Homeostasis, singularities, and networks.
Homeostasis occurs in a biological or chemical system when some output variable remains approximately constant as an input parameter [Formula: see text] varies over some interval. We discuss two main aspects of homeostasis, both related to the effect of coordinate changes on the input-output map. The first is a reformulation of homeostasis in the context of singularity theory, achieved by replacing 'approximately constant over an interval' by 'zero derivative of the output with respect to the input at a point'. Unfolding theory then classifies all small perturbations of the input-output function. In particular, the 'chair' singularity, which is especially important in applications, is discussed in detail. Its normal form and universal unfolding [Formula: see text] is derived and the region of approximate homeostasis is deduced. The results are motivated by data on thermoregulation in two species of opossum and the spiny rat. We give a formula for finding chair points in mathematical models by implicit differentiation and apply it to a model of lateral inhibition. The second asks when homeostasis is invariant under appropriate coordinate changes. This is false in general, but for network dynamics there is a natural class of coordinate changes: those that preserve the network structure. We characterize those nodes of a given network for which homeostasis is invariant under such changes. This characterization is determined combinatorially by the network topology.


Yeast contains small nuclear RNAs encoded by single copy genes.
We have identified a group of RNA molecules in Saccharomyces cerevisiae that appears to be equivalent to the U class of small nuclear RNAs previously described in other eucaryotes, resembling them in size, metabolic stability, 5' cap structure, presence of modified bases, and nuclear localization. However, the yeast snRNAs differ from their counterparts in several potentially important ways. First, they are present in very low abundance, less than 200 copies per cell, as compared to 10(5)-10(6) for mammalian U1-U6. Second, there appear to be more species in yeast than in any cell type previously examined. Finally, we have cloned five yeast snRNA genes, and find that each is present in a single copy per haploid genome, whereas all previously characterized snRNAs are encoded by multiple (5 to 100) gene copies. The presence of single copy genes in yeast will greatly facilitate the genetic analysis of snRNA function.


Phosphorylation of FADD at serine 194 by CKIalpha regulates its nonapoptotic activities.
FADD is essential for death receptor (DR)-induced apoptosis. However, it is also critical for cell cycle progression and proliferation, activities that are regulated by phosphorylation of its C-terminal Ser194, which has also been implicated in sensitizing cancer cells to chemotherapeutic drugs and in regulating FADD's intracellular localization. We now demonstrate that casein kinase Ialpha (CKIalpha) phosphorylates FADD at Ser194 both in vitro and in vivo. FADD-CKIalpha association regulates the subcellular localization of FADD, and phosphorylated FADD was found to colocalize with CKIalpha on the spindle poles in metaphase. Inhibition of CKIalpha diminished FADD phosphorylation, prevented the ability of Taxol to arrest cells in mitosis, and blocked mitogen-induced proliferation of mouse splenocytes. In contrast, a low level of cycling splenocytes from mice expressing FADD with a mutated phosphorylation site was insensitive to CKI inhibition. These data suggest that phosphorylation of FADD by CKI is a crucial event during mitosis.


Nanosecond time-resolved studies of long-lived photoinduced charge separation in the dyad fluorescein-anthraquinone-methyl ester adsorbed on TiO2 colloids.
A dyad composed of fluorescein and 2-methyl-anthraquinone (FL-AQ) was synthesized and its photophysical properties were examined by absorption, fluorescence spectroscopy, and fluorescence lifetime. The charge-separated state formed by photoinduced intramolecular electron transfer was detected by nanosecond transient absorption spectroscopy for the first time. When FL is excited in solution, the photoinduced electron transfer from FL to AQ proceeds efficiently. The rate constant and the efficiency of intramolecular electron transfer are 3.95 x 10(9) s(-1) and 95%, respectively. Its charge-separated state lifetime is too short to detect by transient absorption spectroscopy. Adding nanometer colloidal TiO(2) to an FL-AQ ethanol solution prolongs the lifetime of the charge-separated state, so its transient absorption signal is recorded significantly. The lifetimes of FL(+). at 480 nm and AQ(-). at 560 nm in the FL-AQ/TiO(2) colloidal system are 11.1 and 8.93 mivros, respectively.


Hydrophilic and opened canals in honey bee tongue rods endow elastic structures with multiple functions.
The honey bee (Apis mellifera L.) tongue is a sophisticated and dexterous probing device that can bend and twist, adapting to various surfaces for liquid imbibition and/or gustatory sensing. The tongue exhibits remarkable extendibility, flexibility, and durability, which may be essentially ascribed to the internal elastic rod that supports the entire tongue. However, neither the material composition nor the structural features of the rod, especially a peculiar inner canal that facilitates feeding, have been studied in relation to their function. Herein, by combining a set of imaging techniques, including optical microscopy, high-speed videography, scanning electron microscopy, micro-computed tomography (micro-CT), and confocal laser scanning microscopy, we characterize the spatial morphology, surface wettability and material composition of honey bee tongue rods. By performing mechanical testing, including atomic force microscopy, fracture testing, and finite element analysis, we provide the first evidence that the internal canal of the rod may represent a specialized structure for water retention due to the specific chemistry of resilin, which is an elastomeric protein that dominates the entire rod and renders it highly elastic, compliant and robust. Numerical simulations also suggest that the opening of the canal may facilitate larger deformations in twisting, extending the flexibility of the rod. STATEMENT OF SIGNIFICANCE: The honey bee is one of the most important pollinators around the world and is capable of foraging a wide spectrum of liquid sources by dipping into them with a miniature hairy tongue. However, there are no direct muscles distributed inside the tongue, instead, there is a conspicuous elastic rod with a hollow core. The rod extends for its full length and, according to our study, structurally reinforces the entire tongue to achieve functional versatility, and suggests a water containing function of the rod canal for maintaining the elasticity of the protein (resilin) that constitutes the rod. Our results broaden understandings of the relationship among morphology, materials science, and function of a honey bee tongue.


Antihypertensive efficacy of olmesartan compared with other antihypertensive drugs.
The therapeutic profile of olmesartan medoxomil, which is a recently developed angiotensin II (A II) receptor blocker, has been compared with four commonly used antihypertensive therapeutic drugs (atenolol, captopril, felodipine and losartan) in five separate multicentre, randomised, double-blind, parallel-group, phase III trials. The trials were designed to compare the efficacy of individually optimised dosages of olmesartan medoxomil and the comparator agent. The primary efficacy variable in all trials was the mean change from baseline to week 12 in trough mean sitting diastolic blood pressure (DBP). Olmesartan medoxomil (10-20 mg once daily (o.d.)) showed similar efficacy to atenolol (50-100 mg o.d.), both in patients with mild-to-moderate hypertension and, when given together with hydrochlorothiazide (HCTZ) 25 mg o.d., in patients with moderate-to-severe hypertension. Olmesartan medoxomil (20-40 mg o.d.) was also similar in efficacy to felodipine (5-10 mg o.d.) in reducing BP in patients with mild-to-moderate hypertension. Compared with captopril (12.5-50 mg twice daily (b.i.d.)) and losartan (50-100 mg o.d.), in patients with mild-to-moderate hypertension, olmesartan medoxomil (5-20 mg o.d. and 10-20 mg o.d., respectively) was significantly superior in terms of lowering DBP from baseline to week 12. In terms of the secondary efficacy variable, which was mean change from baseline to week 12 in trough mean sitting systolic BP, olmesartan showed significant superiority to atenolol, captopril and losartan in patients with mild-to-moderate hypertension. In the longer term, compared with losartan, a lower percentage of olmesartan-treated patients required concomitant HCTZ after 12 weeks of therapy. Olmesartan was well tolerated in all studies.


Phase II study of sequential high-dose methotrexate and fluorouracil combined with doxorubicin as a neoadjuvant chemotherapy for scirrhous gastric cancer.
The prognosis of scirrhous gastric cancer remains poor when it is treated with surgical resection alone or chemotherapy alone. A phase II study of sequential high-dose methotrexate and fluorouracil, combined with doxorubicin, as a neoadjuvant chemotherapy was conducted in an attempt to evaluate the efficacy of this regimen in improving the survival of patients with scirrhous gastric cancer. Patients were eligible if they had potentially resectable scirrhous gastric cancer with adequate organ functions and no prior treatment. The treatment schedule consisted of methotrexate (1 g/m2, day 1) fluorouracil (1.5 g/m2, day 1), leucovorin (15 mg/m2, days 2-4), and doxorubicin (30 mg/m2, day 15), repeated at a 28-day interval, and followed by radical surgery. A total of 20 eligible patients were registered. Objective responses in the neoadjuvant chemotherapy segment were observed in 3 of the 20 (15%) patients. No complete remission was observed. The neoadjuvant chemotherapy was associated with grade 3 or 4 neutropenia in 14 of the 20 (70%) patients. The median time from the initial therapy to the operative day was 82 days. Thirteen of the 20 (65%) patients underwent curative resection. No treatment-related deaths occurred. However, the 2-year survival rate in this treatment program (25%) did not show any superiority over that in historical controls. Sequential high-dose methotrexate and fluorouracil, combined, with doxorubicin, as a neoadjuvant chemotherapy for scirrhous gastric cancer did not improve the survival rate in spite of improving the curative resection rate.


A unique case of reducing body myopathy.
The clinical, electromyographic, and histologic characteristics of a 17-year-old girl with reducing body myopathy are described. She is, to our knowledge, the oldest reported case and the only patient described with severe mitral valve prolapse and scoliosis. Electromyography demonstrated spontaneous positive sharp waves and fibrillation potentials with many low-amplitude, short, polyphasic motor unit potentials. The right deltoid muscle was characterized by focal areas with large fibers associated with increased endomysial connective tissue and "split" fibers. Purple-gray sarcoplasmic masses stained with trichrome were PAS-negative, appeared as "empty" spaces with both ATPase and NADH-TR, and stained darkly with menadione NBT. The features described expand the clinical presentation of this myopathy, and may lead to a better understanding of its etiology.


