A pilot trial of decision aids to give truthful prognostic and treatment information to chemotherapy patients with advanced cancer.
Most cancer patients do not have an explicit discussion about prognosis and treatment despite documented adverse outcomes. Few decision aids have been developed to assist the difficult discussions of palliative management. We developed decision aids for people with advanced in curable breast, colorectal, lung, and hormone-refractory prostate cancers facing first-, second-, third-, and fourth-line chemotherapy. We recruited patients from our urban oncology clinic after gaining the permission of their treating oncologist. We measured knowledge of curability and treatment benefit before and after the intervention. Twenty-six of 27 (96%) patients completed the aids, with ameanage of 63, 56% female, 56% married, 56% African American, and 67% with a high school education or more. Most patients (14/27, 52%) thought a person with their advanced cancer could be cured, which was reduced (to 8/26, 31%, P = 0.15) after the decision aid. Nearly all overestimated the effect of palliative chemotherapy. No distress was noted, and hope did not change. The majority (20/27, 74%) found the information helpful to them, and almost all (25/27, 93%) wanted to share the information with their family and physicians. It is possible to give incurable patients their prognosis, treatment options, and options for improving end-of-life care without causing distress or lack of hope. Almost all find the information helpful and want to share it with doctors and family. Research is needed to test the findings in a larger sample and measure the outcomes of truthful information on quality of life, quality of care, and costs.


First Identification of a Large Set of Serine Hydrolases by Activity-Based Protein Profiling in Dibutyl Phthalate-Exposed Zebrafish Larvae.
Despite the involvement of several serine hydrolases (SHs) in the metabolism of xenobiotics such as dibutyl phthalate (DBP), no study has focused on mapping this enzyme class in zebrafish, a model organism frequently used in ecotoxicology. Here, we survey and identify active SHs in zebrafish larvae and search for biological markers of SH type after exposure to DBP. Zebrafish were exposed to 0, 5, and 100 µg/L DBP from 4 to 120 h post-fertilization. A significant decrease in vitellogenin expression level of about 2-fold compared to the control was found in larvae exposed to 100 µg/L DBP for 120 h. The first comprehensive profiling of active SHs in zebrafish proteome was achieved with an activity-based protein profiling (ABPP) approach. Among 49 SHs identified with high confidence, one was the carboxypeptidase ctsa overexpressed in larvae exposed to 100 µg/L DBP for 120 h. To the best of our knowledge, this is the first time that a carboxypeptidase has been identified as deregulated following exposure to DBP. The overall results indicate that targeted proteomics approaches, such as ABPP, can, therefore, be an asset for understanding the mechanism of action related to xenobiotics in ecotoxicology.


Temporal retinal nerve fibre layer thinning in cluster headache patients detected by optical coherence tomography.
The exact pathophysiology of cluster headache (CH) is still not fully clarified. Various studies confirmed changes in ocular blood flow during CH attacks. Furthermore, vasoconstricting medication influences blood supply to the eye. We investigated the retina of CH patients for structural retinal alterations with optical coherence tomography (OCT), and how these changes correlate to headache characteristics, oxygen use and impaired visual function. Spectral domain OCT of 107 CH patients - 67 episodic, 35 chronic, five former chronic sufferers - were compared to OCT from 65 healthy individuals. Visual function tests with Sloan charts and a substantial ophthalmologic examination were engaged. Reduction of temporal and temporal-inferior retinal nerve fibre layer (RNFL) thickness was found in both eyes for CH patients with a predominant thinning on the headache side in the temporal-inferior area. Chronic CH patients revealed thinning of the macula compared to episodic suffers and healthy individuals. Bilateral thinning of temporal RNFL was also found in users of 100% oxygen compared to non-users and healthy controls. Visual function did not differ between patients and controls. Our OCT findings show a systemic effect causing temporal retinal thinning in both eyes of CH patients possibly due to attack-inherent or medication-induced frequent bilateral vessel diameter changes. The temporal retina with its thinly myelinated parvo-cellular axons and its more susceptible vessels for the vasoconstricting influence of oxygen inhalation seems to be predisposed for tissue damage-causing processes related to CH.


DNA repair is activated in early stages of p53-induced apoptosis.
p53 is a complex molecule involved in apoptosis, cell cycle arrest, and DNA repair. Since apoptosis may play an important role in deletion of neoplastic cells, an understanding of the mechanism of p53-induced apoptosis may be critical for possible future therapeutic interventions. Recent evidence suggests that p53-induced apoptosis may involve members of the nucleotide excision repair (NER) family, linking these two cellular events. Our work using a temperature-sensitive p53 construct further analyzes p53-induced apoptosis in cultured murine mammary epithelial cells and also suggests that DNA repair plays a role in that process. Although p21 is induced in our system, apoptosis occurs without a detectable preceding G1 cell cycle arrest and independent of cellular alterations brought on by the temperature shift. In addition, clonogenic assays suggest that early stages of p53-induced apoptosis may be reversible upon removal of the apoptosis stimulus. As a possible explanation for this reversibility, our results show that general DNA repair activity increases early in p53-induced apoptosis. We also show that caspase-3 is activated at a timepoint when colony formation begins to drop, suggesting a possible mechanism for the point of no return in p53-induced apoptosis.


[Differentiation of human leukemia K-562 cells in diffusion chambers].
The human leukemia K562 cells differentiation is studied in diffusion chambers implanted in rats intraperitoneally. The investigations revealed the possibility of explantation of leukemic K562 cells in diffusion chambers in a heterogeneous host. The ability of these cells to follow the myeloid lineage of differentiation is shown.


Nurse-led care vs. usual care for patients with atrial fibrillation: results of a randomized trial of integrated chronic care vs. routine clinical care in ambulatory patients with atrial fibrillation.
The management of patients with atrial fibrillation (AF) is often inadequate due to deficient adherence to the guidelines. A nurse-led AF clinic providing integrated chronic care to improve guideline adherence and activate patients in their role, may effectively reduce morbidity and mortality but such care has not been tested in a large randomized trial. Therefore, we performed a randomized clinical trial to compare the AF clinic with routine clinical care in patients with AF. We randomly assigned 712 patients with AF to nurse-led care and usual care. Nurse-led care consisted of guidelines based, software supported integrated chronic care supervised by a cardiologist. The primary endpoint was a composite of cardiovascular hospitalization and cardiovascular death. Duration of follow-up was at least 12 months. Adherence to guideline recommendations was significantly better in the nurse-led care group. After a mean of 22 months, the primary endpoint occurred in 14.3% of 356 patients of the nurse-led care group compared with 20.8% of 356 patients receiving usual care [hazard ratio: 0.65; 95% confidence interval (CI) 0.45-0.93; P= 0.017]. Cardiovascular death occurred in 1.1% in the nurse-led care vs. 3.9% in the usual care group (hazard ratio: 0.28; 95% CI: 0.09-0.85; P= 0.025). Cardiovascular hospitalization amounted (13.5 vs. 19.1%, respectively, hazard ratio: 0.66; 95% CI: 0.46-0.96, P= 0.029). Nurse-led care of patients with AF is superior to usual care provided by a cardiologist in terms of cardiovascular hospitalizations and cardiovascular mortality. Trial registration information: Clinicaltrials.gov identifier number: NCT00391872.


Association between C807T(C/T) polymorphism of platelet glycoprotein gene and sensitivity to ischemic stroke: a meta-analysis.
Ischemic stroke can lead to loss of neurologic functions. It occurs due to obstruction in blood supply to the brain. It has been proposed that C807T(C/T) polymorphism within the platelet glycoprotein gene may be associated with density and function of glycoprotein Ia/IIa receptors and contributes to the pathogenesis of thrombotic disease. We assessed the association between C807T(C/T) and risk of ischemic stroke. Databases such as PubMed, Medline, Springer, Elsevier Science Direct, Cochrane Library, Google scholar, Wanfang Data (Chinese), and Chinese National Knowledge Infrastructure (CNKI, Chinese) were used to search for relevant studies. We found 16 eligible studies, which totaled to 4897 (case group 2340; control group 2557) participants. Overall, our results showed significant associations between C807T(C/T) polymorphism and risk of ischemic stroke based on T-allele comparisons (T vs C, pooled OR = 0.78, 95%CI = 0.68-0.90, P < 0.01), TT vs CC comparisons (pooled OR = 0.58, 95%CI = 0.42-0.81, P < 0.01), recessive models (TT vs TC + CC, pooled OR = 0.72, 95%CI = 0.59-0.87, P < 0.01) and dominant models (TT + TC vs CC, pooled OR = 0.70, 95%CI = 0.54-0.92, P < 0.05). There was no association in TC vs CC comparisons (pooled OR = 0.81, 95%CI = 0.63-1.04, P > 0.05). Subgroup analyses stratified according to Hardy-Weinberg equilibrium, sample size, and ethnicity also demonstrated significant associations between the two variables. Therefore, C807T(C/T) polymorphism in the platelet glycoprotein gene may be associated with susceptibility to ischemic stroke, and the T allele at this locus may decrease risk to ischemic stroke.


Patterns of intellectual development among survivors of pediatric medulloblastoma: a longitudinal analysis.
To examine two competing hypotheses relating to intellectual loss among children treated for medulloblastoma (MB): Children with MB either: (1) lose previously learned skills and information; or (2) acquire new skills and information but at a rate slower than expected compared with healthy same-age peers. Forty-four pediatric MB patients were evaluated who were treated with postoperative radiation therapy (XRT) with or without chemotherapy. After completion of XRT, a total of 150 examinations were conducted by use of the child version of the Wechsler Intelligence SCALES: These evaluations provided a measure of intellectual functioning called the estimated full-scale intelligence quotient (FSIQ). Changes in patient performance corrected for age (scaled scores) as well as the uncorrected performance (raw scores) were analyzed. At the time of the most recent examination, the obtained mean estimated FSIQ of 83.57 was more than one SD below expected population norms. A significant decline in cognitive performance during the time since XRT was demonstrated, with a mean loss of 2.55 estimated FSIQ points per year (P =.0001). An analysis for the basis of the intelligence quotient (IQ) loss revealed that subtest raw score values increased significantly over time since XRT, but the rate of increase was less than normally expected, which resulted in decreased IQ scores. These results support the hypothesis that MB patients demonstrate a decline in IQ values because of an inability to acquire new skills and information at a rate comparable to their healthy same-age peers, as opposed to a loss of previously acquired information and skills.


