Characterization of Vasorelaxant Principles from the Needles of Pinus morrisonicola Hayata.
Pinus morrisonicola Hayata, usually called Taiwan five-leaf pine (5LP), is an endemic species in Taiwan and is traditionally used to relieve hypertension symptoms and improve cardiovascular function. In this study, the needle extract of 5LP was fractionated and analyzed by LC/MS/MS to search for possible antihypertensive candidates. In addition, bioassay-guided purification of the bioactive components was performed by Ca2+ fluorescent signal (Fluo 4-AM) assays. Two dihydrobenzofuran lignans, pinumorrisonide A (1) and icariside E4 (2), and one acylated flavonoid glycoside, kaempferol 3-O-α-(6‴-p-coumaroylglucosyl-β-1,4-rhamnoside) (3) were characterized from the active fractions. The structure of a new compound 1 was established on the basis of 2D NMR spectroscopic and mass spectrometric analyses, and the known compounds 2 and 3 were identified by comparison of their physical and spectroscopic data with those reported in the literature. The purified compounds 1-3 exhibited significant inhibition of Ca2+ fluorescence with IC50 values of 0.71, 0.36, and 0.20 mM, respectively. A mechanism study showed that these compounds showed vasorelaxant effects by blocking the voltage-operated Ca2+ channel (VOCC) and inhibiting Ca2+ influx to the cytoplasmic. These results suggested that 5LP and the three characterized components could be promising antihypertensive candidates for the use as VOCC blockers.


Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome-Associated Calmodulin Missense Variant, E141G.
Calmodulin (CaM) is encoded by 3 genes, CALM1, CALM2, and CALM3, all of which harbor pathogenic variants linked to long QT syndrome (LQTS) with early and severe expressivity. These LQTS-causative variants reduce CaM affinity to Ca(2+) and alter the properties of the cardiac L-type calcium channel (CaV1.2). CaM also modulates NaV1.5 and the ryanodine receptor, RyR2. All these interactions may play a role in disease pathogenesis. Here, we determine the spectrum and prevalence of pathogenic CaM variants in a cohort of genetically elusive LQTS, and functionally characterize the novel variants. Thirty-eight genetically elusive LQTS cases underwent whole-exome sequencing to identify CaM variants. Nonsynonymous CaM variants were over-represented significantly in this heretofore LQTS cohort (13.2%) compared with exome aggregation consortium (0.04%; P<0.0001). When the clinical sequelae of these 5 CaM-positive cases were compared with the 33 CaM-negative cases, CaM-positive cases had a more severe phenotype with an average age of onset of 10 months, an average corrected QT interval of 676 ms, and a high prevalence of cardiac arrest. Functional characterization of 1 novel variant, E141G-CaM, revealed an 11-fold reduction in Ca(2+)-binding affinity and a functionally dominant loss of inactivation in CaV1.2, mild accentuation in NaV1.5 late current, but no effect on intracellular RyR2-mediated calcium release. Overall, 13% of our genetically elusive LQTS cohort harbored nonsynonymous variants in CaM. Genetic testing of CALM1-3 should be pursued for individuals with LQTS, especially those with early childhood cardiac arrest, extreme QT prolongation, and a negative family history.


Stereotype threat and the intellectual test performance of African Americans.
Stereotype threat is being at risk of confirming, as self-characteristic, a negative stereotype about one's group. Studies 1 and 2 varied the stereotype vulnerability of Black participants taking a difficult verbal test by varying whether or not their performance was ostensibly diagnostic of ability, and thus, whether or not they were at risk of fulfilling the racial stereotype about their intellectual ability. Reflecting the pressure of this vulnerability, Blacks underperformed in relation to Whites in the ability-diagnostic condition but not in the nondiagnostic condition (with Scholastic Aptitude Tests controlled). Study 3 validated that ability-diagnosticity cognitively activated the racial stereotype in these participants and motivated them not to conform to it, or to be judged by it. Study 4 showed that mere salience of the stereotype could impair Blacks' performance even when the test was not ability diagnostic. The role of stereotype vulnerability in the standardized test performance of ability-stigmatized groups is discussed.


Dosimetric evaluation of the mean glandular dose for mammography in Korean women: a preliminary report.
The purpose of this study was to evaluate the thickness of the compressed breast in mediolateral oblique (MLO) and craniocaudal (CC) mammograms, to relate these thickness and breast patterns to mean glandular dose (MGD) in Korean women, and to evaluate the suitability of using the American College of Radiology's Recommendations for Korean women from a quality assurance standpoint. The study population consisted of 92 paired MLO and CC mammograms obtained on one mammographic unit. The digital readouts of compressed breast thickness, applied compression force and tube voltage were recorded. Entrance skin exposure was measured by dosimetry. MGD was calculated by multiplying entrance skin exposure by the exposure-to-absorbed dose conversion factor. The range of breast thickness was 1.3-6.2 cm in CC mammograms with a mean breast thickness of 3.6 cm, and 1.6-6.5 cm in MLO mammograms with a mean breast thickness of 3.9 cm. MGDs in CC and MLO mammograms were 1.77 mSv and 1.88 mSv per view, respectively. Breast composition patterns were divided into 4 groups according to ACR BI-RADS; P1 (n=20), P2 (n=16), P3 (n=48) and P4 (n=8). The MGDs for these groups were: 1.82, 1.84, 1.84, and 1.91 mSv, respectively. When subjects were subdivided by breast thickness into three groups, namely, below 3 cm, 3 cm to 4.2 cm, aaa and above 4.2 cm, the corresponding MGDs were 1.83, 1.86, and 1.91 mSv. According to our initial trial, the mean breast thickness and the MGDs of Korean women are lower than recommended by the American College of Radiology, which are commonly used for quality assurance purposes.


Characterization of the auxin-regulated par gene from tobacco mesophyll protoplasts.
The auxin-regulated par gene from tobacco mesophyll protoplasts was characterized in detail to deduce its possible function. An homology search of the par gene in the NBRF databases revealed that the par gene has homology to the stringent starvation protein (ssp) gene of Escherichia coli, which is induced under starved conditions and binds in an equimolar ratio to a holoenzyme of RNA polymerase. Hence, it is supposed that the par gene product could play a similar role to that of ssp. Although sequence homology of the par gene to the Gmhsp 26-A gene from soybean was observed, both genes were shown to respond differently to plant hormones and stresses. Gmhsp 26-A is induced by heat shock, 2,4-dichlorophenoxyacetic acid (2,4-D), cytokinin and abscisic acid (ABA), whereas the par gene was induced only by auxins. Furthermore, cycloheximide treatment prevents 2,4-D-mediated accumulation of Gmhsp 26-A mRNA, but not that of par mRNA. Both par and Gmhsp 26-A respond to CdCl2, but splicing of the par pre-mRNA proceeded in a normal way, whereas splicing off the Gmhsp 26-A pre-mRNA was inhibited. Hence, the par and Gmhsp 26-A genes should have a common ancestor, but have evolved in different directions. Detailed time-course experiments confirmed that the par gene was induced immediately after the addition of auxin and expressed upon the initiation of meristematic activity in tobacco mesophyll protoplasts. As the par gene was induced by the sole treatment of cycloheximide, it was proposed that the par gene belongs to a category of 'superinduction' genes.(ABSTRACT TRUNCATED AT 250 WORDS)


A Deletion of More than 800 kb Is the Most Recurrent Mutation in Chilean Patients with SHOX Gene Defects.
Deletions in the SHOX gene are the most frequent genetic cause of Leri-Weill syndrome and Langer mesomelic dysplasia, which are also present in idiopathic short stature. To describe the molecular and clinical findings observed in 23 of 45 non-consanguineous Chilean patients with different phenotypes related to SHOX deficiency. Multiplex ligation-dependent probe amplification was used to detect the deletions; the SHOX coding region and deletion-flanking areas were sequenced to identify point mutations and single-nucleotide polymorphisms (SNPs). The main genetic defects identified in 21 patients consisted of deletions; one of them, a large deletion of >800 kb, was found in 8 patients. Also, a smaller deletion of >350 kb was observed in 4 patients. Although we could not precisely determine the deletion breakpoint, we were able to identify a common haplotype in 7 of the 8 patients with the larger deletion based on 22 informative SNPs. These results suggest that the large deletion-bearing allele has a common ancestor and was either introduced by European immigrants or had originated in our Amerindian population. This study allowed us to identify one recurrent deletion in Chilean patients; also, it contributed to expanding our knowledge about the genetic background of our population.


Brodie's Abscess of Posterior Ilium with Gluteal Syndrome, an Unusual Cause of Paediatric Low Back Pain: A Case Report.
Brodie's abscess is a variety of subacute osteomyelitis with a long duration of presentation and intermittent pain. It usually involves the metaphyseal region of long bones of the lower limbs. Brodie's abscess of pelvic bone is very rare. Involvement of posterior ilium with gluteal syndrome is extremely unusual and can be easily missed or misdiagnosed. We present a 9-year old boy who reported to us with intermittent low back pain of three months duration without any other constitutional symptoms. Clinically, there was mild tenderness over the posterior ilium. Computed tomography showed a lytic lesion in the posterior ilium with a breach in the outer cortex. MRI and bone scan were suggestive of inflammatory pathology. Keeping infective, tubercular and benign bone tumors as differential diagnoses, open biopsy and curettage were done. Staphylococcus aureus was cultured and histopathology was suggestive of osteomyelitis. The patient received appropriate antibiotics for six weeks. He was asymptomatic till 18 months of follow up without any recurrence. We present this case because of its rarity and unusual presentation as gluteal syndrome and low back pain, and its resemblance to other pelvic and sacroiliac joint pathologies which are often missed or misdiagnosed in paediatric patients.


Frequency analysis of body sway in the upright posture. Statistical study in cases of peripheral vestibular disease.
The frequency component of shift in the centre of gravity while standing upright was investigated in 14 normal subjects and 30 patients with peripheral vestibular disease. Relative changes in the square root value of the power in each small frequency band of 0.1 and 0.2 Hz in frequencies of less than 2 Hz were evaluated statistically for four groups, viz. a group of normal subjects, and patients with Ménière's disease, benign paroxysmal positional vertigo, and vestibular neuritis. The influence of visual control in each group and the difference between each pathological group and the normal subjects were examined statistically. The combination of a minor change in each small frequency band is considered to be utilizable to establish a differential diagnosis for the three groups of peripheral vestibular disease and versus the normal group.


