Each of the receptors could couple to multiple G-proteins and induced LPA-dependent inositol phosphate production, mitogen-activated protein kinase activation, and arachidonic acid release while inhibiting forskolin-induced cAMP accumulation, although the efficacy and potency of LPA varied from receptor to receptor. These results indicate both shared and distinct functions among the three mammalian LPA receptors. The retroviruses developed in this study should provide tools for addressing these functions in vivo.


An ultrasensitive SERS sensor for simultaneous detection of multiple cancer-related miRNAs.
Simultaneous detection of multiple trace cancer associated serum miRNA biomarkers is considered as a feasible method for early cancer screening and diagnosis. In the present work, an ultrasensitive SERS sensor was prepared based on an Ag nanorod array SERS substrate by assembling special hairpin-shaped molecular beacons (MBs) for the detection of multiple lung cancer-related miRNA biomarkers. The portable SERS sensor exhibits excellent performance for the qualitative and quantitative detection of miRNAs, with advantages of ultra-sensitivity, good specificity, uniformity, reproducibility and stability, as well as remarkable reusability. By monitoring the SERS signal quenching of the MBs in the presence of target miRNA biomarkers, three lung cancer related-miRNAs (miRNA-21, miRNA-486, and miRNA-375) in buffer and human serum were simultaneously assayed using the SERS sensor array, and the limits of detection of the three miRNAs in human serum are 393 aM, 176 aM, and 144 aM, respectively. The reliable results demonstrate that the proposed SERS sensor array can be a promising candidate with great potential for the screening and clinical diagnosis of cancer in the early stage.


Plasmodium falciparum dihydrofolate reductase alleles and pyrimethamine use in pregnant Ghanaian women.
Drug resistance in Plasmodium falciparum affects prevention of malaria in pregnancy. In a cross-sectional study of 530 pregnant Ghanaian women, P. falciparum dihydrofolate reductase (DHFR) gene mutations linked with pyrimethamine resistance were assessed and associations with pyrimethamine intake were analyzed. P. falciparum infected 69% of women without pyrimethamine use, 59% of those who had a history of pyrimethamine consumption but a negative urine test, and 53% of individuals with a positive urine test. Eighty-one percent, 43%, and 74% of the isolates contained the mutations Asn-108, Ile-51, and Arg-59, respectively. Thr-108 occurred in 8%. Pyrimethamine use was associated with increased frequencies of Asn-108 and Arg-59 but not of Ile-51 or Thr-108. In women with prophylaxis, wild-type parasites were absent and anemia tended to be more common with an increasing number of DHFR gene mutations. Pyrimethamine appears to be not adequately effective in this part of Ghana, most likely due to the predominance of resistant parasites. Selection for resistance following insufficient prophylaxis could possibly affect the efficacy of future intermittent sulfadoxine-pyrimethamine treatment.


Disseminated chlorellosis in a dog.
An adult dog with ataxia and a lingual mass, previously diagnosed as protothecosis, was euthanized. At the postmortem examination, the lingual mass, regions of the lungs and hilar lymph nodes, liver, mesenteric and sublumbar lymph nodes, and spinal meninges had pronounced green discoloration. Histologically, pyogranulomatous inflammation and algal organisms were found in the tongue, spinal meninges, hilar and mesenteric lymph nodes, liver, and lung. The algae had cell walls positive for periodic acid-Schiff and cytoplasmic granules. Ultrastructurally, the algae had a well-defined cell wall, stacks of grana and thylakoid membrane, and dense bodies, typical of starch granules. The organisms were identified as Chlorella, a green alga, based on the results of histochemistical and electron microscopic examination. To the author's knowledge this is the first report of disseminated Chlorella infection and the first report in a companion animal.


Periodontal maintenance following scaling and root planing. A randomized single-center study comparing minocycline treatment and daily oral irrigation with water.
Objective: Trying to limit the use of antimicrobial drugs in periodontitis is a general trend. Thus, the aim of the present study was to assess the efficacy of daily water irrigation in comparison with subgingival minocycline in periodontal maintenance, in subjects with moderate to severe periodontitis. This was done by evaluating probing pocket depth (the primary outcome), other clinical parameters such as clinical attachment level, plaque index and bleeding on probing, and bacterial flora changes inside periodontal pockets. Materials and Methods: In this single-center, parallel, single blind, randomized clinical study, thirty subjects (12 men, mean age 56 ± 2.2 years) with moderate to severe periodontitis were randomized 1:1 into a minocycline-treated group (M-group, n=15) and a water-treated group (W-group, n=15). Clinical and microbiological parameters were measured at baseline. Scaling and root planing were carried out on all subjects, then to M-group patients minocycline was administered inside the pockets. W-group subjects had instead to daily apply oral irrigation with water. Clinical and microbiological measurements were repeated after 30 days. Results: Both water irrigation and minocycline treatment led to a significant reduction of all the clinical parameters tested at t=30 days with respect to baseline. Moreover, both procedures appeared to be able to maintain a low bacterial load inside periodontal pockets, for most of the microorganisms tested. No statistically significant differences were observed between M-group and W-group at t=30 days, concerning both clinical and microbiological parameters. However, further studies are needed to assess the long-term effect. Conclusion: Daily oral irrigation with water showed comparable efficacy to a single administration of minocycline in periodontal maintenance subjects.


