[A rare case of psychogenic dysarthrophonia or a complex dyskinesia of the pharynx?].
We present the symptomatology of a complex articulation-related dyskinesia of the pharynx with intermittent functional velopharyngeal insufficiency. It became permanent gradually after a writer's cramp had remitted without therapy. No final nosologic assignment can be made on the basis of the described observations in the individual case. The development of the disease in the 56-year old male patient ended in occupational disability. It suggests manifestation of psychopathological events in the patient's life history of threshold situations by premorbid psychic vulnerability. The possibility of the etiopathologic interaction of emotional and neurological factors cannot be excluded. However, therapy with local botulinum toxin injections proved to be just as unsuccessful as logopedic treatment.


Western Europe, state formation, and genetic pacification.
Through its monopoly on violence, the State tends to pacify social relations. Such pacification proceeded slowly in Western Europe between the 5th and 11th centuries, being hindered by the rudimentary nature of law enforcement, the belief in a man's right to settle personal disputes as he saw fit, and the Church's opposition to the death penalty. These hindrances began to dissolve in the 11th century with a consensus by Church and State that the wicked should be punished so that the good may live in peace. Courts imposed the death penalty more and more often and, by the late Middle Ages, were condemning to death between 0.5 and 1.0% of all men of each generation, with perhaps just as many offenders dying at the scene of the crime or in prison while awaiting trial. Meanwhile, the homicide rate plummeted from the 14th century to the 20th. The pool of violent men dried up until most murders occurred under conditions of jealousy, intoxication, or extreme stress. The decline in personal violence is usually attributed to harsher punishment and the longer-term effects of cultural conditioning. It may also be, however, that this new cultural environment selected against propensities for violence.


Stimulation through the T cell receptor leads to interactions between SHB and several signaling proteins.
Shb is a recently described Src homology 2 (SH2) domain-containing adaptor protein. Here we show that Shb is expressed in lymphoid tissues, and is recruited into signaling complexes upon activation of Jurkat T cells. Grb2 binds proline-rich motifs in Shb via its SH3 domains. As a result, a number of proteins detected in anti-Shb and anti-Grb2 immunoprecipitates are shared, including phosphoproteins of 22, 36/38, 55/57 and 70 kDa. Shb-association with p22, which represents the T cell receptor associated zeta chain, occurs through the Shb SH2 domain. The central region of Shb binds p36/38. Since this interaction was inhibited by phosphotyrosine, this region of Shb is likely to contain a non-SH2 PTB (phosphotyrosine binding) domain. The Shb PTB domain was found to preferentially bind the sequence Asp-Asp-X-pTyr when incubated with a phosphopeptide library. A peptide corresponding to a phosphorylation site in 34 kDa Lnk inhibited association between Shb and p36/38. Overexpression of Shb in Jurkat cells led to increased basal phosphorylation of Shb-associated p36/38 and p70 proteins. Inactivation of the Shb SH2 domain by an R522K mutation resulted in a reduced stimulation of tyrosine phosphorylation of several proteins in response to CD3 crosslinking when expressed in Jurkat cells. Together, our results show three distinct domains of Shb all participate in the formulation of multimeric signaling complexes in activated T cells. These results indicate that the Shb protein functions in T cell receptor signaling.


Antioxidant effects of secondary metabolites from Geranium psilostemon.
An investigation was made of the effects on endogenous antioxidant enzyme activities and H2O2-induced lipid peroxidation inhibition in human red blood cells of the crude MeOH extract and its EtOAc, n-BuOH, and H2O sub-extracts obtained from aerial parts of Geranium psilostemon Ledeb., as well as compounds isolated from the most active EtOAc extract. Gallic acid (1), methyl gallate (2), pusilagin (3), 1,3,6-tri-O-galloyl-beta-glucopyranoside (4), 1,2,3,4,6-penta-O-galloyl-beta-glucopyranoside (5), kaempferol (6), quercetin (7), kaempferol 7-O-alpha-rhamnopyranoside (8), and quercetin 7-O-alpha-rhamnopyranoside (9) were isolated from the aerial parts of the title plant, and their structures identified from spectroscopic (UV, 1D- and 2D- NMR) and spectrometric (TOF-MS) data. All extracts and isolated compounds inhibited H2O2-induced lipid peroxidation and also enhanced the activity of superoxide dismutase (SOD) and catalase (CAT).


Acquired autoimmune thrombotic thrombocytopenic purpura.
Acquired autoimmune thrombotic thrombocytopenic purpura (TTP)-the most common form of TTP-is a life-threatening hematologic disease characterized by hemolytic anemia and thrombocytopenia. Acquired autoimmune TTP can cause signs and symptoms of neurologic and other organ involvement, with mortality approaching 90% if the disease is not promptly recognized and treated. Since the introduction of plasma exchange in 1991, the acquired autoimmune TTP survival rate has increased to 78%.


BMPR1a signaling determines numbers of oligodendrocytes and calbindin-expressing interneurons in the cortex.
Progenitor cells that express the transcription factor olig1 generate several neural cell types including oligodendrocytes and GABAergic interneurons in the dorsal cortex. The fate of these progenitor cells is regulated by a number of signals including bone morphogenetic proteins (BMPs) secreted in the dorsal forebrain. BMPs signal by binding to heteromeric serine-threonine kinase receptors formed by type I (BMPR1a, BMPR1b, Alk2) and type II (BMPRII) subunits. To determine the specific role of the BMPR1a subunit in lineage commitment by olig1-expressing cells, we used a cre/loxP genetic approach to ablate BMPR1a in these cells while leaving signaling from other subunits intact. There was a reduction in numbers of immature oligodendrocytes in the BMPR1a-null mutant brains at birth. However, by postnatal day 20, the BMPR1a-null mice had a significant increase in the number of mature and immature oligodendrocytes compared with wild-type littermates. There was also an increase in the proportion of calbindin-positive interneurons in the dorsomedial cortex of BMPR1a-null mice at birth without any change in the number of parvalbumin- or calretinin-positive cells. These effects were attributable, at least in part, to a decrease in the length of the cell cycle in subventricular zone progenitor cells. Thus, our findings indicate that BMPR1a mediates the suppressive effects of BMP signaling on oligodendrocyte lineage commitment and on the specification of calbindin-positive interneurons in the dorsomedial cortex.


Impairment of human dopaminergic neurons at different developmental stages by perfluoro-octanoic acid (PFOA) and differential human brain areas accumulation of perfluoroalkyl chemicals.
Perfluoroalkyl substances (PFASs) are synthetic chemicals widely used in industrial and consumer products. The environmental spreading of PFASs raises concerns for their impact on human health. In particular, the bioaccumulation in humans due to environmental exposure has been reported also in total brain samples and PFAS exposure has been associated with neurodevelopmental disorders. In this study we aimed to investigate the specific PFAS bioaccumulation in different brain areas. Our data reported major accumulation in the brainstem region, which is richly populated by dopaminergic neurons (DNs), in brain autopsy samples from people resident in a PFAS-polluted area of Italy. Since DNs are the main source of dopamine (DA) in the mammalian central nervous system (CNS), we evaluated the possible functional consequences of perfluoro-octanoic acid (PFOA) exposure in a human model of DNs obtained by differentiation of human induced pluripotent stem cells (hiPSCs). Particularly, we analyzed the specific effect of the exposure to PFOA for 24 h, at the concentration of 10 ng/ml, at 3 different steps of dopaminergic differentiation: the neuronal commitment phase (DP1), the neuronal precursor phase (DP2) and the mature dopaminergic differentiation phase (DP3). Interestingly, compared to untreated cells, exposure to PFOA was associated with a reduced expression of Tyrosine Hydroxylase (TH) and Neurofilament Heavy (NFH), both markers of dopaminergic maturation at DP2 phase. In addition, cells at DP3 phase exposed to PFOA showed a severe reduction in the expression of the Dopamine Transporter (DAT), functionally involved in pre-synaptic dopamine reuptake. In this proof-of-concept study we show a significant impact of PFOA exposure, mainly on the most sensitive stage of neural dopaminergic differentiation, prompting the way for further investigations more directly relevant to risk assessment of these chemicals.


Adult rat myocardial slices: A tool for studies of comparative cardiotoxicity.
The applicability of myocardial slices in comparative cardiotoxicity studies was investigated using the known cardiotoxicants allylamine (AAM) and doxorubicin (DOX). Precision-cut adult rat myocardial slices are a recently developed in vitro system. Previously, it has been demonstrated that myocardial slices are viable for up to 24 hr in organ culture. Myocardial slices exhibited a concentration- and time-dependent loss of viability in response to exposure to AAM or DOX (10(-7), 10(-6) or 10(-5)m) during 24 hr in culture, as assessed by biochemical parameters including protein synthesis, ATP content, lipid peroxidation and the loss of the cytosolic enzyme creatine kinase. Protein synthesis and ATP content were sensitive indicators of slice viability, while lipid peroxidation was affected only by 10(-5)m DOX. Myocardial slices appear to be a useful in vitro system for the study of the cardiotoxic potential of chemicals. The maintenance of normal cellular architecture makes myocardial slices uniquely attractive for these studies.


Progressive chloroquine retinopathy.
Chloroquine retinopathy is a well-documented toxic manifestation of a commonly used systemic medication. The major retinal findings are those of macular retinal pigment epithelial changes, narrowed retinal vessels, and scotomatous visual field defects. The fluorescein angiographic findings are those of a retinal pigment epithelial transmission defect that takes on a bull's-eye configuration. We present a patient who had taken chloroquine for two years while in the military service. Two years after discharge, he was examined and reported to have a mild granular appearance to the macula. Over a period of nine years, progressive decreased central acuity prompted repeated fluorescein angiograms, which revealed a progressive bull's-eye maculopathy compatible with chloroquine retinopathy. Evaluation of offspring failed to reveal any evidence of a hereditary macular dystrophy. To our knowledge, this is the first reported case of delayed onset and progression of chloroquine maculopathy documented by fluorescein angiography.