Improving Prediction of Risk of Admission to Long-Term Care or Mortality Among Home Care Users With IDD.
Frailty is an established predictor of admission into long-term care (LTC) and mortality in the elderly population. Assessment of frailty among adults with intellectual and developmental disabilities (IDD) using a generic frailty marker may not be as predictive, as some lifelong disabilities associated with IDD may be interpreted as a sign of frailty. This study set out to determine if adding the Home Care-Intellectual and Developmental Disabilities Frailty Index (HC-IDD Frailty Index), developed for use in home care users with IDD, to a basic list of predictors (age, sex, rural status, and the Johns Hopkins Frailty Marker) increases the ability to predict admission to long-term care or death within one year. A retrospective cohort study was conducted using Residential Assessment Instrument for Home Care (RAI-HC) data for adult home care users with IDD who had a home care assessment between January 1, 2010 and December 31, 2013 (N = 6,169). The HC-IDD Frailty Index was found to significantly improve prediction of transitions into LTC or death by explaining an additional 5.95% of the variance in such transitions among home care users with IDD (p value < .0001). We recommend the use of the HC-IDD Frailty Index in care planning and in further research related to the effectiveness of interventions to reduce or delay adverse age-related outcomes among adults with IDD.


Bioptic Telescope Use and Driving Patterns of Drivers with Age-Related Macular Degeneration.
To investigate the telescope use and driving patterns of bioptic drivers with age-related macular degeneration (AMD). A questionnaire addressing telescope use and driving patterns was administered by telephone interview to three groups of bioptic drivers: AMD (n = 31; median 76 years); non-AMD first licensed with a bioptic (n = 38; 53 years); and non-AMD first licensed without a bioptic (n = 47; 37 years). Driving patterns of bioptic AMD drivers were also compared with those of normal vision (NV) drivers (n = 36; 74 years) and nonbioptic AMD drivers (n = 34; 79 years). Bioptic usage patterns of AMD drivers did not differ from those of the younger bioptic drivers and greater visual difficulty without the bioptic was strongly correlated with greater bioptic helpfulness. Bioptic AMD drivers were more likely to report avoidance of night driving than the age-similar NV drivers (P = 0.06). However, they reported less difficulty than the nonbioptic AMD drivers in all driving situations (P ≤ 0.02). Weekly mileages of bioptic AMD drivers were lower than those of the younger bioptic drivers (P < 0.001), but not the NV group (P = 0.54), and were higher than those of the nonbioptic AMD group (P < 0.001). Our results suggest that bioptic telescopes met the visual demands of drivers with AMD and that those drivers had relatively unrestricted driving habits. Licensure with a bioptic telescope may prolong driving of older adults with AMD; however, objective measures of bioptic use, driving performance, and safety are needed.


The potential effects of changing HIV treatment policy on tuberculosis outcomes in South Africa: results from three tuberculosis-HIV transmission models.
Many countries are considering expanding HIV treatment following recent findings emphasizing the effects of antiretroviral therapy (ART) on reducing HIV transmission in addition to already established survival benefits. Given the close interaction of tuberculosis (TB) and HIV epidemics, ART expansion could have important ramifications for TB burden. Previous studies suggest a wide range of possible TB impacts following ART expansion. We used three independently developed TB-HIV models to estimate the TB-related impact of expanding ART in South Africa. We considered two dimensions of ART expansion--improving coverage of pre-ART and ART services, and expanding CD4-based ART eligibility criteria (from CD4 <350 to CD4 <500 or all HIV-positive). Three independent mathematical models were calibrated to the same data pertaining to the South African HIV-TB epidemic, and used to assess standardized ART policy changes. Key TB impact indicators were projected from 2014 to 2033. Compared with current eligibility and coverage, cumulative TB incidence was projected to decline by 6-30% over the period 2014-2033 if ART eligibility were expanded to all HIV positive individuals, and by 28-37% if effective ART coverage were additionally increased to 80%. Overall, expanding ART was estimated to avert one TB case for each 10-13 additional person-years of ART. All models showed that TB incidence and mortality reductions would grow over time, but would stabilize towards the end of the projection period. ART expansion could substantially reduce TB incidence and mortality in South Africa and could provide a platform for collaborative HIV-TB programs to effectively halt HIV-associated TB.


Primary care physician practice styles and quality, cost, and productivity.
To assess quality, cost, physician productivity, and patient experience for 2 primary care physician (PCP) practice styles: the focused, who typically address only the patient's acute problem, versus the max-packers, who typically address additional conditions also. Retrospective observational study using administrative data, electronic health record (EHR) data, and patient surveys. Data represent 285 PCPs (779 PCP-years) in a large, multispecialty group practice during 2011, 2012, and 2013. PCPs were ranked each year by their number of additional conditions addressed during acute care visits. The top one-third (max-packers) addressed 25.4% more "other problems" than expected, while focused PCPs (bottom one-third) addressed 20.3% fewer than expected. Outcomes were resource use, clinical quality metrics, patient-reported experience, physician time using the EHR, and physician productivity. All measures were risk-adjusted to account for patient mix. T tests were used to compare measures. Relative to a focused pattern of care, max-packing was associated with 3.4% lower overall resource use, consistently better scores for the available clinical quality metrics, and comparable patient experience (except for worse wait time ratings). Patients of focused PCPs used 7.3% more specialist services, in terms of costs, than patients of max-packers ($1218 vs $1136; P <.001). Max-packers spent 40 minutes more per clinical day using the EHR. PCPs with less appointment availability and who used a mix of appointment slots were more likely to be max-packers. Max-packing behavior yields desirable outcomes at lower overall cost but involves more conventionally uncompensated PCP time. Alternatives to compensation just for face-to-face visits and using more flexible scheduling may be needed to support max-packing.


Wnt/Β-catenin and sex hormone signaling in endometrial homeostasis and cancer.
A delicate balance between estrogen and progestagen signaling underlies proper functioning of the female reproductive tract and, in particular, the monthly re- and degenerative phases characteristic of the menstrual cycle. Here, we propose that the canonical Wnt/β-catenin signaling pathway may underlie this finely tuned hormonal equilibrium in endometrial homeostasis and, upon its constitutive activation, lead to neoplastic transformation of the endometrium. During the menstrual cycle, estradiol will enhance Wnt/β-catenin signaling in the proliferative phase, while progesterone inhibits Wnt/β-catenin signaling, thus restraining estrogens' proliferative actions, during the secretory phase. In case of enhanced or unopposed estrogen signaling, constitutive activation of Wnt/β-catenin signaling will trigger endometrial hyperplasia, which may develop further into endometrial cancer.


Antigen expression during murine gamma-herpesvirus infection.
Gammaherpesviruses (gammaHV) establish a life-long latency in the host and are associated with a number of malignant human diseases. It is generally believed that T cells play a major role in controlling the initial acute infection and subsequently maintaining the virus in a quiescent state. However, the nature of the T cell response to gamma-herpesvirus infections is poorly understood. In the current report we took advantage of a mouse model of gammaHV infection (murine herpesvirus-68, MHV-68) to investigate the T cell response to different phases of the infection. Intranasal infection with MHV-68 induces an acute infection in lung epithelial cells and long-term latency in B cells. The kinetics of the CD8+ T cell response to different lytic cycle and latency-associated antigens was highly complex and distinct patterns of response could be identified. These responses were regulated by multiple factors including differences in temporal expression of the relevant antigens, differences in the presentation of antigen in different organs, and differential expression of antigen in different types of antigen presenting cells. For example, some antigens were expressed at distinct phases of the infection and in specific organs or subsets of antigen presenting cells. In addition, recent data suggest that in addition to B cells, both macrophages and dendritic cells harbor latent MHV-68 infection, adding further complexity to their role in controlling the T cell response to this infection.


Multiscale computational analysis of Xenopus laevis morphogenesis reveals key insights of systems-level behavior.
Tissue morphogenesis is a complex process whereby tissue structures self-assemble by the aggregate behaviors of independently acting cells responding to both intracellular and extracellular cues in their environment. During embryonic development, morphogenesis is particularly important for organizing cells into tissues, and although key regulatory events of this process are well studied in isolation, a number of important systems-level questions remain unanswered. This is due, in part, to a lack of integrative tools that enable the coupling of biological phenomena across spatial and temporal scales. Here, we present a new computational framework that integrates intracellular signaling information with multi-cell behaviors in the context of a spatially heterogeneous tissue environment. We have developed a computational simulation of mesendoderm migration in the Xenopus laevis explant model, which is a well studied biological model of tissue morphogenesis that recapitulates many features of this process during development in humans. The simulation couples, via a JAVA interface, an ordinary differential equation-based mass action kinetics model to compute intracellular Wnt/beta-catenin signaling with an agent-based model of mesendoderm migration across a fibronectin extracellular matrix substrate. The emergent cell behaviors in the simulation suggest the following properties of the system: maintaining the integrity of cell-to-cell contact signals is necessary for preventing fractionation of cells as they move, contact with the Fn substrate and the existence of a Fn gradient provides an extracellular feedback loop that governs migration speed, the incorporation of polarity signals is required for cells to migrate in the same direction, and a delicate balance of integrin and cadherin interactions is needed to reproduce experimentally observed migratory behaviors. Our computational framework couples two different spatial scales in biology: intracellular with multicellular. In our simulation, events at one scale have quantitative and dynamic impact on events at the other scale. This integration enables the testing and identification of key systems-level hypotheses regarding how signaling proteins affect overall tissue-level behavior during morphogenesis in an experimentally verifiable system. Applications of this approach extend to the study of tissue patterning processes that occur during adulthood and disease, such as tumorgenesis and atherogenesis.