Development and assessment of stressful life events subscales - A preliminary analysis.
Stress affects people of all ages, genders, and cultures and is associated with physical and psychological complications. Stressful life events are an important research focus and a psychometrically valid measure could provide useful clinical information. The purpose of the study was to develop a reliable and valid measurement of stressful life events and to assess its reliability and validity using established measures of social support, stress, depression, anxiety and maternal and child health. The authors used an adaptation from the Social Readjustment Rating Scale (SRRS) to describe the prevalence of life events; they developed a 4-factor stressful life events subscales and used Medical Outcomes Social Support Scale, Social Support Scale, Depression, Anxiety and Stress Scale and 14 general health items for validity analysis. Analyses were performed with descriptive statistics, Cronbach's alpha, Spearman's rho, Chi-square test or Fisher's exact test and Wilcoxon 2-sample test. The 4-factor stressful life events subscales showed acceptable reliability. The resulting subscale scores were significantly associated with established measures of social support, depression, anxiety, stress, and caregiver health indicators. The study presented a number of limitations in terms of design and recall bias. Despite the presence of a number of limitations, the study provided valuable insight and suggested that further investigation is needed in order to determine the effectiveness of the measures in revealing the family's wellbeing and to develop and strengthen a more detailed analysis of the stressful life events/health association.


Relationship between Age and Thickness of Carotid Arteries in a Population without Risk Factors for Atherosclerosis.
The intima-media thickness (IMT) of carotid arteries is a marker of subclinical atherosclerosis associated with risk factors for atherosclerosis and a predictor of vascular disease. The aim of the research was to determine the correlation of IMT and age, and above normal IMT values in healthy adults in Slavonia (eastern Croatia). The study included 275 subjects of both sexes, aged between 20 and 79, who had no clinical manifestations of vascular disease or presence of major risk factors for atherosclerosis (hypertension, hypercholesterolemia, diabetes mellitus, cigarette smoking). Ultrasonic measurement of IMT in the B-mode was performed on far walls of the carotid arteries on both sides at three locations (common and internal carotid artery, carotid bifurcation). At all three sites of measurement a high correlation between the IMT values and age was found in both sexes, including the maximum for IMT of carotid bifurcation (men r=0.92, women 0.91). Upper normal values (75th percentile) IMT of common carotid arteries were determined for the ten year age groups. It is the same for both men and women in age groups both 20-29 and 30-39 (0.41, 0.46 mm). On the other hand, in age groups 40-49, 50-59, 60-69 and 70-79 upper normal values for men are 0.57, 0.62, 0.77 and 0.96 mm, and for women 0.50, 0.57, 0.71 and 0.81 mm. Our study in healthy adults in Slavonia (eastern Croatia) established a clear con- nection between carotid IMT and age, which implies a need for taking the age as an essential factor into account when conducting researches that involve the IMT.


Localization of peripheral autonomic neurons innervating the boar urinary bladder trigone and neurochemical features of the sympathetic component.
The urinary bladder trigone (UBT) is a limited area through which the majority of vessels and nerve fibers penetrate into the urinary bladder and where nerve fibers and intramural neurons are more concentrated. We localized the extramural post-ganglionic autonomic neurons supplying the porcine UBT by means of retrograde tracing (Fast Blue, FB). Moreover, we investigated the phenotype of sympathetic trunk ganglion (STG) and caudal mesenteric ganglion (CMG) neurons positive to FB (FB+) by coupling retrograde tracing and double-labeling immunofluorescence methods. A mean number of 1845.1±259.3 FB+ neurons were localized bilaterally in the L1-S3 STG, which appeared as small pericarya (465.6±82.7 µm2) mainly localized along an edge of the ganglion. A large number (4287.5±1450.6) of small (476.1±103.9 µm2) FB+ neurons were localized mainly along a border of both CMG. The largest number (4793.3±1990.8) of FB+ neurons was observed in the pelvic plexus (PP), where labeled neurons were often clustered within different microganglia and had smaller soma cross-sectional area (374.9±85.4 µm2). STG and CMG FB+ neurons were immunoreactive (IR) for tyrosine hydroxylase (TH) (66±10.1% and 52.7±8.2%, respectively), dopamine beta-hydroxylase (DβH) (62±6.2% and 52±6.2%, respectively), neuropeptide Y (NPY) (59±8.2% and 65.8±7.3%, respectively), calcitonin-gene-related peptide (CGRP) (24.1±3.3% and 22.1±3.3%, respectively), substance P (SP) (21.6±2.4% and 37.7±7.5%, respectively), vasoactive intestinal polypeptide (VIP) (18.9±2.3% and 35.4±4.4%, respectively), neuronal nitric oxide synthase (nNOS) (15.3±2% and 32.9±7.7%, respectively), vesicular acetylcholine transporter (VAChT) (15±2% and 34.7±4.5%, respectively), leu-enkephalin (LENK) (14.3±7.1% and 25.9±8.9%, respectively), and somatostatin (SOM) (12.4±3% and 31.8±7.3%, respectively). UBT-projecting neurons were also surrounded by VAChT-, CGRP-, LENK-, and nNOS-IR fibers. The possible role of these neurons and fibers in the neural pathways of the UBT is discussed.


Patterning the eye: A role for the cell cycle?
Although highly regulated cell cycle behavior accompanies specification of cell types in the Drosophila retina, no evidence has previously existed that cell cycle phase influences cell fate choice. Meserve and Duronio have now used genetic techniques to trace the fate of a sub-population of cells that accumulate in G2-phase of the cell cycle, discovering that they contribute to a particular fate, the precursor of the sensory inter-ommatidial bristles. Meserve and Duronio further show that G2 cells have an advantage acquiring inter-ommatidial bristle fate. This is the first evidence for a functional contribution of cell cycle phase to cell fate determination in the Drosophila eye and indicates that the fate of one population of retinal cells is established much earlier than previously recognized, during the larval stages when cell-cell interactions influence cell cycle phase. Inter-ommatidial bristle fate had been thought to arise much later, in the pupal stage, and models for how these neuronal eye structures arise will now have to be revised.


Penetration of ticarcillin/clavulanate into cartilage.
The penetration of ticarcillin and clavulanate into cartilage was investigated in 20 subjects undergoing funnel chest correction. Cartilage samples, obtained 120 or 180 min after administration of ticarcillin/clavulanate (mean dose: ticarcillin 70.0 mg/kg, clavulanate 4.7 mg/kg), were divided into core samples and outer covering portions. After 120 min, the mean ticarcillin in the outer portion was 11.0 mg/kg and that in the core sample was 0.81 mg/kg; at 180 min the mean concentration in the outer portion was 6.47 mg/kg and ticarcillin was undetectable in all but two core samples. Clavulanate was shown to decline with time in spiked cartilage preparations and the results in this investigation may underestimate penetration. Clavulanate was undetectable in most core samples. In the outer portion the mean concentration was 1.30 mg/kg at 120 min and 0.62 mg/kg at 180 min. The penetration gradient requires further elucidation and should be considered when chemotherapy for infection in cartilage is discussed.


[Isolation and synthesis of espintanol, a new antiparasitic monoterpene].
The in vitro leishmanicidal and trypanocidal activities of a petroleum ether extract of Oxandra espintana have been investigated. Four aromatic monoterpenes were isolated, of which two are novel: espintanol [3a], responsible for the antiparasite activity, and O-methylespintanol [4]. Espintanol was tested in vitro on 20 strains of Trypanosoma cruzi and 12 strains of Leishmania spp. Its structure was determined by spectroscopic methods and confirmed by its preparation starting from carvacrol.


What can water utilities do to improve risk management within their business functions? An improved tool and application of process benchmarking.
We present a model for benchmarking risk analysis and risk based decision making practice within organisations. It draws on behavioural and normative risk research, the principles of capability maturity modelling and our empirical observations. It codifies the processes of risk analysis and risk based decision making within a framework that distinguishes between different levels of maturity. Application of the model is detailed within the selected business functions of a water and wastewater utility. Observed risk analysis and risk based decision making practices are discussed, together with their maturity of implementation. The findings provide academics, utility professionals, and regulators a deeper understanding of the practical and theoretical underpinnings of risk management, and how distinctions can be made between organisational capabilities in this essential business process.


Comparing digraph and Petri net approaches to deadlock avoidance in FMS.
Flexible manufacturing systems (FMSs) are modern production facilities with easy adaptability to variable production plans and goals. These systems may exhibit deadlock situations occurring when a circular wait arises because each piece in a set requires a resource currently held by another job in the same set. Several authors have proposed different policies to control resource allocation in order to avoid deadlock problems. These approaches are mainly based on some formal models of manufacturing systems, such as Petri nets (PNs), directed graphs, etc. Since they describe various peculiarities of the FMS operation in a modular and systematic way, PNs are the most extensively used tool to model such systems. On the other hand, digraphs are more synthetic than PNs because their vertices are just the system resources. So, digraphs describe the interactions between jobs and resources only, while neglecting other details on the system operation. The aim of this paper is to show the tight connections between the two approaches to the deadlock problem, by proposing a unitary framework that links graph-theoretic and PN models and results. In this context, we establish a direct correspondence between the structural elements of the PN (empty siphons) and those of the digraphs (maximal-weight zero-outdegree strong components) characterizing a deadlock occurrence. The paper also shows that the avoidance policies derived from digraphs can be implemented by controlled PNs.


Static electric fields modify the locomotory behaviour of cockroaches.
Static electric fields are found throughout the environment and there is growing interest in how electric fields influence insect behaviour. Here we have analysed the locomotory behaviour of cockroaches (Periplaneta americana) in response to static electric fields at levels equal to and above those found in the natural environment. Walking behaviour (including velocity, distance moved, turn angle and time spent walking) were analysed as cockroaches approached an electric field boundary in an open arena, and also when continuously exposed to an electric field. On approaching an electric field boundary, the greater the electric field strength the more likely a cockroach would be to turn away from, or be repulsed by, the electric field. Cockroaches completely exposed to electric fields showed significant changes in locomotion by covering less distance, walking slowly and turning more often. This study highlights the importance of electric fields on the normal locomotory behaviour of insects.