Human antibody recognition of H7N9 influenza virus HA following natural infection.
Avian H7N9 influenza viruses cause sporadic outbreaks of human infections and threaten to cause a major pandemic. The breadth of B cell responses to natural infection and the dominant antigenic sites recognized during first exposure to H7 HA following infection are incompletely understood. Here, we studied the B cell response to H7 HA of 2 individuals who had recovered from natural H7N9 virus infection. We used competition binding, hydrogen-deuterium mass spectrometry, and single-particle negative stain electron microscopy to identify the patterns of molecular recognition of the antibody responses to H7 HA. We found that circulating H7-reactive B cells recognized a diverse antigenic landscape on the HA molecule, including HA head domain epitopes in antigenic sites A and B and in the trimer interface-II region and epitopes in the stem region. Most H7 antibodies exhibited little heterosubtypic breadth, but many recognized a wide diversity of unrelated H7 strains. We tested the antibodies for functional activity and identified clones with diverse patterns of inhibition, including neutralizing, hemagglutination- or egress-inhibiting, or HA trimer-disrupting activities. Thus, the human B cell response to primary H7 natural infection is diverse, highly functional, and broad for recognition of diverse H7 strains.


Travelers' diarrhea.
Travelers' diarrhea affects 20-60% of travelers to low-income regions of the world. Much of the evidence for the clinical description and management of travelers' diarrhea was generated years ago, however, there is new information on geographic and host risk, etiology, and prevention strategies. Travel to South Asia, followed by sub-Saharan Africa and South America, carries the highest risk for diarrheal syndromes in returned travelers. Women are more susceptible to travel-related diarrhea than men. Host genetic studies have demonstrated that single nucleotide polymorphisms in the lactoferrin, osteoprotegerin, and IL-10 genes are associated with small but increased risks for diarrhea and enteric pathogens. Enterotoxigenic Bacteroides fragilis is likely to be a new agent identified as causing travelers' diarrhea, and heat-stable toxin-producing Escherichia coli appears to be more common than heat-labile toxin E. coli. Overall levels of sanitation at the travel destination, including individual eating establishments, are strong predictors for acquisition of travelers' diarrhea. A new transdermal LT vaccine shows promise in modifying the severity of travelers' diarrhea. It remains uncertain whether prophylaxis or prompt self-treatment of travelers' diarrhea will prevent late-onset irritable bowel syndrome. For self-treatment, azithromycin is the drug of choice in travelers to areas where there is a high risk of fluoroquinolone-resistant Campylobacter spp., such as South and Southeast Asia and possibly North Africa, Central and South America. There is increased understanding of the determinants of travelers' diarrhea. Despite this travelers' diarrhea remains one of the most common illnesses in travelers. Continued focus on intervention strategies may ultimately lead to decreased incidence.


Alcohol Consumption and Common Carotid Intima-Media Thickness: The USE-IMT Study.
Epidemiological evidence indicates a protective effect of light to moderate alcohol consumption compared to non-drinking and heavy drinking. Although several mechanisms have been suggested, the effect of alcohol on atherosclerotic changes in vessel walls is unclear. Therefore, we explored the relationship between alcohol consumption and common carotid intima media thickness, a marker of early atherosclerosis in the general population. Individual participant data from eight cohorts, involving 37,494 individuals from the USE-IMT collaboration were used. Multilevel age and sex adjusted linear regression models were applied to estimate mean differences in common carotid intima-media thickness (CIMT) with alcohol consumption. The mean age was 57.9 years (SD 8.6) and the mean CIMT was 0.75 mm (SD 0.177). About, 40.5% reported no alcohol consumed, and among those who drank, mean consumption was 13.3 g per day (SD 16.4). Those consuming no alcohol or a very small amount (<5 g per day) had significantly lower common CIMT values than those consuming >10 g per day, after adjusting for a range of confounding factors. In this large CIMT consortium, we did not find evidence to support a protective effect of alcohol on CIMT.