Tumor-specific killer cells in paraneoplastic cerebellar degeneration.
Models for immune-mediated tumor regression in mice have defined an essential role for cytotoxic T lymphocytes (CTLs); however, naturally occurring tumor immunity in humans is poorly understood. Patients with paraneoplastic cerebellar degeneration (PCD) provide an opportunity to explore the mechanisms underlying tumor immunity to breast and ovarian cancer. Although tumor immunity and autoimmune neuronal degeneration in PCD correlates with a specific antibody response to the tumor and brain antigen cdr2, this humoral response has not been shown to be pathogenic. Here we present evidence for a specific cellular immune response in PCD patients. We have detected expanded populations of MHC class I-restricted cdr2-specific CTLs in the blood of 3/3 HLA-A2.1+ PCD patients, providing the first description, to our knowledge, of tumor-specific CTLs using primary human cells in a simple recall assay. Cross-presentation of apoptotic cells by dendritic cells also led to a potent CTL response. These results indicate a model whereby immature dendritic cells that engulf apoptotic tumor cells can mature and migrate to draining lymph organs where they could induce a CTL response to tissue-restricted antigens. In PCD, peripheral activation of cdr2-specific CTLs is likely to contribute to the subsequent development of the autoimmune neuronal degeneration.


Superior temporal sulcus--It's my area: or is it?
The superior temporal sulcus (STS) is the chameleon of the human brain. Several research areas claim the STS as the host brain region for their particular behavior of interest. Some see it as one of the core structures for theory of mind. For others, it is the main region for audiovisual integration. It plays an important role in biological motion perception, but is also claimed to be essential for speech processing and processing of faces. We review the foci of activations in the STS from multiple functional magnetic resonance imaging studies, focusing on theory of mind, audiovisual integration, motion processing, speech processing, and face processing. The results indicate a differentiation of the STS region in an anterior portion, mainly involved in speech processing, and a posterior portion recruited by cognitive demands of all these different research areas. The latter finding argues against a strict functional subdivision of the STS. In line with anatomical evidence from tracer studies, we propose that the function of the STS varies depending on the nature of network coactivations with different regions in the frontal cortex and medial-temporal lobe. This view is more in keeping with the notion that the same brain region can support different cognitive operations depending on task-dependent network connections, emphasizing the role of network connectivity analysis in neuroimaging.


Methodological considerations in estimating adherence and persistence for a long-acting injectable medication.
Measures of medication adherence and persistence are important for researchers and policymakers to assess quality of care. Lack of adherence has been associated with adverse outcomes and higher costs of care. Long-acting medication formulations, including injectable forms, have been proposed as interventions to increase adherence and in turn improve health outcomes and costs. Standard measures of adherence/persistence were developed for orally administered medications. Methods for assessing adherence/persistence of long-acting injectable dose forms are understudied. To compare the consistency between standard measures of adherence/persistence versus proposed variations that consider the data quality and injectable administration method for a long-acting injectable second-generation antipsychotic (SGA) using an orally administered SGA as the reference. Standard adherence/persistence measures were designed for oral tablet formulations, in particular accounting for accumulation of pills caused by early refills. To address this limitation and the accuracy of the days supply field for long-acting injectable SGAs in pharmacy claims, 2 alternatives are proposed. The first approach calculates days supply using the labeled dosing schedule for the given injectable. The second approach builds on the first and sets days supply to the minimum of the time between injections and the time frame according to the labeled dosing schedule. Administrative health care claims data from the Missouri Medicaid system were analyzed to compare adherence/persistence measures between formulations. Common adherence/persistence measures, including medication possession ratio (MPR) and proportion of days covered (PDC), were evaluated in this study. The analysis cohorts comprised 195 adult patients with schizophrenia who initiated a long-acting injectable SGA (LA-SGA) and 369 patients initiating an oral SGA (O-SGA) from August 1, 2009, through April 30, 2010. Chi-squared tests, the Kruskal-Wallis test, and Kaplan-Meier curves were used to compare adherence/persistence measures between cohorts. Days supply was most frequently recorded as 30 days for O-SGA and 28 days for LA-SGA. Time between claim fills was most commonly 28 days for both cohorts. Using the LA-SGA pharmacy claims data, MPR was 0.91 and did not vary significantly from MPR of O-SGA (0.90; test statistic = 0.29, P = 0.590). When applying the labeled dosing schedule to compute days supply, the LA-SGA MPR rose to 0.97 and varied significantly from MPR of O-SGA (test statistic = 9.60, P = 0.002). Additionally controlling for the inability for excess medication accumulation, MPR for LA-SGA dropped to 0.86, which varied significantly from MPR of O-SGA (test statistic = 4.01, P = 0.045). PDC varied from 0.55 to 0.61 for LA-SGA but was consistently significantly different from the 0.37 PDC value of O-SGA (P less than 0.05 for each comparison). Standard medication adherence/persistence measures yielded different conclusions when comparing a LA-SGA and an O-SGA, depending on the measure and underlying assumption for days supply. Adherence/persistence measures that address pharmacological differences in terms of formulation and duration of therapeutic drug levels between medications may be necessary and are particularly important as more injectable antipsychotic medications are approved in the United States. Therefore, payers and investigators should consider sensitivity analysis using different adherence/persistence definitions when making product comparisons to ensure confidence in conclusions.


Divergent whole-genome methylation maps of human and chimpanzee brains reveal epigenetic basis of human regulatory evolution.
DNA methylation is a pervasive epigenetic DNA modification that strongly affects chromatin regulation and gene expression. To date, it remains largely unknown how patterns of DNA methylation differ between closely related species and whether such differences contribute to species-specific phenotypes. To investigate these questions, we generated nucleotide-resolution whole-genome methylation maps of the prefrontal cortex of multiple humans and chimpanzees. Levels and patterns of DNA methylation vary across individuals within species according to the age and the sex of the individuals. We also found extensive species-level divergence in patterns of DNA methylation and that hundreds of genes exhibit significantly lower levels of promoter methylation in the human brain than in the chimpanzee brain. Furthermore, we investigated the functional consequences of methylation differences in humans and chimpanzees by integrating data on gene expression generated with next-generation sequencing methods, and we found a strong relationship between differential methylation and gene expression. Finally, we found that differentially methylated genes are strikingly enriched with loci associated with neurological disorders, psychological disorders, and cancers. Our results demonstrate that differential DNA methylation might be an important molecular mechanism driving gene-expression divergence between human and chimpanzee brains and might potentially contribute to the evolution of disease vulnerabilities. Thus, comparative studies of humans and chimpanzees stand to identify key epigenomic modifications underlying the evolution of human-specific traits.


Solid-phase synthesis of protein-polymers on reversible immobilization supports.
Facile automated biomacromolecule synthesis is at the heart of blending synthetic and biologic worlds. Full access to abiotic/biotic synthetic diversity first occurred when chemistry was developed to grow nucleic acids and peptides from reversibly immobilized precursors. Protein-polymer conjugates, however, have always been synthesized in solution in multi-step, multi-day processes that couple innovative chemistry with challenging purification. Here we report the generation of protein-polymer hybrids synthesized by protein-ATRP on reversible immobilization supports (PARIS). We utilized modified agarose beads to covalently and reversibly couple to proteins in amino-specific reactions. We then modified reversibly immobilized proteins with protein-reactive ATRP initiators and, after ATRP, we released and analyzed the protein polymers. The activity and stability of PARIS-synthesized and solution-synthesized conjugates demonstrated that PARIS was an effective, rapid, and simple method to generate protein-polymer conjugates. Automation of PARIS significantly reduced synthesis/purification timelines, thereby opening a path to changing how to generate protein-polymer conjugates.


Kinetics of conversion of dihydroxyacetone to methylglyoxal in New Zealand mānuka honey: Part III--A model to simulate the conversion.
A kinetic model for the conversion of dihydroxyacetone (DHA) to methylglyoxal (MGO) in honey is proposed; a building block approach was used to create the model. Artificial honeys doped with DHA and individual perturbants were fitted first, then multiple perturbants (alanine, proline and iron, and combinations of these) were fitted before comparing the simulation to real honey samples (doped clover and mānuka honey). The main responses in the prediction model were DHA, MGO, proline, primary amino acids, acidity, 3-phenyllactic acid and 4-methoxyphenyllactic acid. Three temperatures (20, 27 and 37°C) were studied and the conversion of DHA to MGO was monitored over at least 1year. Differences in the conversion between clover doped with DHA and mānuka honey were observed. The simulation fitted well for the honeys tested.


Open tibia fracture with compartment syndrome.
In a series of 104 open tibia fractures, six patients developed compartment syndromes involving all four compartments of the lower leg, four of which developed after initial debridement and reduction. The presence of an open tibia fracture with a displaced, comminuted, fibula fracture should suggest the possibility of a developing compartment syndrome. Clinical symptoms include: increasing muscle pain which can be exaggerated by stretching; loss of sensation; decrease in muscle strength; and palpably swollen compartments. Double fasciotomy incisions may lead to adequate decompression, but result in marked loss of soft tissue support for the fracture. To sustain stability, a single posterolateral incision is recommended for compartmental decompression.


Açai improves non-alcoholic fatty liver disease (NAFLD) induced by fructose.
the excessive consumption of fructose can cause liver damage, characteristic of non-alcoholic fatty liver disease (NAFLD) associated with changes in lipid metabolism and antioxidant defenses. Açai, the fruit of Euterpe oleraceaMart., has demonstrated numerous biological activities, including anti-inflammatory, antioxidant, and lipid metabolism modulating action. we evaluated the benefits of açai supplementation on liver damage caused by replacing starch with fructose in rats. thirty male Fischerrats were divided into two groups, the control group (C, 10 animals), which consumed a standard diet (AIN-93M), and the fructose (F, 20 animals) group, which consumed a diet containing 60% of fructose. After eight weeks, 10 animals from the fructose group received 2% of lyophilized açai, and were called the açai fructose group (FA). The animals were fed ad libitumwith these diets for another ten weeks. Serum, hepatic and fecal lipid profile, antioxidant enzymes and carbonylated protein were assessed and histopathological characterization of the liver was performed. açai promoted the reduction of ALT activity in relation to the fructose group (F), reduced alkaline phosphatase to a level similar to that of the control group (C) in relation to the fructose group (F), and reduced catalase activity. The fruit also increased the ratio of total/oxidized glutathione (GSH/GSSG) and reduced the degree of macrovesicular steatosis and the number of inflammatory cells. the replacement of starch by fructose during this period was effective in promoting NAFLD. Açai showed attenuating effects on some markers of hepatic steatosis and inflammation.


