Antiplatelet activity of soy sauce as functional seasoning.
In seeking the functionality of foodstuffs applicable to medicine, soy sauce was found to show antiplatelet activity. Therefore, the active components in soy sauce were purified, structurally identified, and studied for their inhibitory effects on the aggregation of human platelets. Aqueous 2-fold diluents of soy sauce inhibited platelet aggregation induced by collagen and epinephrine depending on the dilution factor. Since a basic extract with diethyl ether completely inhibited collagen-induced aggregation, it was subjected to serial extractions and multistep HPLC fractionations for purifying antiplatelet components. The finally obtained isolates were identified as 1-methyl-1,2,3,4-tetrahydro-beta-carboline and 1-methyl-beta-carboline on the basis of EI-MS, (1)H NMR, diode array, and fluorescence spectra. Their spectral data and chromatographic behaviors were the same as those of synthetic ones. 1-Methyl-1,2,3, 4-tetrahydro-beta-carboline showed mean concentrations (n = 5-6) of 4.6, 4.2, 28.6, 11.6, and 65.8 microgram/mL to produce 50% inhibition of the maximal aggregation response induced by epinephrine, platelet-activating factor, collagen, adenosine 5'-diphosphate, and thrombin, respectively. Its inhibitory effect was much greater than that of 1-methyl-beta-carboline on platelet aggregation by all the tested inducers. The quantitative HPLC analysis revealed that the significant amounts of both antiplatelet compounds were uniformly contained in commercially available soy sauce. From these results, soy sauce may be referred to as functional seasoning containing alkaloidal components with the potent preventive effect on thrombus formation.


Correlations between monthly enhanced MRI lesion rate and changes in T2 lesion volume in multiple sclerosis.
Magnetic resonance imaging (MRI) provides a powerful tool for assessing disease activity in multiple sclerosis (MS), and its role as a surrogate marker for monitoring treatment efficacy is now becoming established. The most commonly used MRI parameters in treatment trials are (1) monthly gadolinium-enhanced MRI, with the number of active lesions serving as the outcome measure, and (2) annual lesion load quantification, in which change in MS lesion volume provides the MRI endpoint. We evaluated clinical/MRI correlations and the relationship between these two markers of disease activity in 73 patients with clinically definite MS. Quantification of T2 lesion load was performed at study entry and exit, with a median study duration of 11 months (range, 9 to 14 months). Monthly postgadolinium T1-weighted images were acquired between these time points. Lesion load at study entry was significantly correlated with the baseline Expanded Disability Status Scale (EDSS) score, but no significant longitudinal correlation was demonstrated. The number of enhancing lesions on the entry scan was predictive of subsequent relapse rate over the study duration and also correlated with the subsequent enhancing lesion activity over the study period. A significant correlation was found between change in lesion load and disease activity on the monthly scans. Our results suggest that annual lesion load quantification provides an efficient measure of ongoing disease activity, and this supports its application as a surrogate marker of disease evolution in phase III treatment trials.


Pregnancy and Zika: The Quest for Quality Care and Reproductive Justice.
On February 1, 2016, the World Health Organization (WHO) declared the ZIKV virus outbreak a Public Health Emergency of International Concern (PHEIC). Pregnant women and their infants, are vulnerable to the impact of this vector-borne illness (mosquito) and sexually transmitted viral infection. The uncertainty surrounding the possibility of congenital anomalies due to ZIKV infection during pregnancy bring a renewed debate about the rights of women to control their reproductive decisions. Current strategies, resources and services aimed at prevention priorities fall short of responding to a clear framework regarding sexual reproductive health, rights and justice. A comprehensive approach to reproduction, in times of Zika, needs to empower women of reproductive age and their families to make decisions and to act on those decisions. This paper highlights the contributions of the Maternal-Infant Studies Center (CEMI-Spanish Acronym) in close collaboration with the Department of Obstetrics and Gynecology of the University of the Puerto Rico School of Medicine and the University Hospital in providing comprehensive health care to pregnant women with ZIKV or at risk of ZIKV, at the very onset of the epidemic. CEMI approaches the care of pregnant women from a reproductive justice perspective, integrating clinical services, education, research, and advocacy. Transformación Prenatal (Centering Group Prenatal Care, GPC) currently implemented at the Puerto Rico University Hospital High Risk Clinics has been pivotal to achieve this aim. Based on the health professionals' experiences and women's testimonies, we articulate a set of principles and key actions that would benefit women, their family and children.


A novel HIV-1 gp41 tripartite model for rational design of HIV-1 fusion inhibitors with improved antiviral activity.
During HIV-1 fusion process, the N-terminal heptad repeat (NHR) of the HIV-1 glycoprotein 41 (gp41) interacts with the C-terminal heptad repeat (CHR) to form the fusion active six-helix bundle, thus being an effective target for the design of CHR peptide-based HIV-1 fusion inhibitors. To overcome the limitations of the simplified helix wheel model of six-helix bundle, we herein developed a novel HIV-1 gp41 NHR-CHR-NHR tripartite model for the rational design of HIV-1 fusion inhibitors with improved antiviral activities. Based on the crystal structure of six-helix bundle, we evaluated the NHR-binding properties of each residue in CHR. In this new tripartite model, CHR residues were divided into three groups: major binding, nonbinding, and assistant binding sites. Eight CHR peptides were designed and synthesized to confirm the validity of the tripartite model. Their affinities to NHR and inhibitory activities were analyzed. In this tripartite model, replacements in assistant binding sites either increased or decreased the inhibition of HIV-1 infection. We identified three peptides with mutations of the residues in CHR at the assistant binding sites in our tripartite model but nonbinding sites in the helical wheel model. These mutant peptides had anti-HIV-1 activity up to 26-fold more potent than that of C34, a CHR peptide designed on the basis of the helix wheel model. These data verified the superiority and validity of our new tripartite model for the rational design of HIV-1 fusion inhibitors. This approach can be adapted for designing viral fusion inhibitors against other enveloped viruses with class I membrane fusion protein.


Potential costs of inappropriate use of proton pump inhibitors.
Proton pump inhibitors (PPIs) are commonly overused in hospitalized patients. The objectives of this study were to determine the extent of their inappropriate initiation in patients with low risk for gastrointestinal hemorrhage, factors associated with their continuation on discharge and potential cost of this trend. Retrospective examination of patients with low risk for gastrointestinal hemorrhage admitted to a tertiary-care teaching hospital over a 3-month period who received esomeprazole. The following information was collected: age, gender, PPI status (de novo or continued) and admitting diagnoses. Additional information collected from the de novo subgroup included indication for PPI, number of days on PPI and continuation of the drug on discharge. The cost of the medication was obtained from pharmacy records. Four hundred nine patients were admitted during the study period and 204 (49.9%) received PPI de novo. Among these, 155 patients (76%) had an inappropriate indication for PPI. Of these, 62 (40%) patients were continued on PPI on discharge. Older age was a significant predictor of continuation of PPI at discharge. The estimated cost of the inpatient and outpatient inappropriate use of PPI was $12,272 and $59,272, respectively. PPIs are overused in the majority of hospitalized patients with low risk for gastrointestinal bleeding and this practice gets perpetuated at discharge, especially in older patients. The cost of this phenomenon is alarming.


Met receptors induce Sam68-dependent cell migration by activation of alternate extracellular signal-regulated kinase family members.
The hepatocyte growth factor (HGF)/Met receptor signaling pathway is deregulated in diverse human malignancies and plays a central role in oncogenesis, tumor progression, and invasive cancer growth. Similarly, altered expression and splicing (i.e. inclusion of variant exon 5, "v5") of the cell adhesion marker, CD44, is associated with advanced cancer phenotypes. We sought to further understand how HGF regulates CD44v5 expression. Immortalized nontumorigenic keratinocyte (HaCaT) cells abundantly express both Met receptors and CD44v5 transmembrane glycoproteins. HGF stimulated CD44v5 protein expression and HaCaT cell migration; these events required activation of the ERK1/2 MAPK module and Sam68, a protein involved in RNA processing, splicing, and v5 inclusion. Similar to HaCaT cells, highly migratory MDA-MB-231 breast cancer cells also required Sam68 expression for HGF-induced migration. However, MDA-MB-231 cell migration occurred independently of ERK1/2 and CD44v5 expression and instead required ERK5 signaling to Sam68. Phospho-mutant, but not WT-Sam68, blocked HGF-induced cell migration in both cell types; MDA-MB-435 cells behaved similarly. These results suggest that Sam68 acts as a convergence point for ERK signaling to cell migration; blockade of phospho-Sam68 may provide a new avenue for therapeutic inhibition of metastatic cancers.


Development of a novel liquid crystal based cell traction force transducer system.
Keratinocyte traction forces play a crucial role in wound healing. The aim of this study was to develop a novel cell traction force (CTF) transducer system based on cholesteryl ester liquid crystals (LC). Keratinocytes cultured on LC induced linear and isolated deformation lines in the LC surface. As suggested by the fluorescence staining, the deformation lines appeared to correlate with the forces generated by the contraction of circumferential actin filaments which were transmitted to the LC surface via the focal adhesions. Due to the linear viscoelastic behavior of the LC, Hooke's equation was used to quantify the CTFs by associating Young's modulus of LC to the cell induced stresses and biaxial strain in forming the LC deformation. Young's modulus of the LC was profiled by using spherical indentation and determined at approximately 87.1±17.2kPa. A new technique involving cytochalasin-B treatment was used to disrupt the intracellular force generating actin fibers, and consequently the biaxial strain in the LC induced by the cells was determined. Due to the improved sensitivity and spatial resolution (∼1μm) of the LC based CTF transducer, a wide range of CTFs was determined (10-120nN). These were found to be linearly proportional to the length of the deformations. The linear relationship of CTF-deformations was then applied in a bespoke CTF mapping software to estimate CTFs and to map CTF fields. The generated CTF map highlighted distinct distributions and different magnitude of CTFs were revealed for polarized and non-polarized keratinocytes.