Alternative New Mono-scaled Quantitative Benefit-Risk Assessment of Human Papillomavirus Vaccine in Japan.
The human papillomavirus (HPV) vaccine coverage is very low in Japan since the government suspended the active encouragement of the vaccination. We aimed to conduct a benefit-risk assessment of HPV vaccination and explore different consequent scenarios to identify potential improvements to the current Japanese immunization program. To calculate social benefit-risk of HPV vaccine, we used the Markov model to represent the natural history of HPV and adverse events (AEs) using disability-adjusted life year (DALY) as the outcome. Benefits and risks were calculated as the sum of negative and positive outcomes corresponding to all preventable diseases and AEs associated with HPV vaccination, respectively. The benefit-risk balance in 2050 was estimated using published data. Our model was confirmed by published cervical cancer incidence and mortality rates. The benefit-risk balance in 2050 showed that the most effective scenario was the introduction of 9-valent HPV vaccine targeting female individuals aged 10-29 years for routine vaccination starting in 2020, although there is possibility of increased risks of AEs for the vaccinated age group post resumption of recommendations. Our benefit-risk assessment of HPV vaccine helped estimate various scenarios pertaining to HPV vaccination and identify the best strategy regarding HPV vaccination. This benefit-risk assessment approach may be used for other vaccines and vaccination programs.


Residual stress and strain in aortic segments.
In the study of stresses and strains in vascular segments, it is generally assumed that the traction-free configuration assumed by a segment when there is no axial force and there are no intravascular and extravascular pressures is stress-free. To investigate the degree of validity of this assumption, 286 oval shaped rings were excised from three bovine and six porcine aortas and photographed. Radial cuts were made in these rings which opened up into horseshoe shapes and were also photographed. Smoothed boundary lengths at intimal and adventitial levels in the rings and their cut open configurations were measured from the photographs and the residual strains in the annular configuration relative to the open configuration were computed. It was found that: the average maximum residual intimal engineering strain in the uncut configuration was -0.082 for all nine aortas and -0.096 and -0.077 for the bovine and porcine aortas alone, respectively; the average maximum residual adventitial strain was 0.085 for all aortas, and 0.102 and 0.078 for the bovine and porcine aortas alone, respectively; an estimated average beneficial compressive stress of -0.188 X 10(5) Pa (corresponding to a strain level of -0.082) is available at the intimal level to counteract the in vivo tensile stress due to the intravascular pressure; an estimated average initial tensile stress of 0.195 X 10(5) Pa (corresponding to a strain level of 0.085) exists at the adventitial level which adds to the in vivo tensile stress due to the intravascular pressure. Although these stress levels are not large in comparison with the in vivo stress in the arterial wall, a detailed stress analysis must take into account these initial stresses.


Electron paramagnetic resonance studies of magnetically aligned phospholipid bilayers utilizing a phospholipid spin label: the effect of cholesterol.
X-band EPR spectroscopy has been employed to study the dynamic properties of magnetically aligned phospholipid bilayers (bicelles) utilizing a variety of phosphocholine spin labels (n-PCSL) as a function of cholesterol content. The utilization of both perpendicular and parallel aligned bicelles in EPR spectroscopy provides a more detailed structural and orientational picture of the phospholipid bilayers. The magnetically aligned EPR spectra of the bicelles and the hyperfine splitting values reveal that the addition of cholesterol increases the phase transition temperature and alignment temperature of the DMPC/DHPC bicelles. The corresponding molecular order parameter, Smol, of the DMPC/DHPC bicelles increased upon addition of cholesterol. Cholesterol also decreased the rotational motion and increased the degree of anisotropy in the interior region of the bicelles. This report reveals that the dynamic properties of DMPC/DHPC bicelles agree well with other model membrane systems and that the magnetically aligned bicelles are an excellent model membrane system.


Population biology of Avena : IX. Gene flow and neighborhood size in relation to microgeographic variation in Avena barbata.
Pollen and seed dispersal patterns were analyzed in both natural and experimental populations of Avena barbata. Localized estimates of gene flow rates and plant densities gave estimates of neighborhood size in the range of 40 to 400 plants; the estimates of mean rate and distance of gene flow seemed to vary widely due to variable wind direction, rodent activity, microsite heterogeneity, etc. The relative sizes of neighborhoods in several populations were correlated with the patchy distribution of different genotypes (scored for lemma color and leaf sheath hairiness) within short distances, but patch sizes had a wide range among different sites. Highly localized gene flow patterns seemed to account for the observed pattern of highly patchy variation even when the dispersal curves for both pollen and seed were platykurtic in many cases. Measures of the stability of patches in terms of their size, dispersion in space and genetic structure in time are needed in order to sort out the relative roles of founder effects, random drift (due to small neighborhood size), and highly localized selection. However, our observations suggest that many variables and stochastic processes are involved in such studies so as to allow only weak inference about the underlying role of natural selection, drift and factors of population regulatien.


Rare cardiac sequelae of a hump-nosed viper bite.
The hump-nosed pit viper (Hypnale hypnale) is the commonest cause for venomous snakebites in Sri Lanka. Previously, it was thought to cause only local envenomation. However recently, several systemic effects and even mortality has been reported. Along with other snakes, such as the Indian cobra (Naja naja), the common krait (Bungarus caeruleus), the Russell's viper (Daboia russelii) and the saw-scaled viper (Echis carinatus), the hump-nosed viper is now also considered capable of causing lethal envenomation. Unlike other snake species, the systemic manifestations occurring through the bite of a hump-nosed viper, such as acute renal failure, thrombotic microangiopathy etc are rare and unpredictable. A 49-year-old Sri Lankan Tamil male presented with a hump-nosed viper bite, which had resulted in a cardiac arrest within half an hour of envenomation. On arrival to the Emergency Treatment Unit, he was unconscious and without spontaneous breathing. Electrocardiography monitoring revealed ST elevation in leads II, III and aVF with reciprocal changes in leads I and aVL-indicating inferior wall infarction-as well as atrial fibrillation. Glasgow Coma Scale was 7/15, which indicated severe brain injury and electroencephalogram on day 10 revealed a low amplitude pattern compatible with diffuse brain damage. This case describes an authenticated case of myocardial infarction in a 49-year-old male following envenomation by a hump-nosed viper in Sri Lanka. This systemic effect of this viper's bite has not previously been described in the literature. This case report is intended to increase the vigilance for myocardial infarction following hump-nosed viper envenomation.


Effects of short-term pistachio consumption before and throughout recovery from an intense exercise bout on cardiometabolic markers.
Although pistachios have been shown to improve cardiometabolic biomarkers in diseased and at-risk populations, less research has been conducted on young, healthy individuals. Furthermore, some but not all research indicates that exercise acutely improves cardiometabolic markers; however, it remains unclear as to why outcomes vary among studies. This research evaluated secondary aims of a study designed to assess the impacts of pistachios on recovery from vigorous eccentrically-biased exercise. Here we examined the short-term (two weeks) effects of two different doses (1.5 oz/d and 3.0 oz/d) of pistachios and a water-only control on the biomarkers of metabolic health in young adult men. This was followed by daily blood collection for three consecutive days after a 40-min downhill run. Twenty-seven participants completed each of three conditions in a counterbalanced randomized order. Plasma biomarkers (lipid profile, glucose, and insulin) were measured at the end of each 2-week feeding period immediately before the exercise bout and again 24, 48, and 72 h thereafter. Two weeks of pistachio consumption failed to elicit changes in any biomarker (p < .05).. Exercise reduced LDL-cholesterol at the end of the recovery period; however, positive effects were limited to when subjects were consuming the higher dose of pistachios. Follow up t-tests revealed significant reductions in LDL-C in the high dose group at 72-H compared to that at 0-H (8.2 ± 19.4; p < .04), 24-H (8.0 ± 18.6; p < .04), and 48-H (9.3 ± 15.8; p < .005) post exercise within the same trial. Overall, in healthy young men with normal blood lipid and glucose metabolism, little effect of either pistachios or intense exercise on cardiometabolic risk indicators was detected. More research is needed to determine the influence of usual diet consumption on outcomes following an acute exercise bout.


Leg length discrepancy and lower limb alignment after total hip arthroplasty in unilateral hip osteoarthritis patients.
Leg length discrepancy (LLD) following total hip arthroplasty (THA) is a leading cause of patient dissatisfaction. However, no reports have described the influence of lower limb alignment on LLD after THA. In the present study, we firstly investigated the change in lower limb alignment after THA. Secondly, we determined the influence of lower limb alignment on LLD after THA. Thirdly, we evaluated the influence of LLD in the entire lower leg on the clinical outcomes after THA. We followed up with 54 unilateral hip osteoarthritis (OA) patients 1 year after THA. For the radiological assessment of LLD and lower limb alignment, we obtained anteroposterior radiographs of the pelvis and both lower legs in entirety in a standing position before and 1 year after THA. The Harris Hip Score (HHS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Medical Outcomes Study Short-Form 36-Item Health Survey (SF-36) were also obtained to assess the clinical outcome. The alignment of the affected leg, which was more valgus than the unaffected leg before THA, tended toward varus after THA, and the discrepancy between the lower limb alignments on both sides decreased. However, the alignment discrepancies that remained after THA influenced the LLD measured on the radiograph of the entire lower leg, and this LLD influenced the clinical outcome as measured by the HHS and the WOMAC score. LLD in the entire lower leg should be corrected for a better clinical outcome after THA.


Description of Participation in Daily and Social Activities for Individuals with COPD.
This study described the participation in daily and social activities and the perceived barriers and facilitators to participation of individuals with chronic obstructive pulmonary disease (COPD). Individuals, recruited from outpatient clinics, responded to a survey on their participation in, and barriers and facilitators towards, 26 daily and social activities, divided into 3 categories: (1) physical activity and movement (PAM); (2) self-care; and (3) social engagement. For each activity, chi-square analyses were used to examine participation differences by individuals': quartiles of airflow obstruction [percent predicted forced expiratory volume in 1 second (FEV1%predicted)] and breathlessness burden and exacerbation risk. Of the 200 participants (47% women; mean ± standard deviation age = 68 ± 9 years), most wanted to increase their participation in PAM activities (range 21-75%) and significant differences were found in 5/10 PAM activities for individuals' breathlessness burden and exacerbation risk (e.g., more individuals than expected in group A (modified Medical Research Council breathlessness score <2 and 0-1 exacerbations in past 12 months) participated in regular exercise as much as they wanted (χ(9)2=20.43, Cramer's V=.23)). Regardless of the degree of airflow obstruction or breathlessness burden and exacerbation risk, the most common barrier to participation was breathlessness (p<.001, η2p=.86) and the most common facilitator was engaging as part of their routine (p<.001, η2p=.75). Individuals with COPD want to increase their participation in daily and social activities but are limited by breathlessness. Strategies to alleviate breathlessness should be identified/prioritized and incorporated into individuals' daily routines to meet their self-reported participation objectives in daily and social activities.


