Surgical complications after different therapeutic approaches for locally advanced rectal cancer.
Preoperative radiochemotherapy is widely used in locally advanced rectal cancer. It can improve local control of rectal cancer. However, some researchers believe it increases the incidence of surgical complications. They doubt its safety. Patients with locally advanced rectal cancer receive three different treatments in our hospital, including long-course radiochemotherapy, short-course radiotherapy, and surgery directly. We can compare their differences in postoperative complications. To investigate surgical complications caused by different preoperative radiotherapy regimens. We retrospectively analyzed 1197 patients admitted between 2008 and 2010 with locally advanced rectal cancer. Three hundred and forty-six patients were treated with preoperative long-course radiochemotherapy (25 × 2 Gy) followed by total mesorectal excision (TME) 6-8 wk later, and 259 patients received short-course radiotherapy (10 × 3 Gy) and subsequently TME 7-10 d later. The remaining 592 patients underwent TME alone without neoadjuvant therapy. According to Clavien-Dindo classification, surgical complications were evaluated for up to 30 d after discharge from hospital. There were no deaths in 30 d in all groups after treatment. The major complications were anastomotic leakage and perineal wound complications. The results suggested that both long-course [odds ratio (OR) = 3.624, 95% confidence interval (CI): 1.689-7.775, P = 0.001] and short-course (OR = 5.150, 95%CI: 1.828-14.515, P = 0.002) radiotherapy were associated with anastomotic leakage. Temporary ileostomy was a protective factor for anastomotic leakage (OR = 6.211, 95%CI: 2.525-15.385, P < 0.001). The severity of anastomotic leakage did not increase in patients following preoperative radiotherapy (P = 0.411). Compared with TME alone, short-course radiotherapy was associated with an increase in perineal wound complications (OR = 5.565, 95%CI: 2.203-14.057, P < 0.001), but long-course radiotherapy seemed safe regarding this complication (OR = 1.692, 95%CI: 0.651-4.394, P = 0.280). Although the severity of perineal wound complications increased in patients following short-course radiotherapy (P < 0.001), additional intervention was not necessary. Radiotherapy increased the incidence but not severity of anastomotic leakage. Short-course radiotherapy was also accompanied with perineal wound complications, but intervention appeared unnecessary to ameliorate the complications.


Age and diet modulate the insulin-sensitizing effects of exercise: a tracer-based oral glucose tolerance test.
Diet modulates the development of insulin resistance during aging. This includes tissue-specific alterations in insulin signaling and mitochondrial function, which ultimately affect glucose homeostasis. Exercise stimulates glucose clearance, mitochondrial lipid oxidation and enhances insulin sensitivity. It is not well known how exercise interacts with age and diet in the development of insulin resistance. To investigate this, oral glucose tolerance tests (OGTT) with a tracer were conducted in mice ranging from 4 to 21 months of age, fed a low- (LFD) or high-fat diet (HFD), with or without life-long voluntary access to a running wheel (RW). We developed a computational model to derive glucose fluxes, which were commensurate with independent values from steady-state tracer infusions. Both insulin sensitivity indices derived for peripheral tissues and liver (IS-P and IS-L, respectively) were steeply decreased by aging and a HFD. This preceded the age-dependent decline in the mitochondrial capacity to oxidize lipids. In LFD young animals, RW access enhanced the IS-P concomitantly with the muscle β- oxidation capacity. Surprisingly, RW access completely prevented the age-dependent IS-L decrease, but only in LFD animals. This study indicates, therefore, that endurance exercise can improve the age-dependent decline in organ-specific IS mostly in the context of a healthy diet.


Immune responses against human papillomavirus (HPV) type 16 virus-like particles in a cohort study of women with cervical intraepithelial neoplasia. II. Systemic but not local IgA responses correlate with clearance of HPV-16.
To investigate whether there is an association between local or systemic IgG and IgA responses against human papillomavirus (HPV) type 16 virus-like particles (VLP) containing L1 and L2 and the possible influence of these responses on clearance of HPV-16 and its associated lesions, cervical mucus samples from 125 patients and plasma samples from 100 patients, all participating in a non-intervention cohort study of women with abnormal cytology, were analysed. The results show that local IgG and IgA HPV-16 VLP-specific antibodies do not correlate with virus clearance. However, systemic IgG responses were more frequently detected in patients with a persistent infection (11/24) compared with patients with cleared HPV-16 infections (3/28, P = 0.006). Furthermore, the ultimate development of high-grade lesions was associated with systemic VLP-specific IgG reactivity (P = 0.026). By contrast, systemic IgA responses were correlated with virus clearance (7/28 clearance compared with 1/24 persistence patients, P = 0.06). This correlation was statistically significant when only those clearance patients who tested HPV-16 DNA-positive at more than one visit were included in the analysis (5/11 compared with 1/24, P = 0.007). As these systemic IgA responses were not accompanied by local IgA responses, the systemic IgA responses in HPV-16 clearance patients are suggested to be a by-product of a successful cellular immune response induced at the local lymph nodes, mediated by cytokines.