Regulatory T cells: the cunning fox and its clinical application.
So profound is the potential for regulatory T cells (Tregs) to control unwanted immune responses that in 2008 an entire conference was dedicated to them. The underlying concept of this conference, "China Tregs 2008," was that unraveling the cellular biology of Tregs will lead to important advances for therapies in virtually all human disease processes and in transplantation. The master-switch of immune regulation is the forkhead transcription factor Foxp3; in mice, Foxp3 is a sine qua non for regulatory activity. At "China Tregs 2008," the cell signaling events leading to the expression of Foxp3 and those events downstream were explored together with presentations on how the latest knowledge of the biology of Tregs is being translated in the clinic.


Phenotypic features of myoclonus-dystonia in three kindreds.
Myoclonus-dystonia (M-D) is a movement disorder with involuntary jerks and dystonic contractions. Autosomal dominant alcohol-responsive M-D is associated with mutations in the epsilon-sarcoglycan gene (SGCE) (six families) and with a missense change in the D2 dopamine receptor (DRD2)gene (one family). To investigate the clinical phenotype associated with M-D including motor symptoms, psychiatric disorders, and neuropsychological deficits. Fifty individuals in three M-D families were evaluated and a standardized neurologic examination and DNA analysis were performed. Psychiatric profiles were established with the Diagnostic Interviews for Genetic Studies (DIGS) and the Yale-Brown Obsessive-Compulsive Scale (YBOCS). Cognition was evaluated with standardized neuropsychological tests. Distinct truncating mutations in the SGCE gene were identified in each family. Additionally, a missense alteration in the DRD2 gene was previously found in one family. Motor expression was variable, with onset of myoclonus or dystonia or both affecting the upper body and progression to myoclonus and dystonia in most cases. Psychiatric profiles revealed depression, obsessive-compulsive disorder, substance abuse, anxiety/panic/phobic disorders, and psychosis in two families, and depression only in the third family. Averaged scores from cognitive testing showed impaired verbal learning and memory in one family, impaired memory in the second family, and no cognitive deficits in the third family. Cognitive deficits may be associated with M-D. Psychiatric abnormalities correlate with the motor symptoms in affected individuals. Assessment of additional M-D families with known mutations is needed to determine whether these are characteristic phenotypic manifestations of M-D.


Dual Polarity Ion Confinement and Mobility Separations.
Here, we present simulations and describe the initial implementation of a device capable of performing simultaneous ion mobility (IM) separations of positive and negative ions based upon the structures for lossless ion manipulations (SLIM). To achieve dual polarity ion confinement, the DC fields used for lateral confinement in previous SLIM were replaced with RF fields. Concurrent ion transport and mobility separation in the SLIM device are shown possible due to the nature of the traveling wave (TW) voltage profile which has potential minima at opposite sides of the wave for each ion polarity. We explored the potential for performing simultaneous IM separations of cations and anions over the same SLIM path and the impacts on the achievable IM resolution and resolving power. Initial results suggest comparable IM performance with previous single-polarity SLIM separations can be achieved. We also used ion trajectory simulations to investigate the capability to manipulate the spatial distributions of ion populations based on their polarities by biasing the RF fields and TW potentials on each SLIM surface so as to limit the interactions between opposite polarity ions. Graphical Abstract.


Treatment and outcome of unusual animal bite injuries in young children.
Animal bites are a major cause of preventable traumatic injuries. To provide more epidemiological information on animal bites, and assist in increasing awareness of the problem. A retrospective chart review was performed including children aged >13 years presenting with bite injuries (excluding dog and human bites) to the trauma unit at Red Cross War Memorial Children's Hospital, Cape Town, South Africa, over a 25-year period. Two hundred and thirteen children were eligible to be entered into the study. The median age was 2.9 years (range 1.2 - 6.5), with boys slightly predominating (54.9%). Most (74.6%) of the bite injuries were inflicted by mammals, the majority (64.8) of mammalian bites being rat bites. The proportions of boys and girls in the age group 0 - 4 years bitten by rats significantly differed from the proportions in the age group >4 years (p=0.039). In the age group 0 - 4 years more girls suffered rat bites, while more boys were bitten in the age group >4 years. Of 91 rat bites, 81 (89.0%) occurred inside the house. The hands (43.9%) and the head/face/neck region (39.0%) were most affected. The underdeveloped suburbs of Philippi, Gugulethu and Khayelitsha in Cape Town represented a disproportionate number (41.6%) of rat bites. There is a relationship between poverty, unemployment, poor housing, informal settlements and rodent infestation. These high-risk populations need to be the target for government rat eradication programmes.


Effects of dependent errors in the assessment of diagnostic test performance.
Latent class models can be used to assess diagnostic test performance when there is no perfectly accurate gold standard test available for comparison. These models usually assume independent errors between the tests, conditional on the true disease state of the subject. Maximum likelihood estimates of the prevalence of the disease and the error rates of diagnostic tests are then obtained. This paper examines the impact of error dependencies between binary diagnostic tests on the parameter estimates obtained from the latent class models. The independence model often gives parameter estimates having relatively small bias, but in some situations (for example, when disease prevalence is low and the tests have low specificity, such as in population screening) the bias may be more serious.


The FlowVizMenu and parallel scatterplot matrix: hybrid multidimensional visualizations for network exploration.
A standard approach for visualizing multivariate networks is to use one or more multidimensional views (for example, scatterplots) for selecting nodes by various metrics, possibly coordinated with a node-link view of the network. In this paper, we present three novel approaches for achieving a tighter integration of these views through hybrid techniques for multidimensional visualization, graph selection and layout. First, we present the FlowVizMenu, a radial menu containing a scatterplot that can be popped up transiently and manipulated with rapid, fluid gestures to select and modify the axes of its scatterplot. Second, the FlowVizMenu can be used to steer an attribute-driven layout of the network, causing certain nodes of a node-link diagram to move toward their corresponding positions in a scatterplot while others can be positioned manually or by force-directed layout. Third, we describe a novel hybrid approach that combines a scatterplot matrix (SPLOM) and parallel coordinates called the Parallel Scatterplot Matrix (P-SPLOM), which can be used to visualize and select features within the network. We also describe a novel arrangement of scatterplots called the Scatterplot Staircase (SPLOS) that requires less space than a traditional scatterplot matrix. Initial user feedback is reported.


Ongoing declines of woodland birds: Are restoration plantings making a difference?
Woodland birds are a species assemblage of conservation concern, and their persistence in fragmented agricultural landscapes is dependent on both the preservation of existing woodland remnants and the implementation of restoration plantings. However, little is known about the habitat-use and persistence of birds in fragmented agricultural landscapes. We present a detailed, population-oriented study of woodland birds in temperate eucalypt woodland restoration plantings and remnant woodland patches in the South-west Slopes bioregion of New South Wales, Australia. First, we undertook a 3-yr mark-recapture project to assess annual survival and site fidelity in restoration plantings and woodland remnants. We supplemented our recapture efforts with resightings of color-banded individuals. Second, we tracked individual birds of two species, Superb Fairywren (Malurus cyaneus) and Willie Wagtail (Rhipidura leucophrys), and documented snapshots of their home ranges and movement patterns during the breeding season. Annual survival in the woodland bird assemblage was lower than expected (51%). Home ranges of the Superb Fairywren were positively correlated with patch size, and were constrained by patch edges in linear sites. Superb Fairywrens and Willie Wagtails were more likely to travel longer distances between substrates while foraging in linear sites. Willie Wagtails engaged in significant gap-crossing (up to 400 m) between adjacent habitat patches. Our findings indicate that (1) patch isolation and certain patch configurations place resident birds at an energetic disadvantage, and (2) in our study area, woodland bird populations are continuing to decline. We recommend landscape-scale habitat restoration programs aim to address ongoing population declines. Studies such as ours conducted over longer time periods would provide a deeper understanding of habitat use and population processes of woodland birds in fragmented agricultural landscapes.


Understanding health systems to improve community and facility level newborn care among displaced populations in South Sudan: a mixed methods case study.
Targeted clinical interventions have been associated with a decreased risk of neonatal morbidity and mortality. In conflict-affected countries such as South Sudan, however, implementation of lifesaving interventions face barriers and facilitators that are not well understood. We aimed to describe the factors that influence implementation of a package of facility- and community-based neonatal interventions in four displaced person camps in South Sudan using a health systems framework. We used a mixed method case study design to document the implementation of neonatal interventions from June to November 2016 in one hospital, four primary health facilities, and four community health programs operated by International Medical Corps. We collected primary data using focus group discussions among health workers, in-depth interviews among program managers, and observations of health facility readiness. Secondary data were gathered from documents that were associated with the implementation of the intervention during our study period. Key bottlenecks for implementing interventions in our study sites were leadership and governance for comprehensive neonatal services, health workforce for skilled care, and service delivery for small and sick newborns. Program managers felt national policies failed to promote integration of key newborn interventions in donor funding and clinical training institutions, resulting in deprioritizing newborn health during humanitarian response. Participants confirmed that severe shortage of skilled care at birth was the main bottleneck for implementing quality newborn care. Solutions to this included authorizing the task-shifting of emergency newborn care to mid-level cadre, transitioning facility-based traditional birth attendants to community health workers, and scaling up institutions to upgrade community midwives into professional midwives. Additionally, ongoing supportive supervision, educational materials, and community acceptance of practices enabled community health workers to identify and refer small and sick newborns. Improving integration of newborn interventions into national policies, training institutions, health referral systems, and humanitarian supply chain can expand emergency care provided to women and their newborns in these contexts.