Silane coupling agent for attaching fusion-bonded epoxy to steel.
We describe the possibility of using γ-aminopropyltriethoxysilane (γ-APS) to increase the durability of epoxy powder coating/steel joints. The curing temperature of epoxy powder coatings is frequently above 200 °C, which is seen so far as a major limitation for the use of the heat-sensitive aminosilane coupling agent. Despite this limitation, we demonstrate that aminosilane is a competitive alternative to traditional chromate conversion to enhance the durability of epoxy powder coatings/steel joints. Fourier-transform reflection-absorption infrared spectroscopy (FT-RAIRS), X-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM) were used to identify the silane deposition conditions that influence the adhesion of epoxy powder coatings on steel. We show that AFM analysis provides highly sensitive measurements of mechanical property development and, as such, the degree of condensation of the silane. The joint durability in water at 60 °C was lower when the pH of the γ-APS solution was controlled at 4.6 using formic acid, rather than that at natural pH (10.6). At the curing temperature of 220 °C, oxidation of the carbon adjacent to the amine headgroup of γ-APS gives amide species by a pseudofirst-order kinetics. However, a few amino functionalities remain to react with oxirane groups of epoxy resin and, thus, strengthen the epoxy/silane interphase. The formation of ammonium formate in the acidic silane inhibits the reaction between silane and epoxy, which consequently decreases the epoxy/silane interphase cohesion. We find that the nanoroughness of silane deposits increases with the cure temperature which is beneficial to the wet stability of the epoxy/steel joints, due to increased mechanical interlocking.


Intraspecific diversity of nucleotide sequences within the adenine + thymine-rich region of mitochondrial DNA molecules of Drosophila mauritiana, Drosophila melanogaster and Drosophila simulans.
Mitochondrial DNA (mtDNA) molecules from Drosophila mauritiana, D. melanogaster, and D. simulans contain a single adenine + thymine (A+T)-rich region, which is similarly located in all molecules, but varies in size among these species. Using agarose gel electrophoresis and electron microscopy, a difference in occurrence of one EcoRI site, and a difference in size (approximately 0.7 kb) of the A+T-rich regions was found between mtDNA molecules of flies of two female lines of D. mauritiana. In heteroduplexes constructed between these two kinds of mtDNA molecules, two or three regions of strand separation, each comprising single strands of unequal length, were apparent near the center of the A+T-rich region. Using the structural differences between D. mauritiana mtDNA molecules it was demonstrated the mtDNA of this species is maternally inherited. Differences in length of A+T-rich regions were also found between mtDNA molecules of two geographically separated strains of D. melanogaster, and between mtDNA molecules of two geographically separated strains of D. simulans. However, in both cases, in heteroduplexes constructed between mtDNA molecules of different strains of one species, the A+T-rich regions appeared completely paired.


Growth-phase-dependent expression of the lipolytic system of Acinetobacter calcoaceticus BD413: cloning of a gene encoding one of the esterases.
Acinetobacter calcoaceticus BD413, when grown in batch culture in nutrient broth, produces both extracellular lipase activity and cell-bound esterase activity during and after the transition between exponential growth and the stationary phase. From a library of A. calcoaceticus DNA in Escherichia coli, plasmids were isolated that enabled E. coli to grow on media with tributyrin as the sole carbon source. Assays with model substrates classified the product of the cloned gene as an esterase. Via deletion analysis, the esterase gene was mapped on a 1.8 kbp chromosomal DNA fragment. This fragment was sequenced and found to contain one open reading frame, termed estA, which encodes a protein of 40.0 kDa. The amino acid sequence of this protein shows homology to a number of lipolytic enzymes, most notably to esterases. Deletion of estA only partially abolished cell-bound esterase activity in A. calcoaceticus, indicating that BD413 forms at least two esterases. Both esterases show the same temporal regulation of expression. beta-Galactosidase activity was measured in strains in which a promoterless lacZ gene was inserted into estA. Induction of lacZ expression in these strains also occurred at the end of exponential growth in batch cultures, indicating that production of the esterase is regulated at the genetic level.


Lipoprotein (a) Evolution: Possible Benefits and Harm. Genetic and Non-Genetic Factors Influencing its Plasma Levels.
The limited distribution of lipoprotein (a) (Lp(a)) to humans, Old World primates and to the European hedgehog, has raised considerable interest and speculation regarding its possible physiological role. Lp(a) has variable circulating concentrations (<0.1 - >100 mg/ml) which are highly genetically determined in humans. These characteristics gave rise to several theories concerning the origins and evolution of Lp(a). Lp(a) has a protective role after injury since Lp(a) particles bind to macrophages and platelets membrane receptors, leading to fibrin activation and injury healing. On the other hand, Lp(a) seems to be implicated in the formation of atheromatic plaques but also in cerebrovascular events and stenosis of the aortic valve. The main genetic factor determining plasma Lp(a) levels is the Lp(a) gene (LPA). Most Caucasian people have normal plasma Lp(a) concentrations, but there is important distribution variation according to race. Women seem to have increased Lp(a) levels compared with men, while diabetes mellitus type 2 favours lower plasma Lp(a) levels. Nutrition, hormones and several drugs may also influence circulating Lp(a) levels.


[Diagnosis and treatment of neuroparalytic zoster keratitis (author's transl)].
In severe zoster keratitis many pathogenic factors are involved. In addition to viral manifestations, the cornea is often affected by anterior uveitis or secondary glaucoma. Neuroparalytic keratitis causes lowered blinking frequency and decreased tear secretion. In addition, zoster ulcerations of the upper lid margin mechanically disturb reformation of the tear film and weaken the lipid layer by necrosis of the Meibomian glands. Ointments reduce break-up time and parasympathicolytic mydriatics further decrease tear secretion. When the average time between two blinks is shorter than the tear film break-up time, a "dry eye" condition usually develops. The appropriate treatment in such cases is thorough prevention of evaporation.


Consistency of pressure injury documentation across interfacility transfers.
Hospital-acquired pressure injuries (HAPIs) are publicly reported in the USA and used to adjust Medicare payment to acute inpatient facilities. Current methods used to identify HAPIs in administrative claims rely on hospital-reported present-on-admission (POA) data instead of prior patient health information. To study the reliability of claims data for HAPIs and pressure injury (PI) stage by evaluating diagnostic coding agreement across interfacility transfers. Using the 2012 100% Medicare Provider and Analysis Review file, we identified all fee-for-service acute inpatient discharge records with a PI diagnosis among Medicare patients 65 years and older. We then identified additional facility claims (eg, acute inpatient, long-stay inpatient or skilled nursing facility) belonging to the same patient who had either (1) admission within 1day of hospital discharge or (2) discharge within 1day of hospital admission. Multivariable logistic regression and stratified kappa statistics were used to measure coding agreement between transferring and receiving facilities in the presence or absence of a PI diagnosis at the time of patient transfer and PI stage category (early vs advanced). In our comparison of claims data between transferring and receiving facilities, we observed poor agreement in the presence or absence of a PI diagnosis at the time of transfer (36.3%, kappa=0.03) and poor agreement in PI stage category (74.3%, kappa=0.17). Among transfers with a POA PI reported by the receiving hospital, only 34.0% had a PI documented at the prior transferring facility. The observed discordance in PI documentation and staging between transferring and receiving facilities may indicate inaccuracy of HAPI identification in claims data. Future research should evaluate the accuracy of hospital-reported POA data and its impact on PI quality measurement.


Histologic observation of soft tissue acquired from maxillary tuberosity area for root coverage.
The palatal area has been the major donor site for obtaining connective tissue for root-coverage procedures. This study evaluated the long-term outcome of using a gingival cuff from the maxillary tuberosity area as a donor site for root coverage procedures. Case 1: A 26-year-old female patient complaining of tooth hypersensitivity and gingival recession on the maxillary left canine was treated with root coverage using a pouch technique. A connective tissue graft was obtained from the gingival cuff of the maxillary tuberosity area. An additional gingivectomy was performed at 3 months after surgery to trim the bulk of the grafted tissue. Regular recall check-up visits, including oral hygiene maintenance, occurred every 6 months. The patient was followed for 35 months after surgery. Case 2: A 24-year-old female patient with a chief complaint of tooth hypersensitivity and multiple areas of gingival recession in the maxilla was treated with a pouch and semilunar technique. The patient was treated with the same surgical protocol as in case 1. The patient was followed for 31 months after surgery. Full coverage was achieved in both cases with uneventful healing. The gingival biotype changed from a thin scalloped biotype to a thick flat biotype, and the overall color match was successful. The histologic findings of case 1 revealed good adaptation of the grafted tissue with continuous epithelial lining into the recipient site. The grafted tissue remained consistently stable with no change in the probing depths. The long-term evaluation of root coverage with a gingival cuff of the maxillary tuberosity area showed it to be an easier method than obtaining the graft from palatal masticatory mucosa, with a highly predictable prognosis.


Olfactory system of highly trained dogs detects prostate cancer in urine samples.
We established diagnostic accuracy in terms of the sensitivity and specificity with which a rigorously trained canine olfactory system could recognize specific volatile organic compounds of prostate cancer in urine samples. Two 3-year-old female German Shepherd Explosion Detection Dogs were trained to identify prostate cancer specific volatile organic compounds in urine samples. They were tested on 362 patients with prostate cancer (range low risk to metastatic) and on 540 healthy controls with no nonneoplastic disease or nonprostatic tumor. This cross-sectional design for diagnostic accuracy was performed at a single Italian teaching hospital and at the Italian Ministry of Defense Military Veterinary Center. For dog 1 sensitivity was 100% (95% CI 99.0-100.0) and specificity was 98.7% (95% CI 97.3-99.5). For dog 2 sensitivity was 98.6% (95% CI 96.8-99.6) and specificity was 97.6% (95% CI 95.9-98.7). When considering only men older than 45 years in the control group, dog 1 achieved 100% sensitivity and 98% specificity (95% CI 96-99.2), and dog 2 achieved 98.6% sensitivity (95% CI 96.8-99.6) and 96.4% specificity (95% CI 93.9-98.1). Analysis of false-positive cases revealed no consistent pattern in participant demographics or tumor characteristics. A trained canine olfactory system can detect prostate cancer specific volatile organic compounds in urine samples with high estimated sensitivity and specificity. Further studies are needed to investigate the potential predictive value of this procedure to identify prostate cancer.


Improving communication skills--a randomized controlled behaviorally oriented intervention study for residents in internal medicine.
We investigated whether patient-centered communication skills can be taught to residents in Internal Medicine by using a time-limited behaviorally oriented intervention. Residents working at the Department of Internal Medicine were randomly assigned to an intervention group (IG; N = 19) or a control group (CG; N = 23). In addition to 6 hours of standard medical education per week, the IG received specific communication training of 22.5 hours duration within a 6-month period. Initially and 10 months later, participants performed interviews with simulated patients. Interviews were rated by blinded raters who used the Maastricht History and Advice Checklist-Revised. Compared with the CG, the IG improved substantially in many specific communication skills. Both groups improved in the "amount of medical information identified" and in the ability to "communicate about feasibility of treatment." Patient-centered communication skills such as those presented in this intervention study can be taught. The ability to gain medical information and the readiness to communicate about aspects of medical treatment seem to improve with more professional experience; however, they also profit from the intervention.