Troponin elevations only detected with a high-sensitivity assay: clinical correlations and prognostic significance.
With clinical use of high-sensitivity troponin I (hsTnI), more frequent troponin elevations will occur. However, the burden and implications of these elevations are not well understood. The authors quantified the prevalence of elevated hsTnI in patients presenting with possible acute coronary syndrome (ACS) who do not have elevated troponin with a current generation assay (cardiac troponin I [cTnI]) and determined the association of these newly detected elevations with a composite of all-cause mortality and subsequent cardiac hospitalization. This was a prospective observational study of 808 subjects evaluated for possible ACS and followed for up to 1 year. Troponin values were measured with hsTnI (Abbott Laboratories) and cTnI (Abbott and Beckman Coulter). Cardiac hospitalization was defined as hospitalization for ACS, revascularization, acute heart failure (AHF), or tachy/brady arrhythmia that occurred after the index emergency department (ED) visit or hospital discharge. Forty subjects (5%) were diagnosed with ACS (26 myocardial infarction and 14 unstable angina). On the initial sample, the prevalence of elevated hsTnI among subjects with nonelevated cTnI was 9.2% using a gender-neutral cutoff (95% confidence interval [CI] = 7.1% to 11.4%) and 11.1% using a gender-specific cutoff (95% CI = 8.8% to 13.4%). Adjudicated diagnoses for subjects whose initial samples had elevated hsTnI but nonelevated cTnI (gender-neutral cutoff) were as follows: three (4.6%) ACS, 15 (23.1%) AHF, three (4.6%) volume overload etiology unclear/noncardiac, three (4.6%) cardiac (non-ACS), and 41 (63.1%) other. Of the 65 patients whose initial samples had hsTnI but nonelevated cTnI, eight developed cTnI elevation on subsequent serial sampling. After traditional cardiovascular risk factors and renal function were adjusted for, subjects with elevated initial hsTnI but nonelevated cTnI (initial and serial sampling) had a higher risk of all-cause mortality and subsequent cardiac hospitalization than subjects with both nonelevated hsTnI and nonelevated cTnI (hazard ratio [HR] = 1.91, 95% CI = 1.14 to 3.19). On the initial sample, 9% to 11% of subjects without cTnI elevation had hsTnI elevation. Although the majority of the patients with these newly detected hsTnI elevations did not have ACS, they had a higher risk for all-cause mortality and subsequent cardiac hospitalization.


Ceramic inlays: a case presentation and lessons learned from the literature.
Ceramic dental restorative materials offer an esthetic alternative to dental amalgam or gold. There is uncertainty relative to the longevity of ceramic inlay restorations. Recently published long-term research studies reveal general clinical performance trends. These trends are discussed while presenting a ceramic inlay case. Successful clinical use of ceramic inlay materials is absolutely dependent on the creation of an uncompromised adhesive tooth/ceramic interface. Ceramic inlay restorations perform well in terms of long-term retention, color match, and anatomic contour stability. These restorations all experience limited margin deterioration that does not predispose to marginal discoloration or secondary caries. Patients rarely suffer from postoperative sensitivity secondary to ceramic inlay placement. Ceramic inlays fail predominantly as a result of crack propagation from material flaws leading to bulk fracture. Some superficial ceramic defects may be repaired with composite resin. Internal material flaws are minimized by industrial production of indirect pressable glass-ceramic materials or ceramic blocks designed for computer-aided design/computer-assisted manufacturing (CAD/CAM). External surface flaws are limited by careful polishing techniques. Strategic placement of ceramic inlays in teeth that are not subject to heavy occlusal loading will result in more predictable long-term performance. Preparation design to prevent flexure of ceramic inlay materials is essential. Use of ceramic inlays to restore defects in posterior teeth requires careful attention to detail. Placement of ceramic inlay materials in high-stress areas may result in less predictable long-term performance. Ceramic inlays are advantageous for restoring moderately sized defects when optimal control of restoration contours and esthetics is desired.


Higher blood loss and transfusion requirement in surface arthroplasty versus conventional total hip replacement.
Surface replacement arthroplasty (SRA) is an alternative to stemmed total hip arthroplasty (THA) providing a femoral bone preserving procedure. Because of the wider surgical dissection, an increased blood loss could be expected. This retrospective study evaluates the transfusion requirement in two homogeneous groups of patients who underwent primary hip replacement electively. Perioperative haematological data of 42 hip resurfacing procedures and 41 conventional cementless THAs were compared. The pre- and post-operative haemoglobin (Hb) levels and the amount of blood transfusions were registered. The median values were compared with use of the non-parametric Wilcoxon signedrank test. In the SRA group, a significantly increased (p<0.02) preoperative Hb concentration (13.1 g/dL, range 10.9 to 15.6) was detected in comparison with the THA group (12.5 g/dL, range 10.4 to 15.2). In the resurfacing procedures a median of 900 mL (range 600 to 1500) were transfused vs. 600 (range 300 to 1500) in the conventional THAs, demonstrating a significantly higher transfusion requirement (p<0.04). Whereas hip resurfacing is a femoral bone preserving alternative to conventional THA with comparable clinical and radiographic outcomes, higher blood loss and transfusion requirement may occur.


Characterization of bovine miRNAs by sequencing and bioinformatics analysis.
MicroRNAs (miRNAs) are a family of approximately 22 nucleotide small RNA molecules which regulate gene expression by fully or partially binding to their complementary sequences in mRNAs or promoters. A large number of miRNAs and their expression patterns have been reported in human, mouse and rat. However, miRNAs and their expression patterns in live stock species such as beef cattle are not well studied. We constructed and sequenced small-RNA libraries to yield a total of 13,541 small-RNA sequences from 11 bovine tissues including brain, subcutaneous fat, muscle, liver, kidney, spleen and thymus. In total, 228 miRNAs including 29 novel miRNA candidates were identified. Of the 199 miRNAs, 101 have been previously reported as bovine miRNAs and the other 98 are bovine orthologs of known miRNAs that have been identified in at least one other mammalian species. Of the 29 novel miRNA candidates, 17 appeared at this point in time to be bovine specific, while the remaining 12 had evidence of evolutionary conservation in other mammalian species. Five miRNAs (miR-23a, -23b, -99a, -125b and -126-5p) were very abundant across the 11 tissues, accounting for 44.3% of all small RNA sequences. The expression analysis of selected miRNAs using qRT-PCR also showed that miR-26a and -99a were highly expressed in all tissues, while miR-122 and miR-133a were predominantly expressed in liver and muscle, respectively. The miRNA expression patterns among 11 tissues from beef cattle revealed that most miRNAs were ubiquitously expressed in all tissues, while only a few miRNAs were tissue specific. Only 60% miRNAs in this study were found to display strand bias, suggesting that there are some key factors for mature miRNA selection other than internal stability. Most bovine miRNAs are highly conserved in other three mammalian species, indicating that these miRNAs may have a role in different species that are potential molecular markers for evolution.