Maternal clinic and home blood pressure measurements during pregnancy and infant birth weight: the BOSHI study.
This prospective cohort study compared measurements of maternal home blood pressure (HBP) with clinic blood pressure (CBP) before 20 weeks' gestation to determine associations with the risk of delivering a lower birth weight infant. A total of 605 Japanese women were included. Exposures were initial CBP, made between 10 weeks 0 days and 19 weeks 0 days, and HBP for comparison made within 1 week of CBP. Outcome was infant's birth weight, categorized and ranked as follows: ⩾3500 g, 3000-3499 g, 2500-2999 g and <2500 g. The proportional odds model with possible confounding factors was applied to compare the associations between CBP and HBP on infant birth weight. When both CBP and HBP were included simultaneously, the adjusted odds ratios (ORs) per 1 standard deviation (1s.d.) increase in clinic and home diastolic BP (DBP) were 1.06 (95% confidence interval (CI): 0.87-1.30) and 1.28 (95% CI: 1.04-1.58), respectively. The adjusted ORs per 1s.d. increase in clinic and home mean arterial pressure (MAP) were 1.02 (95% CI: 0.83-1.24) and 1.29 (95% CI: 1.04-1.59), respectively. Systolic BP measurement was not associated with infant birth weight. In conclusion, high maternal home DBP and MAP before 20 weeks' gestation was associated with a higher risk of lower infant birth weight than clinic DBP and MAP. Therefore, in addition to CBP, it may be worth having pregnant women measure HBP to determine the risk of lower infant birth weight.


Association Between Dental Caries and Body Mass Index in Schoolchildren Aged Between 14 and 16 Years in Riyadh, Saudi Arabia.
Dental caries and obesity are multifactorial diseases that have common risk factors. Studies worldwide reported varied outcomes about the association between dental caries and obesity. There is no published study that investigates this association among schoolchildren in Arabic countries. The aim of this study was to evaluate the relationship between dental caries (DMFT) and body mass index (BMI) for children aged between 14 and 16 years old in Riyadh, Saudi Arabia. The role of oral hygiene habits, parent's education, sugar consumption and physical activity in causing both diseases was also evaluated. This is a cross-sectional study that involved 610 schoolchildren aged between 14 and 16 years. The children were selected from 12 boy's intermediate schools distributed in Riyadh city. A questionnaire that asked about demographic data, oral hygiene habits, parents' education, sugar consumption and physical activity was distributed. Then, the mean DMFT and BMI were calculated by collecting the information from dental examination, body weight and height. Multivariate logistic regression model was used to explain the relationship between the teeth health and the BMI. Moreover, multivariate linear regression was conducted to model the relationship between DMFT and BMI and the socioeconomic score, sugar consumption and physical activity. The prevalence of dental caries (DMFT > 0) was 54.1%. Around 32% of the schoolchildren were either overweight or obese. A statistically significant association between dental caries (DMFT) and BMI was found (P = 0.008). It was found that obese schoolchildren are 1.79 times higher to be with healthy teeth (P = 0.02). In addition, it was found that schoolchildren with higher socioeconomic status are 1.26 times higher to be with healthy teeth group (P = 0.005). Similarly, schoolchildren who reported that they are using the fluoridated toothpaste were 1.63 times higher to be within the healthy teeth group (DMFT = 0) when everything else is controlled. Physical activity level affects the schoolchildren BMI significantly (P < 0.001). The study showed a statistically significant association between dental caries and BMI for this study sample. Obese schoolchildren showed healthier teeth than others did. Fluoride toothpaste usage and socioeconomic score were associated significantly with dental caries.


Prevalence of suicide attempt and clinical characteristics of suicide attempters with obsessive-compulsive disorder: a report from the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS).
Obsessive-compulsive disorder (OCD) is associated with variable risk of suicide and prevalence of suicide attempt (SA). The present study aimed to assess the prevalence of SA and associated sociodemographic and clinical features in a large international sample of OCD patients. A total of 425 OCD outpatients, recruited through the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS) network, were assessed and categorized in groups with or without a history of SA, and their sociodemographic and clinical features compared through Pearson's chi-squared and t tests. Logistic regression was performed to assess the impact of the collected data on the SA variable. 14.6% of our sample reported at least one SA during their lifetime. Patients with an SA had significantly higher rates of comorbid psychiatric disorders (60 vs. 17%, p<0.001; particularly tic disorder), medical disorders (51 vs. 15%, p<0.001), and previous hospitalizations (62 vs. 11%, p<0.001) than patients with no history of SA. With respect to geographical differences, European and South African patients showed significantly higher rates of SA history (40 and 39%, respectively) compared to North American and Middle-Eastern individuals (13 and 8%, respectively) (χ2=11.4, p<0.001). The logistic regression did not show any statistically significant predictor of SA among selected independent variables. Our international study found a history of SA prevalence of ~15% in OCD patients, with higher rates of psychiatric and medical comorbidities and previous hospitalizations in patients with a previous SA. Along with potential geographical influences, the presence of the abovementioned features should recommend additional caution in the assessment of suicide risk in OCD patients.


Single-cell transcriptomic atlas of the human retina identifies cell types associated with age-related macular degeneration.
Genome-wide association studies (GWAS) have identified genetic variants associated with age-related macular degeneration (AMD), one of the leading causes of blindness in the elderly. However, it has been challenging to identify the cell types associated with AMD given the genetic complexity of the disease. Here we perform massively parallel single-cell RNA sequencing (scRNA-seq) of human retinas using two independent platforms, and report the first single-cell transcriptomic atlas of the human retina. Using a multi-resolution network-based analysis, we identify all major retinal cell types, and their corresponding gene expression signatures. Heterogeneity is observed within macroglia, suggesting that human retinal glia are more diverse than previously thought. Finally, GWAS-based enrichment analysis identifies glia, vascular cells, and cone photoreceptors to be associated with the risk of AMD. These data provide a detailed analysis of the human retina, and show how scRNA-seq can provide insight into cell types involved in complex, inflammatory genetic diseases.


Fisetin enhances behavioral performances and attenuates reactive gliosis and inflammation during aluminum chloride-induced neurotoxicity.
Aluminum (Al) is an environmental neurotoxin that affects cerebral functions and causes health complications. However, the role of Al in arbitrating glia homeostasis and pathophysiology remains obscure. Astrocyte, microglia activation (reactive gliosis), and associated inflammatory events play a decisive role in neurodegeneration and may represent a target for treating neurodegenerative disorders. In this study, we have analyzed the role of aluminum chloride (AlCl3) in causing reactive gliosis in the brain of mice and the ability of fisetin, a flavonoid to attenuate reactive gliosis and neuronal inflammation. Reports suggest that fisetin exerts antioxidant and anti-inflammatory actions. Fisetin at a dose of 15 mg/kg body weight was orally administered, daily (pre-treated for 4 weeks before AlCl3 induction and co-treated until experimental period of 8 weeks) to mice induced with AlCl3 (200 mg/kg b.wt./day/8 weeks, orally). Administration of AlCl3 developed behavioral deficits, triggered lipid peroxidation (LPO), compromised acetylcholine esterase (AChE) activity, and reduced the levels of superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), and reduced glutathione (GSH), and caused histologic aberrations. These effects were accompanied by increased expressions of Glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1. Pro-inflammatory cytokines, such as tumor necrosis factor alpha, interleukin-1β, inducible nitric oxide synthase, were increased upon AlCl3 administration. AlCl3-induced alterations in the activities of SOD, CAT, GST, AChE and levels of GSH, LPO, activity of AChE, behavioral deficits, histologic aberrations, reactive gliosis, and inflammatory niche were attenuated on treatment with fisetin. Collectively, our results indicate that fisetin exerts neuroprotection against AlCl3-induced brain pathology.


The morphology of submicronsized core-shell latex particles: an electron microscopy study.
The core-shell structure of a range of acrylic-acrylic latexes has been investigated by combining different specimen preparation methods with transmission electron microscopy (TEM), dark-field scanning transmission electron microscopy (DSTEM) and low-voltage scanning electron microscopy (LV-SEM), including the first reported use of LV-SEM to observe composite latex particles at ambient and subambient temperatures. Spin-coating of liquid latex dispersions directly onto TEM grids or SEM stubs is shown to be a relatively straightforward mean of avoiding film formation during specimen preparation. In conjunction with double staining techniques, it has been found to be particularly convenient for characterizing the fine structure of particles with diameters down to below 100 nm.


Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome.
TNF, acting through p55 tumor necrosis factor receptor 1 (TNFR1), contributes to the pathogenesis of many inflammatory diseases. TNFR-associated periodic syndrome (TRAPS, OMIM 142680) is an autosomal dominant autoinflammatory disorder characterized by prolonged attacks of fevers, peritonitis, and soft tissue inflammation. TRAPS is caused by missense mutations in the extracellular domain of TNFR1 that affect receptor folding and trafficking. These mutations lead to loss of normal function rather than gain of function, and thus the pathogenesis of TRAPS is an enigma. Here we show that mutant TNFR1 accumulates intracellularly in peripheral blood mononuclear cells of TRAPS patients and in multiple cell types from two independent lines of knockin mice harboring TRAPS-associated TNFR1 mutations. Mutant TNFR1 did not function as a surface receptor for TNF but rather enhanced activation of MAPKs and secretion of proinflammatory cytokines upon stimulation with LPS. Enhanced inflammation depended on autocrine TNF secretion and WT TNFR1 in mouse and human myeloid cells but not in fibroblasts. Heterozygous TNFR1-mutant mice were hypersensitive to LPS-induced septic shock, whereas homozygous TNFR1-mutant mice resembled TNFR1-deficient mice and were resistant to septic shock. Thus WT and mutant TNFR1 act in concert from distinct cellular locations to potentiate inflammation in TRAPS. These findings establish a mechanism of pathogenesis in autosomal dominant diseases where full expression of the disease phenotype depends on functional cooperation between WT and mutant proteins and also may explain partial responses of TRAPS patients to TNF blockade.