Chronic wound microbiome colonization on mouse model following cryogenic preservation.
Chronic wound infections are increasingly recognized to be dynamic and polymicrobial in nature, necessitating the development of wound models which reflect the complexities of infection in a non-healing wound. Wound slough isolated from human chronic wounds and transferred to mice was recently shown to create polymicrobial infection in mice, and there is potential this tool may be improved by cryogenic preservation. The purpose of this study was to investigate the application of cryogenic preservation to transferring polymicrobial communities, specifically by quantifying the effects of cryopreservation and wound microbiome transplantation. Slough from an established murine polymicrobial surgical excision model and five patients were subjected to three preservation strategies: refrigeration until infection, freezing in liquid nitrogen, or freezing in liquid nitrogen with glycerol solution prior to infection in individual mice. Four days following inoculation onto mice, wound microbiota were quantified using either culture isolation or by 16s rRNA gene community profiling and quantitative PCR. Cryogenic preservation did not significantly reduce bacterial viability. Reestablished microbial communities were significantly associated with patient of origin as well as host context (i.e., originally preserved from a patient versus mouse infection). Whereas preservation treatment did not significantly shape community composition, the transfers of microbiomes from human to mouse were characterized by reduced diversity and compositional changes. These findings indicated that changes should be expected to occur to community structure after colonization, and that compositional change is likely due to the rapid change in infection context as opposed to preservation strategy. Furthermore, species that were present in higher relative abundance in wound inoculate were more likely to colonize subsequent wounds, and wound inoculate with higher bacterial load established wound communities that were more compositionally similar. Results inform expectations for the complementation of chronic wound in vivo modeling with cryogenic preservation archives.


Evaluation of σ-1 receptor radioligand 18F-FTC-146 in rats and squirrel monkeys using PET.
The noninvasive imaging of σ-1 receptors (S1Rs) could provide insight into their role in different diseases and lead to novel diagnostic/treatment strategies. The main objective of this study was to assess the S1R radiotracer (18)F-FTC-146 in rats. Preliminary squirrel monkey imaging and human serum/liver microsome studies were performed to gain information about the potential of (18)F-FTC-146 for eventual clinical translation. The distribution and stability of (18)F-FTC-146 in rats were assessed via PET/CT, autoradiography, γ counting, and high-performance liquid chromatography (HPLC). Preliminary PET/MRI of squirrel monkey brain was conducted along with HPLC assessment of (18)F-FTC-146 stability in monkey plasma and human serum. Biodistribution studies showed that (18)F-FTC-146 accumulated in S1R-rich rat organs, including the lungs, pancreas, spleen, and brain. Pretreatment with known S1R compounds, haloperidol, or BD1047, before radioligand administration, significantly attenuated (18)F-FTC-146 accumulation in all rat brain regions by approximately 85% (P < 0.001), suggesting radiotracer specificity for S1Rs. Similarly, PET/CT and autoradiography results demonstrated accumulation of (18)F-FTC-146 in rat brain regions known to contain S1Rs and that this uptake could be blocked by BD1047 pretreatment. Ex vivo analysis of (18)F-FTC-146 in the brain showed that only intact radiotracer was present at 15, 30, and 60 min, whereas rapid metabolism of residual (18)F-FTC-146 was observed in rat plasma. Preliminary monkey PET/MRI studies demonstrated specific accumulation of (18)F-FTC-146 in the brain (mainly in cortical structures, cerebellum, and vermis) that could be attenuated by pretreatment with haloperidol. HPLC of monkey plasma suggested radioligand metabolism, whereas (18)F-FTC-146 appeared to be stable in human serum. Finally, liver microsome studies revealed that (18)F-FTC-146 has a longer half-life in human microsomes, compared with rodents. Together, these results indicate that (18)F-FTC-146 is a promising tool for visualizing S1Rs in preclinical studies and that it has potential for mapping these sites in the human brain.