Self-organization leads to supraoptimal performance in public transportation systems.
The performance of public transportation systems affects a large part of the population. Current theory assumes that passengers are served optimally when vehicles arrive at stations with regular intervals. In this paper, it is shown that self-organization can improve the performance of public transportation systems beyond the theoretical optimum by responding adaptively to local conditions. This is possible because of a "slower-is-faster" effect, where passengers wait more time at stations but total travel times are reduced. The proposed self-organizing method uses "antipheromones" to regulate headways, which are inspired by the stigmergy (communication via environment) of some ant colonies.


Cognitive Control and Flexibility in the Context of Stress and Depressive Symptoms: The Cognitive Control and Flexibility Questionnaire.
Cognitive control and (cognitive) flexibility play an important role in an individual's ability to adapt to continuously changing environments. In addition to facilitating goal-directed behaviors, cognitive control and flexibility have been implicated in emotion regulation, and disturbances of these abilities are present in mood and anxiety disorders. In the context of stressful experiences, the reported studies examined processes related to cognitive control and flexibility, emotional regulation and depressive symptoms. To this end, a brief (18-item) self-report measure - the Cognitive Control and Flexibility Questionnaire (CCFQ) - was developed. This questionnaire measures an individual's perceived ability to exert control over intrusive, unwanted (negative) thoughts and emotions, and their ability to flexibly cope with a stressful situation. In Study 1, the CCFQ was assessed among both university students (N = 300) and a community sample (N = 302). Preliminary analyses suggested a stable and reliable two-factor structure, that of cognitive control over emotion, and appraisal and coping flexibility. Scores on the CCFQ were strongly associated with greater depressive symptoms, even after controlling for other measures that had been taken to reflect cognitive control and (in)flexibility (e.g., the Ruminative Response Scale; Perseverative Thinking Questionnaire). In Study 2 (N = 368), lower scores on the CCFQ were related to more negative stressor appraisals (i.e., greater perceived threat and uncontrollability) of a personally meaningful stressful event. Perceptions of threat and uncontrollability, in turn, partially accounted for the association between CCFQ subscale scores and depressive symptoms. The relation between lower CCFQ scores and heightened depressive symptoms was also partially accounted for by less frequent engagement in problem-focused coping and more use of emotion-focused methods. In Study 3 (N = 47 females), lower scores on the cognitive control over emotion component of the CCFQ predicted elevated negative affect and an exacerbated cortisol response following an acute psychosocial stressor (Trier Social Stress Test). The present research points to the CCFQ as a useful self-report tool to identify ways through which cognitive control and flexibility might be manifested in stressful situations, and how reductions in flexibility might be accompanied by elevated symptoms of depression.


Rings in random environments: sensing disorder through topology.
In this paper we study the role of topology in DNA gel electrophoresis experiments via molecular dynamics simulations. The gel is modelled as a 3D array of obstacles from which half edges are removed at random with probability p, thereby generating a disordered environment. Changes in the microscopic structure of the gel are captured by measuring the electrophoretic mobility of ring polymers moving through the medium, while their linear counterparts provide a control system as we show they are insensitive to these changes. We show that ring polymers provide a novel, non-invasive way of exploiting topology to sense microscopic disorder. Finally, we compare the results from the simulations with an analytical model for the non-equilibrium differential mobility, and find a striking agreement between simulation and theory.


Ethanol extract of Psoralea corylifolia L. and its main constituent, bakuchiol, reduce bone loss in ovariectomised Sprague-Dawley rats.
The aim of the present study was to investigate whether ethanol extracts of Psoralea corylifolia L. (PCE) and its active component protect against bone loss in ovariectomised rats. We screened oestrogenic activities of the main extract fractions using in vitro assays and identified bakuchiol as the most active oestrogenic component by HPLC and LC/MS, and then demonstrated that bakuchiol had strong binding affinity for oestrogen receptor (ER) alpha. Seventy female Sprague-Dawley rats were assigned to either a sham-operated group (n 10) or an ovariectomised group (n 60). The ovariectomised group was subdivided into six groups, each containing ten rats: vehicle group, two bakuchiol-treated groups (dose of 15 mg/kg per d or 30 mg/kg per d; ten rats for each group), two PCE-supplemented groups (0.25 % or 0.5 % extracts of diets; ten rats for each group) and a 17beta-oestradiol (E2)-treated group (20 microg/kg per d). We recorded weight and feed intake every week, and killed all animals after 6 weeks. Blood was collected, and the uterus, kidneys and livers were removed. Bakuchiol has a three-fold higher binding affinity for ERalpha than for ERbeta. Bakuchiol and PCE treatments had no uterotrophic activity even though they demonstrated oestrogenic activity in the in vitro assays. Bakuchiol and PCE treatments reduced postmenopausal bone loss by increasing alkaline phosphatase, Ca concentrations, serum E2 concentration and bone mineral density, and by decreasing the inorganic P level. The present study indicated that bakuchiol and PCE treatments could protect against bone loss.


Disease caused by non-tuberculous mycobacteria: diagnostic procedures and treatment evaluation in the North of Buenos Aires Province.
Non-tuberculous mycobacteria (NTM) have emerged as pathogens frequently associated to HIV co-infection. The aims of this study were to describe the clinical importance of NTM in patients from the North of Buenos Aires Province and the drug-susceptibility patterns in relation with the therapy used. A total of 23,624 clinical specimens were investigated during the period 2004-2010. Ziehl-Neelsen stain and cultures were used for diagnosis. Molecular and biochemical tests were performed to identify the mycobacteria. TB and mycobacterioses cases were 2 118 and 108 respectively. Sixteen NTM species were found: Mycobacterium avium and Mycobacterium intracellulare as the main causative agents. Infections produced by more than one species at the same time were confirmed (4 cases). Macrolides and fluoroquinolones were the most active in vitro drugs. Treatment evaluation showed that 68.0 % of the cases completed the therapy, 20 % died; and 12 % were relapses. The cases in which the treatment outcome was evaluated received an individual tailor-made therapeutic scheme including those drugs showing in vitro activity and presumed in vivo usefulness. More than a quarter of the patients had HIV co-infection and the majority of the deaths were associated with this co-infection.