Direct behavioral and neurophysiological evidence for retronasal olfaction in mice.
The neuroscience of flavor perception is hence becoming increasingly important to understand food flavor perception that guides food selection, ingestion and appreciation. We recently provided evidence that rats can use the retronasal mode of olfaction, an essential element of human flavor perception. We showed that in rats, like humans, odors can acquire a taste. We and others also defined how the input of the olfactory bulb (OB) -not functionally imageable in humans- codes retronasal smell in anesthetized rat. The powerful awake transgenic mouse, however, would be a valuable additional model in the study of flavor neuroscience. We used a go/no-go behavioral task to test the mouse's ability to detect and discriminate the retronasal odor amyl acetate. In this paradigm a tasteless aqueous odor solution was licked by water-restricted head-fixed mice from a lick spout. Orthonasal contamination was avoided. The retronasal odor was successfully discriminated by mice against pure distilled water in a concentration-dependent manner. Bulbectomy removed the mice's ability to discriminate the retronasal odor but not tastants. The OB showed robust optical calcium responses to retronasal odorants in these awake mice. These results suggest that mice, like rats, are capable of smelling retronasally. This direct neuro-behavioral evidence establishes the mouse as a useful additional animal model for flavor research.


Allometric scaling of Wingate anaerobic power test scores in men.
This study examined the appropriate magnitude of allometric scaling of the Wingate anaerobic test (WAnT) power data for body mass (BM) and established normative data for the WAnT for adult men. Eighty-three men completed a standard WAnT using 0.1 kg·kg(-1) BM resistance. Allometric exponents and percentile ranks for 1-second peak power (PP), 5-second PP, and mean power (MP) were established. The Predicted Residual Sum of Squares (PRESS) procedure was used to assess external validity while avoiding data splitting. The mean 1-second PP, 5-second PP, and MP were 1,049.1 ± 168.8 W, 1,013.4 ± 158.6 W, and 777.9 ± 105.0 W, respectively. Allometric exponents for 1-second PP, 5-second PP, and MP scaled for BM were b = 0.89, 0.88, and 0.86, respectively. Correlations between allometrically scaled 1-second PP, 5-second PP, and MP, and BM were r = -0.03, -0.03, and -0.02, respectively, suggesting that the allometric exponents derived were effective in partialling out the effect of BM on WAnT values. The PRESS procedure values resulted in small decreases in R² (0.03, 0.04, and 0.02 for 1-second PP, 5-second PP, and MP, respectively) suggesting acceptable levels of external validity when applied to independent samples. The allometric exponents and normative values provide a useful tool for comparing WAnT scores in college-aged females without the confounding effect of BM. It is suggested that exponents of b = 0.89 (1-second PP), b = 0.88 (5-second PP), and b = 0.86 (MP) be used for allometrically scaling WAnT power values in healthy adult men and that the confidence limits for these allometric exponents be considered as 0.66-1.0 for PP and 0.69-1.0 for MP. The use of these exponents in allometric scaling of male WAnT power values provide coaches and practitioners with valid means for comparing power production between individuals without the confounding influence of BM.


Reevaluating recovery: perceived violations and preemptive interventions on emergency psychiatry rounds.
Contemporary error research suggests that the quest to eradicate error is misguided. Error commission, detection, and recovery are an integral part of cognitive work, even at the expert level. In collaborative workspaces, the perception of potential error is directly observable: workers discuss and respond to perceived violations of accepted practice norms. As perceived violations are captured and corrected preemptively, they do not fit Reason's widely accepted definition of error as "failure to achieve an intended outcome." However, perceived violations suggest the aversion of potential error, and consequently have implications for error prevention. This research aims to identify and describe perceived violations of the boundaries of accepted procedure in a psychiatric emergency department (PED), and how they are resolved in practice. Clinical discourse from fourteen PED patient rounds was audio-recorded. Excerpts from recordings suggesting perceived violations or incidents of miscommunication were extracted and analyzed using qualitative coding methods. The results are interpreted in relation to prior research on vulnerabilities to error in the PED. Thirty incidents of perceived violations or miscommunication are identified and analyzed. Of these, only one medication error was formally reported. Other incidents would not have been detected by a retrospective analysis. The analysis of perceived violations expands the data available for error analysis beyond occasional reported adverse events. These data are prospective: responses are captured in real time. This analysis supports a set of recommendations to improve the quality of care in the PED and other critical care contexts.


Cycling biomechanics: a literature review.
Submitted in partial fulfillment for a Master of Science degree at the University of Pittsburgh, School of Health Related Professions, Pittsburgh, PA 1.5213 This review of current literature on cycling biomechanics emphasizes lower extremity muscle actions and joint excursions, seat height, pedal position, pedaling rate, force application, and pedaling symmetry. Guidelines are discussed for optimal seat height, pedal position, and pedaling rate. Force application in the power and recovery phases of cycling and the relationship of force application to pedaling symmetry are discussed. The need for a biomechanical approach to cycling exists since a great deal of the literature is primarily physiologic in nature. The purpose of this review is to make cyclists and their advisors aware of the biomechanics of cycling and guidelines to follow. This approach is also important because cycling is a very common form of exercise prescribed by physical therapists for clinic or home programs. Biomechanical aspects of cycling should be considered by cyclists at any level of participation and by physical therapists in order for goal-oriented, efficient cycling to occur. J Orthop Sports Phys Ther 1991;14(3):106-113.


Aquatic foods to nourish nations.
Despite contributing to healthy diets for billions of people, aquatic foods are often undervalued as a nutritional solution because their diversity is often reduced to the protein and energy value of a single food type ('seafood' or 'fish')1-4. Here we create a cohesive model that unites terrestrial foods with nearly 3,000 taxa of aquatic foods to understand the future impact of aquatic foods on human nutrition. We project two plausible futures to 2030: a baseline scenario with moderate growth in aquatic animal-source food (AASF) production, and a high-production scenario with a 15-million-tonne increased supply of AASFs over the business-as-usual scenario in 2030, driven largely by investment and innovation in aquaculture production. By comparing changes in AASF consumption between the scenarios, we elucidate geographic and demographic vulnerabilities and estimate health impacts from diet-related causes. Globally, we find that a high-production scenario will decrease AASF prices by 26% and increase their consumption, thereby reducing the consumption of red and processed meats that can lead to diet-related non-communicable diseases5,6 while also preventing approximately 166 million cases of inadequate micronutrient intake. This finding provides a broad evidentiary basis for policy makers and development stakeholders to capitalize on the potential of aquatic foods to reduce food and nutrition insecurity and tackle malnutrition in all its forms.


Realistic environmental exposure to microplastics does not induce biological effects in the Pacific oyster Crassostrea gigas.
The aim of the present study was to evaluate the presence and potential toxic effects of plastic fragments (<400 μm) of polyethylene and polypropylene on the Pacific oyster Crassostrea gigas. Oysters were exposed to environmentally relevant concentrations (0, 0.008, 10, 100 μg of particles/L) during 10 days, followed by a depuration period of 10 days in clean seawater. Effects of microplastics were evaluated on the clearance rate of organisms, tissue alteration, antioxidant defense, immune alteration and DNA damage. Detection and quantification of microplastics in oyster's tissues (digestive gland, gills and other tissues) and biodeposits using infrared microscopy were also conducted. Microplastics were detected in oyster's biodeposits following exposure to all tested concentrations: 0.003, 0.006 and 0.05 particles/mg of biodeposits in oysters exposed to 0.008, 10 and 100 μg of particles/L, respectively. No significant modulation of biological markers was measured in organisms exposed to microplastics in environmentally relevant conditions.


Effectiveness of gefitinib against non-small-cell lung cancer with the uncommon EGFR mutations G719X and L861Q.
In non-small-cell lung cancer, an exon 19 deletion and an L858R point mutation in the epidermal growth factor receptor (EGFR) are predictors of a response to EGFR-tyrosine kinase inhibitors. However, it is uncertain whether other uncommon EGFR mutations are associated with sensitivity to EGFR-tyrosine kinase inhibitors. A post-hoc analysis to assess prognostic factors was performed with the use of patients with EGFR mutations (exon 19 deletion, L858R, G719X, and L861Q) who were treated with gefitinib in the NEJ002 study, which compared gefitinib with carboplatin-paclitaxel as the first-line therapy. In the NEJ002 study, 225 patients with EGFR mutations received gefitinib at any treatment line. The Cox proportional hazards model indicated that performance status, response to chemotherapy, response to gefitinib, and mutation types were significant prognostic factors. Overall survival (OS) was significantly shorter among patients with uncommon EGFR mutations (G719X or L861Q) compared with OS of those with common EGFR mutations (12 versus 28.4 months; p = 0.002). In the gefitinib group (n = 114), patients with uncommon EGFR mutations had a significantly shorter OS (11.9 versus 29.3 months; p < 0.001). By contrast, OS was similar between patients with uncommon mutations and those with common mutations in the carboplatin-paclitaxel group (n = 111; 22.8 versus 28 months; p = 0.358). The post-hoc analyses clearly demonstrated shorter survival for gefitinib-treated patients with uncommon EGFR mutations compared with the survival of those with common mutations and suggest that the first-line chemotherapy may be relatively effective for non-small-cell lung cancer with uncommon EGFR mutations.


Gradient scaffold with spatial growth factor profile for osteochondral interface engineering.
Osteochondral (OC) matrix design poses a significant engineering challenge due to the complexity involved with bone-cartilage interfaces. To better facilitate the regeneration of OC tissue, we developed and evaluated a biodegradable matrix with uniquely arranged bone and cartilage supporting phases: a poly(lactic-co-glycolic) acid (PLGA) template structure with a porosity gradient along its longitudinal axis uniquely integrated with hyaluronic acid hydrogel. Micro-CT scanning and imaging confirmed the formation of an inverse gradient matrix. Hydroxyapatite was added to the PLGA template which was then plasma-treated to increase hydrophilicity and growth factor affinity. An osteogenic growth factor (bone morphogenetic protein 2; BMP-2) was loaded onto the template scaffold via adsorption, while a chondrogenic growth factor (transforming growth factor beta 1; TGF-β1) was incorporated into the hydrogel phase. Confocal microscopy of the growth factor loaded matrix confirmed the spatial distribution of the two growth factors, with chondrogenic factor confined to the cartilaginous portion and osteogenic factor present throughout the scaffold. We observed spatial differentiation of human mesenchymal stem cells (hMSCs) into cartilage and bone cells in the scaffoldsin vitro: cartilaginous regions were marked by increased glycosaminoglycan production, and osteogenesis was seen throughout the graft by alizarin red staining. In a dose-dependent study of BMP-2, hMSC pellet cultures with TGF-β1 and BMP-2 showed synergistic effects on chondrogenesis. These results indicate that development of an inverse gradient matrix can spatially distribute two different growth factors to facilitate chondrogenesis and osteogenesis along different portions of a scaffold, which are key steps needed for formation of an OC interface.