Hyaluronidase inhibitors: a biological and therapeutic perspective.
The hyaluronidases (HAases) are a group of less extensively studied glycosidases distributed throughout the animal kingdom and are popularly known as 'spreading factors'. In recent years, HAases received much attention due to their ability to abruptly alter the hyaluronic acid (HA) homeostasis. HAases preferentially degrade HA, which is a megadalton acidic structural polysaccharide found exclusively in the extracellular matrix (ECM) of animals. The HA-HAase system has been suggested to participate in many pathophysiological conditions. The HA degradation in ECM, crack down the structural integrity with an eventual increased tissue permeability that is attributed for the spreading property. The spreading property has been widely accepted in functions including envenomation, acrosomal reaction/ovum fertilization, cancer progression, microbial pathogenesis such as wound infections, pneumonia, and other sepses like, bacteremia and meningitis. HA fragmentation has dual effects; generation of a wide molecular range bioactive oligosaccharides of angiogenic, pro-inflammatory, and immunostimulatory properties; and impairment in the reservoir capacity of ECM that holds metal ions, growth factors, cytokines and various enzymes for signal transduction. Hence, inhibition of HA degradation appears critical and imperative in HAase mediated pathological conditions. HAase inhibitors are thus potent regulators that maintain HA homeostasis and they might serve as anti-inflammatory, anti-aging, anti-microbial, anticancer and anti-venom/toxin and contraceptive agents. In addition, HAase inhibitors may serve as tools to understand several unexplained and complex functions of HAases in HA metabolism. Therefore, this review is expected to provide an integrated update as of 2008 on the HAase inhibitors and their possible role as therapeutics in the management of a wide range of pathological conditions.


Reduced Maternal Circulating Cell-Free Mitochondrial DNA Is Associated With the Development of Preeclampsia.
Background Circulating cell-free mitochondrial DNA (ccf-mtDNA) is a damage-associated molecular pattern that reflects cell stress responses and tissue damage, but little is known about ccf-mtDNA in preeclampsia. The main objectives of this study were to determine (1) absolute concentrations of ccf-mtDNA in plasma and mitochondrial DNA content in peripheral blood mononuclear cells and (2) forms of ccf-mtDNA transport in blood from women with preeclampsia and healthy controls. In addition, we sought to establish the association between aberrance in circulating DNA-related metrics, including ccf-mtDNA and DNA clearance mechanisms, and the clinical diagnosis of preeclampsia using bootstrapped penalized logistic regression. Methods and Results Absolute concentrations of ccf-mtDNA were reduced in plasma from women with preeclampsia compared with healthy controls (P≤0.02), while mtDNA copy number in peripheral blood mononuclear cells did not differ between groups (P>0.05). While the pattern of reduced ccf-mtDNA in patients with preeclampsia remained, DNA isolation from plasma using membrane lysis buffer resulted in 1000-fold higher ccf-mtDNA concentrations in the preeclampsia group (P=0.0014) and 430-fold higher ccf-mtDNA concentrations in the control group (P<0.0001). Plasma from women with preeclampsia did not induce greater Toll-like receptor-9-induced nuclear factor kappa-light-chain enhancer of activated B cells-dependent responses in human embryonic kidney 293 cells overexpressing the human TLR-9 gene (P>0.05). Penalized regression analysis showed that women with preeclampsia were more likely to have lower concentrations of ccf-mtDNA as well as higher concentrations of nuclear DNA and DNase I compared with their matched controls. Conclusions Women with preeclampsia have aberrant circulating DNA dynamics, including reduced ccf-mtDNA concentrations and DNA clearance mechanisms, compared with gestational age-matched healthy pregnant women.


Developing breeding schemes to assist mitigation of greenhouse gas emissions.
Genetic improvement of livestock is a particularly effective technology, producing permanent and cumulative changes in performance. This paper highlights some of the options for including mitigation in livestock breeding schemes, focusing on ruminant species, and details three routes through which genetic improvement can help to reduce emissions per kg product via: (i) improving productivity and efficiency, (ii) reducing wastage in the farming system and (iii) directly selecting on emissions, if or when these are measurable. Selecting on traits that improve the efficiency of the system (e.g. residual feed intake, longevity) will have a favourable effect on the overall emissions from the system. Specific examples of how genetic selection will have a favourable effect on emissions for UK dairy systems are described. The development of breeding schemes that incorporate environmental concerns is both desirable and possible. An example of how economic valuation of public good outcomes can be incorporated into UK dairy selection indices is given. This paper focuses on genetic selection tools using, on the whole, currently available traits and tools. However, new direct and indirect measurement techniques for emissions will improve the potential to reduce emissions by genetic selection. The complexities of global forces on defining selection objectives are also highlighted.


Interaction of preimplantation factor with the global bovine endometrial transcriptome.
Preimplantation factor (PIF) is an embryo derived peptide which exerts an immune modulatory effect on human endometrium, promoting immune tolerance to the embryo whilst maintaining the immune response to invading pathogens. While bovine embryos secrete PIF, the effect on the bovine endometrium is unknown. Maternal recognition of pregnancy is driven by an embryo-maternal cross talk, however the process differs between humans and cattle. As many embryos are lost during the early part of pregnancy in cattle, a greater knowledge of factors affecting the embryo-maternal crosstalk, such as PIF, is needed to improve fertility. Therefore, for the first time, we demonstrate the effect of synthetic PIF (sPIF) on the bovine transcriptome in an ex vivo bovine endometrial tissue culture model. Explants were cultured for 30h with sPIF (100nM) or in control media. Total RNA was analysed via RNA-sequencing. As a result of sPIF treatment, 102 genes were differentially expressed compared to the control (Padj<0.1), although none by more than 2-fold. The majority of genes (78) were downregulated. Pathway analysis revealed targeting of several immune based pathways. Genes for the TNF, NF-κB, IL-17, MAPK and TLR signalling pathways were down-regulated by sPIF. However, some immune genes were demonstrated to be upregulated following sPIF treatment, including C3. Steroid biosynthesis was the only over-represented pathway with all genes upregulated. We demonstrate that sPIF can modulate the bovine endometrial transcriptome in an immune modulatory manner, like that in the human endometrium, however, the regulation of genes was much weaker than in previous human work.


Gender Differences in Quality of Life of Metastatic Lung Cancer Patients.
Gender aspects in lung cancer patients are a topic of growing interest. But little is known about gender aspects affecting the quality of life (QoL) for those with this life-threatening disease. The aim of the following study was to investigate how gender differences affect QoL in metastatic lung cancer patients. In a prospective, multicenter study patients filled out the EORTC QLQ-C30 questionnaire and the recently updated lung cancer module QLQ-LC29 at an undefined point in time during first-line therapy. Gender differences were calculated for all QoL scores using ANCOVAs, which controlled for confounders. A total of 130 patients with metastatic lung cancer (UICC stage IV) (46 female and 84 male, mean age 66 years) were enrolled in this study by completing the questionnaires. The only significant gender difference in QoL was found regarding hair loss (mean women= 42.498, mean men=25.490, p-value= 0.010), although women received fewer chemotherapy treatments than men (women n=34, 74% and men n=68, 84%). This study provides evidence that the typical cancer related gender difference effect on QoL, suggesting that men suffer less than women, cannot be found in metastatic tumor stages of lung cancer patients.


Dietary-atherosclerosis study on deceased persons. Relation of eating pattern to raised coronary lesions.
Eating patterns of 456 New Orleans males, ages twenty to sixty years, indicate that clock-time and frequency of ingesting foods may help define life styles related to raised coronary lesions. Age, race, and occupation were also related to raised coronary lesions. The multiplicity of variables and strong interrelationships make evaluation difficult, but results from correlation studies, analyses of variance, and discriminant function analyses suggest that the number of meals plus heavy snacks, frequency of intake of caffeine and alcoholic beverages, and cigarette smoking rate for the last ten years of life may be valid factors in relation to development of atherosclerotic lesions. In other words, not only what we eat, as is now generally accepted, but how and when we eat it, merit consideration in studying the etiology of atherosclerosis.


Mechanism of recognition of herpes simplex virus type 1-infected cells by natural killer cells.
Human fibroblast FS-4 cells when infected with herpes simplex virus type 1 (HSV-1) become susceptible to lysis by purified populations of T3- human natural killer (NK) lymphocytes. Blocking of HSV-1 protein synthesis or N-linked glycosylation with pactamycin or tunicamycin, respectively, prevented HSV-1-infected cells from being lysed, suggesting that HSV-1 glycoprotein synthesis is required for recognition by NK cells. However, pactamycin- and tunicamycin-treated cells expressed on their membranes a detectable amount (20 to 40% of the untreated control) of HSV-1 glycoproteins gB, gC and gD, left by the virus during its internalization. Phosphonoformic acid (PFA) blocked HSV-1 DNA replication and inhibited the synthesis and surface expression of newly made gC, gD and gB by 90, 80 and 60% respectively. Despite this reduction, PFA treatment had no effect on NK susceptibility. The target structure recognized seems to be different from those expressed on tumour target cells since there was no competition for the lysis of HSV-1-infected FS-4 by K-562 or HeLa tumour target cells. However, a monoclonal antibody specific for the human transferrin receptor which inhibited NK recognition of tumour cells also blocked NK cytotoxicity of HSV-1-infected cells. In summary our results indicate that although viral glycoprotein synthesis is required, gB, gC and/or gD alone are not the targets for NK recognition of HSV-1-infected cells. In addition, they suggest the involvement of the host cell transferrin receptor in the NK killing process.


Update on diagnosis and treatment of mastocytosis.
Mastocytosis is a disorder characterized by increased numbers of mast cells in tissues. Recent clinical observations highlight the association of mastocytosis with an increased risk of anaphylaxis and underline the diversity of this disease. At the molecular level, recent studies have attempted to unravel specific gene expression profiles for activating c-kit mutations in the etiology of mastocytosis. The diagnosis may be facilitated by surrogate markers and detection of aberrant immunophenotypic surface markers. New therapeutic strategies are in development based on intracellular signal pathways, or on application of topical treatments, as are novel forms of cytoreductive therapy, including tyrosine kinase inhibitors.