Genetically informed ecological niche models improve climate change predictions.
We examined the hypothesis that ecological niche models (ENMs) more accurately predict species distributions when they incorporate information on population genetic structure, and concomitantly, local adaptation. Local adaptation is common in species that span a range of environmental gradients (e.g., soils and climate). Moreover, common garden studies have demonstrated a covariance between neutral markers and functional traits associated with a species' ability to adapt to environmental change. We therefore predicted that genetically distinct populations would respond differently to climate change, resulting in predicted distributions with little overlap. To test whether genetic information improves our ability to predict a species' niche space, we created genetically informed ecological niche models (gENMs) using Populus fremontii (Salicaceae), a widespread tree species in which prior common garden experiments demonstrate strong evidence for local adaptation. Four major findings emerged: (i) gENMs predicted population occurrences with up to 12-fold greater accuracy than models without genetic information; (ii) tests of niche similarity revealed that three ecotypes, identified on the basis of neutral genetic markers and locally adapted populations, are associated with differences in climate; (iii) our forecasts indicate that ongoing climate change will likely shift these ecotypes further apart in geographic space, resulting in greater niche divergence; (iv) ecotypes that currently exhibit the largest geographic distribution and niche breadth appear to be buffered the most from climate change. As diverse agents of selection shape genetic variability and structure within species, we argue that gENMs will lead to more accurate predictions of species distributions under climate change.


Cancer risk after cyclophosphamide treatment in idiopathic membranous nephropathy.
Cyclophosphamide treatment improves renal survival in patients with idiopathic membranous nephropathy. However, use of cyclophosphamide is associated with cancer. The incidence of malignancies in patients with idiopathic membranous nephropathy was evaluated, and the cancer risk associated with cyclophosphamide use was estimated. Patients who attended the clinic were included prospectively from 1995 on. A crude incidence ratio for the occurrence of malignancy was calculated. Incidence ratios were subsequently standardized to potential confounders. Latency between cyclophosphamide therapy and the occurrence of cancer was estimated by stratifying for time since the start of treatment. Finally, Poisson regression was used to obtain a multiple adjusted incidence ratio and investigate the dose-response relationship between cyclophosphamide and cancer. Data were available for 272 patients; the mean age was 51 years, and 70% of the patients were men. Median follow-up was 6.0 years (interquartile range=3.6-9.5), and 127 patients were treated with cyclophosphamide. Cancer incidence was 21.2 per 1000 person-years in treated patients compared with 4.6 per 1000 person-years in patients who did not receive cyclophosphamide, resulting in crude and adjusted incidence ratios of 4.6 (95% confidence interval, 1.5 to 18.8) and 3.2 (95% confidence interval, 1.0 to 9.5), respectively. Cyclophosphamide therapy in idiopathic membranous nephropathy gives a threefold increase in cancer risk. For the average patient, this finding translates into an increase in annual risk from approximately 0.3% to 1.0%. The increased risk of malignancy must be balanced against the improved renal survival.


Predictability as a personality trait: consistent differences in intraindividual behavioral variation.
Although animal behavior is generally repeatable, most behavioral variation apparently occurs within rather than across individuals. With the exception of very recent interest in individual behavioral plasticity (consistent differences in responsiveness), this within-individual variation has been largely ignored despite its importance in the study of proximate and ultimate questions about behavior. Here, we repeatedly scored the undisturbed activity of 30 adult male mosquitofish across multiple observation bouts spanning 132 days ([Formula: see text] observations per fish). We found that the behavior of some individuals was consistently more predictable in a given context than others. Repeatability for this "intraindividual variation" (IIV; [Formula: see text]) was evident after accounting for individual differences in activity trends across days, and activity responses due to fine-scale temperature variation (i.e., individual plasticity in response to both variables). To our knowledge, this is the first evidence that predictability of behavior is a repeatable characteristic of individual animals. We suggest that IIV represents an important axis of consistent behavioral variation that has previously not been formally considered. Finally, individual differences in predictability may similarly exist for labile morphological and physiological traits but have seemingly not been studied.


Chondromyxoid fibroma of bone. An electron microscopic observation.
A resected case of chondromyxoid fibroma of the right fibula in a 31-year-old male is presented. The histology was composed of characteristic lobular features of this tumor with abundant cartilaginous matrix. The ultrastructural study exhibited stellate, ovoid or elongated tumor cells with features of cartilage cells and abundant loose matrix with many fine filamentous structures. The nuclei were often of peculiarly indented contour and revealed thick fibrous lamina. The villous cell processes and intracytoplasmic fine filaments were prominent. No cells suggesting a fibroblast were recognized in this study. From the light microscopical and ultrastructural findings of this case, it is supported that this tumor might be derived from adult cartilage cells most likely related to the epiphyseal cartilage rather than fibroblasts.


The oxidative dealkylation of insecticidal phosphoric acid triesters by mammalian liver enzymes.
1. The dealkylation of the insecticidal phosphoric acid triester, 2-chloro-1-(2,4-dichlorophenyl)vinyl diethyl phosphate, proceeds in mammalian liver slices via an oxidative mechanism and not by hydrolysis. 2. The enzyme that catalyses the reaction is located in the microsomal fraction of liver homogenate and is dependent for activity on molecular oxygen and NADPH. 3. There are large species differences between rat, mouse, rabbit and dog in the activity of the enzymes, the relative rates of dealkylation being 1, 8, 24 and 88 respectively in liver slices. 4. Dimethyl and di-isopropyl phosphate triesters are also dealkylated by rabbit liver microsomal preparations. 5. The mechanism of dealkylation involves hydroxylation at the alpha-carbon atom of an alkyl group, which is removed as the corresponding aldehyde, and is thus analogous to that of similar reactions catalysed by the microsomal mixed-function oxidases. 6. The relevance of these findings in the toxicology of phosphoric acid triesters is discussed.


Expression and immune function of tenascin-C.
Our immune system is designed to protect us from danger. Upon pathogen invasion and tissue injury, activation of both innate and adaptive immunity enables us to combat infection and to repair tissue damage. Tenascin-C is a large, extracellular matrix glycoprotein that has a very tightly controlled pattern of expression. Little or no tenascin-C is expressed in most healthy adult tissues; however, it is rapidly and transiently induced at sites of tissue injury and infection. Persistent tenascin-C expression is associated with pathologies such as chronic, non-healing wounds, autoimmune diseases, cancer, and fibrotic diseases. We discuss the myriad roles that this multifunctional molecule plays during the immune response, with a focus on how tissue levels of tenascin-C are regulated and the consequences of misregulated tenascin-C expression in immune regulated disease pathogenesis.


Is extracellular calcium required for insulin action?
Isolated hepatocytes and isolated adipocytes incubated in the absence of added calcium ions respond to insulin with a decrease in tissue cyclic AMP levels, and an increase in low Km phosphodiesterase activity. Isolated hepatocytes also showed a diminution of glucagon stimulated glucose output in response to insulin, while adipocytes responded with increased rates of glucose oxidation, lipid synthesis and decreased glycerol output. These responses to insulin are the same as those seen when the cells are incubated in buffers containing physiological concentrations of calcium ions. When extracellular concentrations of calcium ions were made extremely low by using either gelatine or albumin which had been pretreated to remove calcium, and/or the incubation buffers contained EGTA, both the hepatocytes and adipocytes continued to respond to insulin. These results suggest that extracellular calcium ions are not required for insulin action.


Zoledronic acid slows down rat primary chondrosarcoma development, recurrent tumor progression after intralesional curretage and increases overall survival.
Chondrosarcoma is a difficult musculoskeletal tumor to treat. Surgical treatment leads to severe disability, with high rates of local recurrence and life threat. No adjuvant therapy is effective in differentiated chondrosarcomas. Bisphosphonates (BPs) are a class of molecules which is effective in malignant bone diseases. The aim of the present study was to determine the effects of zoledronic acid (ZOL) on chondrosarcoma tumor progression. ZOL was tested in vivo (s.c. 100 microg/kg, twice a week) in a rat chondrosarcoma model and in vitro (10(-7)-10(-4) M) on cells derived from this model. Two types of animal models were assessed, the first simulated development after intralesional curettage, the second nonoperative development of the tumor. Cell proliferation, caspase-1, -3 activities and cell cycle analysis were studied. The results revealed that ZOL slows down primary tumor development, tumor progression after intralesional curretage and increases overall survival. ZOL inhibits cell proliferation and increases cell death, with no significant variation of caspase-1 and -3 activities and cell cycle profiles. The present study demonstrates for the first time that in addition to surgery, the therapy of chondrosarcoma with BPs might be beneficial. Because of these first results, new therapeutic approaches of chondrosarcoma must be considered, mainly for low grade chondrosarcoma when disabling operation is planned and when only intralesional resection can be undertaken.


An evaluation of preceptors' perceptions of educational preparation and organizational support for their role.
This longitudinal, descriptive study evaluated nurse preceptors' perceptions of a 2-day educational workshop and subsequent organizational support offered to prepare them for their roles as preceptors. Thirty-six registered nurses who attended preceptor workshops and then acted as preceptors participated in focus groups or interviews 2 to 3 months and 6 to 9 months after their educational preparation to identify the usefulness of the preparation, the subsequent support by management, and the potential changes in their perceptions. Respondents identified intrinsic rewards and opportunities for growth for nurses who take on the preceptor role. However, adequate preparation and organizational support are essential to effectively perform their duties as clinicians and preceptors. Although a 2-day educational preparation program was perceived as adequate, the practice setting must be reorganized to provide greater support for preceptors. Preceptors should be supported by providing continuing education, effective scheduling, and adequate time for learning and feedback in the clinical environment.


Intravenous Vitamin C for Patients Hospitalized With COVID-19: Two Harmonized Randomized Clinical Trials.
The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain. To determine whether vitamin C improves outcomes for patients with COVID-19. Two prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents. Patients were randomized to receive vitamin C administered intravenously or control (placebo or no vitamin C) every 6 hours for 96 hours (maximum of 16 doses). The primary outcome was a composite of organ support-free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from -1 organ support-free days for patients experiencing in-hospital death to 22 organ support-free days for those who survived without needing organ support. The primary analysis used a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented efficacy (improved survival, more organ support-free days, or both), an OR less than 1 represented harm, and an OR less than 1.2 represented futility. Enrollment was terminated after statistical triggers for harm and futility were met. The trials had primary outcome data for 1568 critically ill patients (1037 in the vitamin C group and 531 in the control group; median age, 60 years [IQR, 50-70 years]; 35.9% were female) and 1022 patients who were not critically ill (456 in the vitamin C group and 566 in the control group; median age, 62 years [IQR, 51-72 years]; 39.6% were female). Among critically ill patients, the median number of organ support-free days was 7 (IQR, -1 to 17 days) for the vitamin C group vs 10 (IQR, -1 to 17 days) for the control group (adjusted proportional OR, 0.88 [95% credible interval {CrI}, 0.73 to 1.06]) and the posterior probabilities were 8.6% (efficacy), 91.4% (harm), and 99.9% (futility). Among patients who were not critically ill, the median number of organ support-free days was 22 (IQR, 18 to 22 days) for the vitamin C group vs 22 (IQR, 21 to 22 days) for the control group (adjusted proportional OR, 0.80 [95% CrI, 0.60 to 1.01]) and the posterior probabilities were 2.9% (efficacy), 97.1% (harm), and greater than 99.9% (futility). Among critically ill patients, survival to hospital discharge was 61.9% (642/1037) for the vitamin C group vs 64.6% (343/531) for the control group (adjusted OR, 0.92 [95% CrI, 0.73 to 1.17]) and the posterior probability was 24.0% for efficacy. Among patients who were not critically ill, survival to hospital discharge was 85.1% (388/456) for the vitamin C group vs 86.6% (490/566) for the control group (adjusted OR, 0.86 [95% CrI, 0.61 to 1.17]) and the posterior probability was 17.8% for efficacy. In hospitalized patients with COVID-19, vitamin C had low probability of improving the primary composite outcome of organ support-free days and hospital survival. ClinicalTrials.gov Identifiers: NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP).