HPUI: Hand Proximate User Interfaces for One-Handed Interactions on Head Mounted Displays.
We explore the design of Hand Proximate User Interfaces (HPUIs) for head-mounted displays (HMDs) to facilitate near-body interactions with the display directly projected on, or around the user's hand. We focus on single-handed input, while taking into consideration the hand anatomy which distorts naturally when the user interacts with the display. Through two user studies, we explore the potential for discrete as well as continuous input. For discrete input, HPUIs favor targets that are directly on the fingers (as opposed to off-finger) as they offer tactile feedback. We demonstrate that continuous interaction is also possible, and is as effective on the fingers as in the off-finger space between the index finger and thumb. We also find that with continuous input, content is more easily controlled when the interaction occurs in the vertical or horizontal axes, and less with diagonal movements. We conclude with applications and recommendations for the design of future HPUIs.


Fusion rates after thoracoscopic release and bone graft substitutes in idiopathic scoliosis.
A retrospective assessment of fusion rates using either morselized allograft bone or demineralized bone matrix (DBM) following video-assisted thoracoscopic surgery (VATS) in idiopathic scoliosis. To compare fusion rates between allograft bone and demineralized bone matrix (Grafton DBM Flex) following VATS using on standard standing lateral spine radiographs. Both VATS and bone graft substitutes are accepted surgical techniques. However, their concomitant use in spinal deformity surgery has not been previously reported. Bone graft substitute has the advantage of decreasing operative time, blood loss, and donor site morbidity associated with autografts. Anterior thoracic discectomies were performed using VATS. Forty patients with 1 year or more follow-up were evaluated-12 with morselized allograft bone (Allograft group) and 28 with folded Grafton DBM Flex (DBM group). Factors analyzed included age, number of anterior levels fused, operative time, anterior perioperative blood loss, curve correction, and fusion rates. Clinical and radiographic evaluations were performed before surgery and at month, 1 year, and at most recent follow-up. Interbody fusion was assessed on standing lateral radiographs using the Newton et al 4-level grading scale. There were no significant differences in age at surgery, number of anterior vertebral levels fused, anterior operative time per level, anterior intraoperative blood loss, chest tube drainage and duration, or total perioperative anterior blood loss between the 2 groups. Percent curve correction from before surgery to the most recent follow-up were very similar in both Allograft (68%) and DBM groups (67%). At most recent assessment, 60 of 73 disc spaces (82%) in the Allograft group and 100 of 109 disc spaces (92%) in the DBM group were rated as radiographically fused (Newton et al Grade I and II). There was no significant difference between the 2 groups (P = 0.088). No patients were observed to have crankshaft, pseudoarthrosis or hardware failure. There were no complications related to the bone graft material used. Demineralized bone matrix (Grafton DBM Flex) seem to be an effective bone graft substitute in thoracoscopic surgery for idiopathic scoliosis.


Correlation of alkaline phosphatase activity to normal T-cell differentiation and to radiation leukemia virus-induced preleukemic cells in the C57BL mouse thymus.
Cytochemical methods at the light and electron microscopic level were used to define the pattern of alkaline phosphatase (APase) activity in normal thymus and to study its modifications after inoculation with the thymotropic leukemogenic radiation leukemia virus in correlation with the emergence of preleukemic cells and their thymus dependency. APase was found in numerous lymphoblasts of the fetal thymus. The enzyme was also detected in a few lymphoid blast cells of the normal young adult thymus, which were closely associated with thymic nurse cells. The observed distribution of APase in normal thymus suggests that its expression could be limited to an early stage of the T-cell differentiation pathway. After inoculation with radiation leukemia virus, APase activity remained normal for almost the entire latency period, during which virus replication spread to the cortex and thymus-dependent preleukemic cells appeared. An important increase in the number of APase-positive cells occurred later, i.e., at the end of the latency period, in nontumoral thymus, which displayed lymphocytic depletion and contained autonomous thymus-independent preleukemic cells. These latter features obviously reflected the malignant transformation of thymus lymphoblasts, which eventually led to the development of the thymic lymphomas. The results raise the question of the possible filiation between the thymic nurse cell-associated APase-positive lymphoid cells of the normal thymus and the target cells susceptible to productive infection and to neoplastic transformation after radiation leukemia virus infection.


Circulation of bovine viral diarrhea virus--1 (BVDV-1) in dairy cattle and buffalo farms in Ismailia Province, Egypt.
Bovine viral diarrhea (BVD) is one of the most economically significant diseases in the bovine industry causing losses due to diarrhea, reproductive disorders, immunosuppression and mortalities. The aim of our investigation was to detect and subtype BVDV from calves on two dairy cattle and two buffalo farms in Ismailia province, Egypt as an indicator of BVDV infection status in the province. A total of 298 blood samples were collected and tested using an optimized one-step, real-time multiplex Taqman-based RT-PCR. All the positive samples by the multiplex real-time RT-PCR were tested using conventional RT-PCR to amplify multiple areas of the genome for further phylogenetic analysis and subtyping. Thirty one (10.4%) of the tested samples were positive for BVDV-1. Only three samples, all from a single dairy cattle farm, had enough viral RNA to be amplified by RT-PCR. The PCR products were sequenced and phylogenetic analysis revealed detection of BVDV-1b. The detected strain is closely related to worldwide BVDV-1b strains, making it difficult to trace its origin. Nucleotide and amino acid alignments of the E2 glycoprotein region of the detected strain with other BVDV-1b strains showed high divergence, with identity ranging from 81.3% to 93.6% and 85.3% to 93.6%, respectively. To our knowledge, this is the first report describing the circulation of BVDV-1b in Egyptian dairy cattle populations.


Simvastatin attenuates ventilator-induced lung injury in mice.
Mechanical ventilation (MV) is a life saving intervention in acute respiratory failure without alternative. However, particularly in pre-injured lungs, even protective ventilation strategies may evoke ventilator-induced lung injury (VILI), which is characterized by pulmonary inflammation and vascular leakage. Adjuvant pharmacologic strategies in addition to lung protective ventilation to attenuate VILI are lacking. Simvastatin exhibited anti-inflammatory and endothelial barrier stabilizing properties in vitro and in vivo. Mice were ventilated (12 ml/kg; six hours) and subjected to simvastatin (20 mg/kg) or sham treatment. Pulmonary microvascular leakage, oxygenation, pulmonary and systemic neutrophil and monocyte counts and cytokine release in lung and blood plasma were assessed. Further, lung tissue was analyzed by electron microscopy. Mechanical ventilation induced VILI, displayed by increased pulmonary microvascular leakage and endothelial injury, pulmonary recruitment of neutrophils and Gr-1high monocytes, and by liberation of inflammatory cytokines in the lungs. Further, VILI associated systemic inflammation characterized by blood leukocytosis and elevated plasma cytokines was observed. Simvastatin treatment limited pulmonary endothelial injury, attenuated pulmonary hyperpermeability, prevented the recruitment of leukocytes to the lung, reduced pulmonary cytokine levels and improved oxygenation in mechanically ventilated mice. High-dose simvastatin attenuated VILI in mice by reducing MV-induced pulmonary inflammation and hyperpermeability.


Assembly of splicing complexes on exon 11 of the human insulin receptor gene does not correlate with splicing efficiency in-vitro.
Incorporation of exon 11 of the insulin receptor gene is both developmentally and hormonally-regulated. Previously, we have shown the presence of enhancer and silencer elements that modulate the incorporation of the small 36-nucleotide exon. In this study, we investigated the role of inherent splice site strength in the alternative splicing decision and whether recognition of the splice sites is the major determinant of exon incorporation. We found that mutation of the flanking sub-optimal splice sites to consensus sequences caused the exon to be constitutively spliced in-vivo. These findings are consistent with the exon-definition model for splicing. In-vitro splicing of RNA templates containing exon 11 and portions of the upstream intron recapitulated the regulation seen in-vivo. Unexpectedly, we found that the splice sites are occupied and spliceosomal complex A was assembled on all templates in-vitro irrespective of splicing efficiency. These findings demonstrate that the exon-definition model explains alternative splicing of exon 11 in the IR gene in-vivo but not in-vitro. The in-vitro results suggest that the regulation occurs at a later step in spliceosome assembly on this exon.


Association between reported elder abuse and rates of admission to skilled nursing facilities: findings from a longitudinal population-based cohort study.
Elder abuse is common and is a frank violation of an older adult's fundamental rights to be safe and free of violence. Our prior study indicates elder abuse is independently associated with mortality. This study aims to quantify the relationship between overall elder abuse and specific subtypes of elder abuse and rate of admission to skilled nursing facilities (SNF). A prospective population-based study conducted in Chicago of community-dwelling older adults who participated in the Chicago Health and Aging Project (CHAP). Of the 6,674 participants in the CHAP study, 106 participants were reported to the social services agency for elder abuse. The primary predictor was elder abuse reported to the social services agency. The outcome of interest was the annual rate of admission to SNF obtained from the Center for Medicare and Medicaid Services. Poisson regression models were used to assess these longitudinal relationships. The average annual rate of SNF for those without elder abuse was 0.14 (0.58) and for those with elder abuse was 0.66 (1.63). After adjusting for sociodemographic and socioeconomic variables, medical comorbidities, cognitive and physical function, and psychosocial wellbeing, older adults who have been abused had higher rates of SNF admission (RR 4.60 (2.85-7.42)). Psychological abuse (RR 2.31 (1.17-4.56)), physical abuse (RR 2.36 (1.19-4.66)), financial exploitation (RR 2.81 (1.53-5.17)) and caregiver neglect (RR 4.73 (3.03-7.40)) were associated with increased rates of admission to SNF, after considering the same confounders. Elder abuse is associated with a higher rate of SNF stay longer than 30 days (RR 6.27 (3.68-10.69)). Elder abuse was associated with increased rates of admission to SNF in this community population. Specific subtypes of elder abuse had a differential association with an increased rate of admission to SNF.