Mapping centromeres of microchromosomes in the zebra finch (Taeniopygia guttata) using half-tetrad analysis.
Centromeres usually consist of hundreds of kilobases of repetitive sequence which renders them difficult to assemble. As a consequence, centromeres are often missing from assembled genomes and their locations on physical chromosome maps have to be inferred from flanking sequences via fluorescence in situ hybridization (FISH). Alternatively, centromere positions can be mapped using linkage analyses in accidentally triploid individuals formed by half-tetrads (resulting from the inheritance of two chromatids from a single meiosis). The current genome assembly of the zebra finch (Taeniopygia guttata) comprises 32 chromosomes, but only for the ten largest chromosomes centromere positions have been mapped using FISH. We here map the positions of most of the remaining centromeres using half-tetrad analyses. For this purpose, we genotyped 37 zebra finches that were triploid or tetraploid due to inheritance errors (and mostly died as embryos) together with their parents at 64 microsatellite markers (at least two per chromosome). Using the information on centromere positions on the ten largest chromosomes, we were able to identify 12 cases of non-disjunction in maternal meiosis I and 10 cases of non-disjunction in maternal meiosis II. These 22 informative cases allowed us to infer centromere positions on additional 19 microchromosomes in reference to the current genome assembly. This knowledge will be valuable for studies of chromosome evolution, meiotic drive and species divergence in the avian lineage.


Cross-sectional analysis of COVID-19 vaccine intention, perceptions and hesitancy across Latin America and the Caribbean.
Determinants of vaccine acceptance are multifactorial, complex, and in most cases, context-dependent. We determined the prevalence of COVID-19 vaccination intention (VI) and fear of its adverse effects (FAE) as well as their associated factors in Latin America and the Caribbean (LAC). We conducted a secondary cross-sectional analysis of a database collected by the University of Maryland and Facebook. We included participants aged 18 and over from LAC surveyed, January 15 to February 1, 2021. We evaluated VI, FAE, sociodemographic characteristics, COVID-19 symptomatology, compliance with community mitigation strategies, food and economic insecurity, mental health evaluation and the influence in VI when recommended by different stakeholders. We calculated crude and adjusted prevalence ratios with their 95%CIs. We analyzed 472,521 responses by Latin American adults, finding a VI and FAE prevalence of 80.0% and 81.2%, respectively. We found that female and non-binary genders were associated with a lower probability of VI and a higher probability of FAE. Besides, living in a town, village or rural area and economic insecurity was associated with a higher FAE probability. The fears of becoming seriously ill, a family member becoming seriously ill from COVID-19 and having depressive symptoms were associated with a higher probability of VI and FAE. Eight out of 10 adults in LAC have VI and FAE. The factors identified are useful for the development of communication strategies to reduce FAE frequency. It is necessary to guarantee mass vaccination and support the return of economic activities.


Physician characteristics and organizational factors influencing use of ambulatory tests.
A number of studies have suggested that there is considerable variation in the frequency with which physicians order particular tests. This paper reviews the relationship of variations in ambulatory testing to characteristics of physicians' training and practice; and organizational factors such as physician group size, method of reimbursement, and ease of access to technical services. Results from previous investigations suggest that specialty training, more recent physician graduation, and large group practice settings are associated with significantly higher test use. Information available about other physician characteristics and organizational factors is equivocal. The extent of variations in practice has important implications for the cost and quality of medical care. Greater effort should be made to document the effects of nonmedical factors and to clarify how those effects are mediated and how they might be modified to improve the use of medical resources.


The use of glucosamine, devil's claw (Harpagophytum procumbens), and acupuncture as complementary and alternative treatments for osteoarthritis.
Osteoarthritis is one of the most common chronic inflammatory conditions seen in the general population. Current pharmacological treatments focus on reduction of pain and increased mobility to improve overall quality of life. However, the relief afforded by current standard care is often insufficient and can be associated with significant side effects. Many patients, therefore, seek the option of non-standard therapies, such as nutritional and herbal supplements, acupuncture, and exercise regimens. Glucosamine, Harpagophytum procumbens, and acupuncture are among the most commonly used complementary and alternative medicine approaches utilized by patients suffering from osteoarthritis. Their clinical relevance, safety, and potential mechanisms of action are discussed in this review.


Effects of Popular Diets on Anthropometric and Cardiometabolic Parameters: An Umbrella Review of Meta-Analyses of Randomized Controlled Trials.
The prevalence of overweight, obesity, and their related complications is increasing worldwide. The purpose of this umbrella review was to summarize and critically evaluate the effects of different diets on anthropometric parameters and cardiometabolic risk factors. Medline, Embase, Scopus, Cochrane Database of Systematic Reviews, and Web of Science, from inception to April 2019, were used as data sources to select meta-analyses of randomized controlled trials that examined the effects of different diets on anthropometric parameters and cardiometabolic risk factors. Strength and validity of the evidence were assessed through a set of predefined criteria. Eighty articles reporting 495 unique meta-analyses were examined, covering a wide range of popular diets: low-carbohydrate (n = 21 articles), high-protein (n = 8), low-fat (n = 9), paleolithic (n = 2), low-glycemic-index/load (n = 12), intermittent energy restriction (n = 6), Mediterranean (n = 11), Nordic (n = 2), vegetarian (n = 9), Dietary Approaches to Stop Hypertension (DASH) (n = 6), and portfolio dietary pattern (n = 1). Great variability in terms of definition of the intervention and control diets was observed. The methodological quality of most articles (n = 65; 81%), evaluated using the "A MeaSurement Tool to Assess systematic Reviews-2" questionnaire, was low or critically low. The strength of evidence was generally weak. The most consistent evidence was reported for the Mediterranean diet, with suggestive evidence of an improvement in weight, BMI, total cholesterol, glucose, and blood pressure. Suggestive evidence of an improvement in weight and blood pressure was also reported for the DASH diet. Low-carbohydrate, high-protein, low-fat, and low-glycemic-index/load diets showed suggestive and/or weak evidence of a reduction in weight and BMI, but contrasting evidence for lipid, glycemic, and blood pressure parameters, suggesting potential risks of unfavorable effects. Evidence for paleolithic, intermittent energy restriction, Nordic, vegetarian, and portfolio dietary patterns was graded as weak. Among all the diets evaluated, the Mediterranean diet had the strongest and most consistent evidence of a beneficial effect on both anthropometric parameters and cardiometabolic risk factors. This review protocol was registered at www.crd.york.ac.uk/PROSPERO/ as CRD42019126103.