Variability in Psychiatric Facility Seclusion and Restraint Rates as Reported on Hospital Compare Site.
This study examined variability among U.S. hospitals in rates of seclusion and physical restraint, including the effects of hospital type and ownership, as reported on Hospital Compare. Broader aims were to highlight the wide variability in use of these measures, the need for improved data reporting, and the data source itself, which deserves further development and more attention from regulatory agencies, researchers, and others. Facility-level data from Hospital Compare for 2013-2017 were analyzed. Rates of seclusion and restraint were computed by aggregating across study years and compared by hospital type and ownership. Rates were also examined by year. Data cleaning revealed hundreds of errors. The final sample comprised 7,416 seclusion rates and 7,398 restraint rates from 1,642 hospitals. For both acute care and psychiatric hospitals, marked differences were noted in seclusion and restraint rates above the median, with for-profit hospitals reporting markedly lower rates compared with government and nonprofit hospitals. Rates above the median declined substantially during the study period. Although 67% of hospitals reported comparably low rates of seclusion (≤0.09 hours per 1,000 patient-hours) and restraint (≤0.15 hours per 1,000 patient-hours), 10% of hospitals reported rates at least five to 10 times higher. Despite some progress, many hospitals continue to report very high rates of seclusion and restraint. It is unlikely that this variability can be fully accounted for by patient-level factors. Centers for Medicare and Medicaid Services data reporting should be expanded to include frequency of seclusion and restraint use and duration of episodes.


Role of diamine oxidase during the treatment of tumour-bearing mice with combinations of polyamine anti-metabolites.
Treatment of mice bearing L1210 leukaemia with 2-difluoromethylornithine, a specific inhibitor of ornithine decarboxylase (EC 126.96.36.199), produced a profound depletion of putrescine and spermidine in the tumour cells. Sequential combination of methylglyoxal bis(guanylhydrazone), an inhibitor of adenosylmethionine decarboxylase (EC 220.127.116.11), with difluoromethylornithine largely reversed the polyamine depletion and led to a marked accumulation of cadaverine in the tumour cells. Experiments carried out with the combination of difluoromethylornithine and aminoguanidine, a potent inhibitor of diamine oxidase (EC 184.108.40.206), indicated that the methylglyoxal bis(guanylhydrazone)-induced reversal of polyamine depletion was mediated by the known inhibition of diamine oxidase by the diguanidine. In spite of the normalization of the tumour cell polyamine pattern upon administration of methylglyoxal bis(guanylhydrazone) to difluoromethylornithine-treated animals, the combination of these two drugs produced a growth-inhibitory effect not achievable with either of the compounds alone.


EXTERNAL PRINGLE MANEUVER IN LAPAROSCOPIC LIVER RESECTION: A SAFE, CHEAP AND REPRODUCIBLE WAY TO PERFORM IT.
Tourniquet for right hepatectomy tightened and secured with forceps (arrow). Laparoscopic liver resection is performed worldwide. Hemorrhage is a major complication and bleeding control during hepatotomy is an important concern. Pringle maneuver remains the standard inflow occlusion technique. Describe an extracorporeal, efficient, fast, cheap and reproducible way to execute the Pringle maneuver in laparoscopic surgery, using a chest tube. From January 2014 to March 2020, our team performed 398 hepatectomies, 63 by laparoscopy. We systematically encircle the hepatoduodenal ligament and prepare a tourniquet to perform Pringle maneuver. In laparoscopy, we use a 24 Fr chest tube, which is inserted in the abdominal cavity through a small incision. We thread the cotton tape through the tube, pulling it out through the external end, outside the abdomen. To perform the tourniquet, we just need to push the tube as we hold the tape, clamping both with one forceps. The 24 Fr chest tube is firm and works perfectly to occlude blood inflow as the cotton band is tightened. It has an internal diameter of 5,5 mm, sufficient for a laparoscopic grasper pass through it to catch the cotton band, and an external diameter of 8 mm, which allows to be inserted in the abdomen through a tiny incision. The cost of this tube and the cotton band is less than US$ 1. No complications related to the method were identified in our patients. The extracorporeal Pringle maneuver presented here is a safe, cheap and reproducible method, that can be used for bleeding control in laparoscopic liver surgery.


Renal cell tumors with an entrapped papillary component: a collision with predilection for oncocytic tumors.
Renal cell tumors with mixed morphology resembling multiple renal cell carcinoma (RCC) subtypes are generally regarded as unclassified RCC. However, occasionally, papillary adenoma or RCC appears admixed with a larger, different tumor histology. We retrieved 17 renal tumors containing a papillary adenoma or papillary RCC component admixed with another tumor histology and studied them with immunohistochemistry and fluorescence in situ hybridization (FISH). Larger tumors were oncocytomas (n = 10), chromophobe RCCs (n = 5), borderline oncocytic tumor (n = 1), and clear cell RCC (n = 1). The size of papillary component ranged from 1 to 34 mm. One tumor was an oncocytoma encircled by a cyst (2.0 cm) with papillary hyperplasia of the lining. The papillary lesions were diffusely cytokeratin 7 positive (17/17), in contrast to "host" tumors. Alpha-methylacyl-coA-racemase labeling was usually stronger in the papillary lesions (13/15). KIT was negative in all papillary lesions and the clear cell RCC and positive in 16/16 oncocytic or chromophobe tumors. Eight of 15 (53%) collision tumors had differing FISH results in the two components. A papillary renal cell proliferation within another tumor is an uncommon phenomenon with predilection for oncocytoma and chromophobe RCC, possibly related to their common entrapment of benign tubules. When supported by distinct morphology and immunohistochemistry in these two components, this phenomenon should be diagnosed as a collision of two processes. A diagnosis of unclassified RCC should be avoided, due to potential misrepresentation as an aggressive renal cancer.


Effects of different angiotensin-converting enzyme (ACE) inhibitors on ischemic isolated rat hearts: relationship between cardiac ACE inhibition and cardioprotection.
We determined the relationship between cardiac angiotensin-converting enzyme (ACE) inhibition and anti-ischemic efficacy of several structurally different ACE inhibitors or their prodrug esters perfused through the isolated rat heart. Seven ACE inhibitors inhibited cardiac ACE to varying degrees due to differences in uptake during perfusion through nonischemic rat hearts. Zofenopril-sulfhydryl and fosinoprilic acid were the most effective of the free inhibitors. Among the prodrugs, zofenopril and S-benzoylcaptopril, hydrolyzed rapidly by cardiac esterase, were more effective than their component ACE-inhibitors, whereas fosinopril, ramipril and enalapril were poorly active. For studies in ischemic rat hearts, vehicle or drug treatment was initiated 10 min before a 25-min period of global ischemia and during a 30-min reperfusion period. Of five unesterified ACE inhibitors studied for anti-ischemic activity, only captopril and zofenopril-sulfhydryl were found to improve postischemic contractile function and reduce cell death in the isolated rat hearts. Fosinoprilic acid, ramiprilat and enalaprilat were not cardioprotective at high perfusion concentrations, despite the fact that nearly complete inhibition of cardiac ACE was achieved with all of the compounds studied. The S-benzoyl prodrugs of zofenopril-sulfhydryl and captopril were at least as potent as their component ACE inhibitors in reducing ischemic-reperfusion damage in the same model. Neither zofenopril nor captopril, however, had any effect on coronary flow before or after ischemia. Thus, it appears that the cardioprotective effects of zofenopril and captopril are independent of cardiac ACE inhibition or, at least, that ACE inhibition alone is not sufficient. Both captopril and zofenopril are sulfhydryl-containing compounds whereas the inactive compounds are not; and, thus, this group appears to be important in mediating their cardioprotective actions.


Possible involvement of P2Y2 metabotropic receptors in ATP-induced transient receptor potential vanilloid receptor 1-mediated thermal hypersensitivity.
The capsaicin receptor transient receptor potential V1 (TRPV1; also known as vanilloid receptor 1) is a sensory neuron-specific ion channel that serves as a polymodal detector of pain-producing chemical and physical stimuli. It has been reported that extracellular ATP potentiates the TRPV1 currents evoked by capsaicin or protons and reduces the temperature threshold for its activation through metabotropic P2Y receptors in a PKC-dependent pathway, suggesting that TRPV1 activation could trigger the sensation of pain at normal body temperature in the presence of ATP. Here, we show that ATP-induced thermal hyperalgesia was abolished in mice lacking TRPV1, suggesting the functional interaction between ATP and TRPV1 at a behavioral level. However, thermal hyperalgesia was preserved in P2Y1 receptor-deficient mice. Patch-clamp analyses using mouse dorsal root ganglion neurons indicated the involvement of P2Y2 rather than P2Y1 receptors. Coexpression of TRPV1 mRNA with P2Y2 mRNA, but not P2Y1 mRNA, was determined in the rat lumbar DRG using in situ hybridization histochemistry. These data indicate the importance of metabotropic P2Y2 receptors in nociception through TRPV1.