A novel autophagy-related lncRNA prognostic risk model for breast cancer.
Long non-coding RNAs (lncRNAs) are well known as crucial regulators to breast cancer development and are implicated in controlling autophagy. LncRNAs are also emerging as valuable prognostic factors for breast cancer patients. It is critical to identify autophagy-related lncRNAs with prognostic value in breast cancer. In this study, we identified autophagy-related lncRNAs in breast cancer by constructing a co-expression network of autophagy-related mRNAs-lncRNAs from The Cancer Genome Atlas (TCGA). We evaluated the prognostic value of these autophagy-related lncRNAs by univariate and multivariate Cox proportional hazards analyses and eventually obtained a prognostic risk model consisting of 11 autophagy-related lncRNAs (U62317.4, LINC01016, LINC02166, C6orf99, LINC00992, BAIAP2-DT, AC245297.3, AC090912.1, Z68871.1, LINC00578 and LINC01871). The risk model was further validated as a novel independent prognostic factor for breast cancer patients based on the calculated risk score by Kaplan-Meier analysis, univariate and multivariate Cox regression analyses and time-dependent receiver operating characteristic (ROC) curve analysis. Moreover, based on the risk model, the low-risk and high-risk groups displayed different autophagy and oncogenic statues by principal component analysis (PCA) and Gene Set Enrichment Analysis (GSEA) functional annotation. Taken together, these findings suggested that the risk model of the 11 autophagy-related lncRNAs has significant prognostic value for breast cancer and might be autophagy-related therapeutic targets in clinical practice.


Radial artery aneurysm secondary to dynamic entrapment by extensor pollicis longus tendon: a case of snapping thumb.
Aneurysms of the distal radial artery at the level of the wrist are rare. Most reported cases are posttraumatic, either from iatrogenic arterial puncture for radial arterial access or from a penetrating injury. Other causes include infection and connective tissue disorders. Early diagnosis is important to avoid the potential complications of thrombus formation, distal digital ischemia, and rupture. Evaluation of the radial artery is typically performed using non-invasive modalities like ultrasonography, computed tomographic angiography (CTA), and magnetic resonance angiography (MRA). Invasive angiography can also be performed, particularly if minimally invasive treatment options are being considered. We report a case of a 35-year-old male mechanic who presented with pain at the base of the left thumb dorsally, with reproducible painful snapping on dynamic exam. Ultrasound demonstrated a fusiform aneurysm of the radial artery. At the level of the aneurysm, there was dynamic entrapment of the artery between the extensor pollicis longus (EPL) tendon and the underlying trapezium. The patient's symptoms improved with conservative management and avoidance of the snapping-producing maneuvers. To our knowledge, this is the first published case of snapping at the base of the thumb resulting in repetitive entrapment of the radial artery by the EPL tendon captured on dynamic ultrasound examination.


Type 1 diabetes mellitus in a child with phenobarbital hypersensitivity syndrome.
To report a case of type 1 diabetes mellitus (T1DM) in a child with phenobarbital hypersensitivity syndrome with an emphasis on the clinical presentation, diagnostic modalities and treatment options. A 5-yr-old girl developed fever, rash and hepatic inflammation after receiving phenobarbital. Infection and connective tissue diseases were excluded and an adverse event following phenobarbital administration [anticonvulsant hypersensitivity syndrome (AHS)] was considered. Clinical manifestation was somewhat improved after systemic hydrocortisone and other antiallergic drugs were administrated. However, polyuria, polydipsia, dehydration, severe metabolic acidosis with increased anion gap and hyperglucosemia were found about 4 weeks after stopping phenobarbital. Increased blood ketone and glycosylated hemoglobin (HbA1c), and decreased blood insulin and C-peptide confirmed the diagnosis of T1DM. Insulin was used and gamma-immunoglobulin was administered on the 25th day after admission. Since then, clinical symptoms and signs improved significantly and the patient was discharged on the 45th day after admission. Postdischarge course was uneventful and the patient is well with sequential HbA1c of 7.3% 1 month after discharge. AHS should be suspected in patients who develop unexplained systemic manifestations following exposure to aromatic antiepileptics, including phenobarbital. The timely recognition and treatment with corticosteroids and immunoglobulin is required and useful. The potential damage of beta-cells should be considered in patients with AHS.


Transmission of ER stress response by ATF6 promotes endochondral bone growth.
We reported earlier that X-box binding protein1 spliced (XBP1S), a key regulator of the unfolded protein response (UPR), as a bone morphogenetic protein 2 (BMP2)-inducible transcription factor, positively regulates endochondral bone formation by activating granulin-epithelin precursor (GEP) chondrogenic growth factor. Under the stress of misfolded or unfolded proteins in the endoplasmic reticulum (ER), the cells can be protected by the mammalian UPR. However, the influence of activating transcription factor 6 (ATF6), another transcriptional arm of UPR, in BMP2-induced chondrocyte differentiation has not yet been elucidated. In the current study, we investigate and explore the role of ATF6 in endochondral bone formation, focus on associated molecules of hypertrophic chondrocyte differentiation, as well as the molecular events underlying this process. High-cell-density micromass cultures were used to induce ATDC5 and C3H10T1/2 cell differentiation into chondrocytes. Quantitative real-time PCR, immunoblotting analysis, and immunohistochemistry were performed to examine (1) the expression of ATF6, ATF6α, collagen II, collagen X, and matrix metalloproteinase-13 (MMP13) and (2) whether ATF6 stimulates chondrogenesis and whether ATF6 enhances runt-related transcription factor 2 (Runx2)-mediated chondrocyte hypertrophy. Culture of fetal mouse bone explants was to detect whether ATF6 stimulates chondrocyte hypertrophy, mineralization, and endochondral bone growth. Coimmunoprecipitation was employed to determine whether ATF6 associates with Runx2 in chondrocyte differentiation. ATF6 is differentially expressed in the course of BMP2-triggered chondrocyte differentiation. Overexpression of ATF6 accelerates chondrocyte differentiation, and the ex vivo studies reveal that ATF6 is a potent stimulator of chondrocyte hypertrophy, mineralization, and endochondral bone growth. Knockdown of ATF6 via a siRNA approach inhibits chondrogenesis. Furthermore, ATF6 associates with Runx2 and enhances Runx2-induced chondrocyte hypertrophy. And, the stimulation effect of ATF6 is reduced during inhibition of Runx2 via a siRNA approach, suggesting that the promoting effect is required for Runx2. Our observations demonstrate that ATF6 positively regulates chondrocyte hypertrophy and endochondral bone formation through activating Runx2-mediated hypertrophic chondrocyte differentiation.


The training needs for gender-sensitive care in a pediatric rehabilitation hospital: a qualitative study.
Gender is an important social determinant of health; however, clinicians often lack training in how to provide gender-sensitive care. Offering appropriate and relevant training could help to address some gender-based health inequalities. Our objective was to identify and describe the training needs for gender-sensitive care among pediatric rehabilitation healthcare providers. This study used an interpretive descriptive qualitative design to conduct interviews with 23 pediatric rehabilitation healthcare providers (19 women, 3 men, 1 transgender man), from a pediatric rehabilitation hospital in a large urban center, in Ontario, Canada from a range of disciplines. Interviews were transcribed verbatim and analyzed using an open-coding inductive thematic analysis. Our analysis revealed the following themes: [1] lack of knowledge about gender-sensitive care and the need for more training; [2] content of the desired training (i.e., gender differences, effective communication and how to practice gender-sensitive care) and [3] delivery method of the training. Enhanced gender-sensitive training for healthcare providers is required for optimizing patient outcomes and addressing gender-based health inequalities. Educators in pediatric rehabilitation should consider developing gender-sensitive care training that is embedded within post-graduate education and also continuing education within hospitals and community care centers.


Over half of contemporary clinical Gleason 8 on prostate biopsy are downgraded at radical prostatectomy.
Contemporary clinical guidelines utilize the highest Gleason sum (HGS) in any one core on prostate biopsy to determine prostate cancer treatment. Here, we present a large discrepancy between prostate cancer risk stratified as high risk on biopsy and their pathology after radical prostatectomy. We retrospectively reviewed 1424 men who underwent either open or robotic-assisted prostatectomy between 2004 and 2015. We analyzed 148 men who were diagnosed with HGS 8 on prostate biopsy. Biopsy and prostatectomy pathology were compared in aggregate and over 1 year time intervals. Chi-squared test, Fisher's exact test, Student's t-test, and Wilcoxon Rank-Sum test were used for statistical analysis. A total of 61.5% (91/148) of clinical HGS 8 diagnoses were downgraded on prostatectomy, with 58.8% (87/148) downgraded to Gleason 7 (Gleason 4 + 3 n = 59; Gleason 3 + 4 n = 28). Factors associated with downgrading include lower prostate-specific antigen (PSA) at biopsy (median 6.8 ng/mL versus 9.1 ng/mL, p < 0.001), number of Gleason 8 biopsy cores (median 1 versus 2, p < 0.02), presence of Gleason pattern 3 on biopsy cores (67.9% versus 44.8%, p < 0.03), pT2 staging (72.4% versus 55.1%, p < 0.04), positive margins (53.9% versus 69.1%, p < 0.04), extracapsular extension (53.4% versus 74.1%, p < 0.02), and smaller percent tumor (median 10% versus 15%, p < 0.004). The large percentage of pathology downgrading of biopsy-diagnosed HGS 8 suggests suboptimal risk-stratification that may lead to suboptimal treatment strategies and much patient distress. Our study adds great urgency to the efforts refining prostate cancer clinical assessment.


Conventional second-line salvage chemotherapy regimens are not warranted in patients with malignant lymphomas who have progressive disease after first-line salvage therapy regimens.
This study aimed to determine the outcome of patients with relapsed or refractory lymphoma who have an inadequate response to first-line salvage therapy (1 degrees ST) and who subsequently receive a second-line salvage regimen (2 degrees ST) with the intention of ultimately proceeding to high-dose therapy. The outcome of 57 patients [Hodgkin's Lymphoma 17, histologically-aggressive non-Hodgkin's Lymphoma (NHL) 26, histologically-indolent NHL 14] who received more than one modality of conventional-dose salvage therapy was analysed. Sixteen patients had a partial response (PR) to 1 degrees ST, but subsequently received 2 degrees ST because the PR was judged to be inadequate (iPR) because of persisting disease bulk or marrow infiltration. Of these 16 patients, 10 (63%) continued to respond to 2 degrees ST. Of the 15 patients who had stable disease following 1 degrees ST, 5 (33%) responded to 2 degrees ST. Only one of the 24 (4%) with progressive disease (PD) following 1 degrees ST, responded to 2 degrees ST. 25 of the 57 patients ultimately underwent stem cell transplantation. The 2-year progression-free survival (PFS) and the 3-year overall survival (OS) for all patients was 24% and 31%, respectively. Long-term survival was highly dependent on response to 1 degrees ST (P = 0.0001); in patients with PD following 1 degrees ST, the PFS and OS at 3 years was only 4%. This analysis indicates that patients with malignant lymphomas, who have PD on 1 degrees ST, are not rescued by subsequent salvage regimens. They should either be treated palliatively or novel approaches should be explored.