Selective placement of bronchial suction catheters in intubated full term and premature neonates.
Flexible straight suction catheters were passed through nasal endotracheal tubes in 30 newborn infants (gestation age 26-42 weeks; birth weight 800-4,100 g) undergoing mechanical ventilation just before chest radiographic examination for clinical purpose. With the head in midline position, 63% (19/30) and 37% (11/30) of the catheters, entered the right and left main bronchus, respectively. With the head turning to either the left or right side, 87% (26/30) and 73% (22/30) of the catheters, entered the contralateral bronchus, respectively. Both success rates increased significantly (p less than 0.05 and p less than 0.01). Thus, turning the head facilitates passage of the cather into the contralateral mainstem bronchus in full term and premature neonates.


A review of clinical decision making: models and current research.
The aim of this paper was to review the current literature clinical decision-making models and the educational application of models to clinical practice. This was achieved by exploring the function and related research of the three available models of clinical decision making: information-processing model, the intuitive-humanist model and the clinical decision-making model. Clinical decision making is a unique process that involves the interplay between knowledge of pre-existing pathological conditions, explicit patient information, nursing care and experiential learning. Historically, two models of clinical decision making are recognized from the literature; the information-processing model and the intuitive-humanist model. The usefulness and application of both models has been examined in relation the provision of nursing care and care related outcomes. More recently a third model of clinical decision making has been proposed. This new multidimensional model contains elements of the information-processing model but also examines patient specific elements that are necessary for cue and pattern recognition. Literature review. Evaluation of the literature generated from MEDLINE, CINAHL, OVID, PUBMED and EBESCO systems and the Internet from 1980 to November 2005. The characteristics of the three models of decision making were identified and the related research discussed. Three approaches to clinical decision making were identified, each having its own attributes and uses. The most recent addition to the clinical decision making is a theoretical, multidimensional model which was developed through an evaluation of current literature and the assessment of a limited number of research studies that focused on the clinical decision-making skills of inexperienced nurses in pseudoclinical settings. The components of this model and the relative merits to clinical practice are discussed. It is proposed that clinical decision making improves as the nurse gains experience of nursing patients within a specific speciality and with experience, nurses gain a sense of saliency in relation to decision making. Experienced nurses may use all three forms of clinical decision making both independently and concurrently to solve nursing-related problems. It is suggested that O'Neill's clinical decision-making model could be tested by educators and experienced nurses to assess the efficacy of this hybrid approach to decision making.


Ultrafast charge transfer in atomically thin MoS₂/WS₂ heterostructures.
Van der Waals heterostructures have recently emerged as a new class of materials, where quantum coupling between stacked atomically thin two-dimensional layers, including graphene, hexagonal-boron nitride and transition-metal dichalcogenides (MX2), give rise to fascinating new phenomena. MX2 heterostructures are particularly exciting for novel optoelectronic and photovoltaic applications, because two-dimensional MX2 monolayers can have an optical bandgap in the near-infrared to visible spectral range and exhibit extremely strong light-matter interactions. Theory predicts that many stacked MX2 heterostructures form type II semiconductor heterojunctions that facilitate efficient electron-hole separation for light detection and harvesting. Here, we report the first experimental observation of ultrafast charge transfer in photoexcited MoS2/WS2 heterostructures using both photoluminescence mapping and femtosecond pump-probe spectroscopy. We show that hole transfer from the MoS2 layer to the WS2 layer takes place within 50 fs after optical excitation, a remarkable rate for van der Waals coupled two-dimensional layers. Such ultrafast charge transfer in van der Waals heterostructures can enable novel two-dimensional devices for optoelectronics and light harvesting.


Cytological screening for cervical cancer in the province of Limburg, Belgium.
Cervical cancer screening in Belgium is mainly opportunistic with periodic attempts to organize it according to the European guidelines. In the province of Limburg (north-east Belgium), a cervical cytology registry was set up in collaboration with local cytopathological laboratories, provincial health authorities and the Limburg Cancer Registry. Laboratories regularly communicated coded results of Pap smears from women residents in Limburg to the provincial cytological registry. All individual records contained a virtually unique identifying code allowing the study of longitudinal histories and linkage with the cancer registry. The screening coverage (percentage of women with a Pap smear in a defined period), the prevalence and incidence of squamous intraepithelial lesions and changes over time and geographical area were evaluated using a database of more than 600 000 Pap smear interpretations between 1996 and 2005. In 2000, 47% of women aged between 25 and 64 years had at least one Pap smear recorded in the last 3 years, and the average number of smears screened for each woman was 1.5. On account of incomplete registration, the coverage was 8% lower than estimated from health insurance data. The modal screening interval was in the range of 12-14 months; the first quartile, median and third quartile were 355, 440 and 676 days, respectively. Over the 10 years, 82% of the target population had their Pap smear recorded. The prevalence of cytological abnormalities was 3.7% (atypical squamous cells of undetermined significance: 2.2%, atypical glandular cells of undetermined significance: 0.1%, low-grade squamous intraepithelial lesion: 1.1%, high-grade squamous intraepithelial lesion or more serious lesions: 0.4%), but varied substantially among laboratories. The prevalence of atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion increased significantly over time. Pathologists from Limburg have pioneered cytology registration in the context of opportunistic screening in Belgium. The estimated screening coverage was slightly underestimated. Obligatory registration, use of a uniform terminology and linkage with population and follow-up data are needed to give a cytology registry its full role in an organized screening programme.


Vector-borne pathogen spread through ticks on migratory birds: a probabilistic spatial risk model for South-Western europe.
Tick-borne pathogens can spread easily through the movements of infested birds. An important example is viruses that pose a threat to humans and that are carried in Hyalomma ticks that move from Africa into south-western Europe. This study evaluates the probability of arrival of migrating birds from Africa into Spain and the environmental suitability of different regions of Spain for the survival of tick stages introduced by these birds. This evaluation produced a spatial risk index measuring the probability that foreign tick populations will survive in the target area. Periods of highest risk were observed for large areas of Spain, from the second fortnight of April to the second fortnight of May. Although birds may arrive as early as January and massive migrations may take place in March, the environmental suitability for Hyalomma marginatum ticks is low in these periods and high mortality of the spread stages (nymphs) is expected. This study introduces new methods of objective analysis based on spatial and process-driven models for both ticks and hosts and critically evaluates the usefulness of spatial spreading methods for assessing the risk of tick-borne pathogens.


End of life or end of the road? Are rising cancer costs sustainable? Is it time to consider alternative incentive and funding schemes?
The number of cancer therapies is increasing. Treatment costs, largely reflecting increasing prices, are also increasing. The regulatory process is increasing in intensity. Countries have initiated risk sharing agreements and/or special cancer funds to accommodate this expenditure growth. Given increasing pressures elsewhere on healthcare budgets, even this response is not sustainable. With many more cancer drugs in the pipeline and the prospects of combination therapy, it is unlikely that the existing policies being applied by payers can maintain budget constraints. Unless payers increase reimbursement and/or extend flexible reimbursement schemes, solutions will be required to ensure access to new cancer therapies - this includes looking at ways of reducing R&D costs. This perspective outlines the problems faced and suggests some solutions.


Emergence of a new multidrug-resistant serotype X variant in an epidemic clone of Shigella flexneri.
Shigella spp. are the causative agent of shigellosis with Shigella flexneri serotype 2a being the most prevalent in developing countries. Epidemiological surveillance in China found that a new serotype of S. flexneri appeared in 2001 and replaced serotype 2a in 2003 as the most prevalent serotype in Henan Province. The new serotype also became the dominant serotype in 7 of the 10 other provinces under surveillance in China by 2007. The serotype was identified as a variant of serotype X. It differs from serotype X by agglutination to the monovalent anti-IV type antiserum and the group antigen-specific monoclonal antibody MASF IV-I. Genome sequencing of a serotype X variant isolate, 2002017, showed that it acquired a Shigella serotype conversion island, also as an SfX bacteriophage, containing gtr genes for type X-specific glucosylation. Multilocus sequence typing of 15 genes from 37 serotype X variant isolates and 69 isolates of eight other serotypes, 1a, 2a, 2b, 3a, 4a, 5b, X, and Y, found that all belong to a new sequence type (ST), ST91. Pulsed-field gel electrophoresis revealed 154 pulse types with 655 S. flexneri isolates analyzed and identified 57 serotype switching events. The data suggest that S. flexneri epidemics in China have been caused by a single epidemic clone, ST91, with frequent serotype switching to evade infection-induced immunity to serotypes to which the population was exposed previously. The clone has also acquired resistance to multiple antibiotics. These findings underscore the challenges to the current vaccine development and control strategies for shigellosis.


Physical properties and Extracellular Polymeric Substances pattern of aerobic granular sludge treating hypersaline wastewater.
The modification of the physical properties of aerobic granular sludge treating fish-canning wastewater is discussed in this paper. The structure and composition of the Extracellular Polymeric Substances (EPSs) were analyzed at different salinity levels and related to granules stability. Results outlined that the total EPSs content increased with salinity, despite the EPSs increment was not proportional to the salt concentration. Moreover, the EPSs structure was significantly modified by salinity, leading to a gradual increase of the not-bound EPSs fraction, which was close to the 50% of the total EPSs content at 75gNaClL-1. The increasing salt concentration modified also the EPSs composition, causing the gradual reduction of protein content resulting in a decrease of granule hydrophobicity. The results pointed out that the granules stability significantly reduced above 50gNaClL-1, suggesting the existence of a salinity threshold above which granules stability is compromised.


Venous complications of pancreatitis: a review.
Pancreatitis is notorious to cause vascular complications. While arterial complications include pseudoaneurysm formation with a propensity to bleed, venous complications can be quite myriad. Venous involvement in pancreatitis often presents with thrombosis. From time to time case reports and series of unusual venous complications associated with pancreatitis have, however, been described. In this article, we review multitudinous venous complications in the setting of pancreatitis and propose a system to classify pancreatitis associated venous complications.


Acetylcholine concentrations in rat brain: diurnal oscillation.
A diurnal oscillation of acetylcholine concentrations in rat brain has been demonstrated by gas chromatography. Peak concentrations occur at 2 hours of light, and a trough is seen at 6 hours of darkness. This pattern is observed only in grouped rats, and emerges after at least 18 days of prior conditioning in an environment with controlled light, humidity, and temperature.