Quadratic adaptive algorithm for solving cardiac action potential models.
An adaptive integration method is proposed for computing cardiac action potential models accurately and efficiently. Time steps are adaptively chosen by solving a quadratic formula involving the first and second derivatives of the membrane action potential. To improve the numerical accuracy, we devise an extremum-locator (el) function to predict the local extremum when approaching the peak amplitude of the action potential. In addition, the time step restriction (tsr) technique is designed to limit the increase in time steps, and thus prevent the membrane potential from changing abruptly. The performance of the proposed method is tested using the Luo-Rudy phase 1 (LR1), dynamic (LR2), and human O'Hara-Rudy dynamic (ORd) ventricular action potential models, and the Courtemanche atrial model incorporating a Markov sodium channel model. Numerical experiments demonstrate that the action potential generated using the proposed method is more accurate than that using the traditional Hybrid method, especially near the peak region. The traditional Hybrid method may choose large time steps near to the peak region, and sometimes causes the action potential to become distorted. In contrast, the proposed new method chooses very fine time steps in the peak region, but large time steps in the smooth region, and the profiles are smoother and closer to the reference solution. In the test on the stiff Markov ionic channel model, the Hybrid blows up if the allowable time step is set to be greater than 0.1ms. In contrast, our method can adjust the time step size automatically, and is stable. Overall, the proposed method is more accurate than and as efficient as the traditional Hybrid method, especially for the human ORd model. The proposed method shows improvement for action potentials with a non-smooth morphology, and it needs further investigation to determine whether the method is helpful during propagation of the action potential.


The phenotypic differentiation of locus ceruleus noradrenergic neurons mediated by brain-derived neurotrophic factor is enhanced by corticotropin releasing factor through the activation of a cAMP-dependent signaling pathway.
We have developed a model system of locus ceruleus (LC) neurons in culture, in which brain-derived neurotrophic factor (BDNF) induces the emergence of noradrenergic neurons attested by the presence of tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase and the absence of phenylethanolamine N-methyl-transferase. Although inactive in itself, the neuropeptide corticotropin releasing factor (CRF) strongly amplified the effect of BDNF, increasing the number of cells expressing TH and the active accumulation of noradrenaline by a factor of 2 to 3 via a mechanism that was nonmitogenic. CRF also acted cooperatively with neurotrophin-4, which like BDNF is a selective ligand of the TrkB tyrosine kinase receptor. The effect of CRF but not that of BDNF was prevented by astressin, a nonselective CRF-1/CRF-2 receptor antagonist. However, only CRF-1 receptor transcripts were detectable in LC cultures, suggesting that this receptor subtype mediated the effect of CRF. Consistent with the positive coupling of CRF-1 receptors to adenylate cyclase, the trophic action of CRF was mimicked by cAMP elevating agents. Epac, a guanine nucleotide exchange factor directly activated by cAMP, contributed to the effect of CRF through the stimulation of extracellular signal-regulated kinases (ERKs) 1/2. However, downstream of ERK1/2 activation by CRF, the phenotypic induction of noradrenergic neurons relied upon the stimulation of the phosphatidylinositol-3-kinase/Akt transduction pathway by BDNF. Together, our results suggest that CRF participates to the phenotypic differentiation of LC noradrenergic neurons during development. Whether similar mechanisms account for the high degree of plasticity of these neurons in the adult brain remains to be established.


The 2021 room-temperature superconductivity roadmap.
Designing materials with advanced functionalities is the main focus of contemporary solid-state physics and chemistry. Research efforts worldwide are funneled into a few high-end goals, one of the oldest, and most fascinating of which is the search for an ambient temperature superconductor (A-SC). The reason is clear: superconductivity at ambient conditions implies being able to handle, measure and access a single, coherent, macroscopic quantum mechanical state without the limitations associated with cryogenics and pressurization. This would not only open exciting avenues for fundamental research, but also pave the road for a wide range of technological applications, affecting strategic areas such as energy conservation and climate change. In this roadmap we have collected contributions from many of the main actors working on superconductivity, and asked them to share their personal viewpoint on the field. The hope is that this article will serve not only as an instantaneous picture of the status of research, but also as a true roadmap defining the main long-term theoretical and experimental challenges that lie ahead. Interestingly, although the current research in superconductor design is dominated by conventional (phonon-mediated) superconductors, there seems to be a widespread consensus that achieving A-SC may require different pairing mechanisms.In memoriam, to Neil Ashcroft, who inspired us all.


Phloem Exudate Protein Profiles during Drought and Recovery Reveal Abiotic Stress Responses in Tomato Vasculature.
Drought is the leading cause of agricultural yield loss among all abiotic stresses, and the link between water deficit and phloem protein contents is relatively unexplored. Here we collected phloem exudates from Solanum lycopersicum leaves during periods of drought stress and recovery. Our analysis identified 2558 proteins, the most abundant of which were previously localized to the phloem. Independent of drought, enrichment analysis of the total phloem exudate protein profiles from all samples suggests that the protein content of phloem sap is complex, and includes proteins that function in chaperone systems, branched-chain amino acid synthesis, trehalose metabolism, and RNA silencing. We observed 169 proteins whose abundance changed significantly within the phloem sap, either during drought or recovery. Proteins that became significantly more abundant during drought include members of lipid metabolism, chaperone-mediated protein folding, carboxylic acid metabolism, abscisic acid signaling, cytokinin biosynthesis, and amino acid metabolism. Conversely, proteins involved in lipid signaling, sphingolipid metabolism, cell wall organization, carbohydrate metabolism, and a mitogen-activated protein kinase are decreased during drought. Our experiment has achieved an in-depth profiling of phloem sap protein contents during drought stress and recovery that supports previous findings and provides new evidence that multiple biological processes are involved in drought adaptation.


Primary and secondary bone lymphomas.
Recent studies have contributed to the enhancement of clinical and molecular knowledge on bone lymphomas, a group of rare malignancies with particular characteristics. Nevertheless, several questions remain unanswered and the level of evidence supporting some diagnostic and therapeutic decisions remains low. Currently, three different forms of bone lymphomas can be distinguished: the primary bone lymphoma, consisting of a single bone lesion with or without regional lymphadenopathies; the polyostotic lymphoma, consisting of multifocal disease exclusively involving the skeleton; and the disseminated lymphoma with secondary infiltration of the skeleton. The first two forms exhibit a good prognosis, requiring treatments similar to those commonly used for nodal lymphomas of the same category, but several issues regarding the role of surgery and local control of the disease, the sequence of treatment, radiation volumes and doses, management of pathological fractures and prevention of late sequelae deserve particular attention. Due to its rarity, prospective trials exclusively focused on bone lymphomas appear unrealistic, thus, critical revision of our own experience and analyses of large cumulative series as well as molecular studies on archival cases remain valid alternatives to improve our knowledge on this obscure lymphoproliferative malignancy. The present review is based on the analysis of the largest available database of bone lymphomas established under the sponsorship of the International Extranodal Lymphoma Study Group (IELSG) as well as on the critical revision of related literature. We provide recommendations for diagnosis, staging, treatment, and response assessment of these patients in everyday practice as well as for the management of special conditions like pathological fractures, indolent forms and central nervous system prophylaxis.


BRANEnet: embedding multilayer networks for omics data integration.
Gene expression is regulated at different molecular levels, including chromatin accessibility, transcription, RNA maturation, and transport. These regulatory mechanisms have strong connections with cellular metabolism. In order to study the cellular system and its functioning, omics data at each molecular level can be generated and efficiently integrated. Here, we propose BRANENET, a novel multi-omics integration framework for multilayer heterogeneous networks. BRANENET is an expressive, scalable, and versatile method to learn node embeddings, leveraging random walk information within a matrix factorization framework. Our goal is to efficiently integrate multi-omics data to study different regulatory aspects of multilayered processes that occur in organisms. We evaluate our framework using multi-omics data of Saccharomyces cerevisiae, a well-studied yeast model organism. We test BRANENET on transcriptomics (RNA-seq) and targeted metabolomics (NMR) data for wild-type yeast strain during a heat-shock time course of 0, 20, and 120 min. Our framework learns features for differentially expressed bio-molecules showing heat stress response. We demonstrate the applicability of the learned features for targeted omics inference tasks: transcription factor (TF)-target prediction, integrated omics network (ION) inference, and module identification. The performance of BRANENET is compared to existing network integration methods. Our model outperforms baseline methods by achieving high prediction scores for a variety of downstream tasks.


Typical Skin Injuries in Children With Autism Spectrum Disorder.
Pediatric skin injuries have primarily been described in typically developing children. Our objectives were to describe the prevalence and pattern of skin injuries of children with autism spectrum disorder (ASD), to describe how this compared with previously demonstrated skin injury locations in typically developing children, and to identify differences in skin injury frequency and locations between autistic children with and without self-injurious behaviors (SIBs). Children with ASD were recruited between September of 2011 and September of 2014. Demographic information was obtained from the caregiver. All skin injuries and their locations were documented. Of the 41 children enrolled, half were reported to have SIBs. The most identified skin injury locations were the legs, knees, and back. Children with autism (1) obtain skin injuries frequently and in similar locations as typically developing children and (2) rarely obtain skin injuries to locations that are considered uncommon for accidental injuries despite reports of SIBs.


Structural basis for reductive radical formation and electron recycling in (R)-2-hydroxyisocaproyl-CoA dehydratase.
The radical enzyme (R)-2-hydroxyisocaproyl-CoA dehydratase catalyzes the dehydration of (R)-2-hydroxyisocaproyl-CoA in the fermentation of l-leucine by the human pathogenic bacterium Clostridium difficile. In contrast to other radical enzymes, such as bacterial class II ribonucleotide reductase or biotin synthase, the Fe/S cluster containing (R)-2-hydroxyisocaproyl-CoA dehydratase requires no special cofactors such as coenzyme B(12) or S-adenosylmethionine for radical generation. Instead it uses a single high-energy electron that is recycled after each turnover. The catalyzed reaction, an atypical α/β-dehydration, depends on the reductive formation of ketyl radicals on the substrate generated by injection of a single electron from the ATP-dependent activator protein. So far, it is unknown how the active electron is recycled and how unwanted side reactions are prevented, allowing for up to 10,000 turnovers. The crystal structure reveals that the heterodimeric protein contains two [4Fe-4S] clusters at a distance of 12 Å, each coordinated by three cysteines and one terminal ligand. The cluster in the α-subunit is part of the active site. In the absence of substrate, a water/hydroxide ion acts as the fourth ligand. The substrate replaces this ligand and coordinates the cluster via the carbonyl-oxygen of the thioester group. The cluster in the β-subunit has a terminal sulfhydryl/sulfido ligand and can act as a reservoir to protect the electron from unwanted side reactions via a recycling mechanism. The crystal structure of (R)-2-hydroxyisocaproyl-CoA dehydratase serves as a model for the reductively radical-generating metalloenzymes of the (R)-2-hydroxyacyl-CoA dehydratase and benzoyl-CoA reductase families.