Immunoelectron microscopic localization of dentin gamma-carboxyglutamic acid-containing proteins in differentiating rat odontoblasts.
The intracellular synthesis of the dentin-gamma-carboxyglutamic acid-containing proteins (DGPs) by rat odontoblasts was investigated at the electron microscopic level using a sensitive pre-embedding immunoperoxidase technique. The DGPs were detected in the rough endoplasmic reticulum and secretory vesicles, but not in the Golgi apparatus of the odontoblasts, while dentin matrix is not yet reactive. These results suggest that the DGPs synthesis is independent of mineral deposition.


Risk factor-based optimal endoscopic surveillance intervals after endoscopic submucosal dissection for gastric adenoma.
To date, there exists no established endoscopic surveillance interval strategy after endoscopic submucosal dissection (ESD) for gastric adenoma. In this study, we suggest a risk factor-based statistical model for optimal surveillance intervals for gastric adenoma after ESD with curative resection. A cox proportional hazard model was applied to identify risk factors for recurrence after ESD. Patients (n = 698) were categorized into groups based on the identified risk factors. The cumulative density of recurrence over time was computed using a cubic splined baseline hazard function, and the customized surveillance interval was modeled for each risk group. The overall cumulative incidence of recurrence was 7.3% (n = 51). Risk factors associated with recurrence were male (hazard ratio [HR], 2.60, P = 0.030), protruded scar (HR, 3.18, P < 0.001), and age ≥ 59 years (HR, 1.05, P < 0.001). The surveillance interval for each group was developed by using the recurrence limit for the generated risk groups. According to the developed schedule, high-risk patients would have a maximum of seven surveillance visits for 5 years, whereas low-risk patients would have biennial surveillance for cancer screening. We proposed a simple and promising strategy for determining a better endoscopic surveillance interval by parameterizing diverse and group-specific recurrence risk factors into a well-known survival model.


Rapid loss of response after withdrawal of treatment with azacitidine: a case series in patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukemia.
In patients with myelodysplastic syndromes (MDS), the likelihood of having a sustained response to azacitidine is increased by maximizing treatment duration. This is important as prognosis postrelapse is poor. There is also the concern that early termination of treatment may result in rapid disease progression. We reviewed outcomes in 13 patients who discontinued azacitidine (decitabine in one patient) while still responding to the treatment. Most patients rapidly relapsed; median time to progression was 5.4 months. Reasons for treatment discontinuation included comorbidities, infections, and patient choice. These findings illustrate the risk of prematurely terminating azacitidine therapy in MDS.


Ghrelin/GHS-R1a signaling plays different roles in anxiety-related behaviors after acute and chronic caloric restriction.
The brain-gut hormone ghrelin and its receptor GHS-R1a, the growth hormone secretagogue receptor 1a, regulates diverse functions of central nervous system including stress response and mood. Both acute and chronic caloric restrictions (CR) were reported to increase endogenous ghrelin level meanwhile regulate anxiety-related behaviors; however, the causal relationship between CR-induced ghrelin elevation and anxiety are not fully established. Here, we introduced an acute (24 h) and a chronic (10wks) CR procedure to both GHS-R1a KO (Ghsr-/-) mice and WT (Ghsr+/+) littermates, and compared their anxiety-related behaviors. We found that acute CR induced anxiolytic and anti-despairing behaviors in Ghsr+/+ mice but not in Ghsr-/- mice. Ad-libitum refeeding abolished the effect of acute CR on anxiety-related behaviors. In contrast, chronic CR for 10wks facilitated despair-like behavior meanwhile inhibited anxiety-like behavior in Ghsr+/+ mice. GHS-R1a deficiency rescued despair-like behavior while did not affect anxiolytic response induced by chronic CR. In addition, we found elevated interleukin-6 (IL-6) in serum of Ghsr+/+ mice after chronic CR, but not in Ghsr-/- mice. Altogether, our findings indicated that acute CR and chronic CR have different impacts on anxiety-related behaviors, and the former is dependent on ghrelin/GHS-R1a signaling while the latter may not always be. In addition, our findings suggested that GHS-R1a-dependent elevation in serum IL-6 might contribute to increased despair-like behavior in chronic CR state.


Pumpkin rootstock improves the growth and development of watermelon by enhancing uptake and transport of boron and regulating the gene expression.
Boron (B) is an essential trace element that plays a vital role in metabolic and physiological functions of higher plants. The adequate supply of B is important for plant growth and development. Grafting is a technique used to improve the ion uptake and plant growth. In this study, a commercial watermelon cultivar "Zaojia 8424" [Citrullus lanatus (Thunb.) Matsum. and Nakai.] was grafted onto pumpkin (Cucurbita maxima × Cucurbita moschata) rootstock cv. "Qingyan Zhenmu No.1" with an aim to investigate the response of grafted plants to different levels of B supply (0.25 μM, 25 μM and 75 μM B) in the nutrient solution. Self-grafted watermelon plants were used as control. Pumpkin rootstock improved the plant growth, chlorophyll and carotenoid contents, photosynthetic assimilation, stomatal conductance, transpiration rate, B accumulation and up-regulated the expression of NIP5;1, NIP6;1 and B transporter (BOR2, BOR4) genes in the roots and leaves at 25 μM B compared with self-grafted watermelon plants. Moreover, pumpkin rootstock reduced the oxidative stress and cell damage by reducing H2O2 and MDA contents, and down-regulating the expression of PDCD2-1, PDCD2-2 genes. Moreover, it enhanced the antioxidant activity of watermelon by up-regulating the expression of SOD1, SOD2, CAT2-1, and CAT2-2 genes. Based on these observations, we concluded that pumpkin rootstock has ability to improve the plant growth of watermelon by enhancing the B uptake. This study may help adjust the B concentration in the nutrient medium for watermelon production where pumpkin grafted plants are utilized.


Oxytocin system gene methylation is associated with empathic responses towards children.
Empathy is an essential component of sensitive caregiving behavior, which in turn is an important predictor of children's healthy social-emotional development. The oxytocin (OXT) system plays a key role in promoting sensitive parenting and empathy. In this study, we investigated how OXT system gene methylation was associated with empathic processes in nulliparous women (M age = 23.60, SD =0.44)-measuring both physiological facial muscle responses and ratings of compassion and positive affect to affective images depicting children. Linear mixed effects analyses demonstrated that lower methylation levels in the OXT and OXTR genes were related to enhanced empathic responses. The effect of OXT system gene methylation on empathic processes was partly qualified by an interaction with individual variations in women's care motivation. Our findings provide experimental evidence for an association between the methylation of OXT system genes and empathy.


The cancer-inhibitory effects of proliferating tumor-residing fibroblasts.
Initiation, local progression, and metastasis of cancer are associated with specific morphological, molecular, and functional changes in the extracellular matrix and the fibroblasts within the tumor microenvironment (TME). In the early stages of tumor development, fibroblasts are an obstacle that cancer cells must surpass or nullify to progress. Thus, in early tumor progression, specific signaling from cancer cells activates bio-pathways, which abolish the innate anticancer properties of fibroblasts and convert a high proportion of them to tumor-promoting cancer-associated fibroblasts (CAFs). Following this initial event, a wide spectrum of gene expression changes gradually leads to the development of a stromal fibroblast population with complex heterogeneity, creating fibroblast subtypes with characteristic profiles, which may alternate between being tumor-promotive and tumor-suppressive, topologically and chronologically in the TME. These fibroblast subtypes form the tumor's histological landscape comprising areas of cancer growth, inflammation, angiogenesis, invasion fronts, proliferating and non-proliferating fibroblasts, cancer-cell apoptosis, fibroblast apoptosis, and necrosis. These features reflect general deregulation of tissue homeostasis within the TME. This review discusses fundamental and current knowledge that has established the existence of anticancer fibroblasts within the various interacting elements of the TME. It is proposed that the maintenance of fibroblast proliferation is an essential parameter for the activation of their anticancer capacity, similar to that by which normal fibroblasts would be activated in wound repair, thus maintaining tissue homeostasis. Encouragement of research in this direction may render new means of cancer therapy and a greater understanding of tumor progression.


Tetramorium tsushimae Ants Use Methyl Branched Hydrocarbons of Aphids for Partner Recognition.
In mutualisms, partner discrimination is often the most important challenge for interacting organisms. The interaction between ants and aphids is a model system for studying mutualisms; ants are provided with honeydew by aphids and, in turn, the ants offer beneficial services to the aphids. To establish and maintain this system, ants must discriminate mutualistic aphid species correctly. Although recent studies have shown that ants recognize aphids as mutualistic partners based on their cuticular hydrocarbons (CHCs), it was unclear which CHCs are involved in recognition. Here, we tested whether the n-alkane or methylalkane fraction, or both, of aphid CHCs were utilized as partner recognition cues by measuring ant aggressiveness toward these fractions. When workers of Tetramorium tsushimae ants were presented with dummies coated with n-alkanes of their mutualistic aphid Aphis craccivora, ants displayed higher levels of aggression than to dummies treated with total CHCs or methyl alkanes of A. craccivora; responses to dummies treated with n-alkanes of A. craccivora were similar to those to control dummies or dummies treated with the CHCs of the non-mutualistic aphid Acyrthosiphon pisum. By contrast, ants exhibited lower aggression to dummies treated with either total CHCs or the methylalkane fraction of the mutualistic aphid than to control dummies or dummies treated with CHCs of the non-mutualistic aphid. These results suggest that T. tsushimae ants use methylalkanes of the mutualistic aphid's CHCs to recognize partners, and that these ants do not recognize aphids as partners on the basis of n-alkanes.


Testing the thermodynamic approach to granular matter with a numerical model of a decisive experiment.
Edwards has proposed a thermodynamic description of dense, slowly flowing granular matter, in which the grains (the 'atoms' of the system) interact with inelastic forces and enduring contacts. In Edwards' ensemble-one of the very few generalizations of standard statistical mechanics-thermodynamic quantities are computed as flat averages over configurations in which the grains are static or jammed, leading to a natural definition of configurational temperature. But the approach is not justified from first principles and hence, in the absence of explicit tests of its validity, has not been widely accepted. Here we report a numerical experiment involving a realistic model of slowly sheared granular matter; our results strongly support the thermodynamic description. Considering particles of different sizes in a slowly sheared dense granular system, we extract an effective temperature from a relation connecting their diffusivity and mobility. We then perform an explicit computation to show that the effective temperature measured from this relation coincides with the Edwards configurational temperature. Our approach, which is specifically conceived to be reproducible in the laboratory, may thus render the Edwards temperature accessible to experiments.