Sphingosine 1-phosphate elicits proinflammatory responses in ARPE-19 cells.
To investigate the effects of sphingosine 1-phosphate (S1P) on the production of inflammatory mediators and the signaling pathways involved in S1P-mediated production of cytokines by ARPE-19 cells. Expression of S1P receptors was examined using RT-PCR and real-time PCR. ARPE-19 cells were stimulated with S1P or TNF-α, and by coculturing with S1P in the presence or absence of pertussis toxin (PTX) or a series of kinase inhibitors. The induction of inflammatory cytokine production was determined by ELISA. Western blot analysis was used to detect the activation of signaling mediators and S1P(3) receptor. ARPE-19 cells express all the known receptors for S1P. Moreover, exogenously applied S1P induces ARPE-19 cell secretion of interleukin-8 (IL-8) in a dose- and time-dependent manner, but not IL-6 and monocyte chemotactic protein-1 (MCP-1). S1P-mediated IL-8 secretion is regulated by PTX, extracellular regulated protein kinases 1/2 (ERK1/2), and p38 mitogen-activated protein kinase (MAPK). Interestingly, treatment of ARPE-19 cells with TNF-α increases S1P(3) expression and correlates with the enhancement of S1P-induced IL-8 and IL-6 production. This study demonstrates that S1P significantly promoted ARPE-19 cells to secrete inflammatory mediators. extracellular regulated protein kinases 1/2 (ERK1/2), p38 MAPK, and G(i)-dependent pathways are important signaling components in S1P-mediated IL-8 secretion by ARPE-19 cells. Moreover, these results provide evidence that S1P stimulation of RPE cells may play a role in regulating leukocyte function during ocular inflammation.


CD8+ recent thymic emigrants home to and efficiently repopulate the small intestine epithelium.
Prevailing knowledge dictates that naive alphabeta T cells require activation in lymphoid tissues before differentiating into effector or memory T cells capable of trafficking to nonlymphoid tissues. Here we demonstrate that CD8(+) recent thymic emigrants (RTEs) migrated directly into the small intestine. CCR9, CCL25 and alpha(4)beta(7) integrin were required for gut entry of CD8(+) RTEs. After T cell receptor stimulation, intestinal CD8(+) RTEs proliferated and acquired a surface phenotype resembling that of intraepithelial lymphocytes. CD8(+) RTEs efficiently populated the gut of lymphotoxin-alpha-deficient mice, which lack lymphoid organs. These studies challenge the present understanding of naive alphabeta T cell trafficking and suggest that RTEs may be involved in maintaining a diverse immune repertoire at mucosal surfaces.


Blind smell: brain activation induced by an undetected air-borne chemical.
EEG and behavioural evidence suggests that air-borne chemicals can affect the nervous system without being consciously detected. EEG and behaviour, however, do not specify which brain structures are involved in chemical sensing that occurs below a threshold of conscious detection. Here we used functional MRI to localize brain activation induced by high and low concentrations of the air-borne compound oestra-1,3,5(10),16-tetraen-3yl acetate. Following presentations of both concentrations, eight of eight subjects reported verbally that they could not detect any odour (P = 0.004). Forced choice detection performed during the presentations revealed above-chance detection of the high concentration, but no better than chance detection of the low concentration compound. Both concentrations induced significant brain activation, primarily in the anterior medial thalamus and inferior frontal gyrus. Activation in the inferior frontal gyrus during the high concentration condition was significantly greater in the right than in the left hemisphere (P = 0.03). A trend towards greater thalamic activation was observed for the high concentration than the low concentration compound (P = 0.08). These findings localize human brain activation that was induced by an undetectable air-borne chemical (the low concentration compound).


Consanguinity, endogamy and inborn errors of metabolism in Oman: a cross-sectional study.
The Sultanate of Oman, like many other Arab countries, has relatively high rates of consanguinity. Reports suggest that the incidence of inborn errors of metabolism (IEM) is also high in Oman. This retrospective cross-sectional study was designed to evaluate the number of patients with IEM being followed at the only two tertiary centers in Oman treating such patients, and to calculate the consanguinity rates among these families. The electronic medical records of all patients were reviewed for demographic and clinical characteristics. A total of 285 patients with IEM were being followed at the 2 centers involved; 162 (56.8%) were male and 123 (43.2%) were female. The history of consanguinity was documented or available for 241 patients: 229 patients (95%) were born to consanguineous parents related as second cousins or closer. First-cousin marriages were reported in 191 families (79.3%), while 31 patients (12.9%) were born to second cousins. The parents of 5 patients (2%) were related as double first cousins, and 2 patients (1%) were born to first cousins once removed. The average coefficient of inbreeding (F) in our study was 0.081. Seventeen patients (6%) had associated comorbid conditions other than IEM. Our study highlights the clinical burden of IEM in Oman and emphasizes the high consanguinity rates among the parents of affected patients.


Aligning health and welfare principles and practice in organic dairy systems: a review.
This review provides an assessment of research findings into the current practices and standards and the principles and aspirations for organic dairy production, with respect to the health and welfare of the dairy cow. The relationships between the four main factors: management, environment, genetics and nutrition and their impact on the health and welfare status of organic dairy cows are considered. The concept that good animal health and welfare is more than merely the absence of disease, with behavioural aspects of health and welfare such as physiological and psychological needs, is also discussed. These factors are inter-related and important in all dairy systems, irrespective of whether the system is organic, low-input or intensive. Incidences of individual clinical and sub-clinical diseases that are recorded in conventional dairy systems also occur in organic dairy systems, with infertility, lameness and mastitis being the major problems. However, the magnitude of the incidence of many of these diseases may be either lower or higher in organic systems due to different management practices and the standards defined for organic milk production that, for example, prohibit the routine use of conventional medicines and require the feeding of high-forage diets. In relation to different systems, it is important to note that contrary to a common assumption, good welfare does not necessarily occur with more extensive systems. The type of organic system (self-sufficient, purchased-feed) also has the potential to have a major influence on the incidence of health problems and the reproductive status of organic dairy herds. Health status is also influenced by environmental and welfare factors, including the method of rearing replacement animals, type of housing and the geographical and climatic conditions of individual farms. Overall, this review identifies where conflicts arise between current practice and the organic principles and standards, and aims to provide suggestions to bring about further improvement in organic dairy health and welfare.