Use of anti-CD20 antibody in the treatment of post-transplant glomerulonephritis.
Post-transplant glomerulonephritis (PTGN) accounts for 4-10% of late graft loss. Six consecutive patients who developed PTGN 3-72 months post-transplant presented to our center with deteriorating kidney function and proteinuria. Three had focal segmental glomerulosclerosis; one had membranoproliferative glomerulonephritis Type 1; one recurrent membranous nephropathy; and one recurrent immunoglobin A nephropathy. All six were treated with an aggressive immunosuppression regimen including rituximab, pulse steroids and/or maximization of mycophenolic acid and calcineurin inhibitor therapy. Four of the six patients received plasma exchange. The patients were followed for a minimum of nine months after treatment. Proteinuria decreased from 7.2 ± 4.4 to 1.4 ± 1.5g (p = 0.04), while mean estimated glomerular filtration rate was 31.2 ± 13.1 and 42.5 ± 21.7 mL/min (p = 0.07) at nine months. No adverse events were noted. These observations suggest that immune modulating therapy may be of benefit in the treatment of PTGN.


A study of dendritic and endothelial cell interactions in colon cancer in a cell line and small mammal model.
Historically, cancer therapy directly targeting tumor cells have yielded suboptimal clinical results, and therefore anti-angiogenic therapy that targets tumor cells indirectly through impairing tumor vasculature is now considered to be one of the novel approaches potentially effective against various types of cancer. In this study, we evaluated whether lysates of endothelium could be effectively pulsed in dendritic cells (DCs), to enhance their anti-tumor effects. For this purpose, we prepared DCs of BALB/c mouse, incubated them with lysates of autologous or xenogeneic endothelium, and tested their anti-tumor effects in two syngeneic models of colon cancer. DCs pulsed with the respective endothelium lysates significantly inhibited the growth of subcutaneous tumors as well as pulmonary metastases in mice, and their anti-tumor effect was superior to that of unpulsed DCs. Immunohistopathological analysis showed significant decrease in the mean vascular density of tumors, correlating well with the extent of tumor inhibition. In vitro analysis of splenocytes isolated from immunized mice revealed an induction of cytotoxic T lymphocytes and activation of natural killer cells, with a lytic activity against activated endothelium but not tumor cells. In addition, antibodies reacting with activated endothelium, but not tumor cells, were detected in murine sera by ELISA, and their function was confirmed by complement-dependent cytotoxicity assay. Our present results suggest that lysates of endothelium can be effectively pulsed in DCs and enhance their anti-tumor effects through induction of anti-angiogenesis, and therefore should have important clinical implications for adjuvant cancer therapy.


Growth performance, gastrointestinal and digestibility responses in growing pigs when fed corn-soybean meal-based diets with corn DDGS treated with fiber degrading enzymes with or without liquid fermentation.
Fermenting high fiber ingredients such as distillers dried grains with solubles (DDGS) with feed enzymes may improve their feeding value. We investigated the effects of fermenting corn DDGS with a blend of β-glucanase and xylanases (XB) on growth performance, gut parameters, and apparent total tract digestibility (ATTD) of nutrients and energy in growing pigs. Dietary treatments were: (1) corn soybean meal-based diet + 30% DDGS (control), (2) control + XB without fermentation (XBNS), and (3) control + DDGS fermented with XB (16% DM) for 3 to 10 d at 40 °C (XBS). Target activities in XB were 1,050 and 5,500 U/g of DDGS for XB, respectively. Diets contained phytase at 750 FTU/kg. Feed samples were taken during fermentation and at feeding for analysis of pH and organic acids. A total of 144 pigs (25 ± 1.0 kg BW) were assigned to pens (three barrows and three gilts) and allocated to the three diets in a two-phase feeding program (3 wk/phase). Diets were fed on ad libitum and were delivered by a computer-controlled liquid feeding system at a feed to water ratio of 1:4, four times per day. Pigs had free access to water. Fecal samples were taken in the final 3 d of phase 2 to determine ATTD using TiO2 marker method and one pig per pen was euthanized for gastrointestinal (GIT) measurements. The pH of diets at feeding time was lower (P < 0.01) for XBS (4.72) compared with control (5.45) and XBNS (5.45). Pigs fed XBNS had higher (P = 0.04) ADG than control in phase 1. In phase 2 and the overall (weeks 0 to 6), ADG and final BW were higher (P = 0.01) for XBNS than XBS but were not different (P > 0.05) from control. There were no diet effects (P > 0.05) on ADFI. Feed to gain (FCR) for XBNS (1.68) and XBS pigs (1.69) was better (P < 0.01) than for control pigs (1.78) in phase 1. There were no diet effects (P > 0.05) on FCR in phase 2 or in the overall. Pigs fed XBNS had lower (P < 0.01) ATTD of CP than control and XBS-fed pigs. Although not different (P > 0.05) from control, pigs fed XBNS had lower (P < 0.05) jejunal crypt depth and ATTD of gross energy than pigs fed XBS. In conclusion, treating corn DDGS with XB with or without liquid fermentation improved feed efficiency in phase 1, suggesting degradation of dietary fibrous components that may limit nutrient utilization in younger pigs. However, these benefits were not observed in phase 2.


Theoretical assessment of a synthetic aperture beamformer for real-time 3-D imaging.
A real-time 3-D imaging system requires the development of a beamformer that can generate many beams simultaneously. In this paper, we discuss and evaluate a suitable synthetic aperture beamformer. The proposed beamformer is based on a pipelined network of high speed digital signal processors (DSP). By using simple interpolation-based beamforming, only a few calculations per pixel are required for each channel, and an entire 2-D synthetic aperture image can be formed in the time of one transmit event. The performance of this beamformer was explored using a computer simulation of the radiation pattern. The simulations were done for a full 64-element array and a sparse array with the same receive aperture but only five transmit elements. We assessed the effects of changing the sampling rate and amplitude quantization by comparing the relative levels of secondary lobes in the radiation patterns. The results show that the proposed beamformer produces a radiation pattern equivalent to a conventional beamformer using baseband demodulation, provided that the sampling rate is approximately 10 times the center frequency of the transducer (34% bandwidth pulse). The simulations also show that the sparse array is not significantly more sensitive to delay or amplitude quantization than the full array.


Histone acetylation inhibitors promote axon growth in adult dorsal root ganglia neurons.
Intrinsic mechanisms that guide damaged axons to regenerate following spinal cord injury remain poorly understood. Manipulation of posttranslational modifications of key proteins in mature neurons could reinvigorate growth machinery after injury. One such modification is acetylation, a reversible process controlled by two enzyme families, the histone deacetylases (HDACs) and the histone acetyl transferases (HATs), acting in opposition. Whereas acetylated histones in the nucleus are associated with upregulation of growth-promoting genes, deacetylated tubulin in the axoplasm is associated with more labile microtubules, conducive to axon growth. This study investigates the effects of HAT and HDAC inhibitors on cultured adult dorsal root ganglia (DRG) neurons and shows that inhibition of HATs by anacardic acid or CPTH2 improves axon outgrowth, whereas inhibition of HDACs by TSA or tubacin inhibits axon growth. Anacardic acid increased the number of axons able to cross an inhibitory chondroitin sulfate proteoglycan border. Histone acetylation but not tubulin acetylation level was affected by HAT inhibitors, whereas tubulin acetylation levels were increased in the presence of the HDAC inhibitor tubacin. Although the microtubule-stabilizing drug taxol did not have an effect on the lengths of DRG axons, nocodazole decreased axon lengths. Determining the mechanistic basis will require future studies, but this study shows that inhibitors of HAT can augment axon growth in adult DRG neurons, with the potential of aiding axon growth over inhibitory substrates produced by the glial scar.


Tobacco smoking and risk of hip fracture in men and women.
Previous findings suggest that tobacco smoking increases the risk of hip fracture in women. A similar adverse effect of smoking is suspected to be present in men, but bone mineral density studies have raised the concern that men may be more sensitive to the deleterious effect of smoking on bone than women. In this study we prospectively determined the influence of current, previous, and cumulative smoking history on risk of hip fracture in men and women and addressed the issue of possible gender difference in the susceptibility to tobacco smoking. Pooled data from three population studies conducted in Copenhagen with detailed information on smoking habit. A total of 13,393 women and 17,379 men, initially examined between 1964 and 1992, were followed until 1997 for first admission due to hip fracture. The relative risks (RR) of hip fracture associated with smoking were estimated by means of multiplicative Poisson regression models. During follow-up, 722 hip fractures were identified in women, and 447 in men. After adjustment for potential confounders, including body mass index, female current smokers had an RR of hip fracture of 1.36 (95% CI: 1.12-1.65) and male smokers 1.59 (95% CI: 1.04-2.43) relative to never smokers. In both sexes, the RR of hip fracture gradually increased by current and accumulated tobacco consumption. The RR were consistently higher in men than in women, but the test for interaction between sex and tobacco smoking was insignificant. After 5 years, male ex-smokers had an adjusted RR of 0.73 (95% CI: 0.55-0.98) relative to current smokers, while no significant decrease in risk was observed in female ex-smokers (RR = 0.91; 95% CI: 0.72-1.17)). Approximately 19% of all hip fractures in the present study population were attributable to tobacco smoking. Tobacco smoking is an independent risk factor for hip fracture in men and women, and there appears to be no gender differences in smoking related risk. Smoking cessation reduces the risk of hip fracture in men after 5 years, while the deleterious effect of smoking seems to be more long-lasting in female ex-smokers.