3D Printing of Thermal Insulating Polyimide/Cellulose Nanocrystal Composite Aerogels with Low Dimensional Shrinkage.
Polyimide (PI)-based aerogels have been widely applied to aviation, automobiles, and thermal insulation because of their high porosity, low density, and excellent thermal insulating ability. However, the fabrication of PI aerogels is still restricted to the traditional molding process, and it is often challenging to prepare high-performance PI aerogels with complex 3D structures. Interestingly, renewable nanomaterials such as cellulose nanocrystals (CNCs) may provide a unique approach for 3D printing, mechanical reinforcement, and shape fidelity of the PI aerogels. Herein, we proposed a facile water-based 3D printable ink with sustainable nanofillers, cellulose nanocrystals (CNCs). Polyamic acid was first mixed with triethylamine to form an aqueous solution of polyamic acid ammonium salts (PAAS). CNCs were then dispersed in the aqueous PAAS solution to form a reversible physical network for direct ink writing (DIW). Further freeze-drying and thermal imidization produced porous PI/CNC composite aerogels with increased mechanical strength. The concentration of CNCs needed for DIW was reduced in the presence of PAAS, potentially because of the depletion effect of the polymer solution. Further analysis suggested that the physical network of CNCs lowered the shrinkage of aerogels during preparation and improved the shape-fidelity of the PI/CNC composite aerogels. In addition, the composite aerogels retained low thermal conductivity and may be used as heat management materials. Overall, our approach successfully utilized CNCs as rheological modifiers and reinforcement to 3D print strong PI/CNC composite aerogels for advanced thermal regulation.


Epithelial to mesenchymal transition in an epidermal growth factor receptor-mutant lung cancer cell line with acquired resistance to erlotinib.
Mesenchymal status is related to "inherent resistance" to gefitinib or erlotinib in non-small cell lung cancer without epidermal growth factor receptor(EGFR) mutations. In addition, a recent report showed that the epithelial to mesenchymal transition (EMT) plays a role in acquired resistance to gefitinib in A549 cells, which harbor a KRAS mutation. However, recent clinical studies revealed that gefitinib or erlotinib are highly effective in the treatment of non-small cell lung cancer with EGFR mutations. We developed resistant cells (HCC4006ER) from erlotinib-sensitive HCC4006 cells harboring an EGFR deletion mutation by chronic exposure to increasing concentrations of erlotinib. Acquired resistance mechanisms of HCC4006ER cells were analyzed. Neither known resistance mechanisms nor novel molecules that may confer erlotinib resistance were identified using candidate or comprehensive analyses. In addition, HCC4006ER cells lost dependency for EGFR. However, we found that HCC4006ER cells acquired a mesenchymal phenotype and exhibited down-regulation of E-cadherin expression (2.7 × 10 times compared with parental cells). We also found that the histone deacetylase inhibitor, MS-275, restored E-cadherin expression and moderate sensitivity to erlotinib in HCC4006ER cells, on the other hand, transforming growth factor beta, an inducer of EMT, led to moderate erlotinib resistance in HCC4006 parental cells. This is the first report of a relationship between EMT and erlotinib acquired resistance in an erlotinib sensitive EGFR-mutant lung cancer cell line. Our results indicate that it would be important to consider the influence of EMT in the development of treatments against acquired resistance to gefitinib or erlotinib.


[Exploration of pathogenesis-associated molecules and development of disease models for sporadic ALS].
The mechanism underlying the characteristic selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) has remained elusive. Modest advances in this research field have been achieved by the identification of copper/zinc superoxide dismutase 1 (SOD1) as one of the causative genes for rare familial ALS and by the development and analysis of mutant SOD1 transgenic animal models. However, in sporadic ALS (SALS) with many more patients, causative or critical genes situated upstream of the disease pathway have not yet been elucidated and no available disease models have been established. We have been working on screening these genes employing and combining several new technologies such as cDNA microarray, molecular indexing, and laser capture microdissection. Many of the resultant genes are of intense interest and may provide a powerful tool for determining the molecular mechanisms of SALS. Of these, in this paper, we will focus on Dorfin, a RING finger-type E3 ubiquitin ligase and dynactin1, a major component of dynein/dynactin complex that is important for retrograde axonal transport. We are now challenging creation of the disease models by simulating the gene expression changes specifically observed in SALS patients.


Risk factors for animal-related injury among Iowa large-livestock farmers: a case-control study nested in the Agricultural Health Study.
Although farmers are at risk for injuries from contact with large livestock, few previous studies have examined risk factors for animal-related injuries. This case-control study, nested in the Agricultural Health Study, aimed to assess risk factors for animal-related injury among Iowa large-livestock farmers. A screener questionnaire sent to 6999 farmers identified 116 farmers with large livestock who had an animal-related injury requiring medical advice/treatment in the previous year. Several possible risk factors for injury were assessed by comparing these farmers with 342 farmers who had livestock but were not injured in the previous year. A multiple logistic regression analysis showed significant associations between animal-related injury and the use of a hearing aid (odds ratio [OR] = 5.4 [95% CI, 1.6 to 18.0]), doctor-diagnosed arthritis or rheumatism (OR = 3.0 [95% CI, 1.7 to 5.2]), education beyond high school (OR = 1.8 [95% CI, 1.1 to 2.8]), and a younger age. Farmers engaged in off-farm work were less likely to sustain animal-related injuries (OR = 0.4 [95% CI, 0.2 to 0.8]). This is the first study to show associations between animal-related injury and a younger age, hearing difficulties, and doctor-diagnosed arthritis. Hearing loss and arthritis, which are more common among farmers than among other workers, may be particularly important risk factors to address in future preventive studies.


Mitotic phosphorylation of the dynein light intermediate chain is mediated by cdc2 kinase.
Cytoplasmic dynein, a large minus-end-directed microtubule motor, performs multiple functions during the cell cycle. In interphase, dynein moves membrane organelles, while in mitosis it moves chromosomes and helps to form the mitotic spindle. The cell-cycle regulation of dynein activity may be controlled, at least in part, by the phosphorylation of its light intermediate chains (DLIC), since a 10-fold increase in light intermediate chain phosphorylation correlates with a decrease in dynein-based membrane transport of similar magnitude in mitosis. In this study, we sought to identify the kinase responsible for this potentially important phosphorylation event. We show that bacterially-expressed chicken light intermediate chain (chDLIC) will undergo mitosis-specific phosphorylation when added to Xenopus egg extracts. Mutation of a conserved cdc2 kinase consensus site (Ser197) abolishes this phosphorylation event, and mass spectroscopy analysis confirms that the wild-type DLIC is stoichiometrically phosphorylated at this site when incubated with metaphase but not interphase extracts. We also show that purified cdc2 kinase phosphorylates purified DLICs at Ser197 in vitro and that Ser197 phosphorylation is dramatically reduced in metaphase extracts depleted of cdc2 kinase. These results indicate that cdc2 kinase directly phosphorylates dynein and thus may be an important regulator of dynein activity in the cell cycle.


Effects of intrauterine infusion of Escherichia coli lipopolysaccharide on uterine mRNA gene expression and peripheral polymorphonuclear leukocytes in Jersey cows diagnosed with purulent vaginal discharge.
The objectives of the current experiment were to investigate the effects of intrauterine treatment of cows with purulent vaginal discharge (PVD) using lipopolysaccharide (LPS) from Escherichia coli on uterine mRNA expression of genes related to inflammatory responses, peripheral polymorphonuclear leukocyte (PMN) function, hematological parameters, and blood concentrations of cortisol, haptoglobin, and progesterone (P4). Jersey cows (n = 3,084) were examined for PVD at 35 ± 6 d postpartum using the Metricheck device (Simcro, Hamilton, New Zealand). At examination, 310 cows had PVD (10.1%), but to ensure proper collection and processing of samples, 267 cows were used in this experiment. Cows were balanced for lactation number, body condition score, and milk yield, and randomly assigned to the control treatment [intrauterine infusion of 20 mL of phosphate-buffered saline (PBS); n = 87] or to receive intrauterine infusion of 20 mL of PBS containing 150 µg (LPS150; n = 91) or 300 µg (LPS300; n = 89) of E. coli LPS. Uteri were biopsied in a subgroup of cows at 6 h after infusion and in another subgroup of cows at 24 h after infusion. Peripheral PMN expression of adhesion molecules (L-selectin and MAC-1) and phagocytosis and oxidative burst were evaluated at 0, 2, and 6 h after infusion. Blood sampled 0, 2, 6, 24, 48, and 168 h after infusion was used for complete hemogram and to determine concentrations of cortisol, haptoglobin, and P4. Treatment did not affect uterine mRNA expression of adhesion molecules [endothelial leukocyte adhesion molecule (E-selectin), intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1)], cytokines (tumor necrosis factor-α, IL-1β, IL-6, IL-8, and IL-10), and toll-like receptor-4. Treatment did not affect PMN expression of L-selectin, but intensity of expression of MAC-1 was higher for LPS150 cows than PBS cows, and tended to be higher in LPS150 than LPS300 cows. Furthermore, a greater percentage of PMN from LPS300 cows were positive for phagocytosis and oxidative burst compared with PBS and LPS150 cows. No effects were observed of treatment on hematological parameters and concentrations of cortisol, haptoglobin, and P4. These observations suggest that intrauterine infusion of E. coli LPS moderately stimulates peripheral PMN function, but further research is needed to better understand the immunomodulatory effects of LPS in the uterus of cows with PVD.


Subpicosecond metamagnetic phase transition in FeRh driven by non-equilibrium electron dynamics.
Femtosecond light-induced phase transitions between different macroscopic orders provide the possibility to tune the functional properties of condensed matter on ultrafast timescales. In first-order phase transitions, transient non-equilibrium phases and inherent phase coexistence often preclude non-ambiguous detection of transition precursors and their temporal onset. Here, we present a study combining time-resolved photoelectron spectroscopy and ab-initio electron dynamics calculations elucidating the transient subpicosecond processes governing the photoinduced generation of ferromagnetic order in antiferromagnetic FeRh. The transient photoemission spectra are accounted for by assuming that not only the occupation of electronic states is modified during the photoexcitation process. Instead, the photo-generated non-thermal distribution of electrons modifies the electronic band structure. The ferromagnetic phase of FeRh, characterized by a minority band near the Fermi energy, is established 350 ± 30 fs after the laser excitation. Ab-initio calculations indicate that the phase transition is initiated by a photoinduced Rh-to-Fe charge transfer.


An integrated microfluidic system for isolation, counting, and sorting of hematopoietic stem cells.
This study reports an integrated microfluidic system capable of isolation, counting, and sorting of hematopoietic stem cells (HSCs) from cord blood in an automatic format by utilizing a magnetic-bead-based immunoassay. Three functional modules, including cell isolation, cell counting, and cell sorting modules are integrated on a single chip by using microfluidic technology. The cell isolation module is comprised of a four-membrane-type micromixer for binding of target stem cells and magnetic beads, two pneumatic micropumps for sample transport, and an S-shaped channel for isolation of HSCs using a permanent magnet underneath. The counting and sorting of HSCs are performed by utilizing the cell counting and sorting modules. Experimental results show that a separation efficiency as high as 88% for HSCs from cord blood is achieved within 40 min for a sample volume of 100 mul. Therefore, the development of this integrated microfluidic system may be promising for various applications such as stem cell research and cell therapy.