Central venous pressure as an adjunct to flow-guided volume optimisation after induction of general anaesthesia.
Although the central venous pressure (CVP) is often used as a guide to volume status in major surgery and intensive care, fluid therapy should be guided by the response of the stroke volume (SV) to a fluid bolus. The present study evaluates whether the central venous pressure (CVP) can serve as an adjunct to decisions of whether or not fluid should be infused. Stroke volume (SV) and stroke volume variation (SVV) was monitored with FloTrac/Vigileo and the CVP were measured in 80 patients just before general anaesthesia was induced (baseline) and then, before each of three successive bolus infusions of 3 mL kg⁻¹ of 6% hydroxyethyl starch 130/0.4. A patient showed fluid responsiveness and was denoted a "responder" if SV increased by ≥10% from the bolus infusion. The CVP was higher in non-responders (mean 7.2 mm Hg) than in responders (mean 5.8 mm Hg, P < 0.0001). In non-responders but not in responders, the absence or presence of a rise in CVP improved the prediction of whether the patient would show fluid responsiveness during the next fluid bolus. For example, if no rise in CVP occurred the chance was 48% of subsequent fluid responsiveness, while this chance was only 9% for those who had an increase in CVP (P < 0.004). There was only a fair concordance between fluid responsiveness as indicated by SV and SVV (Cohen´s kappa 0.28). A low CVP suggests that the patient is lower on the Frank-Starling curve than indicated by SV as measured by FloTrac/Vigileo.


Co-option of Membrane Wounding Enables Virus Penetration into Cells.
During cell entry, non-enveloped viruses undergo partial uncoating to expose membrane lytic proteins for gaining access to the cytoplasm. We report that adenovirus uses membrane piercing to induce and hijack cellular wound removal processes that facilitate further membrane disruption and infection. Incoming adenovirus stimulates calcium influx and lysosomal exocytosis, a membrane repair mechanism resulting in release of acid sphingomyelinase (ASMase) and degradation of sphingomyelin to ceramide lipids in the plasma membrane. Lysosomal exocytosis is triggered by small plasma membrane lesions induced by the viral membrane lytic protein-VI, which is exposed upon mechanical cues from virus receptors, followed by virus endocytosis into leaky endosomes. Chemical inhibition or RNA interference of ASMase slows virus endocytosis, inhibits virus escape to the cytosol, and reduces infection. Ceramide enhances binding of protein-VI to lipid membranes and protein-VI-induced membrane rupture. Thus, adenovirus uses a positive feedback loop between virus uncoating and lipid signaling for efficient membrane penetration.


History of maltreatment among unintentional injury deaths: analyses of Texas child fatality review data, 2005-2007.
This report examines unintentional injury deaths among children with and without a history of child maltreatment. Data are from reviews of 1192 unintentional injury deaths occurring among children in Texas during 2005-2007. The study examined differences in child demographic characteristics, injury mechanism, and supervisor status at time of death between children with and without maltreatment history by using descriptive statistics and χ² tests. Separate analyses compared characteristics of asphyxia, drowning, and poisoning deaths. In 10% of the unintentional injury deaths that were reviewed, the child had a history of maltreatment. The prevalence of a history of maltreatment was highest among black decedents and lowest among white decedents. Prevalence of a history of maltreatment was highest among infant decedents and lowest among youth decedents, ages 10-14 years. Among deaths where there was no maltreatment history, 54% were due to motor vehicle related incidents, whereas 51% of deaths among children with maltreatment history were caused by drowning, asphyxia, and poisoning. Supervisors of child decedents with a history of maltreatment were significantly more likely to have been alcohol impaired (6.9% vs 1.6%; p<0.0005), or asleep (12.1% vs 6.6%; p=0.03) at the time of death. Differences between child decedents with and without maltreatment history were observed in infant sleep surface in suffocation deaths, location and barrier type in drowning deaths, and substance type in poisoning deaths. These data show that the mechanisms and circumstances surrounding unintentional injury deaths among children with a history of maltreatment differ from those without a history of maltreatment. This underscores the need for appropriate interventions to prevent unintentional and intentional injuries in families with a history of maltreatment.


One-year mortality prognosis in heart failure: a neural network approach based on echocardiographic data.
This study sought to assess the usefulness and accuracy of artificial neural networks in the prognosis of 1-year mortality in patients with heart failure. Artificial neural networks is a computational technique used to represent and process information by means of networks of interconnected processing elements, similar to neurons. They have found applications in medical decision support systems, particularly in prognosis. Clinical and Doppler-derived echocardiographic data from 95 consecutive patients with diffuse impairment of myocardial contractility were studied. After 1 year, data regarding survival or death were obtained and produced the prognostic variable. The data base was divided randomly into a training data set (47 cases, 8 deaths) and a testing data set (48 cases, 7 deaths). Results of artificial neural network classification were compared with those from linear discriminant analysis, clinical judgment and conventional heuristically based programs. The study group included 57 male (47 survivors) and 38 female patients (33 survivors). Linear discriminant analysis was not efficient for separating survivors from nonsurvivors because the accuracy at the ideal cutoff value was only 67.4%, with a sensitivity of 67.5%, positive predictive value of 27.8% and negative predictive value of 91.5%. In contrast, all artificial neural networks were able to predict outcome with an accuracy of 90%, specificity of 93% and sensitivity of 71.4%, for the best artificial neural network. Both clinical judgment and automatic heuristic methods were also inferior in performance. The artificial neural network method has proved to be reliable for implementing quantitative prognosis of mortality in patients with heart failure. Additional studies with larger numbers of patients are required to better assess the usefulness of artificial neural networks.