Brain macrophages: questions of origin and interrelationship.
Brain tissue appears to contain several distinct types of macrophages. An effort is made here to present a description of the complete cohort of macrophages and sources of phagocytic activity in this tissue. Initially, the criteria and methods used for the identification of tissue macrophages in general are considered. These include some morphological and ultrastructural features, assessment of phagocytic activity, and histochemistry for intracellular and surface components. Each of these methods or criteria has certain advantages but also associated problems and limitations; all have been applied in various instances to brain tissue. In a final analysis, the most reliable means of identification of tissue macrophages involves a combination of all of these approaches. The identification and characterization of macrophages have been rendered extremely confusing in the brain because of so many different sources of these cells, both intrinsic and blood-derived. The classes of macrophages or phagocytic cells in brain tissue are microglia, supraependymal cells, epiplexus cells, meningeal macrophages, pericytes, and direct blood-derived macrophages. The morphology, location, and functional properties of each of these classes is described. In an overall view, brain tissue is very well protected by intrinsic macrophages, and the locations and distribution of these cells are consistent with other tissues. Finally, in a consideration of origin and interrelationship, the idea is presented that the most likely source for all or most brain macrophages is monocytic blood cells. The latter cells appear to migrate into the tissue from several sites during embryogenesis and may continue to enter, at least from blood vessels, in the adult state.


Mechanism of D-Cycloserine Inhibition of D-Amino Acid Transaminase from Haliscomenobacter hydrossis.
D-cycloserine inhibits pyridoxal-5'-phosphate (PLP)-dependent enzymes. Inhibition effect depend on organization of the active site and mechanism of the catalyzed reaction. D-cycloserine interacts with the PLP form of the enzyme similarly to the substrate (amino acid), and this interaction is predominantly reversible. Several products of the interaction of PLP with D-cycloserine are known. For some enzymes formation of a stable aromatic product - hydroxyisoxazole-pyridoxamine-5'-phosphate at certain pH - leads to irreversible inhibition. The aim of this work was to study the mechanism of D-cycloserine inhibition of the PLP-dependent D-amino acid transaminase from Haliscomenobacter hydrossis. Spectral methods revealed several products of interaction of D-cycloserine with PLP in the active site of transaminase: oxime between PLP and β-aminooxy-D-alanine, ketimine between pyridoxamine-5'-phosphate and cyclic form of D-cycloserine, and pyridoxamine-5'-phosphate. Formation of hydroxyisoxazole-pyridoxamine-5'-phosphate was not observed. 3D structure of the complex with D-cycloserine was obtained using X-ray diffraction analysis. In the active site of transaminase, a ketimine adduct between pyridoxamine-5'-phosphate and D-cycloserine in the cyclic form was found. Ketimine occupied two positions interacting with different active site residues via hydrogen bonds. Using kinetic and spectral methods we have shown that D-cycloserine inhibition is reversible, and activity of the inhibited transaminase from H. hydrossis could be restored by adding excess of keto substrate or excess of cofactor. The obtained results confirm reversibility of the inhibition by D-cycloserine and interconversion of various adducts of D-cycloserine and PLP.


A Provider-Based Approach to Address Racial Disparities in Lupus Clinical Trial Participation.
Substantial disparities exist in clinical trial participation, which is problematic in diseases such as lupus that disproportionately affect racial/ethnic minority populations. Our objective was to examine the effectiveness of an online educational course aiming to train medical providers to refer Black and Latino patients to lupus clinical trials (LCTs). The American College of Rheumatology's Materials to Increase Minority Involvement in Clinical Trials (MIMICT) study used an online, randomized, 2-group, pretest/posttest design with medical and nursing providers of multiple specialties. We exposed intervention group participants to an education course, while the control group participants received no intervention. Controlling for the effects of participant characteristics, including specialty, and professional experience with lupus, we modeled relationships among exposure to the education course and changes in knowledge, attitudes, self-efficacy, and intentions to refer Black and Latino patients to LCTs. We also examined education course satisfaction. Compared to the control group, the intervention group had significantly higher posttest scores for knowledge, self-efficacy, and intentions to refer Black and Latino patients to LCTs. Both medical and nursing trained intervention group participants had significantly higher mean posttest scores for knowledge and intentions to refer compared to the medical and nursing trained control group participants. Attitude was insignificant in analysis. The online education course, which received a favorable summary score, indicated that satisfaction and intentions to refer were strongly and positively correlated. The MIMICT education course is an effective method to educate medical providers about LCTs and to improve their intentions to refer Black and Latino patients.


Localization of villin, a cytoskeletal protein specific to microvilli, in human ileum and colon and in colonic neoplasms.
Villin is a cytoskeletal protein of microvilli of epithelial cell brush borders found principally in absorptive cells of the intestine and proximal renal tubule. A marker of both enterocyte differentiation and epithelial cell polarity, it has been studied mainly in experimental animals. We raised monoclonal antibodies to villin and used them to localize it in human ileum and colon and in 22 colonic neoplasms. Villin is localized in the brush border of normal ileum and in the luminal border of normal colon and is expressed with increasing staining intensity as cells migrate from crypt to surface. It was present in the luminal border in all five adenomas and in 16 of 17 adenocarcinomas studied. In addition, villin staining was observed in the cytoplasm of 10 tumors, and in the basement membrane area surrounding tumor in 10 cases. In "transitional" mucosa adjacent to carcinomas it was confined to the luminal border. Abnormal expression of villin by a significant proportion of colonic tumors suggests that it may have a role as a marker of colorectal neoplasia.


Extrahepatic Malignancies in Nonalcoholic Fatty Liver Disease.
Malignancy is the second most common cause of death in individuals with nonalcoholic fatty liver disease (NAFLD). Understanding unique characteristics of malignancy risk beyond hepatocellular carcinoma in NAFLD has significant implications in counseling and personalized preventative measures in this high-risk population. Herein, we systematically review the literature reporting extra-hepatic malignancies in NAFLD and discuss the key biological mechanisms underpinning the association between excess adiposity and cancer risk. Several studies have shown significant associations between NAFLD and extrahepatic malignancies. The strongest association was found with cancers of the gastrointestinal tract and hormone-sensitive cancers. Recent data support sex-specific differences in cancer risk increase in NAFLD: colorectal cancer in men and uterine cancer in women. The risk of cancer development is higher in NAFLD than obesity alone. A growing body of observational evidence over the last decade supports the association between NAFLD and extrahepatic malignancies. This association requires further studies, ideally designed to include more detailed measures of body fat deposition beyond BMI in well-characterized, large cohorts of NAFLD patients, to determine if screening policies should be individualized in this group.


Lamination of the cerebral cortex is disturbed in Gli3 mutant mice.
The layered organization of the cerebral cortex develops in an inside-out pattern, a process which is controlled by the secreted protein reelin. Here we report on cortical lamination in the Gli3 hypomorphic mouse mutant Xt(J)/Pdn which lacks the cortical hem, a major source of reelin(+) Cajal Retzius cells in the cerebral cortex. Unlike other previously described mouse mutants with hem defects, cortical lamination is disturbed in Xt(J)/Pdn animals. Surprisingly, these layering defects occur in the presence of reelin(+) cells which are probably derived from an expanded Dbx1(+) progenitor pool in the mutant. However, while these reelin(+) neurons and also Calretinin(+) cells are initially evenly distributed over the cortical surface they form clusters later during development suggesting a novel role for Gli3 in maintaining the proper arrangement of these cells in the marginal zone. Moreover, the radial glial network is disturbed in the regions of these clusters. In addition, the differentiation of subplate cells is affected which serve as a framework for developing a properly laminated cortex.


Autophosphorylation of plasma membrane bound calcium calmodulin dependent protein kinase from pea seedlings and modification of catalytic activity by autophosphorylation.
We have previously shown that pea seedling plasma membrane contains a protein kinase whose activity towards plasma membrane proteins is markedly increased by micromolar concentrations of calcium and calmodulin. The evidence in this paper suggests that this protein kinase autophosphorylates, that autophosphorylation is increased in a calcium and calmodulin dependent fashion and that prior autophosphorylation modifies activity towards an exogenous substrate. This protein kinase has a molecular weight of approximately 18,000 and is referred to as phosphoprotein18 (pp18).


Elimination of EMG interference during recording of somatosensory evoked potentials elicited by posterior tibial nerve stimulation in patients with cervical spinal cord injury.
Recording SEPs to PTN stimulation in some patients with acute injuries of the cervical spine can be difficult due to the presence of involuntary activity of the neck and jaw muscles. The electrical potentials derived from this myogenic activity have a distribution along the sagittal line of the head which is uniform in amplitude while the amplitude of the SEPs recorded from points along this sagittal line is maximal over a point close to the vertex and less in front and behind this point. This fact has been utilized to devise a 'bipolar' derivation with one electrode on the vertex and two electrodes, one in front and one behind it on the sagittal line tied together as a reference. This effectively eliminates potentials of muscle origin from the SEP record. Other 'bipolar' combinations are not as effective in obtaining evoked potentials free of this muscle interference.


Physicians' mental health and coping during the COVID-19 pandemic: One year exploration.
Numerous cross-sectional studies have examined physicians' health and coping during the COVID-19 pandemic, while longitudinal studies are lacking. This study explores the progression over one year of physicians' physical and mental health symptoms, their strategies used to cope and discusses coping strategies in relation to physical and mental health symptoms. Two surveys, one year apart, exploring physicians' physical, mental health symptoms and employed coping strategies were sent to all physicians practicing in the province of Saskatchewan, Canada. A total of 117 physicians participated in Round I (RI) (November 2020-January 2021) and 158 participated in Round II (RII) (October 2021-February 2022). Physicians' physical and mental health symptoms remained high, irrespective of their specialty or COVID-19 exposure. COVID-related Post-Traumatic Stress Disorder increased by five times at RII (p = 0.02). In RI anxiety was most prevalent in middle-aged females. In RII depression was most prevalent in physicians with no children. Most coping was adaptive (90%) and included Behavioural, Relational, Cognitive, Spiritual, and Interventional strategies. After one-year, Spiritual coping decreased, while Interventional coping increased by eight times (p = 0.01). Despite efforts to employ adaptive coping, physicians' rates of psychological and physical health difficulties remained high or worsened over one year, offering insight into the protracted health care crisis, and the need for solutions. Our observation of physicians' needs for additional supports, camaraderie and appreciation as well as the shift in coping strategies as the pandemic progressed, offer targets for interventions meant to promote recovery.