Immunologic effects of omalizumab in children with severe refractory atopic dermatitis: a randomized, placebo-controlled clinical trial.
Severe refractory atopic dermatitis (AD) is a chronic, debilitating condition that is associated with elevated serum immunoglobulin E (IgE) levels. Thymic stromal lymphopoietin (TSLP), thymus and activation-regulated chemokine (TARC) and OX40 ligand (OX40L) are important immunologic factors involved in the pathogenesis of AD. Omalizumab, an anti-IgE antibody indicated for use in allergic asthma, is implicated in regulating allergen presentation by dendritic cells and the T cell response during the effector phases of allergic disease. We investigated if anti-IgE therapy modulates the allergen-specific responses mediated by the TSLP pathway in young patients with severe refractory AD. This was a randomized, double-blind, placebo-controlled study of 8 patients between the ages of 4 and 22 years (mean = 11.6 years) with severe refractory AD (clinical trials.gov NCT01678092). Serum IgE ranged from 218 to 1,890 (mean = 1,068 IU/ml). Subjects received omalizumab (n = 4) or placebo (n = 4) every 2-4 weeks over 24 weeks using a regimen extrapolated from the package insert. TSLP, TARC, OX40L and other cytokines involved in AD were measured by using cytometric bead arrays. All patients receiving omalizumab had strikingly decreased levels of TSLP, OX40L, TARC (involved in Th2 polarization) and interleukin (IL)-9 compared to placebo. In addition, there was a marked increase in IL-10, a tolerogenic cytokine, in the omalizumab-treated group. Patients on anti-IgE therapy had an improvement in clinical outcomes as measured by the SCORAD system; however, these effects were comparable to improvements in the control group. Anti-IgE therapy with omalizumab decreases levels of cytokines that are involved in Th2 polarization and allergic inflammation, including TSLP, TARC and OX40L.


Immunologic and ionophore-induced generation of leukotriene B4 from mouse bone marrow-derived mast cells.
Mouse bone marrow-derived mast cells differentiated in vitro and sensitized with monoclonal IgE respond to antigen-initiated activation-secretion with the generation of leukotriene B4 (LTB4), a highly potent chemotactic factor. The antigen-initiated net percent release of the secretory granule marker beta-hexosaminidase and the generation of immunoreactive LTB4 and of immunoreactive leukotriene C4 (LTC4) were not diminished by washing the cells before challenge, indicating that interaction of the antigen occurred with the IgE fixed on cell membranes and was not due to phagocytosis of immune complexes formed in the fluid phase. The parallel dose-response relationship for the antigen-induced release of the performed mediator and the generation of both leukotrienes along with the superimposable time courses of their extracellular appearance indicate the origin of these mediators from a common cell type with IgE receptors. Resolution by reverse phase-high performance liquid chromatography (RP-HPLC) of the leukotrienes released from unsensitized cells by ionophore A23187 and from sensitized cells by the specific antigen revealed that the generation of LTB4 was accompanied by the production of the two diastereoisomers of 6-trans-LTB4, which were not immunoreactive. The immunoreactive LTB4 eluted from RP-HPLC at the same retention time as synthetic LTB4 was present in similar nanogram quantities when measured by either radioimmunoassay or integrated absorbance at 269 nm and exhibited a chemotactic activity for human neutrophils on a weight basis comparable to that of synthetic LTB4. The overall recoveries after RP-HPLC of immunoreactive LTB4 released from ionophore A23187-activated, bone marrow-derived mast cells and of added tritiated synthetic LTB4 in separate experiments with ionophore-activated cells were comparable and greater than 78%. The maximum generation of LTB4 by ionophore A23187-activated cells of 7.9 +/- 2.5 ng/10(6) cells (mean +/- SD), occurring at 40 min, was greater than the maximum generation of 4.5 +/- 0.8 ng/10(6) cells, with immunologic stimulation occurring 5 min after antigen challenge of sensitized cells. The initial rate of LTB4 generation after perturbation of the IgE-Fc receptors, however, exceeded that following ionophore A23187 stimulation and may represent one important variable in establishing a significant chemotactic gradient.


Pivotal role of human stearoyl-CoA desaturases (SCD1 and 5) in breast cancer progression: oleic acid-based effect of SCD1 on cell migration and a novel pro-cell survival role for SCD5.
The influence of cell membrane fluidity on cancer progression has been established in different solid tumors. We previously reported that "cancer-associated fibroblasts" (CAFs) induced epithelial-mesenchymal transition and increased cell membrane fluidity and migration in poorly (MCF-7) and highly invasive (MDA-MB-231) breast cancer cells. We also found that the membrane fluidity regulating enzyme stearoyl-CoA desaturase 1 (SCD1) was upregulated in tumor cells co-cultured with CAFs and established its essential role for both intrinsic and CAF-driven tumor cell motility. Here, we further explored the mechanisms involved in the SCD1-based modulation of breast cancer cell migration and investigated the role of the other human SCD isoform, SCD5. We showed that the addition of oleic acid, the main SCD1 product, nullified the inhibitory effects produced on MCF-7 and MDA-MB-231 cell migration by SCD1 depletion (pharmacological or siRNA-based). Conversely, SCD5 seemed not involved in the regulation of cancer cell motility. Interestingly, a clear induction of necrosis was observed as a result of the depletion of SCD5 in MCF-7 cells, where the expression of SCD5 was found to be upregulated by CAFs. The necrotic effect was rescued by a 48-h treatment of cells with oleic acid. These results provide further insights in understanding the role of SCD1 in both intrinsic and CAF-stimulated mammary tumor cell migration, unveiling the metabolic basis of this desaturase-triggered effect. Moreover, our data suggest the ability of CAFs to promote the maintenance of tumor cell survival by the induction of SCD5 levels.


Discrete movements of foot epithelium during adhesive locomotion of a land snail.
During the adhesive locomotion of land snails a series of short dark transverse bands, called pedal or foot waves, is visible ifa moving snail's ventral surface is observed through a sheet of glass. Moreover, the mucus secreted from the pedal glands and some pedal epithelial cells forms a thin layer which acts as a glue augmenting adherence, while also acting as a lubricant under the moving parts of the snail's foot. The relationships between velocity and the frequency of pedal waves as well as changes in the volume of small air bubbles under foot waves were analyzed by means of digital recordings made through a glass sheet on which the snails were moving. On the ventral surface of a moving snail foot, the adhering parts of the foot constituted about 80% of the total area, while several moving parts only about 20%. The single moving region of the foot (the pedal wave) amounted to about 3% of snail length. The epithelium in the region of the pedal wave was arched above the substrate and was also more wrinkled than the stationary epithelium, which enabled the forward motion of each specific point of epithelium during the passage of a pedal wave above it. The actual area of epithelium engaged by a pedal wave was at least 30% greater than the area of the epithelium as recorded through a glass sheet. In the region of the pedal wave, the tiny subepithelial muscles acting on the epithelium move it up in the front part of the wave, and then down at the end of the wave, operating vertically in relation to the substrate. In the middle part of the wave, the epithelium only moves forward. In summary, during the adhesive locomotion of snails, the horizontal movement of the ventral surface epithelium proceeds as temporally separate phases of upward, forward and downward movement.


Analysis of maxillary asymmetry before and after treatment of functional posterior cross-bite: a retrospective study using 3D imaging system and deviation analysis.
Previous evidence would suggest that subjects affected by functional posterior cross-bite (FPXB) present an asymmetric morphology of the maxilla. However, no evidence is available concerning the morphology (symmetry/asymmetry) of the maxilla after treatment of FPXB. This study aimed to investigate the volumetric and morphological changes of the palate in FPXB subjects treated with maxillary expansion and to compare these data with an untreated control group. The study sample included 20 FPXB subjects (mean age 8.1 ± 0.9 years) who underwent maxillary expansion (MEG group) and 21 FPXB subjects (mean age 7.7 ± 1.2 years) as controls (CG group). Digital models were recorded at T0 (first observation) and T1 (12-18 months after first observation) and analyzed to assess palatal volume and symmetry. Deviation analysis and percentage matching calculation were also performed between original and mirrored palatal models for each patient. All data were statistically analyzed for intra-timing, inter-timing and inter-groups assessments. At T0, the cross-bite side (CBS) was significantly smaller than non-cross-bite side (non-CBS) in both groups (p < 0.05). At T1, the CBS/non-CBS difference reduced significantly in the MEG group (p < 0.05) while slightly worsened in the CG, however without statistical significance (p > 0.05). The matching percentage of the palatal models improved significantly at T1 in the MEG group (T0 = 74.02% ± 9.8; T1 = 89.95% ± 7.12) (p < 0.05) while no significant differences were recorded in the CG (T0 = 76.36 ± 8.64; 72.18% ± 9.65) (p > 0.05). The small sample size and the retrospective design of the study represent two limitations that should be overcome with further clinical trials. Subjects with FPXB present an asymmetric development of the maxillary vault that improves after reestablishment of normal occlusion following maxillary expansion.


Filamentation and biofilm formation are regulated by the phase-separation capacity of network transcription factors in Candida albicans.
The ability of the fungus Candida albicans to filament and form biofilms contributes to its burden as a leading cause of hospital-acquired infections. Biofilm development involves an interconnected transcriptional regulatory network (TRN) consisting of nine transcription factors (TFs) that bind both to their own regulatory regions and to those of the other network TFs. Here, we show that seven of the nine TFs in the C. albicans biofilm network contain prion-like domains (PrLDs) that have been linked to the ability to form phase-separated condensates. Construction of PrLD mutants in four biofilm TFs reveals that these domains are essential for filamentation and biofilm formation in C. albicans. Moreover, biofilm PrLDs promote the formation of phase-separated condensates in the nuclei of live cells, and PrLD mutations that abolish phase separation (such as the removal of aromatic residues) also prevent biofilm formation. Biofilm TF condensates can selectively recruit other TFs through PrLD-PrLD interactions and can co-recruit RNA polymerase II, implicating condensate formation in the assembly of active transcriptional complexes. Finally, we show that PrLD mutations that block the phase separation of biofilm TFs also prevent filamentation in an in vivo model of gastrointestinal colonization. Together, these studies associate transcriptional condensates with the regulation of filamentation and biofilm formation in C. albicans, and highlight how targeting of PrLD-PrLD interactions could prevent pathogenesis by this species.