Role of prostaglandins and kinins in the renal pressor reflex.
In previous studies we identified an afferent renal nerve-dependent pressor reflex elicited by acute unilateral renal artery stenosis (50% decrease in renal blood flow) in conscious, instrumented rats with reduced responsiveness of arterial baroreceptor reflexes and the renin-angiotensin system. The pressor reflex involves a neurogenic increase in peripheral resistance. The present study examined the nature of the intrarenal stimulus underlying this renal pressor reflex. Rats were subjected to sinoaortic denervation and, 7 to 10 days later, were chronically instrumented with Doppler flow probes on the right renal artery, superior mesenteric artery, and abdominal aorta and with an occluder on the right renal artery. Following surgical recovery and inhibition of the renin-angiotensin system (captopril), animals received intravenous isotonic saline, 6% of body weight over 60 minutes. Saline infusion did not alter baseline hemodynamics, vascular neurogenic tone, or responsiveness to tyramine, but it attenuated the reflex by 70%. A second series of experiments examined a possible role for intrarenal prostaglandins, kinins, or adenosine in the activation of renal sensory receptors during renal stenosis. Prostaglandin inhibition with intravenous administration of indomethacin and meclofenamate virtually abolished the reflex in the face of enhanced tyramine responsiveness, whereas kallikrein inhibition (aprotinin) attenuated the reflex pressor response by 33%. Adenosine inhibition with aminophylline or adenosine deaminase had no effect on the reflex; these agents and aprotinin did not affect vascular neuroeffector responsiveness (tyramine). The data suggest that the renal pressor reflex may be mediated by renal sensory nerves, possibly chemoreceptors, whose activation could depend on renal excretory function and synthesis of prostaglandins and kinins.


Soluble ST2 is a sensitive clinical marker of ulcerative colitis evolution.
The ST2/IL-33 pathway has been related to ulcerative colitis (UC), and soluble ST2 (sST2), to disease severity. We tested the potential usefulness of sST2 as a predictive marker of treatment response and patients' outcome. Twenty-six patients with active UC were prospectively recruited and grouped according to an endoscopic score and therapy response. Colonoscopic biopsies were collected at baseline and 6 months or when patients showed clinical activity. The protocol was reinitiated in patients requiring rescue therapy. Blood and stool were collected at baseline, 1, 3, 6 and 12 months. Serum and mucosal ST2, and fecal calprotectin (FC) content were determined by ELISA and correlated to Mayo clinical and endoscopic subscore. Intestinal ST2 was evaluated by immunofluorescence. Wilcoxon signed rank test and Spearman correlations (Rs) were applied (p <0.05). Follow-up was completed in 24 patients. sST2 levels (median and range) varied from 173.5 [136.6-274.0] to 86.5 [54.6-133.2] in responders (p < 0.05), and 336.3 [211.0-403.2] to 385.3 pg/mL [283.4-517.3] in non-responders at baseline and 6 months, respectively. sST2 levels correlated with Mayo clinical and endoscopic subscore, mucosal ST2 and FC (Rs = 0.57, 0.66, 0.74 and 0.42, respectively; p < 0.0001) and showed a trend similar to that of FC in responders. Non-responders revealed an increased ST2 content, restricted to the lamina propria's cellular infiltrate. Consecutive sST2 measurement to follow changes in inflammatory activity of UC patients who respond or not to treatment identifies sST2, like FC, as a useful biomarker in predicting clinical outcome of UC patients.


TopoFF: MOF structure prediction using specifically optimized blueprints.
For the structure prediction of MOFs and related crystalline framework materials we have proposed the Reversed Topological Approach (RTA), where the default embedding of a topology is used as a blueprint. The optimal rotational insertion of the building blocks (BBs) at the fixed vertex positions of the blueprint is performed by minimizing the target function of the average angle deviation (AAD). Here we extend this idea by pre-optimizing the maximum symmetry embedding of a topology in order to minimize the overall mean AAD for the given set of BBs. By this fast and essentially parameter-free topoFF method, the vertex positions and cell parameters of the blueprint are further optimized in order to fit the structural needs of the BBs, which speeds up the overall search for the most energetically favorable structure. In addition, different topologies can be ranked in a quantitative and intuitive way. The definition and implementation of topoFF is explained and its application for the RTA-based structure prediction of MOFs is demonstrated with a number of instructive examples.


Optimisation of engineered Escherichia coli biofilms for enzymatic biosynthesis of l-halotryptophans.
Engineered biofilms comprising a single recombinant species have demonstrated remarkable activity as novel biocatalysts for a range of applications. In this work, we focused on the biotransformation of 5-haloindole into 5-halotryptophan, a pharmaceutical intermediate, using Escherichia coli expressing a recombinant tryptophan synthase enzyme encoded by plasmid pSTB7. To optimise the reaction we compared two E. coli K-12 strains (MC4100 and MG1655) and their ompR234 mutants, which overproduce the adhesin curli (PHL644 and PHL628). The ompR234 mutation increased the quantity of biofilm in both MG1655 and MC4100 backgrounds. In all cases, no conversion of 5-haloindoles was observed using cells without the pSTB7 plasmid. Engineered biofilms of strains PHL628 pSTB7 and PHL644 pSTB7 generated more 5-halotryptophan than their corresponding planktonic cells. Flow cytometry revealed that the vast majority of cells were alive after 24 hour biotransformation reactions, both in planktonic and biofilm forms, suggesting that cell viability was not a major factor in the greater performance of biofilm reactions. Monitoring 5-haloindole depletion, 5-halotryptophan synthesis and the percentage conversion of the biotransformation reaction suggested that there were inherent differences between strains MG1655 and MC4100, and between planktonic and biofilm cells, in terms of tryptophan and indole metabolism and transport. The study has reinforced the need to thoroughly investigate bacterial physiology and make informed strain selections when developing biotransformation reactions.


Effect of radiofrequency radiation on reproductive health.
The development of cellular phone system has greatly increased the extent and magnitude of radiofrequency radiation (RFR) exposure. The RFR emitted from mobile phone and mobile phone base stations exerts thermal and non-thermal effects. The short-term and long-term exposure to RFR may have adverse effect on humans as well as animals. Most laboratory studies have indicated a direct link between exposure to RFR and adverse biological effects. Several in vitro studies have reported that RFR induces various types of cancer and DNA or chromosomal damage. On the other hand, some animal studies have not reported adverse effects of this radiation. The present review summarizes information available on the possible effects of RFR on the reproductive health.


Evaluation of the Helicobacteraceae in the oral cavity of dogs.
To determine the Helicobacter spp present in the oral cavity of dogs and the relationship of those organisms with gastric Helicobacter spp to better define the potential for dog-human and dog-dog transmission. Saliva and dental plaque from 28 dogs and gastric biopsy specimens from a subset of 8 dogs. PCR-based screening for Helicobacter spp was conducted on samples obtained from the oral cavity of 28 dogs. Comparative analysis was conducted on Helicobacteraceae 16S rDNA clone libraries from the oral cavity and stomach of a subset of 8 dogs (5 vomiting and 3 healthy) that had positive PCR results for Helicobacter spp. Helicobacteraceae DNA was identified in the oral cavity of 24 of 28 dogs. Analysis of cloned 16S rDNA amplicons from 8 dogs revealed that Wolinella spp was the most common (8/8 dogs) and abundant (52/57 [91%] clones) member of the Helicobacteraceae family in the oral cavity. Only 2 of 8 dogs harbored Helicobacter spp in the oral cavity, and 1 of those was coinfected with Helicobacter heilmannii and Helicobacter felis in samples obtained from the stomach and saliva. Evaluation of oral cavity DNA with Wolinella-specific PCR primers yielded positive results for 16 of 20 other dogs (24/28 samples were positive for Wolinella spp). Wolinella spp rather than Helicobacter spp were the predominant Helicobacteraceae in the oral cavity of dogs. The oral cavity of dogs was apparently not a zoonotically important reservoir of Helicobacter spp that were non-Helicobacter pylori organisms.


Discontinuing antiepileptic drugs in children with epilepsy: a prospective study.
In a prospective study, antiepileptic drugs were discontinued in 264 children with epilepsy after a mean seizure-free interval of 2.9 years. They were then followed for a mean of 58 months to ascertain whether seizures recurred. Seizures recurred in 95 (36%) of the children. Etiology was a significant predictor of outcome (relative risk [RR] = 1.81). On multivariable analysis, significant factors in the idiopathic group included age at onset above 12 years (RR = 5.4), a family history of seizures (RR = 3.1), the presence of slowing on the electroencephalogram prior to medication withdrawal (RR = 2.4), and a history of atypical febrile seizures (RR = 2.8). Specific epileptic syndromes such as juvenile myoclonic epilepsy and benign rolandic epilepsy were also significant predictors of outcome. In the remote symptomatic group, significant predictors of outcome included age at onset older than 12 years (RR = 3.6), moderate to severe mental retardation (IQ < 50) (RR = 2.8), a history of atypical febrile seizures (RR = 2.0), and a history of absence seizures (RR = 0.4). The majority of children with epilepsy in remission while on antiepileptic drug therapy will remain seizure free when medications are withdrawn. A few readily available parameters distinguish those with a good prognosis from those in whom seizures are likely to recur. These data provide the framework for the clinical decision making for withdrawal of medications in these children.


Patient-specific and surgical characteristics in the development of pressure ulcers.
Implementation of the ruling on the Inpatient Prospective Payment System by the Centers for Medicare and Medicaid has challenged nurses to focus on the prevention of pressure ulcers. Despite years of research, pressure ulcers are still one of the most common complications experienced by patients in health care facilities. To examine the relationship between patients' characteristics (age, sex, body mass index, history of diabetes, and Braden Scale score at admission) and care characteristics (total operating room time, multiple surgeries, and vasopressor use) and the development of pressure ulcers. In a cohort study, data from the electronic medical records of 3225 surgical patients admitted to a Midwest hospital, from November 2008 to August 2009 were analyzed statistically to determine predictors of pressure ulcers. A total of 12% of patients (n = 383) had at least 1 pressure ulcer develop during their hospitalization. According to logistic regression analysis, scores on the Braden Scale at admission (P < .001), low body mass index (P < .001), number of vasopressors (P = .03), multiple surgeries during the admission (P < .001), total surgery time (P < .001), and risk for mortality (P < .001) were significant predictors of pressure ulcers. Scores on the Braden Scale at admission can be used to identify patients at increased risk for pressure ulcers. For other high-risk factors, such as low body mass index and long operative procedures, appropriate clinical interventions to manage these conditions can help prevent pressure ulcers.