Robot-assisted laparoscopic vs open radical cystectomy: comparison of complications and perioperative oncological outcomes in 200 patients.
To compare perioperative morbidity and oncological outcomes of robot-assisted laparoscopic radical cystectomy (RARC) to open RC (ORC) at a single institution. A retrospective analysis was performed on a consecutive series of patients undergoing RC (100 RARC and 100 ORC) at Wake Forest University with curative intent from 2006 until 2010. Complication data using the Clavien system were collected for 90 days postoperatively. Complications and other perioperative outcomes were compared between patient groups. Patients in both groups had comparable preoperative characteristics. The overall and major complication (Clavien ≥ 3) rates were lower for RARC patients at 35 vs 57% (P = 0.001) and 10 vs 22% (P = 0.019), respectively. There were no significant differences between groups for pathological outcomes, including stage, number of nodes harvested or positive margin rates. Our data suggest that patients undergoing RARC have perioperative oncological outcomes comparable with ORC, with fewer overall or major complications. Definitive claims about comparative outcomes with RARC require results from larger, randomised controlled trials.


Roles of Polymorphonuclear Neutrophils in Ischemic Brain Injury and Post-Ischemic Brain Remodeling.
Following ischemic stroke, polymorphonuclear neutrophils (PMNs) are rapidly recruited to the ischemic brain tissue and exacerbate stroke injury by release of reactive oxygen species (ROS), proteases and proinflammatory cytokines. PMNs may aggravate post-ischemic microvascular injury by obstruction of brain capillaries, contributing to reperfusion deficits in the stroke recovery phase. Thus, experimental studies which specifically depleted PMNs by delivery of anti-Ly6G antibodies or inhibited PMN brain entry, e.g., by CXC chemokine receptor 2 (CXCR2) or very late antigen-4 (VLA-4) blockade in the acute stroke phase consistently reduced neurological deficits and infarct volume. Although elevated PMN responses in peripheral blood are similarly predictive for large infarcts and poor stroke outcome in human stroke patients, randomized controlled clinical studies targeting PMN brain infiltration did not improve stroke outcome or even worsened outcome due to serious complications. More recent studies showed that PMNs have decisive roles in post-ischemic angiogenesis and brain remodeling, most likely by promoting extracellular matrix degradation, thereby amplifying recovery processes in the ischemic brain. In this minireview, recent findings regarding the roles of PMNs in ischemic brain injury and post-ischemic brain remodeling are summarized.


Mesenchymal Stromal Cell-derived Exosomes Attenuate Experimental Pulmonary Arterial Hypertension.
Pulmonary arterial Hypertension (PH) is a chronic disease that ultimately progresses to right ventricular failure and death. Until now, there is still a lack of effective treatment applied. The purpose of the present study was to observe the protective effect of Mesenchymal Stromal Cell-Derived Exosomes (MSC-EXO) against experimental Pulmonary arterial Hypertension (PH) and right ventricular failure. All the experimental rats received an intraperitoneal injection of 50 mg/kg monocrotaline to induce PH model. Three weeks after the model was successfully established, the cell Culture Media (CM) or MSC-EXO derived from human umbilical cord was administered daily via the tail vein. All animals were randomly divided into 4 groups: Control (saline-treated), MCT-PH, MCT-CM and MCT-EXO groups. Post-operation, hemodynamic data and index of right ventricular hypertrophy (RVHI) were recorded to evaluate the inhibition of MSC-EXO on MCT-induced PH. Histology, immunohistochemistry and western blot were used to analyze the effect of MSC-EXO against vascular remodeling and further reveal the mechanism. In the present study, our results showed that MSC-EXO administration could significantly reduce the Right Ventricular Systolic Pressure (RVSP) and RVHI, suppress the pulmonary vascular remodeling and The Endothelial-Mesenchymal Transition (EndMT) process. Our results provided the firm information for a new method in the treatment of PH; the mechanism may be related to the inhibition of vascular remodeling and EndMT.


Improving Inertial Sensor-Based Activity Recognition in Neurological Populations.
Inertial sensor-based human activity recognition (HAR) has a range of healthcare applications as it can indicate the overall health status or functional capabilities of people with impaired mobility. Typically, artificial intelligence models achieve high recognition accuracies when trained with rich and diverse inertial datasets. However, obtaining such datasets may not be feasible in neurological populations due to, e.g., impaired patient mobility to perform many daily activities. This study proposes a novel framework to overcome the challenge of creating rich and diverse datasets for HAR in neurological populations. The framework produces images from numerical inertial time-series data (initial state) and then artificially augments the number of produced images (enhanced state) to achieve a larger dataset. Here, we used convolutional neural network (CNN) architectures by utilizing image input. In addition, CNN enables transfer learning which enables limited datasets to benefit from models that are trained with big data. Initially, two benchmarked public datasets were used to verify the framework. Afterward, the approach was tested in limited local datasets of healthy subjects (HS), Parkinson's disease (PD) population, and stroke survivors (SS) to further investigate validity. The experimental results show that when data augmentation is applied, recognition accuracies have been increased in HS, SS, and PD by 25.6%, 21.4%, and 5.8%, respectively, compared to the no data augmentation state. In addition, data augmentation contributes to better detection of stair ascent and stair descent by 39.1% and 18.0%, respectively, in limited local datasets. Findings also suggest that CNN architectures that have a small number of deep layers can achieve high accuracy. The implication of this study has the potential to reduce the burden on participants and researchers where limited datasets are accrued.


Sp8 plays a supplementary role to Pax6 in establishing the pMN/p3 domain boundary in the spinal cord.
Progenitor cells are segregated into multiple domains along the dorsoventral axis of the vertebrate neural tube, and each progenitor domain generates particular types of neurons. Selective cross-repressive interactions between pairs of class I and class II transcription factors play important roles in patterning neural progenitors into domains with clear boundaries. Here, we provide evidence that the zinc-finger protein Sp8 plays a supplementary role to Pax6 in establishing the pMN/p3 domain boundary through mutually repressive interactions with the class II protein Nkx2-2. The ventral limit of Sp8 expression is complementary to the dorsal limit of Nkx2-2 expression at the pMN/p3 boundary. Sp8 and Nkx2-2 exert cross-repressive interactions, and changing the expression of Sp8 and Nkx2-2 is coupled with pMN and p3 progenitor fate conversion. Sp8 exerts its neural patterning activities by acting as a transcriptional activator. The expression of a repressive form of Sp8 results in the selective inhibition of motor neuron generation and the ectopic induction of Nkx2-2 expression. Sp8 expression is positively regulated by, but not completely dependent on, Pax6. Furthermore, whereas loss of Pax6 function alone results in disruption of the pMN/p3 domain boundary only in the rostral levels of the spinal cord, loss of both Sp8 and Pax6 functions results in disruption of the pMN/p3 domain boundary along the whole rostrocaudal axis of the spinal cord. We conclude that Sp8 plays a supplementary role to Pax6 in specifying the pMN over p3 progenitor fate through cross-repressive interactions with Nkx2-2.


Prognostic value of early postoperative tumor marker response in gastric cancer.
The clinical usefulness of tumor markers as predictors of treatment outcome in patients with stomach cancer after radical gastrectomy has been poorly defined. The purpose of this study was to evaluate a comprehensive understanding of the impact of early postoperative tumor marker normalization on survival after gastrectomy. Between January 2001 and December 2007, we enrolled 206 patients who had received radical gastrectomy as an initial treatment and had elevated carcinoembryonic antigen (CEA) (>5 ng/mL) or carbohydrate antigen (CA) 19-9 (>37 U/mL) levels. Early tumor marker response was defined as a normalization of preoperative CEA or CA19-9 values 1-2 months after gastrectomy. The mean patient age was 61 years (range 29-84 years), and 139 patients (67.5%) were male. Early tumor marker response was identified in 150 of 206 (72.8%) patients. Of the patients, 49 (23.8%), 41 (19.9%), and 116 (56.4%) were stages I, II, and III, respectively, according to the seventh edition of the American Joint Commission on Cancer (AJCC) staging system. Both disease-free survival (DFS) and overall survival (OS) were significantly longer in patients with tumor marker response compared with nonresponse (61.5 vs. 37.6 months; P = 0.010 and 71.3 vs. 50.9 months; P = 0.008, respectively). Multivariate analyses showed that high CA19-9 level, early tumor marker response, and tumor, node, metastasis classification system stage were independent predictors of DFS and OS (P < 0.05). Early CEA or CA19-9 normalization after radical gastrectomy is a strong prognostic factor for gastric cancer, especially in patients with high preoperative levels of tumor markers.


Sustained pulsatile insulin secretion from adenomatous human beta-cells. Synchronous cycling of insulin, C-peptide, and proinsulin.
The endocrine pancreas secretes insulin in a pulsatile fashion. This rhythm is generated at a site within the pancreas, although its precise location has not been determined. With an in vitro system, we tested the possibility that beta-cells might generate spontaneous pulsatile insulin secretion in the absence of any external influence. Human insulinoma tissue from five patients was perifused for 7-10 h with RPMI-1640 medium and constant concentrations of glucose (5.5 mM). Insulin, C-peptide, and proinsulin were measured in the effluent collected at 3.3-min intervals. All three peptides demonstrated pulsatility of secretion in a similar, synchronous fashion that was sustained throughout each study. The Clifton cycle detection program demonstrated cycling in all five tumors, with an average period for all tumors of 28, 29, and 26 min for insulin, C-peptide, and proinsulin, respectively. Spectral analysis confirmed the regularity and consistency of the hormonal secretory patterns. Mean hormone concentrations secreted by different tumors varied, but insulin and C-peptide were secreted in a nearly 1:1 ratio. This study demonstrates 1) that beta-cells are able to generate spontaneous pulsatile insulin secretory activity, which is independent of innervation or the presence of other islet cells, and 2) proinsulin secretion from the beta-cell also has an inherent pulsatility. The synchrony observed in the cycles of proinsulin and its peptide products confirms their common secretory pathway in the beta-cell. We conclude that the beta-cell may be the originator of insulin cycling.