Chemical fingerprinting of hydrocarbon-contamination in soil.
Chemical fingerprinting analyses of 29 hydrocarbon-contaminated soils were performed to assess the soil quality and determine the main contaminant sources. The results were compared to an assessment based on concentrations of the 16 priority polycyclic aromatic hydrocarbons pointed out by the U.S. Environmental Protection Agency (EPAPAH16) and total petroleum hydrocarbon (TPH). The chemical fingerprinting strategy proposed in this study included four tiers: (i) qualitative analysis of GC-FID chromatograms, (ii) comparison of the chemical composition of both un-substituted and alkyl-substituted polycyclic aromatic compounds (PACs), (iii) diagnostic ratios of selected PACs, and (iv) multivariate data analysis of sum-normalized PAC concentrations. The assessment criteria included quantitative analysis of 19 PACs and C1-C4 alkyl-substituted homologues of naphthalene, fluorene, dibenzothiophene, phenanthrene, pyrene, and chrysene; and 13 oxygenated polycyclic aromatic compounds (O-PACs). The chemical composition of un-substituted and alkyl-substituted PACs and visual interpretation of GC-FID chromatograms were in combination successful in differentiating pyrogenic and petrogenic hydrocarbon sources and in assessing weathering trends of hydrocarbon contamination in the soils. Multivariate data analysis of sum-normalized concentrations could as a stand-alone tool distinguish between hydrocarbon sources of petrogenic and pyrogenic origin, differentiate within petrogenic sources, and detect weathering trends. Diagnostic ratios of PACs were not successful for source identification of the heavily weathered hydrocarbon sources in the soils. The fingerprinting of contaminated soils revealed an underestimation of PACs in petrogenic contaminated soils when the assessment was based solely on EPAPAH16. As alkyl-substituted PACs are dominant in petrogenic sources, the evaluation of the total load of PACs based on EPAPAH16 was not representative. Likewise, the O-PACs are not represented in soil quality assessments based on EPAPAH16 and TPH. The ∑O-PACs ranged between <limit of detection (LOD) (0.03 mg kg(-1) (dw)) and 150.61 mg kg(-1) (dw). The pyrogenic contaminated soils contained considerable amount of O-PACs corresponding to between 6 and 18% of the ∑EPAPAH16.


Promoting better functioning among children exposed to high levels of family adversity: the protective role of childcare attendance.
Children exposed to early adversity are vulnerable to cognitive impairments and externalizing behaviors. Attending childcare may, however, partly buffer this detrimental effect by providing social and cognitive stimulation in a secure environment. The aims of this study were (a) to determine whether the association between exposure to adversity and later externalizing behaviors is mediated by children's cognitive abilities, and (b) to examine if childcare attendance moderates this mediation-thereby highlighting a protective function of children's childcare attendance. Data come from the Avon Longitudinal Study of Children and Parents (N = 6,149). Exposure to adversity was assessed by maternal reports three times from the second trimester of the mother's pregnancy to the child's fourth year of age. Childcare attendance was assessed on four occasions between eight months and three years of age. Factors explaining differences in childcare attendance were controlled using propensity score weights. Children's cognitive abilities were assessed by the Weschler Intelligence Scale for Children at eight years of age, and externalizing behaviors were reported by mothers using the Development and Well-Being Assessment interview at 10, 13, and 15 years of age. Notably, lower cognitive abilities partly accounted for the higher levels of externalizing behaviors in adolescents exposed to adversity (B indirect effect = 0.02, 95% CI = 0.007-0.03, p < .01). Importantly, childcare attendance moderated this indirect effect. For children exposed to adversity, being in maternal care was associated with lower cognitive abilities which were related to higher levels of externalizing behaviors. On the contrary, for children exposed to adversity, attending childcare was associated with higher cognitive abilities which were linked to lower levels of externalizing behaviors. Easily accessible community childcare may be a relatively low-cost public health strategy to prevent the emergence of externalizing behavioral problems in adolescence through its positive effects on cognitive abilities.


Silenced tumor suppressor genes reactivated by DNA demethylation do not return to a fully euchromatic chromatin state.
Histone H3 lysine 9 (H3K9) and lysine 27 (H3K27) trimethylation are properties of stably silenced heterochromatin whereas H3K9 dimethylation (H3K9me2) is important for euchromatic gene repression. In colorectal cancer cells, all of these marks, as well as the key enzymes which establish them, surround the hMLH1 promoter when it is DNA hypermethylated and aberrantly silenced, but are absent when the gene is unmethylated and fully expressed in a euchromatic state. When the aberrantly silenced gene is DNA demethylated and reexpressed following 5-aza-2'-deoxycytidine treatment, H3K9me1 and H3K9me2 are the only silencing marks that are lost. A series of other silenced and DNA hypermethylated gene promoters behave identically even when the genes are chronically DNA demethylated and reexpressed after genetic knockout of DNA methyltransferases. Our data indicate that when transcription of DNA hypermethylated genes is activated in cancer cells, their promoters remain in an environment with certain heterochromatic characteristics. This finding has important implications for the translational goal of reactivating aberrantly silenced cancer genes as a therapeutic maneuver.


CYP2B6 non-coding variation associated with smoking cessation is also associated with differences in allelic expression, splicing, and nicotine metabolism independent of common amino-acid changes.
The Cytochrome P450 2B6 (CYP2B6) enzyme makes a small contribution to hepatic nicotine metabolism relative to CYP2A6, but CYP2B6 is the primary enzyme responsible for metabolism of the smoking cessation drug bupropion. Using CYP2A6 genotype as a covariate, we find that a non-coding polymorphism in CYP2B6 previously associated with smoking cessation (rs8109525) is also significantly associated with nicotine metabolism. The association is independent of the well-studied non-synonymous variants rs3211371, rs3745274, and rs2279343 (CYP2B6*5 and *6). Expression studies demonstrate that rs8109525 is also associated with differences in CYP2B6 mRNA expression in liver biopsy samples. Splicing assays demonstrate that specific splice forms of CYP2B6 are associated with haplotypes defined by variants including rs3745274 and rs8109525. These results indicate differences in mRNA expression and splicing as potential molecular mechanisms by which non-coding variation in CYP2B6 may affect enzymatic activity leading to differences in metabolism and smoking cessation.


The membrane-bound O-acyltransferase domain-containing 7 variant rs641738 increases inflammation and fibrosis in chronic hepatitis B.
Chronic hepatitis B (CHB) is characterized by hepatic inflammation that promotes progression to cirrhosis and predisposes to the development of hepatocellular carcinoma (HCC). Subtle interindividual genetic variation as well as viral and environmental factors interact to determine disease progression between individuals. Recently, the rs641738 membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) polymorphism was demonstrated to influence histological liver damage in alcoholic liver disease, nonalcoholic fatty liver disease, and hepatitis C, but no data are available for CHB. We evaluated rs641738 influence on disease severity in a cohort of 1,101 patients with CHB. Forty-two patients underwent gene expression analysis to assess the functional consequences of rs641738 on hepatic MBOAT7 expression. The minor allele (T) of rs641738 was associated with greater inflammation (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.06-1.95; P = 0.001) and fibrosis (OR = 1.31; 95% CI, 1.19-1.92; P = 0.01). Risk allele frequency in whites (0.43) was greater than in Chinese (0.24), translating to a larger size effect in the former. The rs641738 (T) allele was associated with lower hepatic MBOAT7 expression (P = 0.008), and the latter was associated with serum liver enzymes and inflammation. Neither patatin-like phospholipase domain-containing protein 3 rs738409 nor transmembrane 6 superfamily member 2 rs58542926 polymorphisms influenced disease severity. In patients with CHB, MBOAT7 rs641738 influences hepatic inflammation and fibrosis stage. (Hepatology 2017;65:1840-1850).


Incidence of and risk factors for nodding off at scientific sessions.
We conducted a surreptitious, prospective, cohort study to explore how often physicians nod off during scientific meetings and to examine risk factors for nodding off. After counting the number of heads falling forward during 2 days of lectures, we calculated the incidence density curves for nodding-off episodes per lecture (NOELs) and assessed risk factors using logistic regression analysis. In this article we report our eye-opening results and suggest ways speakers can try to avoid losing their audience.


Nucleotide sequence of soybean chloroplast DNA regions which contain the psb A and trn H genes and cover the ends of the large single copy region and one end of the inverted repeats.
The soybean chloroplast psb A gene (photosystem II thylakoid membrane protein of Mr 32 000, lysine-free) and the trn H gene (tRNAHisGUG), which both map in the large single copy region adjacent to one of the inverted repeat structures (IR1), have been sequenced including flanking regions. The psb A gene shows in its structural part 92% sequence homology with the corresponding genes of spinach and N. debneyi and contains also an open reading frame for 353 aminoacids. The aminoacid sequence of a potential primary translation product (calculated Mr, 38 904, no lysine) diverges from that of spinach and N. debneyi in only two positions in the C-terminal part. The trn H gene has the same polarity as the psb A gene and the coding region is located at the very end of the large single copy region. The deduced sequence of the soybean chloroplast tRNAHisGUG is identical with that of Zea mays chloroplasts. Both ends of the large single copy region were sequenced including a small segment of the adjacent IR1 and IR2.


Autocrine secretion of peptide growth factors by tumor cells.
Transforming growth factors (TGF) are growth-promoting polypeptides that cause phenotypic transformation and anchorage-independent growth of normal cells. They have been isolated from several human and animal carcinoma and sarcoma cells. One TGF is sarcoma growth factor (SGF) which is released by murine sarcoma virus-transformed cells. Whereas the TGF interacts with epidermal growth factor (EGF) cell membrane receptors, it is not detectable in culture fluids from cells which contain high numbers of free EGF cell membrane receptors. The SGF acts as a tumor promoter in cell culture systems, and its effect on the transformed phenotype is blocked by retinoids (vitamin A and synthetic analogs). The production of TGF by transformed cells and the responses of normal cells to the addition of TGF to the culture medium raise the possibility that cells "autostimulate" their growth by releasing factors that rebind at the cell surface. The term "autocrine secretion" has been proposed for this type of situation in which a cell secretes a hormone-like substance for which it has external cell membrane receptors. The autocrine concept may provide a partial explanation for some aspects of tumor cell progression.