Healthcare-associated infection and the patient experience: a qualitative study using patient interviews.
There is an increasing emphasis on the need for further patient involvement within healthcare to ensure that the voice of the patient is heard. This exploratory study utilised in-depth face-to-face interviews with patients to explore narratives from their experiences around healthcare-associated infection (HCAI). Interviews were undertaken with patients who had been diagnosed with a Staphylococcus aureus bloodstream infection and patients who had been in the same hospital but had not been diagnosed with a bloodstream infection. The lack of both verbal and written communications was a major concern for most patients regardless of their infection status. Some patients also stated that they were not comfortable about asking questions, and only a small number of patients and relatives stated that they would challenge staff about their practice. Although some patients retained confidence in the National Health Service (NHS), the majority had very little or no confidence in the NHS in relation to HCAI and would have serious concerns about this if they were to return to hospital. The results suggest that there are a number of issues that must be addressed in order to enhance the quality of care, safety of patients and the patient experience in relation to infection prevention and control. In addition, policy-makers, managers and all healthcare workers must ensure that patients are involved in the design and evaluation of systems change and information.


Signs of change: hormone receptors that regulate plant development.
Hormonal signalling plays a pivotal role in almost every aspect of plant development, and of high priority has been to identify the receptors that perceive these hormones. In the past seven months, the receptors for the plant hormones auxin, gibberellins and abscisic acid have been identified. These join the receptors that have previously been identified for ethylene, brassinosteroids and cytokinins. This review therefore comes at an exciting time for plant developmental biology, as the new findings shed light on our current understanding of the structure and function of the various hormone receptors, their related signalling pathways and their role in regulating plant development.


Cost and outcome of mechanical ventilation for life-threatening stroke.
Hospital mortality rates of 50% to 90% have been reported for stroke patients treated with mechanical ventilation. These data have raised serious questions about the cost-effectiveness of this intervention. We sought to determine how often stroke patients are mechanically ventilated, identify predictors of 30-day survival among ventilated patients, and evaluate the cost-effectiveness of this intervention. We identified mechanically ventilated patients in a population-based multiethnic cohort of 510 incidence stroke patients who were hospitalized between July 1993 and June 1996. Factors affecting 30-day survival were identified in a multiple logistic regression analysis. We calculated the cost per patient discharged alive, life-year saved, and quality-adjusted life-year saved using a zero-cost, zero-life assumption. Ten percent of patients (n=52) were mechanically ventilated. Thirty-day mortality was 65% overall and did not differ significantly by stroke subtype. Glasgow Coma Scale score on the day of intubation (P:<0.01) and subsequent neurological deterioration (P:=0.02) were identified as predictors of 30-day mortality. The cost (1996 US dollars) of hospitalization per patient discharged alive was $89 400; the cost per year of life saved was $37 600; and the cost per quality-adjusted life-year saved was $174 200. Functional status of most survivors was poor; at 6 months, half were severely disabled and completely dependent. In a worst-case scenario of quality of life preferences, mechanical ventilation resulted in a net deficit of meaningful survival. Two thirds of mechanically ventilated stroke patients die during their hospitalization, and most survivors are severely disabled. Survival is particularly unlikely if patients are deeply comatose or clinically deteriorate after intubation. In our multiethnic urban population, mechanical ventilation for stroke was relatively cost-effective for extending life but not for preserving quality of life.


Reductions in 2020 US life expectancy due to COVID-19 and the disproportionate impact on the Black and Latino populations.
COVID-19 has resulted in a staggering death toll in the United States: over 215,000 by mid-October 2020, according to the Centers for Disease Control and Prevention. Black and Latino Americans have experienced a disproportionate burden of COVID-19 morbidity and mortality, reflecting persistent structural inequalities that increase risk of exposure to COVID-19 and mortality risk for those infected. We estimate life expectancy at birth and at age 65 y for 2020, for the total US population and by race and ethnicity, using four scenarios of deaths-one in which the COVID-19 pandemic had not occurred and three including COVID-19 mortality projections produced by the Institute for Health Metrics and Evaluation. Our medium estimate indicates a reduction in US life expectancy at birth of 1.13 y to 77.48 y, lower than any year since 2003. We also project a 0.87-y reduction in life expectancy at age 65 y. The Black and Latino populations are estimated to experience declines in life expectancy at birth of 2.10 and 3.05 y, respectively, both of which are several times the 0.68-y reduction for Whites. These projections imply an increase of nearly 40% in the Black-White life expectancy gap, from 3.6 y to over 5 y, thereby eliminating progress made in reducing this differential since 2006. Latinos, who have consistently experienced lower mortality than Whites (a phenomenon known as the Latino or Hispanic paradox), would see their more than 3-y survival advantage reduced to less than 1 y.


In vivo detection of macrophages in a rabbit atherosclerotic model by time-resolved laser-induced fluorescence spectroscopy.
Accumulation of numerous macrophages in the fibrous cap is a key identifying feature of plaque inflammation and vulnerability. This study investigates the use of time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) as a potential tool for detection of macrophage foam cells in the intima of atherosclerotic plaques. Experiments were conducted in vivo on 14 New Zealand rabbits (6 control, 8 hypercholesterolemic) following aortotomy to expose the intimal luminal surface of the aorta. Tissue autofluorescence was induced with a nitrogen pulse laser (337 nm, 1 ns). Lesions were histologically classified by the percent of collagen or macrophage foam cells as well as thickness of the intima. Using parameters derived from the time-resolved fluorescence emission of plaques, we determined that intima rich in macrophage foam cells can be distinguished from intima rich in collagen with high sensitivity (>85%) and specificity (>95%). This study demonstrates, for the first time, that a time-resolved fluorescence-based technique can differentiate and demark macrophage content versus collagen content in vivo. Our results suggest that TR-LIFS technique can be used in clinical applications for identification of inflammatory cells important in plaque formation and rupture.


BCR repertoire sequencing: different patterns of B-cell activation after two Meningococcal vaccines.
Next-generation sequencing was used to investigate the B-cell receptor heavy chain transcript repertoire of different B-cell subsets (naive, marginal zone (MZ), immunoglobulin M (IgM) memory and IgG memory) at baseline, and of plasma cells (PCs) 7 days following administration of serogroup ACWY meningococcal polysaccharide and protein-polysaccharide conjugate vaccines. Baseline B-cell subsets could be distinguished from each other using a small number of repertoire properties (clonality, mutation from germline and complementarity-determining region 3 (CDR3) length) that were conserved between individuals. However, analyzing the CDR3 amino-acid sequence (which is particularly important for antigen binding) of the baseline subsets showed few sequences shared between individuals. In contrast, day 7 PCs demonstrated nearly 10-fold greater sequence sharing between individuals than the baseline subsets, consistent with the PCs being induced by the vaccine antigen and sharing specificity for a more limited range of epitopes. By annotating PC sequences based on IgG subclass usage and mutation, and also comparing them with the sequences of the baseline cell subsets, we were able to identify different signatures after the polysaccharide and conjugate vaccines. PCs produced after conjugate vaccination were predominantly IgG1, and most related to IgG memory cells. In contrast, after polysaccharide vaccination, the PCs were predominantly IgG2, less mutated and were equally likely to be related to MZ, IgM memory or IgG memory cells. High-throughput B-cell repertoire sequencing thus provides a unique insight into patterns of B-cell activation not possible from more conventional measures of immunogenicity.


Long-term memory of relative reward values.
Long-term memory can be adaptive as it allows animals to retain information that is crucial for survival, such as the appearance and location of key resources. This is generally examined by comparing choices of stimuli that have value to the animal with those that do not; however, in nature choices are rarely so clear cut. Animals are able to assess the relative value of a resource via direct comparison, but it remains unclear whether they are able to retain this information for a biologically meaningful amount of time. To test this, captive red-footed tortoises (Chelonoidis carbonaria) were first trained to associate visual cues with specific qualities and quantities of food, and their preferences for the different reward values determined. They were then retested after an interval of 18 months. We found that the tortoises were able to retain the information they had learned about the cues as indicators of relative reward values over this interval, demonstrating a memory for the relative quantity and quality of food over an extended period of time. This is likely to impact directly on an animal's foraging decisions, such as the exploitation of seasonally varying resources, with obvious fitness implications for the individual; however, the implications may also extend to the ecological interactions in which the animal is involved, affecting processes such as herbivory and seed dispersal.


Piezoelectric scanning of Fabry-Perot spectrometers: nonlinearities.
Piezoelectric materials used in mechanical scanning of Fabry-Perot spectrometers are found to have measurable nonlinearities. Dynamic scanning has been used in the present investigation in order to decrease the effects of some of the variables, such as creep, of the piezoelectric material in static operation. The results show mainly a decrease in the distance between corresponding maxima, or apparent free spectral range, as the driving voltage increases to higher values. A relationship between this voltage and displacement (in terms of orders) has been derived, and it is given by v(i) = In {1 - (x(i) - x(0))/[a/(1 - b) - x(0)]}/In b, where v(i) is the displacement in orders from an arbitrary starting point, x(i) is a quantity directly proportional to the voltage, while x(0) is also a quantity proportional to the voltage at the arbitrary reference point, a is the distance between the arbitrary reference point and the next order, and b is the nonlinearity constant for a given piezoelectric material. Examples are given for emission and absorption measurements where the usually large effects of the piezoelectric material nonlinearities are derived, as well as schemes to minimize or altogether remove the effects by suitable handling of the data or by changing the experiment such that the scanning is forced to be linear.


Targeted expression of mutated ALK induces neuroblastoma in transgenic mice.
Activating anaplastic lymphoma kinase (ALK) mutations were recently detected in most familial and 10% of sporadic neuroblastomas. However, the role of mutated ALK in tumorigenesis remains elusive. We demonstrate that targeted expression of the most frequent and aggressive variant, ALK(F1174L), is tumorigenic in mice. Tumors resembled human neuroblastomas in morphology, metastasis pattern, gene expression, and the presence of neurosecretory vesicles as well as synaptic structures. This ALK-driven neuroblastoma mouse model precisely recapitulated the genetic spectrum of the disease. Chromosomal aberrations were syntenic to those in human neuroblastoma, including 17q gain and MYCN oncogene amplification. Targeted ALK(F1174L) and MYCN coexpression revealed a strong synergism in inducing neuroblastoma with minimal chromosomal aberrations, suggesting that fewer secondary hits are required for tumor induction if both oncoproteins are targeted. Treatment of ALK(F1174L) transgenic mice with the ALK inhibitor TAE-684 induced complete tumor regression, indicating that tumor cells were addicted to ALK(F1174L) activity. We conclude that an activating mutation within the ALK kinase domain is sufficient to induce neuroblastoma development, and ALK inhibitors show promise for treating human neuroblastomas harboring ALK mutations.