Examining the Effects of Temperature on Recombination in Wheat.
Meiotic recombination plays a crucial role in the generation of new varieties. The effectiveness of recombination is limited by the distribution of crossover events, which in wheat and many other crops is skewed toward the distal regions of the chromosomes. Whole-genome sequencing of wheat has revealed that there are numerous important genes in the pericentromeric regions, which are inaccessible to manipulation due to the lack of crossover events. Studies in barley have shown that the distribution of recombination events can be shifted toward the centromeres by increasing temperature during meiosis. Here we present an analysis of the effects of temperature on the distribution and frequency of recombination events in wheat. Our data show that although increased temperature during meiosis does cause an inward shift in recombination distribution for some chromosomes, its overall utility is limited, with many genes remaining highly linked.


Nonfouling behavior of polycarboxybetaine-grafted surfaces: structural and environmental effects.
Zwitterionic carboxybetaine (CB) has unique dual functionality for ligand immobilization on a nonfouling background. The properties of CB groups depend on their spacer groups between the positive quaternary amine groups and the negative carboxyl groups and environmental factors (e.g., ionic strengths and pH values). In this work, five polycarboxybetaines were prepared, including one polycarboxybetaine methacrylate (polyCBMA) and four polycarboxybetaine acrylamides (polyCBAAs) with different spacer groups. The polymers were grafted from a gold surface covered with initiators using surface-initiated atom transfer radical polymerization. Fibrinogen adsorption was measured as a function of ionic strengths and pH values using surface plasmon resonance sensors. The responsive protein adsorption on four polyCBAAs was mapped out. Results show that most of these surfaces exhibit high protein resistance in a wide range of ionic strengths and are more effective than zwitterionic self-assembled monolayers. Although protein adsorption tends to increase at low ionic strength and low pH value, it is still very low for polycarboxybetaines with a methylene, an ethylene, or a propylene spacer group but is more evident for polyCBAA with a longer spacer group (i.e., a pentene group). The response to ionic strengths and pH values can be attributed to the antipolyelectrolyte and protonation/deprotonation properties of polycarboxybetaines, respectively. Both of these properties are related to the spacer groups of CBs.


Selection mapping of loci for quantitative disease resistance in a diverse maize population.
The selection response of a complex maize population improved primarily for quantitative disease resistance to northern leaf blight (NLB) and secondarily for common rust resistance and agronomic phenotypes was investigated at the molecular genetic level. A tiered marker analysis with 151 simple sequence repeat (SSR) markers in 90 individuals of the population indicated that on average six alleles per locus were available for selection. An improved test statistic for selection mapping was developed, in which quantitative trait loci (QTL) are identified through the analysis of allele-frequency shifts at mapped multiallelic loci over generations of selection. After correcting for the multiple tests performed, 25 SSR loci showed evidence of selection. Many of the putatively selected loci were unlinked and dispersed across the genome, which was consistent with the diffuse distribution of previously published QTL for NLB resistance. Compelling evidence for selection was found on maize chromosome 8, where several putatively selected loci colocalized with published NLB QTL and a race-specific resistance gene. Analysis of F2 populations derived from the selection mapping population suggested that multiple linked loci in this chromosomal segment were, in part, responsible for the selection response for quantitative resistance to NLB.


Aerostasis during central venous access: updates in protective sheaths.
Air emboli (AE) complicating central venous catheter (CVC) placement are rare but potentially fatal events. Building on earlier experience, the authors conducted in vitro testing of the aerostatic properties of newly designed protective sheaths. The standard peel-away sheath, the previously studied sliding-valve sheath, and newer fixed-valve and double-valved sheaths were evaluated. Aerostatic stability of the sheaths was evaluated by measuring air flow into the model under standard and stressed conditions. In addition, volumes of AE created during simulated CVC insertion through the sheaths were determined. Under physiologic conditions, significantly smaller volumes of AE occurred with a pinch 2 inches from the sheath hub relative to a pinch at 1 inch. Sliding-, fixed-, and double-valve sheaths yielded leak rates of 0.05 +/- 0.05 mL/sec, 0.06 +/- 0.05 mL/sec, and 0.08 +/- 0.07 mL/sec, respectively. Under stress, protective sheath leak rates increased to 1.8 +/- 0.4 mL/sec, 1.6 +/- 0.5 mL/sec, and 1.8 +/- 0.4 mL/sec, respectively. Use of a double-valved sheath demonstrated no significant difference in leak rates under standard and stressed conditions. In most cases, protective sheaths yielded significantly smaller AE than control sheaths. In comparison of protective sheaths, AE volumes during CVC insertion for sliding-, fixed-, and double-valved sheaths were 22.8 +/- 4.5 mL, 16.6 +/- 7.3 mL, and 10.8 +/- 4.5 mL, respectively. Double-valved sheaths yielded significantly smaller AE volumes than did sliding-valve sheaths (P < .01). In most standard situations, AE volumes and aerostatic stability of protective sheaths tested favorably in comparison with control sheaths. When some sheaths were stressed, their aerostatic properties failed. In a comparison of the three protective sheaths in standard and stressed conditions, the double-valved sheath fared better than the sliding and fixed-valve sheaths.


French military general practitioner: ultrasound practice.
Ultrasound has been used in the field and in emergency departments for more than two decades. In a military setting, its use has grown rapidly as it has gained widespread acceptance among emergency physicians and as the range of diagnostic and triage applications has continued to expand. Technological changes have enabled ultrasound devices to become accessible to general practitioners (GP), and it could be of particular interest for military GPs in isolated environments. We have investigated both the training of French military GPs in the area of ultrasonography and the use of ultrasound devices, in daily practice and abroad, in isolated military settings. In 2011, a questionnaire was sent to all 147 in-the-field GPs of the French southeast regional military health service. The questionnaire evaluated the training of military GPs in ultrasonography, the use of ultrasound in France in daily practice, and during military operations in isolated environments abroad during 2010. The response rate was 52%. On the one hand, half the responding GPs had been specially trained in ultrasound, mainly (97%) in military institutes. On the other hand, only a quarter of doctors used ultrasound in daily practice. Among those GPs performing ultrasound examinations in France, 75% used it in 2010 during isolated operations abroad. Ultrasound examinations performed in such an austere environment were retrospectively declared useful to guide clinical reasoning (41% of examinations carried out), diagnosis (21%) and decision making as regards evacuation (11%). The challenge for the future is to make ultrasound courses mandatory for all military GPs going on overseas operations, to develop daily practice, and to investigate effective triage systems, combining both ultrasound imagery and physical examination.