Quinoline: A versatile heterocyclic.
Quinoline or 1-aza-naphthalene is a weak tertiary base. Quinoline ring has been found to possess antimalarial, anti-bacterial, antifungal, anthelmintic, cardiotonic, anticonvulsant, anti-inflammatory, and analgesic activity. Quinoline not only has a wide range of biological and pharmacological activities but there are several established protocols for the synthesis of this ring. The article aims at highlighting these very diversities of the ring.


Separation and identification of a novel tadalafil analogue adulterant in a dietary supplement.
A novel tadalafil analogue found in a dietary supplement by routine drug-adulteration screening was isolated by column chromatography and HPLC. On the basis of extensive 1D- and 2D-nuclear magnetic resonance (NMR), infrared (IR) and mass spectral analyses, the structure of the new compound YJ-02 was established as 6-(benzo[d][1,3]dioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-(1E,2E)-3-phenylallylidene)amino)pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione. Its common name is N-phenylpropenyltadalafil.


Near-infrared reflectance spectroscopy as a process analytical technology tool in Ginkgo biloba extract qualification.
Here, we describe the use of near-infrared diffuse reflectance spectroscopy for qualification of Ginkgo biloba extract as raw material for use in pharmaceutical products. G. biloba extract shows unpredicted and uncontrolled variability in some of its quality specifications, intrinsic to its natural origin, which have influence on the manufacturing process of solid dosage forms (viz. granulation and compression). Some of these properties could not be determined by conventional quality control tests, so we investigated the use of NIR to qualify the batches of Ginkgo extract accordingly to its different features and establish a relationship with some of the manufacturing steps behaviour based on their qualification. Several approaches were evaluated, and the NIR method developed demonstrated to be sensitive to changes in important quality specifications and therefore adequate to qualify incoming batches of G. biloba extract. This could be considered a process analytical technology (PAT) application since it: (1) establishes the source of variability in a qualitative way, (2) explains its propagation to the final product quality attributes and (3) lays the basis for a control strategy to be applied in the manufacturing process.


Massive osteolysis of the pelvis, femur and sacral bone with a Gorham-Stout syndrome.
We report a case of a 49-year-old white woman with Gorham-Stout syndrome. This very rare massive osteolysis occurred in the left pelvis and included the femur and the sacral bone. Histology study revealed typical ectatic vessels covered with endothelium. The therapy of choice in this region is radiotherapy with a dose of 40 Gy. However, in our case this therapy only led to short-term pain relief and cessation of the osteolysis. Stabilization with corticospongious bone did not seem to be effective against the progressing osteolysis.


Sialic acid-engineered mesoporous polydopamine nanoparticles loaded with SPIO and Fe3+ as a novel theranostic agent for T1/T2 dual-mode MRI-guided combined chemo-photothermal treatment of hepatic cancer.
Hepatic cancer is a serious disease with high morbidity and mortality. Theranostic agents with effective diagnostic and therapeutic capability are highly needed for the treatment of hepatic cancer. Herein, we aimed to develop a novel mesoporous polydopamine (MPDA)-based theranostic agent for T1/T2 dual magnetic resonance imaging (MRI)-guided cancer chemo-photothermal therapy. Superparamagnetic iron oxide (SPIO)-loaded MPDA NPs (MPDA@SPIO) was firstly prepared, followed by modifying with a targeted molecule of sialic acid (SA) and chelating with Fe3+ (SA-MPDA@SPIO/Fe3+ NPs). After that, doxorubicin (DOX)-loaded SA-MPDA@SPIO/Fe3+ NPs (SA-MPDA@SPIO/DOX/Fe3+) was prepared for tumor theranostics. The prepared SAPEG-MPDA@SPIO/Fe3+ NPs were water-dispersible and biocompatible as evidenced by MTT assay. In vitro photothermal and relaxivity property suggested that the novel theranostic agent possessed excellent photothermal conversion capability and photostability, with relaxivity of being r1 = 4.29 mM-1s-1 and r2 = 105.53 mM-1s-1, respectively. SAPEG-MPDA@SPIO/Fe3+ NPs could effectively encapsulate the DOX, showing dual pH- and thermal-triggered drug release behavior. In vitro and in vivo studies revealed that SA-MPDA@SPIO/DOX/Fe3+ NPs could effectively target to the hepatic tumor tissue, which was possibly due to the specific interaction between SA and the overexpressed E-selectin. This behavior also endowed SA-MPDA@SPIO/DOX/Fe3+ NPs with a more precise T1-T2 dual mode contrast imaging effect than the one without SA modification. In addition, SAPEG-MPDA@SPIO/DOX/Fe3+ NPs displayed a superior therapeutic effect, which was due to its active targeting ability and combined effects of chemotherapy and photothermal therapy. These results demonstrated that SAPEG-MPDA@SPIO/DOX/Fe3+ NPs is an effective targeted nanoplatform for tumor theranostics, having potential value in the effective treatment of hepatic cancer.


Separation and quantitative analysis of some carotenoid fatty acid esters of fruits by liquid chromatography.
The adsorption and partition properties of several fatty acid esters of capsanthin, capsorubin, beta-cryptoxanthin, lutein, violaxanthin and beta-citraurin isolated from fruits were studied by normal-phase (silica) and reversed-phase (octadecylsilane) liquid chromatography using Sudan 1 as internal standard. The separation on a normal phase was based on the functional group of the carotenoids and individual esters of the same carotenoid did not resolve. The separation on a reversed phase was more dependent on the number of acyl carbons than the functional group, and individual esters of the same carotenoid differing only two acyl carbons were separated with a resolution of 3. There was a linear relationship between number of acyl carbons and retention times of the same carotenoid on reversed phase. The separation on a normal phase was the reverse of that on a reversed phase, and a combination of normal-phase followed by reversed-phase chromatography was used for the separation of esters with the same or close retention times.


Weakly supervised volumetric prostate registration for MRI-TRUS image driven by signed distance map.
Image registration is a fundamental step for MRI-TRUS fusion targeted biopsy. Due to the inherent representational differences between these two image modalities, though, intensity-based similarity losses for registration tend to result in poor performance. To mitigate this, comparison of organ segmentations, functioning as a weak proxy measure of image similarity, has been proposed. Segmentations, though, are limited in their information encoding capabilities. Signed distance maps (SDMs), on the other hand, encode these segmentations into a higher dimensional space where shape and boundary information are implicitly captured, and which, in addition, yield high gradients even for slight mismatches, thus preventing vanishing gradients during deep-network training. Based on these advantages, this study proposes a weakly-supervised deep learning volumetric registration approach driven by a mixed loss that operates both on segmentations and their corresponding SDMs, and which is not only robust to outliers, but also encourages optimal global alignment. Our experimental results, performed on a public prostate MRI-TRUS biopsy dataset, demonstrate that our method outperforms other weakly-supervised registration approaches with a dice similarity coefficient (DSC), Hausdorff distance (HD) and mean surface distance (MSD) of 87.3 ± 11.3, 4.56 ± 1.95 mm, and 0.053 ± 0.026 mm, respectively. We also show that the proposed method effectively preserves the prostate gland's internal structure.


Structure and function of the Na, K-ion pump or Na, K-ATPase in mammalian kidney.
Information about the purified Na, K-ATPase from the mammalian thick ascending limb of Henle is related to studies on its localization in tubular cells and the environment along the transport pathways to reach a better understanding of the role of this pump in the active transtubular transport of Na+.


Increased choline uptake in macrophages and prostate cancer cells does not allow for differentiation between benign and malignant prostate pathologies.
Inflammatory cells may contribute to the choline uptake in different prostate pathologies. The aim of this study was (i) to assess if inflammatory cells incorporate choline and (ii) to potentially detect differences compared to FDG uptake. Therefore we investigated the uptake of [(3)H]choline and [(18)F]FDG in human prostate carcinoma cells and human inflammatory cells. Macrophages were cultured from isolated mononuclear cells, gained by density gradient centrifugation of human buffy coats. T-lymphocytes, B-lymphocytes and granulocytes were enriched by density gradient centrifugation before cell sorting by means of flow cytometry was performed. [(3)H]choline and [(18)F]FDG uptake of isolated inflammatory cells as well as of LNCaP and PC-3 human prostate carcinoma cells was assessed simultaneously in dual tracer uptake experiments. Macrophages showed highest [(3)H]choline and [(18)F]FDG uptake compared to the tracer uptake rates of leukocytes. [(3)H]choline uptake of macrophages was in the same range as in prostate cancer cells. Lipopolysaccharide stimulation of macrophages resulted in an increase of [(18)F]FDG uptake in macrophages, but not in an increased [(3)H]choline uptake. The high [(3)H]choline uptake in macrophages may be a source of false-positive PET results in diagnosis of prostate cancer by choline-PET/CT. As already known from FDG-PET, discrimination between tumor and inflammation in prostate cancer patients is not possible via choline-PET. The application of choline-PET for reliable primary prostate cancer detection and delineation has to be queried.


Factor XIIIa-catalyzed cross-linking of platelet and muscle actin. Regulation by nucleotides.
Actin from human blood platelets or rabbit skeletal muscle can serve as substrate for factor XIIIa. The latter catalyzes the incorporation of 1.5-2 mol monodansylcadaverine/mol rabbit actin and 0.5 mol/mol platelet actin. Highly cross-linked platelet and muscle actin polymers form in the absence of added amines, indicating the presence of both acceptor and donor sites. As expected, the cross-link was found to be a gamma-glutamyl-epsilon-lysine bone, with an average of 0.3-0.4 mol dipeptide/mol platelet actin. Both cross-linking and amine incorporation are prevented by ATP, ADP, GTP, CTP, but not by AMP and cyclic AMP. These nucleotides may have important regulatory role in muscle and non-muscle systems.