Building developmental gene regulatory networks.
Animal development is an elaborate process programmed by genomic regulatory instructions. Regulatory genes encode transcription factors and signal molecules, and their expression is under the control of cis-regulatory modules that define the logic of transcriptional responses to the inputs of other regulatory genes. The functional linkages among regulatory genes constitute the gene regulatory networks (GRNs) that govern cell specification and patterning in development. Constructing such networks requires identification of the regulatory genes involved and characterization of their temporal and spatial expression patterns. Interactions (activation/repression) among transcription factors or signals can be investigated by large-scale perturbation analysis, in which the function of each gene is specifically blocked. Resultant expression changes are then integrated to identify direct linkages, and to reveal the structure of the GRN. Predicted GRN linkages can be tested and verified by cis-regulatory analysis. The explanatory power of the GRN was shown in the lineage specification of sea urchin endomesoderm. Acquiring such networks is essential for a systematic and mechanistic understanding of the developmental process.


Hepatic epithelioid hemangioendothelioma: case series of a rare vascular tumor mimicking metastases.
Hepatic epithelioid hemangioendothelioma is an extremely rare malignant vascular tumor which is often multifocal and, in many cases, discovered incidentally. Here, we describe the clinicopathological features of hepatic epithelioid hemangioendothelioma cases seen in our practice and present a detailed review of the published literature. All cases of hepatic epithelioid hemangioendothelioma diagnosed in Department of Pathology and Laboratory Medicine, Aga Khan University Hospital between January 1, 2006 and December 31, 2019 were included in the study. Slides were reviewed and follow up was obtained. Seven cases were reported during the study period. There were 4 females and 3 males. Age range was 20 to 77 years, mean age was 45 years. Three patients presented with right upper abdominal pain; 1 patient presented with jaundice while 3 patients were asymptomatic. In all 7 cases, lesions were identified on imaging studies. In 5 cases, liver lesions were multifocal. Clinical differential diagnosis in all cases was metastatic carcinoma and multifocal hepatocellular carcinoma. Liver function tests were normal in 5 cases. In 1 patient, tumor had already metastasized to the right lung. On histological examination of liver core biopsies performed in all 7 cases, classic histological features of epithelioid hemangioendothelioma were seen. Tumor cells expressed positivity for vascular markers (CD 34, CD31 and ERG) and were negative for cytokeratins, Hep par 1 and Glypican 3. Surgical resection was not performed in any of the 7 cases and all patients were treated by chemotherapy. Follow up was available in 5 cases. Of these, 3 patients died of disease and another patient was alive with metastases in both lungs, omentum and colon. Clinicopathological features of the 7 cases in our series and detailed review of published literature is presented. Prognosis was bad in our cases most likely due to fact that surgical resection could not be performed in any of the cases owing to lack of surgical expertise for liver tumor surgery in most parts of the country.


Protein kinase A and mitogen-activated protein kinase pathways antagonistically regulate fission yeast fbp1 transcription by employing different modes of action at two upstream activation sites.
A significant challenge to our understanding of eukaryotic transcriptional regulation is to determine how multiple signal transduction pathways converge on a single promoter to regulate transcription in divergent fashions. To study this, we have investigated the transcriptional regulation of the Schizosaccharomyces pombe fbp1 gene that is repressed by a cyclic AMP (cAMP)-dependent protein kinase A (PKA) pathway and is activated by a stress-activated mitogen-activated protein kinase (MAPK) pathway. In this study, we identified and characterized two cis-acting elements in the fbp1 promoter required for activation of fbp1 transcription. Upstream activation site 1 (UAS1), located approximately 900 bp from the transcriptional start site, resembles a cAMP response element (CRE) that is the binding site for the atf1-pcr1 heterodimeric transcriptional activator. Binding of this activator to UAS1 is positively regulated by the MAPK pathway and negatively regulated by PKA. UAS2, located approximately 250 bp from the transcriptional start site, resembles a Saccharomyces cerevisiae stress response element. UAS2 is bound by transcriptional activators and repressors regulated by both the PKA and MAPK pathways, although atf1 itself is not present in these complexes. Transcriptional regulation of fbp1 promoter constructs containing only UAS1 or UAS2 confirms that the PKA and MAPK regulation is targeted to both sites. We conclude that the PKA and MAPK signal transduction pathways regulate fbp1 transcription at UAS1 and UAS2, but that the antagonistic interactions between these pathways involve different mechanisms at each site.


Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson's disease.
A key driver of patients' well-being and clinical trials for Parkinson's disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 × 10-11), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10-8) and WWOX (HR = 2.12, P = 2.37 × 10-8) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.


An exploratory study of posttraumatic growth in children following a natural disaster.
This study extends L. G. Calhoun and R. G. Tedeschi's (1998) model of posttraumatic growth (PTG), positive change resulting from the struggle with trauma, to children by exploring the construct among youngsters who experienced Hurricane Floyd and the subsequent flooding. Despite burgeoning interest in PTG, few studies have examined the phenomenon among non-adults. This first systematic study of PTG in children explores hypothesized linkages among PTG and social support, competency beliefs, and ruminative thinking. Results suggest that competency beliefs relate to PTG and that a supportive social environment and ruminative thinking are associated with positive competency beliefs. Contrary to expectations, social support did not relate to rumination. Findings testify to the merit of studying the PTG process in children. Clinical implications and future directions are considered.


Identifying breeding hosts of Ixodes ricinus ticks using stable isotope analysis of their larvae - Proof of concept.
Ticks are important vectors of zoonotic pathogens. Ticks are parasites that are dependent on their hosts for blood meal to develop and reproduce. The abundance of ticks is dependent on the availability of suitable breeding hosts, often medium- and large-sized mammals. So far there has been a shortage of direct methods identifying the breeding hosts for the female ticks. In this study, we introduce a stable isotope analysis (SIA) method that enables us to identify the trophic group of the breeding host, i.e. the host on which the tick mother fed, by sampling larval ticks from the field. We established a reference database on the stable isotope (SI) values (δ13C and δ15N) of the blood of potential tick host species, and of larvae from Ixodes ricinus females, which have fed on known hosts. By comparing the SI values from field collected larval ticks to our reference data, we can determine their most likely host species group. Our results show that the isotopic signatures of I. ricinus tick larvae reflect the diet of the breeding host of the mother tick. SIA proved reliable in categorizing the breeding hosts of I. ricinus into two distinguishable trophic groups; herbivores and carni-omnivores. To our knowledge, this is the first time that stable isotope analyses have been applied to detect transovarial (i.e. over-generational) traces of a blood meal in ticks. The method provides an efficient, novel tool for directly identifying tick breeding hosts by sampling field collected larvae. Ixodes ricinus is the most important vector of TBPs (tick-borne pathogens) in Europe, and to predict and mitigate against the future risks that TBPs pose, it is crucial to have detailed knowledge on the hosts that support tick reproduction in nature.


VE-cadherin links tRNA synthetase cytokine to anti-angiogenic function.
A natural fragment of an enzyme that catalyzes the first step of protein synthesis-human tryptophanyl-tRNA synthetase (T2-TrpRS) has potent anti-angiogenic activity. A cellular receptor through which T2-TrpRS exerts its anti-angiogenic activity has not previously been identified. Here T2-TrpRS was shown to bind at intercellular junctions of endothelial cells (ECs). Using genetic knock-outs, binding was established to depend on VE-cadherin, a calcium-dependent adhesion molecule, which is selectively expressed in ECs, concentrated at adherens junctions, and is essential for normal vascular development. In contrast, T2-TrpRS binding to EC junctions was not dependent on platelet endothelial cell adhesion molecule type-1, another adhesion molecule found at EC junctions. Pull-down assays confirmed direct complex formation between T2-TrpRS and VE-cadherin. Binding of T2-TrpRS inhibited VEGF-induced ERK activation and EC migration. Thus, a VE-cadherin-dependent pathway is proposed to link T2-TrpRS to inhibition of new blood vessel formation.


MOF-derived biochar composites for enhanced high performance photocatalytic degradation of tetracycline hydrochloride.
Biochar reinforced advanced nanocomposites are of interest to a wide circle of researchers. Herein, we describe a novel MOF-derived reinforced cow dung biochar composite, which was prepared by a one-step hydrothermal method to form the MOF MIL-125(Ti) onto a nitrogen and sulfur co-doped bio-carbon (NSCDBC). The UV-vis diffuse reflectance spectrum of NSCDBC/MIL-125(Ti) exhibits an extension of light absorption in the visible region (360-800 nm), indicating its higher visible light capture capacity relative to pure MIL-125(Ti). The photocatalytic activity results show that all the NSCDBC/MIL-125(Ti) composite samples, namely NSCM-5, NSCM-10, NSCM-20 and NSCM-30 display good performance in the removal of tetracycline hydrochloride compared to pure MIL-125(Ti). Among them, NSCM-20 exhibits the highest catalytic activity with a removal rate of 94.62%, which is attributed to the excellent adsorption ability of NSCDBC and the ability to inhibit the complexation of photogenerated electron-hole pairs. Photoluminescence verifies that the loading of biochar successfully enhances the separation of photogenerated electron-hole pairs. Subsequently, the active species in the photocatalytic process are identified by using electron spin resonance spin-trap techniques and free radical trapping experiments. Finally, the possible reaction mechanism for the photocatalytic process is revealed. These results confirm that NSCDBC/MIL-125(Ti) is a potentially low-cost, green photocatalyst for water quality improvement.


Impact of a Video-Based Interactive Workshop on Unprofessional Behaviors Among Internal Medicine Residents.
Unprofessional behaviors undermine the hospital learning environment and the quality of patient care. To assess the impact of an interactive workshop on the perceptions of and self-reported participation in unprofessional behaviors. We conducted a pre-post survey study at 3 internal medicine residency programs. For the workshop we identified unprofessional behaviors related to on-call etiquette: "blocking" an admission, disparaging a colleague, and misrepresenting a test as urgent. Formal debriefing tools were utilized to guide the discussion. We fielded an internally developed 20-item survey on perception and participation in unprofessional behaviors prior to the workshop. An online "booster" quiz was delivered at 4 months postworkshop, and the 20-item survey was repeated at 9 months postworkshop. Results were compared to a previously published control from the same institutions, which showed that perceptions of unprofessional behavior did not change and participation in the behaviors worsened over the internship. Of 237 eligible residents, 181 (76%) completed both pre- and postsurvey. Residents perceived blocking an admission and the misrepresentation of a test as urgent to be more unprofessional at a 9-month follow-up (2.0 versus 1.74 and 2.63 versus 2.28, respectively; P < .05), with no change in perception for disparaging a colleague. Participation in unprofessional behaviors did not decrease after the workshop, with the exception of misrepresenting a test as urgent (61% versus 50%, P = .019). The results of this multi-site study indicate that an interactive workshop can change perception and may lower participation in some unprofessional behaviors.