Effects of different methods of general anesthesia on intraoperative awareness in surgical patients.
The purpose of the study was to investigate the effects of total intravenous anesthesia (TIVA) and combined of intravenous and inhaled anesthesia (CIIA) on intraoperative awareness in surgical patients.A total of 678 patients were recruited in the CIIA group, while TIVA group included 566 patients. The clinical characteristics and the occurrence of intraoperative awareness were compared between the groups. Mini-Mental State Examination, Generalized Anxiety Disorder 7, and Patient Health Questionnaire 9 tests were performed to estimate cognitive and psychological functions of the patients. In addition, logistic regression analysis was applied to identify the risk factors for intraoperative awareness in surgical patients.In CIIA group, 3 patients (0.44%) were confirmed with intraoperative awareness, while 11 patients (1.94%) in TIVA group underwent intraoperative awareness. The occurrence rate of intraoperative awareness was significantly higher in VITA group than that in the CIIA group (P = .029). Awareness classification demonstrated that intraoperative awareness mainly included auditory, tactile, and pain perceptions. Moreover, 4 patients showed distress after operation. Patients with intraoperative awareness exhibited poor performance in cognitive and psychological tests (P < .001 for all). Logistic regression analysis demonstrated that CIIA (odds ratio [OR] = 0.198, 95% confidence interval [CI] = 0.047-0.827), age (OR = 0.951, 95% CI = 0.908-0.997), midazolam application (OR = 0.158, 95% CI = 0.034-0.736), awareness history (OR = 10.131, 95% CI = 2.206-45.517), and duration of surgery (OR = 1.016, 95% CI = 1.001-1.032) were significantly associated with intraoperative awareness.Intraoperative awareness can significantly influence the cognitive and psychological functions of surgical patients. CIIA and midazolam application may lower the risk of intraoperative awareness.


Organization and implementation of emergency services in the treatment of major trauma.
Peak medical care for heavy trauma involves a multifaceted approach. Time is the overriding factor in the successful care of these patients, so that a short access time to emergency services is crucial. A well-trained ambulance crew must be involved and should have access to emergency physicians in selected cases. Respiratory and cardiac function must be optimized, shock must be alleviated, and the sites of trauma must be immobilized or otherwise controlled. Finally, the patient should be transported to a center with an emergency department that has the ability to function as a 24-h trauma center.


Use of a Topical Film-Forming Medical Device Containing Repairsomes® in a Patient with Xeroderma Pigmentosum to Avoid Progression to Skin Cancerization.
This paper reports a case of xeroderma pigmentosum in a 78-year-old woman with a 17-year history of multiple basal cell carcinomas, keratoacanthoma, and lentigo maligna melanoma, in different photoexposed facial regions. To prevent aggravation of these medical conditions, for five years, the patient had been applying a film-forming topical medical device (MD) containing the DNA-repair enzyme photolyase in liposomes and high-protection UV filters (Repairsomes) twice a day. During this time, the patient had no clinical or dermatoscopic evidence of new skin cancer lesions. However, at her last visit, the patient had a new basal cell carcinoma on the face, in the right supramaxillary area. After questioning, the patient recognized that she had not been applying the product on a regular basis during the last year. This may have been a coincidence; however, there is clinical evidence of the preventive effect of this MD in reducing the cancerization field and consequently the development of skin cancer. This product contains a light-activated flavoenzyme called photolyase which creates the condition to revert cyclobutane pyrimidine dimer. In the discussion of this case, we review recent publications and stress some important aspects on the role of photoprotection and photorepair as a strategy to more effectively reduce the risk of UV-induced premalignant and malignant skin lesions compared to traditional photoprotection strategies.


Calcium and phosphorus concentrations in native and decellularized semilunar valve tissues.
Native, allograft, xenograft and bioprosthetic semilunar valves are all susceptible to calcific degeneration. However, intrinsic differences in baseline calcium and phosphorus tissue concentrations within mammalian normal valve structural components (e.g., cusps, sinus, vessel wall) additionally subdivided by tripartite regions (e.g., right-, left- and non-coronary leaflets) have never been systematically measured and reported. It was originally hypothesized that variations in normative tissue concentrations of calcium and phosphorus may correspond to subsequent clinical patterns of acquired dystrophic calcification; decellularization was also expected to reduce the tissue concentrations of these elements. Native semilunar valves were freshly harvested from 12 juvenile sheep. Half of the valves were decellularized (six aortic and six pulmonary), while the other valves were flash-frozen at -80 degrees C within minutes of euthanasia as native valves. Elemental calcium and phosphorus concentrations were measured in the great vessels, sinus walls and cusps using inductively coupled plasma optical emission spectrometry (ICP-OES), and analyzed with non-parametric statistical tests. Calcium concentrations (microg/mg tissue; median (range) were similar in aortic native cusps (0.37 (0.21)), sinus walls (0.37 (0.09)) and aorta (0.37 (0.08)) (p = 0.8298). Pulmonary calcium concentrations were similar in cusps, but 10-25% higher in the native sinus (p = 0.0018) and pulmonary artery (p < 0.0001) compared to analogous aortic structures. All cusps had higher phosphorus concentrations than their respective conduit tissues. No tripartite regional variations were observed. Decellularization did not reduce the calcium content of cusps, but removed 50-55% of vessel and sinus wall calcium. However, up to 85% of phosphorus was removed from all valve tissues (p < 0.001). There were no significant differences in normal tissue concentrations of calcium between aortic valve functional structures, and no semilunar tripartite regional differences in either semilunar valve complex. Thus, the distribution of baseline tissue calcium content of healthy young valves is not inherently predictive of selective or asymmetric anatomical patterns of valve degenerative calcification. Native semilunar cusps contain the highest phosphorus concentrations. Decellularization reduces all elemental concentrations except for cuspal calcium.


[Levels of immune complexes in the blood of patients with thyrotoxicosis].
According to the present-day concepts a significant role in the development of thyrotoxicosis is played by autoimmune mechanisms, therefore a study of the problem of the content and role of the circulating immune complexes (IC) in this pathology is of interest. The IC amount was determined in the peripheral blood of 82 patients with thyrotoxicosis using precipitation with polyethylene glycol (mol. m. 6000). An elevated amount of the circulating IC was marked in 75% of the patients. Correlation between the IC content in the peripheral blood, the patients' age and the duration of disease was revealed. No variations of the indices with relation to the disease severity and duration were noted. The absence of the positive time-course of the signs determining the IC amount during thyrostatic therapy necessitates the incorporation of immunomodulators in multimodality therapy in thyrotoxicosis.


Pancolitis Associated With COVID-19 Infection: A Case Report.
Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 infection commonly affects the pulmonary system, ranging from being asymptomatic to having mild upper respiratory tract infection symptoms, to having severe cases causing multi-organ failure. However, COVID-19 infection involving the gastrointestinal (GI) tract leading to pancolitis is an extremely rare complication. We present a rare case of a patient who presented with pancolitis and on testing for admission found to be positive for COVID-19. We will explore the GI tropism and the mechanism of COVID-19 infection with gastrointestinal symptoms of pancolitis.


Cost-effectiveness analysis reveals microsurgical varicocele repair is superior to percutaneous embolization in the treatment of male infertility.
Varicoceles are a common cause of male infertility; repair can be accomplished using either surgical or radiological means. We compare the cost-effectiveness of the gold standard, the microsurgical varicocele repair (MV), to the options of a nonmicrosurgical approach (NMV) and percutaneous embolization (PE) to manage varicocele-associated infertility. A Markov decision-analysis model was developed to estimate costs and pregnancy rates. Within the model, recurrences following MV and NMV were re-treated with PE and recurrences following PE were treated with repeat PE, MV or NMV. Pregnancy and recurrence rates were based on the literature, while costs were obtained from institutional and government supplied data. Univariate and probabilistic sensitivity-analyses were performed to determine the effects of the various parameters on model outcomes. Primary treatment with MV was the most cost-effective strategy at $5402 CAD (Canadian)/pregnancy. Primary treatment with NMV was the least costly approach, but it also yielded the fewest pregnancies. Primary treatment with PE was the least cost-effective strategy costing about $7300 CAD/pregnancy. Probabilistic sensitivity analysis reinforced MV as the most cost-effective strategy at a willingness-to-pay threshold of >$4100 CAD/pregnancy. MV yielded the most pregnancies at acceptable levels of incremental costs. As such, it is the preferred primary treatment strategy for varicocele-associated infertility. Treatment with PE was the least cost-effective approach and, as such, is best used only in cases of surgical failure.


Real-time magnetic resonance imaging-guided transcatheter aortic valve replacement.
To demonstrate the feasibility of Real-time magnetic resonance imaging (rtMRI) guided transcatheter aortic valve replacement (TAVR) with an active guidewire and an MRI compatible valve delivery catheter system in a swine model. The CoreValve system was minimally modified to be MRI-compatible by replacing the stainless steel components with fluoroplastic resin and high-density polyethylene components. Eight swine weighing 60-90 kg underwent rtMRI-guided TAVR with an active guidewire through a left subclavian approach. Two imaging planes (long-axis view and short-axis view) were used simultaneously for real-time imaging during implantation. Successful deployment was performed without rapid ventricular pacing or cardiopulmonary bypass. Postdeployment images were acquired to evaluate the final valve position in addition to valvular and cardiac function. Our results show that the CoreValve can be easily and effectively deployed through a left subclavian approach using rtMRI guidance, a minimally modified valve delivery catheter system, and an active guidewire. This method allows superior visualization before deployment, thereby allowing placement of the valve with pinpoint accuracy. rtMRI has the added benefit of the ability to perform immediate postprocedural functional assessment, while eliminating the morbidity associated with radiation exposure, rapid ventricular pacing, contrast media renal toxicity, and a more invasive procedure. Use of a commercially available device brings this rtMRI-guided approach closer to clinical reality.


Effects of kolaviron on hepatic oxidative stress in streptozotocin induced diabetes.
Alteration in antioxidant defence and increase in oxidative stress that results in tissue injury is characteristic of diabetes. We evaluated the protective effects of kolaviron (a flavonoid complex extracted from the seeds of Garcinia kola) on hepatic antioxidants, lipid peroxidation and apoptosis in diabetic rats. To induce diabetes, rats were injected with streptozotocin intraperitoneally at a single dose of 50 mg/kg. Kolaviron (100 mg/kg) was administered orally for 6 weeks (5 times weekly). Activities of liver antioxidant enzymes was analysed with Multiskan Spectrum plate reader. High performance liquid chromatography (HPLC) was used in the analysis of MDA (malondialdehyde), a product of lipid peroxidation. Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Diabetic rats exhibited a significant increase in the peroxidation of hepatic lipids as observed from the elevated level of malondialdehyde (MDA). In addition, Oxygen Radical Absorbance Capacity (ORAC), level of reduced glutathione (GSH), ratio of reduced to oxidized glutathione (GSH: GSSG) and catalase (CAT) activity were decreased in the liver of diabetic rats. The activities of GPX (glutathione peroxidase) and SOD (superoxide dismutase) were unaltered in diabetic rats. TUNEL assay revealed increased apoptotic cell death in the liver. Kolaviron attenuated lipid peroxidation and apoptosis, increased CAT activity, GSH levels and GSH: GSSG ratio. The ORAC of kolaviron-treated diabetic liver was restored to near-normal values. Kolaviron protects the liver against oxidative and apoptotic damage induced by hyperglycemia.