Structure of the rhesus monkey TRIM5α PRYSPRY domain, the HIV capsid recognition module.
Tripartite motif protein TRIM5α blocks retroviral replication after cell entry, and species-specific differences in its activity are determined by sequence variations within the C-terminal B30.2/PRYSPRY domain. Here we report a high-resolution structure of a TRIM5α PRYSPRY domain, the PRYSPRY of the rhesus monkey TRIM5α that potently restricts HIV infection, and identify features involved in its interaction with the HIV capsid. The extensive capsid-binding interface maps on the structurally divergent face of the protein formed by hypervariable loop segments, confirming that TRIM5α evolution is largely determined by its binding specificity. Interactions with the capsid are mediated by flexible variable loops via a mechanism that parallels antigen recognition by IgM antibodies, a similarity that may help explain some of the unusual functional properties of TRIM5α. Distinctive features of this pathogen-recognition interface, such as structural plasticity conferred by the mobile v1 segment and interaction with multiple epitopes, may allow restriction of divergent retroviruses and increase resistance to capsid mutations.


[Molecular and pharmacogenetic mechanisms of severe asthma].
This review summarizes the results of studies to identify the dominant mechanisms of development and persistence of inflammation in severe asthma and results of pharmacogenetic studies of determination response to drugs. These mechanisms could potentially be used for diagnostic purposes and become the new targets of asthma therapy. Pharmacogenetic information will enable the use of a personalized approach to the asthma management which will adjust the therapy technology and increase the possibility of achieving disease control.


Developing and validating a nutrition knowledge questionnaire: key methods and considerations.
To outline key statistical considerations and detailed methodologies for the development and evaluation of a valid and reliable nutrition knowledge questionnaire. Literature on questionnaire development in a range of fields was reviewed and a set of evidence-based guidelines specific to the creation of a nutrition knowledge questionnaire have been developed. The recommendations describe key qualitative methods and statistical considerations, and include relevant examples from previous papers and existing nutrition knowledge questionnaires. Where details have been omitted for the sake of brevity, the reader has been directed to suitable references. We recommend an eight-step methodology for nutrition knowledge questionnaire development as follows: (i) definition of the construct and development of a test plan; (ii) generation of the item pool; (iii) choice of the scoring system and response format; (iv) assessment of content validity; (v) assessment of face validity; (vi) purification of the scale using item analysis, including item characteristics, difficulty and discrimination; (vii) evaluation of the scale including its factor structure and internal reliability, or Rasch analysis, including assessment of dimensionality and internal reliability; and (viii) gathering of data to re-examine the questionnaire's properties, assess temporal stability and confirm construct validity. Several of these methods have previously been overlooked. The measurement of nutrition knowledge is an important consideration for individuals working in the nutrition field. Improved methods in the development of nutrition knowledge questionnaires, such as the use of factor analysis or Rasch analysis, will enable more confidence in reported measures of nutrition knowledge.


Heat Stress Modulates Brain Monoamines and Their Metabolites Production in Broiler Chickens Co-Infected with Clostridium perfringens Type A and Eimeria spp.
Heat stress has been related to the impairment of behavioral and immunological parameters in broiler chickens. However, the literature is not clear on the involvement of neuroimmune interactions in a heat stress situation associated with bacterial and parasitic infections. The present study evaluated the production of monoamines and their metabolites in brain regions (rostral pallium, hypothalamus, brain stem, and midbrain) in broiler chickens submitted to chronic heat stress and/or infection and co-infection with Eimeria spp. and Clostridium perfringens type A. The heat stress and avian necrotic enteritis (NE) modulated the neurochemical profile of monoamines in different areas of the central nervous system, in particular, those related to the activity of the hypothalamus-hypophysis-adrenal (HPA) axis that is responsible for sickness behavior. C. perfringens and/or Eimeria infection, heat stress increased 5-hydroxytryptamine (5-HT), 4,4 dihydroxyphenylacetic acid (DOPAC), and DOPAC/dopamine (DA) in the rostral pallium; 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), homovanillic acid (HVA), HVA/DA, DOPAC/DA, and 5-hydroxyindoleacetic acid (5-HIAA)/5-HT in the hypothalamus; MHPG, 5-HIAA/5-HT, DOPAC/DA, and HVA/DA in the midbrain; and MHPG, DOPAC, HVA, HVA/DA, DOPAC/DA, and 5-HIAA/5-HT in the brainstem. Heat stress decreased noradrenaline + norepinephrine (NOR + AD) in all brain regions analyzed; 5-HT in the hypothalamus, midbrain, and brainstem; and DA in the midbrain. The results also showed the existence and activity of the brain-gut axis in broiler chickens. The brain neurochemical profile and corticosterone production are consistent with those observed in chronic stressed mammals, in animals with sickness behavior, and an overloading of the HPA axis.


Temporal lobes signs and Jungian dimensions of personality.
Phenomenological experiences that suggest temporal lobe lability were correlated with Jungian personality (Myers-Briggs) indicators. People with frequent temporal lobe indicators were more intuitive than sensing and more perceiving than judging; in the more general population temporal lobe indicators were also weakly associated with feeling rather than thinking. Students who were actively engaged in a drama class also displayed more frequent temporal lobe signs than psychology students. The data are commensurate with the hypothesis that the relationship between belief in psi phenomena, psi experiences, and specific cognitive styles is derived from a temporal lobe lability factor.


Natural Product-Based Nanomedicine in Treatment of Inflammatory Bowel Disease.
: Many synthetic drugs and monoclonal antibodies are currently in use to treat Inflammatory Bowel Disease (IBD). However, they all are implicated in causing severe side effects and long-term use results in many complications. Numerous in vitro and in vivo experiments demonstrate that phytochemicals and natural macromolecules from plants and animals reduce IBD-related complications with encouraging results. Additionally, many of them modify enzymatic activity, alleviate oxidative stress, and downregulate pro-inflammatory transcriptional factors and cytokine secretion. Translational significance of natural nanomedicine and strategies to investigate future natural product-based nanomedicine is discussed. Our focus in this review is to summarize the use of phytochemicals and macromolecules encapsulated in nanoparticles for the treatment of IBD and IBD-associated colorectal cancer.


Aortic stiffness is associated with vascular calcification and remodeling in a chronic kidney disease rat model.
Increased aortic pulse-wave velocity (PWV) reflects increased arterial stiffness and is a strong predictor of cardiovascular risk in chronic kidney disease (CKD). We examined functional and structural correlations among PWV, aortic calcification, and vascular remodeling in a rodent model of CKD, the Lewis polycystic kidney (LPK) rat. Hemodynamic parameters and beat-to-beat aortic PWV were recorded in urethane-anesthetized animals [12-wk-old hypertensive female LPK rats (n = 5)] before the onset of end-stage renal disease and their age- and sex-matched normotensive controls (Lewis, n = 6). Animals were euthanized, and the aorta was collected to measure calcium content by atomic absorption spectrophotometry. A separate cohort of animals (n = 5/group) were anesthetized with pentobarbitone sodium and pressure perfused with formalin, and the aorta was collected for histomorphometry, which allowed calculation of aortic wall thickness, medial cross-sectional area (MCSA), elastic modulus (EM), and wall stress (WS), size and density of smooth muscle nuclei, and relative content of lamellae, interlamellae elastin, and collagen. Mean arterial pressure (MAP) and PWV were significantly greater in the LPK compared with Lewis (72 and 33%, respectively) animals. The LPK group had 6.8-fold greater aortic calcification, 38% greater aortic MCSA, 56% greater EM/WS, 13% greater aortic wall thickness, 21% smaller smooth muscle cell area, and 20% less elastin density with no difference in collagen fiber density. These findings demonstrate vascular remodeling and increased calcification with a functional increase in PWV and therefore aortic stiffness in hypertensive LPK rats.


Vaptans and hyponatremia in critical patients.
Hyponatremia is the most frequent fluid and electrolyte disorder in hospitalized patients (20%), particularly in ICU, associated with an increase in morbility and mortality. While hypovolaemic hyponatremia needs to be corrected with the replacement of the lost extracellular fluid by isotonic saline, euvolaemic (SIADH) and hypervolaemic hyponatremia (oedematous states like decompensated heart failure, liver cirrhosis, i.e.) are treated by restriction of fluid intake, loop diuretics and hypertonic saline. A novel approach consists in use of vaptans, non-peptide arginine vasopressin (AVP) receptor antagonists. Vaptans cause "aquaresis", which results in the correction of plasma osmolality and serum sodium levels, without activation of the renin-angiotensin-aldosterone system or changes in blood pressure and renal function. In this paper we critically reviewed the results of the available randomized controlled critical trials, discussing the effectiveness and safety of vaptans in treating hypervolaemic and euvolaemic hyponatremia in critical patients.


Molecular and phenotypic characterization of seedling and adult plant leaf rust resistance in a world wheat collection.
Genetic resistance is the most effective approach to managing wheat leaf rust. The aim of this study was to characterize seedling and adult plant leaf rust resistance of a world wheat collection. Using controlled inoculation with ten races of Puccinia triticina, 14 seedling resistance genes were determined or postulated to be present in the collection. Lr1, Lr3, Lr10 and Lr20 were the most prevalent genes around the world while Lr9, Lr14b, Lr3ka and/or Lr30 and Lr26 were rare. To confirm some gene postulations, the collection was screened with gene-specific molecular markers for Lr1, Lr10, Lr21 and Lr34. Although possessing the Lr1 and/or Lr10 gene-specific marker, 51 accessions showed unexpected high infection types to P. triticina race BBBD. The collection was tested in the field, where rust resistance ranged from nearly immune or highly resistant with severity of 1 % and resistant host response to highly susceptible with severity of 84 % and susceptible host response. The majority of the accessions possessing the adult plant resistance (APR) gene Lr34 had a maximum rust severity of 0-35 %, similar to or better than accession RL6058, a Thatcher-Lr34 near-isogenic line. Many accessions displayed an immune response or a high level of resistance under field conditions, likely as a result of synergy between APR genes or between APR and seedling resistance genes. However, accessions with three or more seedling resistance genes had an overall lower field severity than those with two or fewer. Immune or highly resistant accessions are potential sources for improvement of leaf rust resistance. In addition, some lines were postulated to have known but unidentified genes/alleles or novel genes, also constituting potentially important sources of novel resistance.