Plasma Amino-Terminal Propeptide of C-Type Natriuretic Peptide Concentration in Normal-Weight and Obese Children.
In studies on the relationship between amino-terminal propeptide of C-type natriuretic peptide (NT-proCNP) concentration and height velocity in children, CNP has been implicated as an emerging new growth marker during childhood. It has been reported that besides its well-studied role in growth, plasma CNP levels are reduced in overweight and/or obese adolescents, suggesting CNP as a potential biomarker in childhood obesity. The primary goal of this study was to test this hypothesis in a Turkish population. Consent was taken from 317 children [ages 0-18 (158 girls, 159 boys)] and their parents. All subjects were physically examined; anthropometric measurements were obtained. Body mass index was calculated. During routine blood work, 1 mL extra blood was taken. Plasma NT-proCNP concentration was measured by enzyme-linked immunosorbent assay. Results confirmed the previously described relationship between plasma NT-proCNP concentration and growth velocity. Plasma NT-proCNP concentration showed a negative correlation with age, weight, and height in children. Gender was not a factor that alters the age-dependent plasma NT-proCNP concentration until puberty. Unlike previous reports, plasma NT-proCNP concentration of overweight/obese children was not significantly lower than that of children with normal weight in age groups analyzed in a Turkish population. Thus, it is too early to conclude that CNP is a potential biomarker in childhood obesity. Further studies are necessary to address this question.


[Clinical and morphological peculiarities of the clinical course of duodenal ulcer in patients with bronchial asthma].
This work was aimed to study clinical features of H. pylori-associated duodenal ulcer (DU) and elucidate morphological features of gastric mucosa (GM) in patients with bronchial asthma (BA). Simultaneous prospective examination of 118 patients aged 18-64 yr included clinical and endoscopic study of the gastroduodenal region with the assessment of gastroenterological symptoms and morphological analysis of GM and duodenal biopsies by histological, histochemical, and morphometric methods. It was shown that GM inflammation in patients with DU and BA is associated not only with H. pylori infection but also with the phase of BA. Structural changes of GM in the patients with DU and BA, unlike those with DU without BA, were apparent not only in the antrum but also in the fundus. Growing density of eosinophil, neutrophil and mast cell infiltration of fundal and antral GM as well as increased total number of cells in the antrum reflects active immune-mediated inflammation in GM lamina propria. It is concluded that negative effect of uncontrolled BA on the clinical course of DU is not restricted to the association of DU exacerbation with the absence of BA control; it is also responsible for enhanced activity of gastritis. One of the possible factors determining combination of H. pylori-associated duodenal ulcer with BA is chronic hyperergic inflammation and marked structural changes in GM.


[Factors related to falls of elderly women residents in a community].
To determine the factors related to falls of a group of independent and autonomous elderly women. This was a descriptive study of 83 elderly women enrolled on the Elderly Health Promotion Project at the Universidade Católica de Brasília. They replied to questionnaires on their age, sociodemographic factors, dizziness, use of continuous medication, self-perception of health and vision and underwent the Yesavage Geriatric Depression Scale, Functional Reach Test and Tinetti Performance-Oriented Mobility Assessment. No statistical relationship was identified between age, social demographic factors, dizziness, or negative self-perception of health and vision and fall phenomena. However there was a significant statistical relationship with the Functional Reach Test and Tinetti Performance-Oriented Mobility Assessment. Elderly women's ability to balance was the major factor related to fall events. Functional Reach Test and Tinetti Performance-Oriented Mobility Assessment were considered effective for predicting risk of falling, indicating that they could be used for assessment and identification of improved balance after training


A comparative histologic study of rapid three-dimensional zygomatic suture expansion osteogenesis.
To explore the histologic changes in zygomatic suture with 3-dimensional (3D) zygomatic suture expansion osteogenesis (SEO). The zygomatic bones were drawn by 3D external expansion appliance, and sutures of the zygomatic were extended. Biopsy specimens of the zygomatic bone were collected after 1, 3, 5, and 8 weeks. Each specimen was stained with Triplex staining as well as hematoxylin and eosin (HE), and the histologic changes were evaluated compared with the control section. With the 1-week study group, there were visible fibroblasts, osteoblasts, and capillary vessels in the expanded suture tissues. The fibers were connected to the sides of suture in an orderly way. In the 3-week group, active bone formation can be seen in expanded sides. The bone trabeculae were matured and oriented in the direction of distraction in the expanded sides of suture and most of them were collagen fibers; but the tissues of both sides of expanded suture were not in order. New woven bones were found in the histologic sections of the 5-week group. In the 8-week group, reticular and elastic fibers could not be observed, and bones were formed completely. Compared with the histologic examination of the same tissue section and its change in different periods of the biopsy specimen with Triplex staining and HE staining, the method of Triplex staining showed more clearly in collagen, reticular, and elastic fiber examination. The superiority of HE staining was in showing fibrous tissue, shape of cells, and bone formation in various degrees of maturation in rapid SEO. It is suggested that the 2 staining methods might be combined in distinguishing the collagen as well as reticular fibers from fibrin in the same section simultaneously. Collagen fibers and new bones were observed to form rapidly in expanded sides with direct SEO. Continual affluent blood supply, integral structure of periosteum and synostoses in the suture, and rapid uniform calcification of the whole new tissues are the histologic characteristics of SEO.


Insights from rare variants into the genetic architecture and biology of youth-onset type 2 diabetes.
Youth-onset type 2 diabetes (T2D) is a growing public health concern. Its genetic basis and relationship to other forms of diabetes are largely unknown. To gain insight into the genetic architecture and biology of youth-onset T2D, we analyzed exome sequences of 3,005 youth-onset T2D cases and 9,777 ancestry matched adult controls. We identified (a) monogenic diabetes variants in 2.1% of individuals; (b) two exome-wide significant (P < 4.3×10-7) common coding variant associations (in WFS1 and SLC30A8); (c) three exome-wide significant (P < 2.5×10-6) rare variant gene-level associations (HNF1A, MC4R, ATX2NL); and (d) rare variant association enrichments within 25 gene sets broadly related to obesity, monogenic diabetes, and β-cell function. Many association signals were shared between youth-onset and adult-onset T2D but had larger effects for youth-onset T2D risk (1.18-fold increase for common variants and 2.86-fold increase for rare variants). Both common and rare variant associations contributed more to youth-onset T2D liability variance than they did to adult-onset T2D, but the relative increase was larger for rare variant associations (5.0-fold) than for common variant associations (3.4-fold). Youth-onset T2D cases showed phenotypic differences depending on whether their genetic risk was driven by common variants (primarily related to insulin resistance) or rare variants (primarily related to β-cell dysfunction). These data paint a picture of youth-onset T2D as a disease genetically similar to both monogenic diabetes and adult-onset T2D, in which genetic heterogeneity might be used to sub-classify patients for different treatment strategies.


Soluble epoxide hydrolase homologs in Strongylocentrotus purpuratus suggest a gene duplication event and subsequent divergence.
The mammalian soluble epoxide hydrolase (sEH) is a multidomain enzyme composed of C- and N-terminal regions that contain active sites for epoxide hydrolase (EH) and phosphatase activities, respectively. We report the cloning of two 60 kDa multidomain enzymes from the purple sea urchin Strongylocentrotus purpuratus displaying significant sequence similarity to both the N- and C-terminal domains of the mammalian sEH. While one urchin enzyme did not exhibit EH activity, the second enzyme hydrolyzed several lipid messenger molecules metabolized by the mammalian sEH, including the epoxyeicosatrienoic acids. Neither of the urchin enzymes displayed phosphatase activity. The urchin EH was inhibited by small molecule inhibitors of the mammalian sEH and is the likely ancestor of the enzyme. Sequence comparisons suggest that the urchin sEH homologs are the result of a gene fusion event between a gene encoding for an EH and a gene for an enzyme of undetermined function. This fusion event was followed by a duplication event to produce the urchin enzymes.


Reduction of Recurrence Risk of Pancreatitis in Cystic Fibrosis With Ivacaftor: Case Series.
The effect of ivacaftor in patients with cystic fibrosis (CF) with recurrent pancreatitis is unknown. We conducted a multicenter retrospective study of patients with CF taking ivacaftor who had a history of recurrent pancreatitis. During the first 3 months of therapy, only 1 of the 6 patients had an episode of pancreatitis, which was managed on an outpatient basis. Between 3 and 12 months on ivacaftor therapy, none of the patients had recurrence of pancreatitis or required hospitalization. The use of ivacaftor was associated with a reduced frequency and recurrence rate of pancreatitis in patients with CF.


Urinary albumin excretion in pregnancy.
Urinary albumin excretion during pregnancy has been studied using a sensitive radioimmunoassay. One hundred pregnant women attending a high-risk antenatal clinic and 14 normal pregnant women were investigated serially, during pregnancy and post-partum. The normal subjects showed a small but significant rise in albumin excretion in the third trimester, which was sustained pre-delivery and in the first postnatal week. Twenty-six women were classified as having mild pre-eclampsia and 44 as having chronic hypertension without evidence of superimposed pre-eclampsia. In neither group was there evidence of proteinuria by conventional testing, nor was the median albumin excretion different from normal antenatally; in the first week after delivery a significant increase was observed, but this regressed to normal 6 weeks later. Eight patients developed severe pre-eclampsia, of whom one had evidence of underlying renal disease. Three presented with proteinuria already established. In the remaining five patients, the shift from normal to high albumin excretion occurred rapidly, usually preceded by a rise in uric acid and a decrease in the platelet count. These data suggest that proteinuric pre-eclampsia, as defined by relatively insensitive routine laboratory measurement, is not preceded by a phase of increasing albumin loss which can be detected by more sensitive assays.