Breaking Boundaries: Toward Consistent Gender-Sensitive Language in Sexual and Reproductive Health Guidelines.
This review assesses gender-sensitive language in sexual and reproductive health (SRH) guidelines, including a guideline for polycystic ovary syndrome. We conducted a systematic search across databases like Medline, EMBASE, and Cochrane until July 31, 2023, using terms related to gender-inclusivity, SRH, and guideline protocols. Criteria for inclusion were gender-sensitive language, SRH focus, and guideline relevance, excluding non-English articles or those without policy considerations. Our search yielded 25 studies, with 6 included for qualitative synthesis. Results showed significant gaps in using gender-sensitive language in SRH guidelines. The debate on this language mirrors broader societal discourse. Recognizing gender diversity is essential for research, clinical practices, and societal norms. While promoting inclusion, drawbacks like unintended erasure or miscommunication should also be addressed. A gender-additive approach balances inclusivity and biological accuracy. Precise and inclusive discourse is crucial. Future research should focus on systemic approaches in the SRH sector.


Tailored vaccines targeting the elderly using whole inactivated influenza vaccines bearing cytokine immunomodulators.
Influenza and its complications disproportionately affect the elderly, leading to high morbidity and mortality in this ever-increasing population. Despite widespread vaccination efforts, the current influenza vaccines are less effective in the elderly; hence newer vaccine strategies are needed to improve their efficacy in this age group. We have previously shown that co-presentation of cytokines on the surface of inactivated influenza virus particles affords better protection from lethal homotypic viral challenge in young adult mice than conventional non-adjuvanted whole inactivated vaccine. Here, we determined the efficacy of these vaccine formulations in Balb/c mice "aged" to 17 months ("aged mice") along with the addition of a membrane-bound interleukin-12 (IL-12) vaccine formulation. Our investigations found that a single low-dose intramuscular vaccination with inactivated whole influenza vaccine co-presenting IL-12 was sufficient to provide enhanced protection from subsequent influenza challenge as compared with non-adjuvanted whole inactivated vaccine. Our results indicate that incorporation of cytokines such as IL-12 in a membrane-bound formulation in whole inactivated vaccine may provide a means to lower the vaccine dose while eliciting enhanced protective responses in the elderly, an age group that responds poorly to current vaccination regimens.


Chronic myeloid leukemia-derived exosomes promote tumor growth through an autocrine mechanism.
Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder in which leukemic cells display a reciprocal t(9:22) chromosomal translocation that results in the formation of the chimeric BCR-ABL oncoprotein, with a constitutive tyrosine kinase activity. Consequently, BCR-ABL causes increased proliferation, inhibition of apoptosis, and altered adhesion of leukemic blasts to the bone marrow (BM) microenvironment. It has been well documented that cancer cells can generate their own signals in order to sustain their growth and survival, and recent studies have revealed the role of cancer-derived exosomes in activating signal transduction pathways involved in cancer cell proliferation. Exosomes are small vesicles of 40-100 nm in diameter that are initially formed within the endosomal compartment, and are secreted when a multivesicular body (MVB) fuses with the plasma membrane. These vesicles are released by many cell types including cancer cells, and are considered messengers in intercellular communication. We have previously shown that CML cells released exosomes able to affect the tumor microenvironment. CML cells, exposed up to one week, to exosomes showed a dose-dependent increased proliferation compared with controls. Moreover, exosome treatment promotes the formation of LAMA84 colonies in methylcellulose. In a CML xenograft model, treatment of mice with exosomes caused a greater increase in tumor size compared with controls (PBS-treated mice). Real time PCR and Western Blot analysis showed, in both in vitro and in vivo samples, an increase in mRNA and protein levels of anti-apoptotic molecules, such as BCL-w, BCL-xl, and survivin, and a reduction of the pro-apoptotic molecules BAD, BAX and PUMA. We also found that TGF- β1 was enriched in CML-exosomes. Our investigations showed that exosome-stimulated proliferation of leukemia cells, as well as the exosome-mediated activation of an anti-apoptotic phenotype, can be inhibited by blocking TGF-β1 signaling. CML-derived exosomes promote, through an autocrine mechanism, the proliferation and survival of tumor cells, both in vitro and in vivo, by activating anti-apoptotic pathways. We propose that this mechanism is activated by a ligand-receptor interaction between TGF-β1, found in CML-derived exosomes, and the TGF- β1 receptor in CML cells.


Effects of maternal environment during gestation on ovarian folliculogenesis and consequences for fertility in bovine offspring.
Mammals such as cattle, swine, sheep and humans are born with a highly variable number of ovarian follicles and oocytes in the ovaries that dwindle during ageing and are never replenished. This variation in the ovarian reserve is reflected in the numbers of antral follicles in the ovaries at all ages after birth. As numbers of follicles in ovaries are determined during gestation, the role of maternal nutrition and health during gestation (at time of ovarian development in their foetuses) has been investigated as factors that may impact oogonia proliferation and thus follicle numbers post-natally. These studies have found that both nutrition and health impact numbers of follicles in their offspring. The idea that numbers of follicles and oocytes in ovaries impact fertility is a long-held belief in reproductive biology. This has recently been tested in cattle, and it has been shown that cows with a relatively high number of antral follicles in ovaries have higher pregnancy rates, shorter calving to conception intervals and fewer artificial inseminations during the breeding season compared with cows with a lower number of follicles, and similarly, heifers with many follicles had higher pregnancy rates than those with fewer follicles. Studies summarized in this review highlight the importance of the maternal environment during gestation in determining the size of the ovarian reserve in their offspring and also the contribution of the ovarian reserve to subsequent fertility in cattle.


Rhopalosiphum padi (Hemiptera: Aphididae) responses to volatile cues from Barley yellow dwarf virus-infected wheat.
In choice bioassays, Rhopalosiphum padi L. nonviruliferous apterae preferentially locate near volatile organic compounds (VOCs) emitted from Barley yellow dwarf virus (BYDV)-infected wheat plants compared with VOCs from noninfected plants. However, the specific VOCs responsible for R. padi responses are unknown. It is unclear also if R. padi responses to BYDV-infected wheat are caused by arrestment or attraction. Additionally, the responses of viruliferous apterae and nonviruliferous alate to BYDV-infected wheat have not been examined. R. padi responses were studied through emigration, immigration, and settling laboratory bioassays using BYDV-infected and noninfected wheat plants. Two wheat genotypes, virus-susceptible Lambert and virus-resistant Lambert-derived transgenic 103.1J expressing the BYDV-PAV coat protein gene, were evaluated. In a settling bioassay, alates preferentially settled on noninfected 103.1J. Responses of viruliferous and nonviruliferous R. padi to virus-infected, noninfected, and sham-inoculated (exposed to nonviruliferous aphids) Lambert and 103.1J were examined in separate bioassays. A paper leaf model served as a control. Immigration by viruliferous apterae was significantly lower toward the paper leaf model, but no significant differences were observed among plant treatments. Nonviruliferous apterae exhibited no significant differences in emigration among treatments, suggesting no arrestment occurred. Nonviruliferous apterae significantly preferred to immigrate toward BYDV-infected Lambert. Immigration toward the paper leaf model was significantly lower compared with plant treatments. Responses of R. padi to VOCs were tested by applying compounds to paper leaf models at concentrations designed to mimic those present in headspace of wheat plants. Nonviruliferous apterae immigrated in significantly greater numbers toward paper leaf models individually treated with nonanal, (Z)-3-hexenyl acetate, decanal, caryophyllene, and undecane than toward paper leaf models that served as controls and toward leaf models treated with synthetic blends made to mimic headspace of BYDV-infected compared with blends made to mimic headspace of noninfected wheat plants. Results suggest responses of R. padi to BYDV-infected plants are caused by attraction rather than arrestment.


Segmenting Cardiac Ultrasound Videos Using Self-Supervised Learning.
Deep learning models trained with an insufficient volume of data can often fail to generalize between different equipment, clinics, and clinicians or fail to achieve acceptable performance. We improve cardiac ultrasound segmentation models using unlabeled data to learn recurrent anatomical representations via self-supervision. In addition, we leverage supervised local contrastive learning on sparse labels to improve the segmentation and reduce the need for large amounts of dense pixel-level supervisory annotations. Then, we implement supervised fine-tuning to segment key temporal anatomical features to estimate the cardiac Ejection Fraction (EF). We show that pretraining the network weights using self-supervised learning for subsequent supervised contrastive learning outperforms learning from scratch, validated using two state-of-the-art segmentation models, the DeepLabv3+ and Attention U-Net.Clinical relevance-This work has clinical relevance for assisting physicians when conducting cardiac function evaluations. We improve cardiac ejection fraction evaluation compared to previous methods, helping to alleviate the burden associated with acquiring labeled images.


The diagnostic accuracy of X-ray arthrography for triangular fibrocartilaginous complex injury: a systematic review and meta-analysis.
The purpose of this study was to evaluate the diagnostic test accuracy of X-ray arthrography in the detection of TFCC tear. Both published and unpublished databases were searched from their inception to August 2010. All studies comparing the diagnostic accuracy of X-ray arthrography (index test) to arthroscopy (reference standard) for patients with suspected TFCC tears were included in this review. Twelve studies assessing 430 patients (430 wrists) satisfied the eligibility criteria and were included. X-ray arthrography presented with a pooled sensitivity of 76.2% and specificity of 92.5% for the detection of complete TFCC tear. The triple-compartment injection X-ray arthrography was superior to the single-compartment injection technique. To conclude, the diagnostic test accuracy of X-ray arthrography is limited. Neither the single- nor the triple-compartment injection arthrography method is acceptable, given their reported low sensitivities. Further evaluation of the diagnostic test accuracy of Magnetic Resonance Arthrography and Magnetic Resonance Imaging is therefore warranted.