Does verapamil improve left ventricular relaxation in patients with myocardial hypertrophy?
A beneficial effect of verapamil on left ventricular relaxation has been reported in patients with hypertrophic cardiomyopathy. The effect of 0.1 mg/kg intravenous verapamil on left ventricular relaxation and diastolic mechanics was studied in 10 patients with hypertrophic cardiomyopathy and 13 patients with aortic stenosis. M mode echocardiograms and left ventricular high-fidelity pressure measurements were obtained simultaneously in patients at rest and 10 to 15 min after verapamil. The time constant of left ventricular pressure decay (T; in msec) and the pressure intercept (PB; in mm Hg) were calculated from left ventricular pressure and negative dP/dt during isovolumetric relaxation with the use of a linear regression analysis. Left ventricular early and mean diastolic filling rates as well as diastolic pressure-diameter relationships before and after verapamil were determined from simultaneous echocardiographic and pressure measurements. After verapamil heart rate, left ventricular peak systolic pressure, and maximum and minimum dP/dt remained unchanged in both groups. Left ventricular end-diastolic pressure increased significantly from 15 to 17 mm Hg (p less than .02) in patients with aortic stenosis but did not change in those with hypertrophic cardiomyopathy. However, the time constant T decreased significantly from 79 to 60 msec (p less than .001) in patients with hypertrophic cardiomyopathy but increased significantly from 53 to 68 msec (p less than .025) in those with aortic stenosis. Parallel to the decrease in time constant, early (5.3 vs 7.3 cm/sec, p less than .05) and mean (3.0 vs 4.3 cm/sec, p less than .06) diastolic lengthening rate increased in patients with hypertrophic cardiomyopathy after verapamil. In contrast, early (7.7 vs 7.6 cm/sec, p = NS) and mean (4.3 vs 4.2 cm/sec, p = NS) diastolic lengthening rate remained unchanged in patients with aortic stenosis. The diastolic pressure-diameter relationship did not change in either group after verapamil. Cycle efficiency of the left ventricular pressure-diameter loop was significantly decreased in patients with hypertrophic cardiomyopathy when compared with that in those with aortic stenosis (71% vs 80%; p less than .01), but improved significantly from 71% to 77% (p less than .02) in patients with hypertrophic cardiomyopathy and remained unchanged in those with aortic stenosis (80% vs 80%) after verapamil. We conclude that verapamil improves left ventricular relaxation in patients with hypertrophic cardiomyopathy but delays relaxation in those with aortic stenosis.(ABSTRACT TRUNCATED AT 400 WORDS)


Cancer-related fatigue: a systematic and meta-analytic review of non-pharmacological therapies for cancer patients.
Cancer-related fatigue (CRF) is a significant clinical problem for more than 10 million adults diagnosed with cancer each year worldwide. No "gold standard" treatment presently exists for CRF. To provide a guide for future research to improve the treatment of CRF, the authors conducted the most comprehensive combined systematic and meta-analytic review of the literature to date on non-pharmacological (psychosocial and exercise) interventions to ameliorate CRF and associated symptoms (vigor/vitality) in adults with cancer, based on 119 randomized controlled trials (RCTs) and non-RCT studies. Meta-analyses conducted on 57 RCTs indicated that exercise and psychological interventions provided reductions in CRF, with no significant differences between these 2 major types of interventions considered as a whole. Specifically, multimodal exercise and walking programs, restorative approaches, supportive-expressive, and cognitive-behavioral psychosocial interventions show promising potential for ameliorating CRF. The results also suggest that vigor and vitality are distinct phenomena from CRF with regard to responsiveness to intervention. With improved methodological approaches, further research in this area may soon provide clinicians with effective strategies for reducing CRF and enhancing the lives of millions of cancer patients and survivors.


Psoriasis and psoriatic arthritis educational initiatives: an update from the 2013 GRAPPA Annual Meeting.
At the 2013 annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), members were updated on educational areas in psoriasis and psoriatic arthritis (PsA). Discussions included (1) the psoriasis and PsA GRAPPA video project, comprising a set of educational online videos that provide standardized psoriatic disease endpoint training to clinicians and researchers; (2) the GRAPPA Educational Outreach Project, focused on cross-disciplinary education for rheumatologists and dermatologists and including several collaborations to expand educational sessions globally; (3) the Dermatology and Rheumatology Trainee Educational Initiative, that provides psoriatic disease education to medical students, residents, and fellows training in dermatology and/or rheumatology; and (4) the GRAPPA Educational Slide Library, developed as a resource for GRAPPA members for their own educational presentations.


Measuring protection: efficacy versus effectiveness.
In the clinical development of a vaccine, an efficacy study asks the question, "Does the vaccine work?" In contrast, an effectiveness study asks the question "Does vaccination help people?". In general, vaccine development proceeds from a study of immunogenicity to a randomized controlled trial that determines vaccine efficacy under ideal conditions. Efficacy studies, however, have several limitations. In an immunogenicity study, when a vaccine is given according to different schedules, the object of the study is not the vaccine itself but the schedules; i.e., what is important is not the "relative immunogenicity" of the vaccine, but which schedule is more protective given the occurrence of the disease that is to be prevented. Furthermore, a clinical trial of vaccine efficacy is unable to predict accurately the level of protection that will be achieved in public health practice. Vaccination effectiveness can be evaluated in a prospective clinical trial, although few such studies have been undertaken. Effectiveness is usually assessed retrospectively, sometimes using a screening test, but more often in a case-control or cohort study. In these studies, rigorous risk adjustment is necessary to ensure the comparability of study populations. Retrospective studies also provide a means for assessing serious but rare vaccine-associated adverse events, an undertaking often needed to maintain public confidence in vaccination programmes. Many vaccines currently under development will be replacement rather than new vaccines, and they are unlikely to be evaluated in traditional efficacy trials. In future years, effectiveness studies, some of them using large administrative databases, will become increasingly important features of vaccine development and the formulation of public policy for immunization.


Enhancement in catalytic activity of Aspergillus niger XynB by selective site-directed mutagenesis of active site amino acids.
XynB from Aspergillus niger ATCC1015 (AnXynB) is a mesophilic glycoside hydrolase (GH) family 11 xylanase which holds great potentials in a wide variety of industrial applications. In the present study, the catalytic activity and stability of AnXynB were improved by a combination of computational and experimental approaches. Virtual mutation and molecular dynamics simulations indicated that the introduction of Glu and Asn altered the interaction network at the - 3 subsite. Interestingly, the double mutant S41N/T43E displayed 72% increase in catalytic activity when compared to the wild type (WT). In addition, it also showed a better thermostability than the WT enzyme. Kinetic determination of the T43E and S41N/T43E mutants suggested that the higher xylanase activity is probably due to the increasing binding affinity of enzyme and substrate. Consequently, the enzyme activity and thermostability of AnXynB was both increased by selective site-directed mutagenesis at the - 3 subsite of its active site architecture which provides a good example for a successfully engineered enzyme for potential industrial application. Moreover, the molecular evolution approach adopted in this study led to the design of a library of sequences that captures a meaningful functional diversity in a limited number of protein variants.


The articular manifestations of progressive systemic sclerosis (scleroderma).
The articular manifestations of progressive systemic sclerosis (PSS) were studied in 38 patients. Of these, 66% experienced joint pain and 61% had signs of joint inflammation. Limitation of joint movement was seen in 45%. Radiological abnormalities included periarticular osteoporosis (42%), joint space narrowing (34%), and erosions (40%). Erosive disease did not correlate with disease duration, presence of rheumatoid factor, antinuclear antibodies, distal tuft resorption, or the extent of the scleroderma skin changes. Calcinosis was seen more frequently in those patients with articular erosions (67%). Erosive osteoarthritis of the distal interphalangeal joints (7 patients) was associated with impaired finger flexion. Joint involvement in PSS occurs frequently and may resemble rheumatoid arthritis in the early stages but is less destructive. The occurrence of unrelated arthropathy, such as primary osteoarthritis, is not uncommon, and its differentiation from true PSS joint disease can be difficult.


Evaluation of drug interaction potential of Labisia pumila (Kacip Fatimah) and its constituents.
Labisia pumila (Kacip Fatimah) is a popular herb in Malaysia that has been traditionally used in a number of women's health applications such as to improve libido, relieve postmenopausal symptoms, and to facilitate or hasten delivery in childbirth. In addition, the constituents of this plant have been reported to possess anticancer, antioxidant, and anti-inflammatory properties. Clinical studies have indicated that cytochrome P450s (CYPs), P-glycoprotein (P-gp), and Pregnane X receptor (PXR) are the three main modulators of drug-drug interactions which alter the absorption, distribution, and metabolism of drugs. Given the widespread use of Kacip Fatimah in dietary supplements, the current study focuses on determining the potential of its constituents to affect the activities of CYPs, P-gp, or PXR using in vitro assays which may provide useful information toward the risk of herb-drug interaction with concomitantly used drugs. Six compounds isolated from the roots of L. pumila (2 saponins and 4 alkyl phenols) were tested, in addition to the methanolic extract. The extract of L. pumila showed a significant time dependent inhibition (TDI) of CYP3A4, reversible inhibition of CYP2C9 and 2C19 and a weak inhibition of 1A2 and 2D6 as well as an inhibition of P-gp and rifampicin-induced PXR activation. The alkyl phenols inhibited CYP3A4 (TDI), CYP2C9, and 2C19 (reversible) while saponins inhibited P-gp and PXR. In conclusion, L. pumila and its constituents showed significant modulation of all three regulatory proteins (CYPs, P-gp, and PXR) suggesting a potential to alter the pharmacokinetic and pharmacodynamic properties of conventional drugs if used concomitantly.


High-density EEG mobile brain/body imaging data recorded during a challenging auditory gait pacing task.
In this report we present a mobile brain/body imaging (MoBI) dataset that allows study of source-resolved cortical dynamics supporting coordinated gait movements in a rhythmic auditory cueing paradigm. Use of an auditory pacing stimulus stream has been recommended to identify deficits and treat gait impairments in neurologic populations. Here, the rhythmic cueing paradigm required healthy young participants to walk on a treadmill (constant speed) while attempting to maintain step synchrony with an auditory pacing stream and to adapt their step length and rate to unanticipated shifts in tempo of the pacing stimuli (e.g., sudden shifts to a faster or slower tempo). High-density electroencephalography (EEG, 108 channels), surface electromyography (EMG, bilateral tibialis anterior), pressure sensors on the heel (to register timing of heel strikes), and goniometers (knee, hip, and ankle joint angles) were concurrently recorded in 20 participants. The data is provided in the Brain Imaging Data Structure (BIDS) format to promote data sharing and reuse, and allow the inclusion of the data into fully automated data analysis workflows.