Sustainable HIV treatment in Africa through viral-load-informed differentiated care.
There are inefficiencies in current approaches to monitoring patients on antiretroviral therapy in sub-Saharan Africa. Patients typically attend clinics every 1 to 3 months for clinical assessment. The clinic costs are comparable with the costs of the drugs themselves and CD4 counts are measured every 6 months, but patients are rarely switched to second-line therapies. To ensure sustainability of treatment programmes, a transition to more cost-effective delivery of antiretroviral therapy is needed. In contrast to the CD4 count, measurement of the level of HIV RNA in plasma (the viral load) provides a direct measure of the current treatment effect. Viral-load-informed differentiated care is a means of tailoring care so that those with suppressed viral load visit the clinic less frequently and attention is focussed on those with unsuppressed viral load to promote adherence and timely switching to a second-line regimen. The most feasible approach to measuring viral load in many countries is to collect dried blood spot samples for testing in regional laboratories; however, there have been concerns over the sensitivity and specificity of this approach to define treatment failure and the delay in returning results to the clinic. We use modelling to synthesize evidence and evaluate the cost-effectiveness of viral-load-informed differentiated care, accounting for limitations of dried blood sample testing. We find that viral-load-informed differentiated care using dried blood sample testing is cost-effective and is a recommended strategy for patient monitoring, although further empirical evidence as the approach is rolled out would be of value. We also explore the potential benefits of point-of-care viral load tests that may become available in the future.


Systemic lymphadenopathy (LAS) in intravenous drug abusers. Histology, immunohistochemistry and electron microscopy: pathogenic correlations.
In the present study we have evaluated the histological, immunohistochemical, ultrastructural and cell surface phenotypic features of lymph nodes from 19 intravenous drug abusers and two homosexual men with persistent lymphadenopathy syndrome and from six control patients. Our investigation has demonstrated that the lymphadenopathy of drug abusers is characterized by: (a) specific histological features with evidence of evolution from an initial hyperplastic-reactive to a late regressive-destructive stage; (b) T-cell surface phenotype distribution similar to that in the peripheral blood of homosexuals; (c) peculiar infiltration of the germinal centres by T8+ cells and by S-100+, T6+ interdigitating reticulum-like cells; (d) electron microscopic features indicating the presence of virus bodies in lymph node cells and in the intercellular spaces. These data suggest that the lymphadenopathy of drug abusers and homosexuals are similar pathological conditions with characteristic features which allow histological differentiation of this entity from those found in other viral infections.


The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome.
We determined the complete genome sequence of Clostridium difficile strain 630, a virulent and multidrug-resistant strain. Our analysis indicates that a large proportion (11%) of the genome consists of mobile genetic elements, mainly in the form of conjugative transposons. These mobile elements are putatively responsible for the acquisition by C. difficile of an extensive array of genes involved in antimicrobial resistance, virulence, host interaction and the production of surface structures. The metabolic capabilities encoded in the genome show multiple adaptations for survival and growth within the gut environment. The extreme genome variability was confirmed by whole-genome microarray analysis; it may reflect the organism's niche in the gut and should provide information on the evolution of virulence in this organism.


Oncostatin M induces an acute phase response but does not modulate the growth or maturation-status of liver progenitor (oval) cells in culture.
Following acute injury, the liver regenerates through hepatocyte division. If this pathway is impaired, liver repair depends on the recruitment of adult liver progenitor (oval) cells. Mice fed a choline deficient, ethionine supplemented (CDE) diet possess substantial numbers of oval cells, which can be isolated, or examined in vivo. Oncostatin M (OSM) has been shown to induce maturation of murine fetal hepatoblasts into hepatocytes. We recently confirmed this in human fetal liver cultures. Here, we show that liver OSM expression increases in mice fed a CDE diet and CDE-derived oval cell isolates express OSM and its receptor (OSMR). Oval cell lines (PIL cells), as well as primary oval cell cultures, displayed STAT-3 phosphorylation following OSM stimulation. OSM had no effect on the growth of primary oval cells, but it was pro-apoptotic to PIL cells, suggesting that the two cell models are not directly comparable. Expression of PCNA and cyclin D1 was not affected by OSM treatment. No evidence was obtained to suggest an effect on oval cell maturation with OSM treatment. However, decreased albumin production, accompanied by increased expression of haptoglobin and fibrinogen, suggests that OSM induced an acute phase reaction in cultured oval cells.


Atrial natriuretic peptide decreases cardiac output independent of coronary vasoconstriction.
Studies were performed in isolated, Langendorff-perfused rat hearts and anesthetized dogs to determine the effects of synthetic atrial natriuretic peptide (ANP 8-33) on the coronary circulation. In vitro studies in the rat examined coronary flow dynamics to ANP 8-33 over a defined range from physiologic to pharmacologic concentrations. No changes in coronary flow or chronotropic and inotropic function of the isolated Langendorff-perfused heart were observed in response to increasing concentrations of ANP 8-33 (10(2) to 10(6) pg/ml). In the dog, a low, nonhypotensive dose of ANP 8-33 (0.05 microgram/kg/min) decreased cardiac output with no change in coronary blood flow or coronary vascular resistance. At a high, hypotensive dose (0.3 microgram/kg/min) ANP 8-33 decreased cardiac output in association with transient coronary vasodilation. Continued infusion resulted in a decrease in coronary blood flow and arterial pressure with no change in coronary vascular resistance. Thus, in vitro physiologic and pharmacologic concentrations of ANP, or in vivo low concentrations of ANP, do not result in an alteration in coronary flow. In vivo ANP 8-33, at both nonhypotensive and hypotensive concentrations, decreased cardiac output in the absence of coronary vasoconstriction.