Molecular manipulator driven by spatial variation of liquid-crystalline order.
Collective long-range interactions between micrometre-sized impurities in liquid crystals result from the elastic distortion of the liquid-crystalline order. For substantially smaller polymeric impurities, what is relevant is not the elastic interaction between them but the coupling between the scalar nematic order parameter S and the polymer concentration φ. This coupling originates from local molecular interactions, but becomes long ranged because the total polymer concentration is conserved over the whole sample. Here, we propose a new mechanism by which the spatial variation of S generates a force, mediated by the coupling between S and φ, that transports nanoscale polymeric impurities. We have designed a prototype of a molecular manipulator that moves molecules along spatial variations of the scalar order parameter, modulated in a controlled manner by spot illumination of an azobenzene-doped nematic phase with ultra-violet light. We also demonstrate the use of the manipulator for the measurement of the anisotropic diffusion constant of a polymer in the nematic phase. The manipulator can control the spatial variation of the polymer concentration, thus showing promise for use in the design of hybrid soft materials.


Molecular taxonomy of cupped oysters (Crassostrea, Saccostrea, and Striostrea) in Thailand based on COI, 16S, and 18S rDNA polymorphism.
Genetic diversity of oysters Crassostrea belcheri (Sowerby, 1871), C. iredalei (Faustino, 1932), Saccostrea cucullata (Born, 1778), S. forskali (Gmelin, 1791), and Striostrea (Parastriostrea) mytiloides (Lamarck, 1819) (Ostreoida, Mollusca) was analyzed by polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) of 16S ribosomal DNA with AcsI, AluI, DdeI, DraI, RsaI, and TaqI, 18S ribosomal DNA with HinfI, and cytochrome oxidase subunit I with AcsI, DdeI and MboI. A total of 54 composite haplotypes were observed. Species-diagnostic markers were specifically found in C. belcheri, C. iredalei, and S. cucullata, but not in S. forskali and Striostrea mytiloides, which shared common composite haplotypes. Neighbor-joining trees constructed from genetic distances between pairs of composite haplotypes and species indicated large genetic differences between Crassostrea and Saccostrea (including Striostrea mytiloides), but closer relationships were observed within each genus. Four groups of unidentified oysters (Crassostrea sp. and Saccostrea sp. groups 1, 2, and 3) were also genetically analyzed. Fixed RFLP markers were found in Crassostrea sp. and Saccostrea sp. group 2, but not in Saccostrea sp. groups 1 and 3. Phylogenetic and genetic heterogeneity analyses indicated that Crassostrea sp. and Saccostrea sp. group 2 should be considered as newly unidentified oyster species in Thailand.


Synergism between particle-based multiplexing and microfluidics technologies may bring diagnostics closer to the patient.
In the field of medical diagnostics there is a growing need for inexpensive, accurate, and quick high-throughput assays. On the one hand, recent progress in microfluidics technologies is expected to strongly support the development of miniaturized analytical devices, which will speed up (bio)analytical assays. On the other hand, a higher throughput can be obtained by the simultaneous screening of one sample for multiple targets (multiplexing) by means of encoded particle-based assays. Multiplexing at the macro level is now common in research labs and is expected to become part of clinical diagnostics. This review aims to debate on the "added value" we can expect from (bio)analysis with particles in microfluidic devices. Technologies to (a) decode, (b) analyze, and (c) manipulate the particles are described. Special emphasis is placed on the challenges of integrating currently existing detection platforms for encoded microparticles into microdevices and on promising microtechnologies that could be used to down-scale the detection units in order to obtain compact miniaturized particle-based multiplexing platforms.


Improvement of in vitro evaluation of chemical disinfectants for efficacy on Cryptosporidium parvum oocysts.
Cryptosporidium parvum has been suggested as a suitable target for in vitro efficacy testing of disinfectants. To improve validity of a method based on exposure of HCT-8 monolayers to C. parvum oocysts we here critically evaluate and we propose certain procedural steps needed for the validation of disinfectants. Within a range of 0.02% to 0.4%, sodium taurocholate at 0.2% stimulated infection most efficiently while preserving host cell integrity. The course of invasion was monitored for periods of 30-240min post infection (p.i.). FACS analysis revealed that the proportion of sporozoites liberated from oocysts in the presence of 0.2% sodium taurocholate increased within 120min of incubation but remained constant thereafter. Maximum invasion of cells measured by qPCR was reached 180min p.i. and therefore set as invasion endpoint. As monolayers harvested 24h or 48h p.i. did not differ in the quantity of parasite hsp70 gene copies, DNA extraction can be performed as early as 24h p.i. Incubation of oocysts with 20% H2O2 for 2h resulted in inactivation of more than 99.5% both at room temperature and 10°C and appeared thus suitable as positive chemical treatment control. Four washing procedures considered to remove potentially toxic residual disinfectant from oocyst suspensions were tested. An application of a combination of DMSO (Dimethylsulfoxid), Tween20 and WSH (water of standardized hardness) appeared most efficient without deleterious effect of disinfectant residuals on the cell monolayer viability when oocysts accordingly washed were applied. In conclusion, for standardized in vitro evaluation of chemical disinfectants in C. parvum infected HTC-8 monolayers. (i) excystation medium should contain 0.2 % sodium taurocholate. (ii) excystation medium should be replaced by growth medium after 180 min. (iii) monolayers should be harvested 24 h p.i. for DNA preparation. (iv) ocysts exposed to 20 % H2O2 should be included as positive controls. (v) disinfected oocysts should be washed with DMSO/Tween20/WSH before they are transferred to monolayers.


A class of finite-time dual neural networks for solving quadratic programming problems and its k-winners-take-all application.
This paper presents a class of recurrent neural networks to solve quadratic programming problems. Different from most existing recurrent neural networks for solving quadratic programming problems, the proposed neural network model converges in finite time and the activation function is not required to be a hard-limiting function for finite convergence time. The stability, finite-time convergence property and the optimality of the proposed neural network for solving the original quadratic programming problem are proven in theory. Extensive simulations are performed to evaluate the performance of the neural network with different parameters. In addition, the proposed neural network is applied to solving the k-winner-take-all (k-WTA) problem. Both theoretical analysis and numerical simulations validate the effectiveness of our method for solving the k-WTA problem.


Taking cues from the extracellular matrix to design bone-mimetic regenerative scaffolds.
There is an ongoing need for effective materials that can replace autologous bone grafts in the clinical treatment of bone injuries and deficiencies. In recent years, research efforts have shifted away from a focus on inert biomaterials to favor scaffolds that mimic the biochemistry and structure of the native bone extracellular matrix (ECM). The expectation is that such scaffolds will integrate with host tissue and actively promote osseous healing. To further enhance the osteoinductivity of bone graft substitutes, ECM-mimetic scaffolds are being engineered with a range of growth factors (GFs). The technologies used to generate GF-modified scaffolds are often inspired by natural processes that regulate the association between endogenous ECMs and GFs. The purpose of this review is to summarize research centered on the development of regenerative scaffolds that replicate the fundamental collagen-hydroxyapatite structure of native bone ECM, and the functionalization of these scaffolds with GFs that stimulate critical events in osteogenesis.


Treatment of chronic gouty arthritis: it is not just about urate-lowering therapy.
The management of gouty arthritis is focused on treating pain and inflammation associated with acute flares and preventing further acute flares and urate crystal deposition. A challenge associated with the successful management of gouty arthritis is an increased risk of acute flares during the first months after initiation of urate-lowering therapy (ULT). This increase in flare frequency can occur regardless of the choice of ULT and is linked to suboptimal patient adherence to ULT. Current treatment recommendations for the use of prophylaxis are limited. There are no definitive recommendations as to which agents should be used or for how long therapy is beneficial after starting ULT. This article aims to improve awareness of the importance of gouty arthritis flare prophylaxis when initiating ULT and to summarize current recommendations and clinical findings related to the efficacy and safety of currently available and investigational new therapies. This review discusses the pathophysiology of acute gouty arthritis flares during initiation of ULT and examines the literature on the use of anti-inflammatory prophylaxis for reduction of these flares. It has recently become clear that, even when the patient is asymptomatic, chronic inflammation is often present in patients with chronic gouty arthritis. Chronic anti-inflammatory therapy should therefore be added to chronic ULT. Prophylaxis with colchicine as well as with nonsteroidal anti-inflammatory drugs (NSAIDs) during ULT initiation can reduce the incidence and severity of gouty arthritis flares substantially; however, safety concerns associated with colchicine and NSAIDs may limit their use. When colchicine and NSAIDs are contraindicated or poorly tolerated, rilonacept and canakinumab, interleukin-1 inhibitors in trials, may prove to be useful alternatives for flare prevention. (Of note, although both inhibit the IL-1β pathway, rilonacept also binds to IL-1α and IL-1RA, in contrast to canakinumab, which binds selectively to IL-1β.).


Magnetic field coupling with lunar soil simulants.
Wireless power transfer (WPT) using magnetically coupled resonators is being integrated into space vehicles destined for the lunar surface. The dusty soil on the Moon, called lunar regolith, is known to adhere to surfaces and is also known to contain iron, including iron oxides and metallic iron. Regolith samples are limited, and lunar soil simulants are commonly used in space science research for efforts in surface vehicle navigation, in-situ resource utilization, and power infrastructure. However, most simulants contain no metallic iron, and research involving electromagnetic field interactions with regolith would benefit from incorporating metallic iron into test samples. This work presents experimental results from tests using WPT with magnetically coupled resonators in the presence of various standard lunar simulants, plus a new iron-enriched simulant and metallic iron powders. Results for power transfer efficiency, thermal response, and frequency response are presented and demonstrate that the presence of metallic iron and its particle size are critical factors affecting the coupling of the incident magnetic field with lunar simulants and iron powder samples. The importance of particle size-to-skin depth ratio is discussed. Attenuation constants for various iron powders are estimated from experimental data and compared to those of lunar regolith and simulants.


The role of epigenetics in hybrid vigour.
Hybrid vigour, or heterosis, refers to the increased yield and biomass of hybrid offspring relative to the parents. Although this has been exploited in plants for agriculture and horticulture, the molecular and cellular mechanisms underlying hybrid vigour are largely unknown. Genetic analyses show that there are a large number of quantitative trait loci (QTLs) that contribute to the heterotic phenotype, indicating that it is a complex phenomenon. Gene expression in hybrids is regulated by the interactions of the two parental epigenetic systems and the underlying genomes. Increasing understanding of the interplay of small RNA (sRNA) molecules, DNA methylation, and histone marks provides new opportunities to define the basis of hybrid vigour and to understand why F1 heterosis is not passed on to subsequent generations. We discuss recent findings that suggest the existence of several pathways that alter DNA methylation patterns, which may lead to transcriptional changes resulting in the heterotic phenotype.