Dietary Polyphenol Intake in US Adults and 10-Year Trends: 2007-2016.
Polyphenols are a class of phytochemicals that have antioxidant, anti-inflammatory, anticancer, and antiviral properties. Previous research suggests that dietary polyphenol intake is protective against major chronic diseases. To our knowledge, no data on polyphenol intake for the US adult population are available. This study explored usual dietary polyphenol intake among US adults in 2013-2016 and examined trends in intake during 2007-2016 by demographic characteristics, and identified major dietary sources of polyphenols. The National Health and Nutrition Examination Survey is a series of cross-sectional surveys representative of the civilian noninstitutionalized US population. This study included 9,773 adults aged 20 years and older. Dietary and supplement data were obtained from two 24-hour dietary recalls. Polyphenol intake was estimated using the Phenol Explorer Database and adjusted for total energy intake. Usual intake was estimated both overall and by demographic characteristics using the National Cancer Institute method. Trends in intake on a given day over 10 years were evaluated using regression analysis. The complex survey design was incorporated in all analyses. In 2013-2016, the usual intake of dietary polyphenols was a mean (standard error) of 884.1 (20.4) mg per 1,000 kcal/d. Polyphenol intake was higher in adults 40 years and older, women, non-Hispanic White adults, and college graduates. During 2007-2016, the mean daily polyphenol intake did not change significantly over time for overall and demographic groups. Main polyphenol classes consumed were phenolic acids (mean [standard error] of 1,005.6 [34.3] mg/d) and flavonoids (mean [standard error] of 379.1 [10.7] mg/d). Foods and beverages contributed 99.8% of polyphenol intake, with coffee (39.6%), beans (9.8%), and tea (7.6%) as major dietary contributors. Findings from this study suggest that polyphenol intake is consistent with the low intake of fruits, vegetables, and whole grains in the US population, and provide more evidence of the need for increased consumption of these food groups.


[Cyclic GMP-induced structural transitions of photoreceptor membranes].
The influence of cyclic GMP on the structural state of photoreceptor membranes was studied. The spin probe technique was used to obtain the dependences of microviscosity of lipid domains of membranes on cGMP concentration. It was shown that microviscosity of 5-doxylsteraric acid environment in rod outer segment, disc and plasma mambranes changed at concentrations of 2.10(7); 5.10(-6) and 6.10(-6). Non-cyclic GMP was ineffective. The ultrasound treatment of membraneous samples resulted on disappearance of the structural changes.


Cardioprotective anti-hyperglycemic drugs ameliorate endoplasmic reticulum (ER) stress.
Cellular stress, notably oxidative, inflammatory and endoplasmic reticulum (ER) stress is implicated in the pathogenesis of cardiovascular disease. Modifiable risk factors for cardiovascular disease such as diabetes, hypercholesterolemia, saturated fat consumption, hypertension and cigarette smoking cause ER stress while currently known cardioprotective drugs with diverse pharmacodynamics share a common pleiotropic effect of reducing ER stress. Selective targeting of oxidative stress with known antioxidative vitamins has been ineffective in reducing cardiovascular risk. This "antioxidant paradox" is partially attributed to the unexpected aggravation of ER stress by the antioxidative agents used. In contrast, some of the contemporary anti-hyperglycemic drugs inhibit both oxidative stress and ER stress in human coronary artery endothelial cells. Unlike sulfonylureas, meglitinides, α glucosidase inhibitors and thiazolidinediones, metformin, glucagon like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors are the only anti-hyperglycemic drugs that reduce ER stress caused by pharmacological agents (tunicamycin) or hyperglycemic conditions. Clinical trials with selective ER stress modifiers are needed to test the suitability of ER stress as a therapeutic target for cardiovascular disease.


Tuberculosis control policies in major metropolitan health departments in the United States. VI. Standard of practice in 1996.
Since 1980, we have surveyed at 4-yr intervals the metropolitan health departments initially reporting > 250 cases of tuberculosis to determine the perceived standard of practice for tuberculosis control and the factors affecting formulation of treatment policies. Between 1992 and 1996, use of supervised short-course (6 to 9 mo) intermittent therapy with multiple drugs including isoniazid, ethambutol, pyrazinamide, and rifampin increased from 4.3% to 46% of all new patients. Pyrazinamide use for initial treatment for children has increased substantially and now predominates (74.2% of patients in 1996 versus 48.1% of patients in 1992). Duration of treatment, which was 20 +/- 2.1 mo in 1980, is now 8.00 +/- 2.29 mo in 1996. The incidence of human immunodeficiency virus-associated tuberculosis, which was virtually unrecognized in 1984, has remained the same between 1992 and 1996 (18.0%). As in previous years, there was a wide variance among health departments in the incidence (< 5% to > 40%) of HIV-associated tuberculosis. After years of funding decreases, there has been an impressive increase in resources in the past 4 yr. In 1988, mean budget allocation for health departments decreased by 7.9% versus the prior 4 yr and, in 1992, there was no overall change in budget allocation after inflation versus 1988. In 1996, however, funds for treatment increased by 84 +/- 33%. This increase in funding has been translated into the greatly expanded use of supervised intermittent therapy and aggressive screening programs, which likely have resulted in the decreased incidence of tuberculosis since the prior survey.


[Pathologic movements of the ventricular septum in complete block of the left branch of the bundle of His and their effect on left ventricular function].
Echocardiographic tools (M-mode and 2D-scanning) were applied to examine 83 patients with complete bundle-branch block and/or its anteroapical bifurcation block. Six types of abnormal ventricular septal motions associated with the intraventricular asynchronism typical of complete bundle-branch block and with the specific features of electric pulse propagation in the His-Purkinje system were identified. There was a reduction in left ventricular ejection fraction that is peculiar to Types I and VI abnormal ventricular septal motions, whereas in patients with complete bundle-branch block, it is associated with anteroapical bifurcation block. A moderate decrease in ejection fraction is more common for Types III and IV abnormal ventricular septal motions (despite the severity of cardiac disease). Complete bundle-branch block alone and in combination with anteroapical bifurcation block contributes to a decrease in left ventricular function and diminished myocardial contractility. Whether the severity of complete bundle-branch block affects cardiodynamics is discussed in the present paper.


IL-13-induced intestinal secretory epithelial cell antigen passages are required for IgE-mediated food-induced anaphylaxis.
Food-induced anaphylaxis (FIA) is an IgE-dependent immune response that can affect multiple organs and lead to life-threatening complications. The processes by which food allergens cross the mucosal surface and are delivered to the subepithelial immune compartment to promote the clinical manifestations associated with food-triggered anaphylaxis are largely unexplored. We sought to define the processes involved in the translocation of food allergens across the mucosal epithelial surface to the subepithelial immune compartment in FIA. Two-photon confocal and immunofluorescence microscopy was used to visualize and trace food allergen passage in a murine model of FIA. A human colon cancer cell line, RNA silencing, and pharmacologic approaches were used to identify the molecular regulation of intestinal epithelial allergen uptake and translocation. Human intestinal organoid transplants were used to demonstrate the conservation of these molecular processes in human tissues. Food allergens are sampled by using small intestine (SI) epithelial secretory cells (termed secretory antigen passages [SAPs]) that are localized to the SI villous and crypt region. SAPs channel food allergens to lamina propria mucosal mast cells through an IL-13-CD38-cyclic adenosine diphosphate ribose (cADPR)-dependent process. Blockade of IL-13-induced CD38/cADPR-dependent SAP antigen passaging in mice inhibited induction of clinical manifestations of FIA. IL-13-CD38-cADPR-dependent SAP sampling of food allergens was conserved in human intestinal organoids. We identify that SAPs are a mechanism by which food allergens are channeled across the SI epithelium mediated by the IL-13/CD38/cADPR pathway, regulate the onset of FIA reactions, and are conserved in human intestine.


In silico clinical trials for anti-aging therapies.
Therapeutic strategies targeting the hallmarks of aging can be broadly grouped into four categories, namely systemic (blood) factors, metabolic manipulation (diet regimens and dietary restriction mimetics), suppression of cellular senescence (senolytics), and cellular reprogramming, which likely have common characteristics and mechanisms of action. In evaluating the potential synergism of combining such strategies, however, we should consider the possibility of constraining trade-off phenotypes such as impairment in wound healing and immune response, tissue dysfunction and tumorigenesis. Moreover, we are rapidly learning that the benefit/risk ratio of aging-targeted interventions largely depends on intra- and inter-individual variations of susceptibility to the healthspan-, resilience-, and/or lifespan-promoting effects of the interventions. Here, we exemplify how computationally-generated proxies of the efficacy of a given lifespan/healthspan-promoting approach can predict the impact of baseline epigenetic heterogeneity on the positive outcomes of ketogenic diet and mTOR inhibition as single or combined anti-aging strategies. We therefore propose that stochastic biomathematical modeling and computational simulation platforms should be developed as in silico strategies to accelerate the performance of clinical trials targeting human aging, and to provide personalized approaches and robust biomarkers of healthy aging at the individual-to-population levels.


Trauma-informed Drug Screens for Veterans with Co-occurring Disorders: A Case Series.
Objective: This case series describes and illustrates the effective use of a trauma-informed approach, GLAPE, to provide drug screens for individuals in substance use treatment programs. The GLAPE approach recognizes that individuals who have experienced traumatic events and are recovering from substance use difficulties may also face unique challenges when engaging in mental health treatment. The nature of drug screening procedures in practice may feel invasive and triggering for clients with trauma histories. Finding ways to decrease barriers to treatment and increase engagement and retention are important components of effective substance use treatment. Methods: This case series involved three veteran cisgender men with posttraumatic stress disorder (PTSD) and co-occurring substance use conditions in an outpatient addiction recovery program in a Veterans' hospital. The cases illustrate how recovery can be aided by trauma-informed approaches for urine drug screens. The treatment team evaluated various monitoring modalities and collaborated with each client to form a treatment plan that implemented the GLAPE approach to bolster their recovery. The GLAPE approach includes five components: Giving detailed instructions prior to the urine screen procedure, listening to and eliciting questions and concerns of the client, articulating options and exhibiting flexibility in the procedure to accommodate the needs of the individual client, giving permission to the client to voice concerns at any point during the procedure, and evaluating the process in collaboration with the client, including what could be improved for next time. Results: Use of the GLAPE approach effectively helped to engage and retain military veterans with co-occurring PTSD and substance use disorder within a trauma informed outpatient program. Preliminary evidence from three cases provides that this approach may be useful for use in substance use treatment with clients who have trauma histories. Conclusions: Given widespread use of observed urine drug screens in substance use treatment programs, and prominent co-occurrence of substance use disorder and PTSD, it is essential that staff approach this procedure in a trauma-informed way. This case series illustrates an approach that can improve client experience, aid clients in treatment engagement, and assist staff in the provision of effective care.