Insights into the chicken IgY with emphasis on the generation and applications of chicken recombinant monoclonal antibodies.
The advantages of chicken (Gallus gallus domesticus) antibodies as immunodiagnostic and immunotherapeutic biomolecules has only been recently recognized. Even so, chicken antibodies remain less-well characterized than their mammalian counterparts. This review aims at providing a current overview of the structure, function, development and generation of chicken antibodies. Additionally, brief but comprehensive insights into current knowledge pertaining to the immunogenetic framework and diversity-generation of the chicken immunoglobulin repertoire which have contributed to the establishment of recombinant chicken mAb-generating methods are discussed. Focus is provided on the current methods used to generate antibodies from chickens with added emphasis on the generation of recombinant chicken mAbs and its derivative formats. The advantages and limitations of established protocols for the generation of chicken mAbs are highlighted. The various applications of recombinant chicken mAbs and its derivative formats in immunodiagnostics and immunotherapy are further detailed.


Validation of a risk prediction model for Barrett's esophagus in an Australian population.
Esophageal adenocarcinoma is a disease that has a high mortality rate, the only known precursor being Barrett's esophagus (BE). While screening for BE is not cost-effective at the population level, targeted screening might be beneficial. We have developed a risk prediction model to identify people with BE, and here we present the external validation of this model. A cohort study was undertaken to validate a risk prediction model for BE. Individuals with endoscopy and histopathology proven BE completed a questionnaire containing variables previously identified as risk factors for this condition. Their responses were combined with data from a population sample for analysis. Risk scores were derived for each participant. Overall performance of the risk prediction model in terms of calibration and discrimination was assessed. Scores from 95 individuals with BE and 636 individuals from the general population were analyzed. The Brier score was 0.118, suggesting reasonable overall performance. The area under the receiver operating characteristic was 0.83 (95% CI 0.78-0.87). The Hosmer-Lemeshow statistic was p=0.14. Minimizing false positives and false negatives, the model achieved a sensitivity of 74% and a specificity of 73%. This study has validated a risk prediction model for BE that has a higher sensitivity than previous models.


Binding Studies of Metal-Salphen and Metal-Bipyridine Complexes towards G-Quadruplex DNA.
The proposed in vivo formation of G-quadruplex DNA (G4 DNA) in promoter regions of oncogenes and in telomeres has prompted the development of small molecules with high affinity and selectivity for these structures. Herein we report the synthesis of a new di-substituted bipyridine ligand and the corresponding complexes with Ni2+ and VO2+ . Both these new complexes have been characterized spectroscopically and by X-ray crystallography. Detailed DNA binding studies of these two complexes, together with three previously reported metal salphen complexes, are presented. Using FRET melting assays, the binding affinity and selectivity of the five metal complexes against six different G4 DNA structures as well as a duplex DNA have been determined. In addition, we present detailed ITC and UV/Vis studies to characterize the interaction of the complexes with human telomeric G4 DNA. Finally, we show via a polymerase stop assay that these complexes are able to stabilize a G4 DNA structure (from the c-Myc oncogene promoter) and halt the activity of Taq polymerase.


Replication-competent human mitochondrial DNA lacking the heavy-strand promoter region.
We identified two patients with progressive external ophthalmoplegia, a mitochondrial disease, who harbored a population of partially deleted mitochondrial DNA (mtDNA) with unusual properties. These molecules were deleted from mtDNA positions 548 to 4,442 and encompassed not only rRNA sequences but the heavy-strand promoter region as well. A 13-bp direct repeat was found flanking the breakpoint precisely, with the repeat at positions 535 to 547 located within the binding site for mitochondrial transcription factor 1 (mtTF1). This is the second mtDNA deletion involving a 13-bp direct repeat reported but is at least 10 times less frequent in the patient population than the former one. In situ hybridization studies showed that transcripts under the control of the light-strand promoter were abundant in muscle fibers with abnormal proliferation of mitochondria, while transcripts directed by the heavy-strand promoter, whether of genes residing inside or outside the deleted region, were not. The efficient transcription from the light-strand promoter implies that the major heavy-and light-strand promoters, although physically close, are functionally independent, confirming previous in vitro studies.