What facilitates return to work? Patients' experiences 3 years after occupational rehabilitation.
We have limited knowledge about the specific elements in an occupational rehabilitation programme that facilitate the process leading to return to work (RTW) as perceived by the patients. The aim of the study was to explore individual experiences regarding contributing factors to a successful RTW, 3 years after a resident occupational rehabilitation programme. The study is based on interviews of 20 individuals who attended an occupational rehabilitation programme 3 years earlier. Ten informants had returned to work (RTW) and ten were receiving disability pension (DP). Data were analysed by systematic text condensation inspired by Giorgi's phenomenological analysis. The core categories describing a successful RTW process included positive encounters, increased self-understanding and support from the surroundings. While the informants on DP emphasized being seen, heard and taken seriously by the professionals, the RTW group highlighted being challenged to increase self-understanding that promoted new acting in every-day life. Being challenged on self-understanding implied increased awareness of own identity, values and resources. Support from the surroundings included support from peer participants, employer and social welfare system. Successful RTW processes seem to comprise positive encounters, opportunities for increased self-understanding and support from significant others. An explicit focus on topics like identity, own values and resources might improve the outcome of the rehabilitation process.


Prediction of surface roughness using X-ray photoelectron spectroscopy and neural networks.
A new model for controlling plasma processes was constructed by combining atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), and neural networks. The applicability of XPS to modeling etch rate was also investigated, as well as the impact of dc bias inclusion. The back-propagation neural network was used to find complex relationships between XPS and AFM data. This technique was evaluated with the etching data characterized by a 2(4) full factorial experiment. Five prediction models of surface roughness were constructed and compared. The Type I model refers to the model constructed with conventional process parameters. The Type II and III models were built with XPS and XPS plus dc bias data, respectively. The remaining Type IV and V models refer to those constructed with principal component analysis (PCA) reduced-XPS and PCA reduced-XPS plus dc bias, respectively. Mode prediction performance was evaluated as a function of training factor. In predicting the surface roughness, the Type II model yielded an improved prediction of 39% with respect to the Type IV model. The improvement was also demonstrated in modeling the etch rate. These results indicate that utilizing full XPS data is more effective for improving the model prediction performance. The advantage of XPS data was more conspicuous in constructing the surface roughness model.


T cell epitope-mapping by cytokine gene expression assay.
The following method describes the identification of candidate immunogenic peptides through their ability to recall an immune T-cell activation from peripheral blood mononuclear cells (PBMCs) of individuals with defined HLA-peptide restrictions that have been previously exposed to the antigen. Isolated PBMCs are plated out at a concentration of 1 x 10(6) cells/ml in a 200 microl medium and incubated overnight to reduce cytokine gene expression due to cell manipulation. After starving, cells are either directly stimulated with individual peptides or not stimulated and incubated from 3 to 12 h according to experimental conditions. Quantitative real-time PCR (qrt-PCR) is performed on reverse-transcribed complementary DNA (cDNA) from total RNA that is isolated from peptide-cultured PBMCs. To perform high quality qrt-PCR, primers and probes are designed to span exon-intron junctions in order to prevent amplification of genomic DNA and to produce amplicons <150 base pairs (bp). Real-time monitoring of fluorescent emission from the cleavage of sequence specific probe by the nuclease activity of Taq polymerase (TaqMan method) defines threshold cycles during exponential phases of amplification. Standard curves of copy numbers of the gene of interest are normalized using as reference copy numbers of control genes.


Effect of a bed covering system in children with asthma and house dust mite hypersensitivity.
Allergen avoidance is regarded as an important approach to management of atopic asthma. The effect of Intervent bed covering systems on house dust mite (HDM) allergen exposure, asthma symptoms and markers of inflammation was investigated in 31 HDM sensitive asthmatic children. Dust concentrations of Dermatophagoides pteronyssinus allergen 1 (Der p 1) were monitored before and after covering the mattress, duvet and pillow with active and placebo covers for 3 months, in a single-blind, cross-over trial. Twice daily peak expiratory flow rate (PEFR), daily symptom scores and treatment schedule were recorded. Bronchial hyperresponsiveness was monitored by histamine challenge (provocative concentration of histamine causing a 20% fall in forced expiratory volume in one second (PC20)), and inflammation by measuring eosinophil cationic protein (ECP), eosinophil protein X (EPX), eosinophil peroxidase (EPO), and soluble interleukin-2 receptor (sIL-2R) in serum. There was a significant reduction in Der p 1 when the mattress, duvet and pillow were covered with the active bedding. There was no significant improvement in symptoms of asthma, PEFR, bronchodilator usage of PC20. Also, ECP, EPX, sIL-2R concentrations did not change for either treatment. EPO concentrations were significantly lower in the active compared to the placebo period. The active bed covers reduced retrievable Dermatophagoides pteronyssinus allergen 1 (Der p 1) from the bedding, with short term clinical benefit.


CYP3A genotypes in Bangladeshi tuberculosis patients.
The purpose of this study is to investigate the genotype and allelic frequencies of CYP3A in Bangladeshi Tuberculosis (TB) patients which may help for individualized drug dosing and improved therapeutics. Genotyping was done using the extracted genomic DNA from 90 TB patients followed by amplification of target alleles by Polymerase Chain Reaction (PCR). Amplified alleles were then digested by restriction enzymes followed by gel electrophoresis & sequencing to identify the targeted alleles namely CYP3A4*1B, CYP3A4*2, CYP3A4*4, CY3A4*5, CYP3A4*6, CYP3A4*10, CYP3A4*18, and CYP3A5*3. In TB patients, no samples were positive for CYP3A4*2, CYP3A4*4, CYP3A4*5, CYP3A4*6, CYP3A4*10, and CYP3A4*18 alleles. One sample was found to be heterozygous for CYP3A4*1B (1.11%). The wild homozygous (CYP3A5*1/*1) genotype frequency was 7.78%, the heterozygous (CYP3A5*1/*3) frequency was 42.22% and the homozygous mutant (CYP3A5*3/*3) frequency was 50% in Bangladeshi TB patients. The absence of the common polymorphic gene suggests that there will be no impact of CYP3A drug metabolizing enzymes on antituberculosis drugs.


Fetal ultrasound: mechanical effects.
In this discussion, any biological effect of ultrasound that is accompanied by temperature increments less than 1 degrees C above normal physiologic levels is called a mechanical effect. However, one should keep in mind that the term mechanical effect also includes processes that are not of a mechanical nature but arise secondary to mechanical interaction between ultrasound and tissues, such as chemical reactions initiated by free oxygen species generated during cavitation and sonoluminescence. Investigations with laboratory animals have documented that pulsed ultrasound can produce damage to biological tissues in vivo through nonthermal mechanisms. The acoustic output used to induce these adverse bio-effects is considerably greater than the output of diagnostic devices when gas bodies are not present. However, low-intensity pulsed ultrasound is used clinically to accelerate the bone fracture repair process and induce healing of nonunions in humans. Low-intensity pulsed ultrasound also has been shown to enhance repair of soft tissue damage and accelerate nerve regeneration in animal models. Although such exposures to low intensity do not appear to cause damage to exposed tissues, they do raise questions about the acoustic threshold that might induce potentially adverse developmental effects in the fetus. To date, bioeffects studies in humans do not substantiate a causal relationship between diagnostic ultrasound exposure during pregnancy and adverse biological effects to the fetus. However, the epidemiologic studies were conducted with commercially available devices predating 1992, having outputs not exceeding a derated spatial-peak temporal-average intensity (ISPTA.3) of 94 mW/cm2. Current limits in the United States allow an ISPTA.3 of 720 mW/cm2 for obstetric modes. At the time of this report, available evidence, experimental or epidemiologic, is insufficient to conclude that there is a causal relationship between obstetric diagnostic ultrasound exposure and adverse nonthermal effects to the fetus. However, low-intensity pulsed ultrasound effects reported in humans and animal models indicate a need for further investigation of potentially adverse developmental effects.


Interpretation of tests for nut allergy in one thousand patients, in relation to allergy or tolerance.
Peanut and tree nut allergy are common, increasing in prevalence and the commonest food cause of anaphylaxis. In the USA, 7.8% are sensitized (have nut-specific IgE), but not all those sensitized are allergic. Lack of data makes interpretation of tests for nut-specific IgE difficult. This is the first study to investigate the clinical significance of test results for peanut and tree nut allergy in allergic or tolerant patients. Findings are related to the severity of the allergy. An observational study of 1000 children and adults allergic to at least one nut. History of reactions (severity graded) or tolerance to up to five nuts was obtained and skin prick test (SPT)/serum-specific IgE (CAP) performed. There was no correlation between SPT size and graded severity of worst reaction for all nuts combined or for peanut, hazelnut, almond and walnut. For CAP, there was no correlation for all nuts. Where patients tolerated a nut, 43% had positive SPT of 3-7 mm and 3% > or = 8 mm. For CAP, 35% were positive (0.35-14.99 kU/L) and 5% > or = 15 kU/L. In SPT range 3-7 mm, 54% were allergic and 46% were tolerant. There was poor concordance between SPT and CAP (66%). Of patients with a clear nut-allergic history, only 0.5% had negative SPT, but 22% negative CAP. Magnitude of SPT or CAP does not predict clinical severity, with no difference between minor urticaria and anaphylaxis. SPT is more reliable than CAP in confirming allergy. Forty-six per cent of those tolerant to a nut have positive tests > or = 3 mm (sensitized but not allergic). One cannot predict clinical reactivity from results in a wide 'grey area' of SPT 3-7 mm; 22% of negative CAPs are falsely reassuring and 40% of positive CAPs are misleading. This emphasizes the importance of the history. Understanding this is essential for accurate diagnosis. Patients with SPT > or = 8 mm and CAP > or = 15 kU/L were rarely tolerant so these levels are almost always (in > or = 95%) diagnostic.