Esophageal achalasia 2011: pneumatic dilatation or laparoscopic myotomy?
This article reviews the changes that have taken place in the treatment of patients with achalasia in the last 20 years. It compares and contrasts treatment preferences in the USA with those of Canada and Europe. It provides a critical analysis of the recent randomized trial between laparoscopic Heller myotomy and pneumatic dilatation that was carried out in several European centers. It supports the use of laparoscopic Heller myotomy as the preferred treatment for the average patient with this disease in the USA.


Choriodecidual inflammation: a potentially preventable cause of perinatal HIV-1 transmission?
The obstetric risk factors for perinatal transmission of HIV-1 include preterm birth, prolonged rupture of the chorioamniotic membranes, and clinical and histological bacterial chorioamnionitis. A chronic chorioamnionitis precedes many cases of preterm labour and spontaneous rupture of membranes, whereas an acute chorioamnionitis is more common after rupture of the membranes at term. Amniotic fluid cytokines are raised in the presence of term and preterm intrauterine bacterial infections, and various cytokines seem able to attract HIV-1-infected leucocytes into the amniotic cavity and to increase replication of HIV-1. We postulate that the association of preterm birth and prolonged rupture of membranes with perinatal transmission of HIV-1 may result from an associated chronic or acute bacterial chorioamnionitis marked by the migration of HIV-1-infected maternal leucocytes into the amniotic cavity. Antibiotic treatment could prevent this sequence of events.


Delineation of tunnel-like-ventricular septal defects in young children by axial cineangiography.
Four children with systolic thrills and harsh pansystolic murmurs in the second left and right intercostal spaces, radiating to the base of the neck, and suspected of having a subaortic ventricular septal defect and possible aortic prolapse underwent angiocardiography using axial projections. All demonstrated an unusual "tunnel-like" track into the right ventricle and no subaortic ventricular septal defect or prolapse. In our opinion, these physical findings suggest this abnormality and that axial angiography clearly delineates the lesion.


Complete reversibility of paraneoplastic acanthosis nigricans after operation.
A patient with widespread acanthosis nigricans is described. No abdominal tumour was found. Explorative thoracotomy disclosed numerous enlarged lymph glands containing squamous cell carcinoma. The left lung was removed but meticulous search did not disclose any tumour. The glands were removed as radically as possible. After the operation the skin improved and the lesions have disappeared completely. The observation time is over three years.


The potential role of combined antioxidant treatment on pancreas of STZ-diabetic mice.
In diabetes, cells and tissues are damaged due to the imbalance between production of free radicals and removal of them. The effective biologic antioxidants for oxidative stress such as α-lipoic acid, vitamin E and selenium are effective in diminishing oxidative damage such as membrane lipid peroxidation. The experiment aimed to investigate the oxidative stress occurring in mitochondrial and cytoplasmic fraction of pancreatic tissues in streptozotocin-diabetic mice and the possible effects of α-lipoic acid + vitamin E + selenium combination on oxidative damage and antioxidative system by using microscopic and biochemical methods. The mice were divided into five groups. These groups were treated by citrate buffer, the solvents of the antioxidants, combined the antioxidants [α-lipoic acid (50 mg/kg), vitamin E (100 mg/kg), selenium (0.25 mg/kg)], streptozotocin (40 mg/kg × 5), combined the antioxidants and streptozotocin. The mice were sacrificed by cervical dislocation. In the experimental group given combined antioxidants following results were observed compared to diabetic group: increased percent insulin-positive cell area; decreased blood glucose levels; increased manganase superoxide dismutase activities and unsignificantly increased superoxide dismutase activities; unsignificantly decreased lipid peroxidase levels in both of fraction; unsignificantly decreased in mitochondrial fraction and unsignificantly increased in cytosolic fraction for catalase levels; not any alteration glutathione levels; not any activity in both of fraction for glutathione peroxidase. We can say that by taking the blood glucose levels and immunohistochemical results into account, the combination of triple antioxidants has a partly positive effect on diabetes. This positive effect could increase when trying different doses of combined antioxidant treatment.


Prostaglandin-stimulated recovery of the human duodenal epithelium: effects of misoprostol on ethanol damage.
This study was designed to determine whether prostaglandins can stimulate the repair of human duodenal epithelium. Ten healthy volunteers were given 50 ml 40% ethanol through an endoscope onto the duodenal mucosa 1-7 cm from the pyloric sphincter; 3 min later, misoprostol (200 micrograms) or inert vehicle (5 ml) was given locally in the same way. One and 5 h later, endoscopy was repeated to evaluate the damage. The conditions of the mucosa were evaluated by endoscopy and by scanning and transmission electron microscopy in biopsies taken at time 0 and 3 min, 1 and 5 h after ethanol. The study was double-blind with a cross-over balanced design. Three minutes after ethanol administration, the duodenal mucosa showed hyperemia with hemorrhagic lesions. Under the electron microscope, the lesions were caused by vascular engorgement or red blood cell extravasation into the submucosa; the epithelium underlining lesions showed loss of superficial cells and damage to the upper layer of the mucosa. One hour after ethanol, there was a striking difference between the two treatment groups, with a substantial recovery of the duodenal epithelium in the misoprostol-treated volunteers. Although spontaneous recovery was evident in the control group, there was also a significant difference at 5 h. Our results suggest that prostaglandins are able to stimulate the recovery of the duodenal epithelium after acute damage.


Time for change in research careers: We as research organizations doing everything we can for postdocs?: Are we as research organizations doing everything we can for postdocs?
Postdocs are at a challenging step in the career ladder and research organisations could do more to help them along the way.


Isolation of Cryptococcus neoformans var. neoformans from canine otitis.
Cryptococcus neoformans was demonstrated in the clinical material of a 15-year-old male dog with a history of chronic otitis externa by employing Helianthus annuus seed agar as a selective medium. The examination of the isolate for sexual compatibility on modified Helianthus annuus seed medium revealed that it belonged to Filobasidiella neoformans var. neoformans 'alpha' mating type. In the authors' view, this appears to be the first report of isolation of Cr. neoformans var. neoformans from diseased ear of a dog.


[Studies on the blood compatibility of the polyurethane/nano-sized carbon composite].
To investigate the effects of nano-sized carbon as a dispersed phase on blood compatibility of polyurethanes. A novel nanoscale polymeric composite film was prepared by dispersing nano-sized carbon fiber (vapor growth carbon fiber) into the polyurethane solutions. The surface blood compatibilities of the composites were analyzed and evaluated through platelet adhesion measurement using epifluorescent video microscopy and the variation of fibrinogen and free hemoglobin concentration in the blood contacting the composite respectively. It was showed that the platelet adhesions were highly suppressed on the composite surfaces pre-adsorbed or non-pre-adsorbed with fibrinogen. The changes of the concentration for both free hemoglobin and fibrinogen in the blood contacting the composite surface in the circulations were less than the ones contacting the reference surface. Introducing nano-sized carbon into the polyurethane matrix showed an improvement of antithrombogenicity for the polyurethane materials. It might be a new promising way to develop biomaterials with good blood compatibility.


Transcriptomic response of Saccharomyces cerevisiae for its adaptation to sulphuric acid-induced stress.
In bioethanol production plants, yeast cells are generally recycled between fermentation batches by using a treatment with sulphuric acid at a pH ranging from 2.0 to 2.5. We have previously shown that Saccharomyces cerevisiae cells exposed to sulphuric acid treatment induce the general stress response pathway, fail to activate the protein kinase A signalling cascade and requires the mechanisms of cell wall integrity and high osmolarity glycerol pathways in order to survive in this stressful condition. In the present work, we used transcriptome-wide analysis as well as physiological assays to identify the transient metabolic responses of S. cerevisiae under sulphuric acid treatment. The results presented herein indicate that survival depends on a metabolic reprogramming of the yeast cells in order to assure the yeast cell viability by preventing cell growth under this harmful condition. It involves the differential expression of a subset of genes related to cell wall composition and integrity, oxidation-reduction processes, carbohydrate metabolism, ATP synthesis and iron uptake. These results open prospects for application of this knowledge in the improvement of industrial processes based on metabolic engineering to select yeasts resistant to acid treatment.


Cloning and characterization of CRF, a novel C1q-related factor, expressed in areas of the brain involved in motor function.
We have isolated and characterized a novel cDNA, C1q-Related Factor (CRF), that is predicted to encode a 258 amino acid polypeptide with a hydrophobic signal sequence, a collagenous region, and a globular domain at the carboxy terminus that shares homology to the C1q signature domain. Human CRF transcript is expressed at highest levels in the brain, particularly in the brainstem. In situ hybridization to mouse brain sections demonstrated that CRF transcripts are most abundant in areas of the nervous system involved in motor function, such as the Purkinje cells of the cerebellum, the accessory olivary nucleus, the pons and the red nucleus. The mouse CRF homolog is highly similar to the human gene at both the nucleotide and protein level, suggesting an important conserved role for this protein.


Sex and age-specific interactions of coronary atherosclerotic plaque onset and prognosis from coronary computed tomography.
The totality of atherosclerotic plaque derived from coronary computed tomography angiography (CCTA) emerges as a comprehensive measure to assess the intensity of medical treatment that patients need. This study examines the differences in age onset and prognostic significance of atherosclerotic plaque burden between sexes. From a large multi-center CCTA registry the Leiden CCTA score was calculated in 24 950 individuals. A total of 11 678 women (58.5 ± 12.4 years) and 13 272 men (55.6 ± 12.5 years) were followed for 3.7 years for major adverse cardiovascular events (MACE) (death or myocardial infarction). The age where the median risk score was above zero was 12 years higher in women vs. men (64-68 years vs. 52-56 years, respectively, P < 0.001). The Leiden CCTA risk score was independently associated with MACE: score 6-20: HR 2.29 (1.69-3.10); score > 20: HR 6.71 (4.36-10.32) in women, and score 6-20: HR 1.64 (1.29-2.08); score > 20: HR 2.38 (1.73-3.29) in men. The risk was significantly higher for women within the highest score group (adjusted P-interaction = 0.003). In pre-menopausal women, the risk score was equally predictive and comparable with men. In post-menopausal women, the prognostic value was higher for women [score 6-20: HR 2.21 (1.57-3.11); score > 20: HR 6.11 (3.84-9.70) in women; score 6-20: HR 1.57 (1.19-2.09); score > 20: HR 2.25 (1.58-3.22) in men], with a significant interaction for the highest risk group (adjusted P-interaction = 0.004). Women developed coronary atherosclerosis approximately 12 years later than men. Post-menopausal women within the highest atherosclerotic burden group were at significantly higher risk for MACE than their male counterparts, which may have implications for the medical treatment intensity.