Functional analysis of secreted and transmembrane proteins critical to mouse development.
We describe the successful application of a modified gene-trap approach, the secretory trap, to systematically analyze the functions in vivo of large numbers of genes encoding secreted and membrane proteins. Secretory-trap insertions in embryonic stem cells can be transmitted to the germ line of mice with high efficiency and effectively mutate the target gene. Of 60 insertions analyzed in mice, one-third cause recessive lethal phenotypes affecting various stages of embryonic and postnatal development. Thus, secretory-trap mutagenesis can be used for a genome-wide functional analysis of cell signaling pathways that are critical for normal mammalian development and physiology.


Projecting land-use change and its consequences for biodiversity in northern Thailand.
Rapid deforestation has occurred in northern Thailand over the last few decades and it is expected to continue. The government has implemented conservation policies aimed at maintaining forest cover of 50% or more and promoting agribusiness, forestry, and tourism development in the region. The goal of this paper was to analyze the likely effects of various directions of development on the region. Specific objectives were (1) to forecast land-use change and land-use patterns across the region based on three scenarios, (2) to analyze the consequences for biodiversity, and (3) to identify areas most susceptible to future deforestation and high biodiversity loss. The study combined a dynamic land-use change model (Dyna-CLUE) with a model for biodiversity assessment (GLOBIO3). The Dyna-CLUE model was used to determine the spatial patterns of land-use change for the three scenarios. The methodology developed for the Global Biodiversity Assessment Model framework (GLOBIO 3) was used to estimate biodiversity intactness expressed as the remaining relative mean species abundance (MSA) of the original species relative to their abundance in the primary vegetation. The results revealed that forest cover in 2050 would mainly persist in the west and upper north of the region, which is rugged and not easily accessible. In contrast, the highest deforestation was expected to occur in the lower north. MSA values decreased from 0.52 in 2002 to 0.45, 0.46, and 0.48, respectively, for the three scenarios in 2050. In addition, the estimated area with a high threat to biodiversity (an MSA decrease >0.5) derived from the simulated land-use maps in 2050 was approximately 2.8% of the region for the trend scenario. In contrast, the high-threat areas covered 1.6 and 0.3% of the region for the integrated-management and conservation-oriented scenarios, respectively. Based on the model outcomes, conservation measures were recommended to minimize the impacts of deforestation on biodiversity. The model results indicated that only establishing a fixed percentage of forest was not efficient in conserving biodiversity. Measures aimed at the conservation of locations with high biodiversity values, limited fragmentation, and careful consideration of road expansion in pristine forest areas may be more efficient to achieve biodiversity conservation.


Change in Work-Related Income Following the Uptake of Treatment for Mental Disorders Among Young Migrant and Non-migrant Women in Norway: A National Register Study.
Background: Women, and migrant women in particular, are at increased risk of many common mental disorders, which may potentially impact their labor market participation and their work-related income. Previous research found that mental disorders are associated with several work-related outcomes such as loss of income, however, not much is known about how this varies with migrant background. This study investigated the change in work-related income following the uptake of outpatient mental healthcare (OPMH) treatment, a proxy for mental disorder, in young women with and without migrant background. Additionally, we looked at how the association varied by income level. Methods: Using data from four national registries, the study population consisted of women aged 23-40 years residing in Norway for at least three consecutive years between 2006 and 2013 (N = 640,527). By using a stratified linear regression with individual fixed effects, we investigated differences between majority women, descendants and eight migrant groups. Interaction analysis was conducted in order to examine differences in income loss following the uptake of OPMH treatment among women with and without migrant background. Results: Results showed that OPMH treatment was associated with a decrease in income for all groups. However, the negative effect was stronger among those with low income. Only migrant women from Western and EU Eastern Europe with a high income were not significantly affected following OPMH treatment. Conclusion: Experiencing a mental disorder during a critical age for establishment in the labor market can negatively affect not only income, but also future workforce participation, and increase dependency on social welfare services and other health outcomes, regardless of migrant background. Loss of income due to mental disorders can also affect future mental health, resulting in a vicious circle and contributing to more inequalities in the society.


Subcategories of tendinopathy using ultrasound tissue characterization (utc): dorsal mid-portion achilles tendinopathy is more severe than ventral achilles tendinopathy.
To evaluate the association between tendon structure and clinical severity. Looking specifically at location of pathology, comparing ventral versus dorsal tendinopathy. Patients were recruited from a tertiary tendinopathy center between Jan 2015 - June 2016. Inclusion criteria included patients with midportion Achilles tendinopathy, aged between 1870. Patients with insertional Achilles tendinopathy or other suspected etiology were excluded. Patients were assessed using ultrasound tissue characterization (UTC) scanning. UTC software was used to analyse a 2 cm block 24 cm from the calcaneum for percentage of echo type I, II, III and IV. With percentage echo type I+II used as the primary outcome. A doctor also categorised patients into predominately dorsal or ventral pathology based on UTC imaging. VISAA and VAS scores were used for clinical outcome measures. Statistics were undertaken using SPSS, data was not normally distributed RESULTS: Overall 33 tendons with mid portion Achilles tendinopathy were analysed, the overall percentage echo type I+II showed no correlation to either VISAA (p=0.745, r=0.0600) or VAS (p=0.157, r=0.248). When divided into dorsal and ventral Achilles tendinopathy there was a significant difference between baseline VISAA scores with a lower VISAA score 35 (SD±19) in dorsal group compared with the ventral group 60 (SD±17.1) (p=0.009). There was also a higher VAS score in the dorsal group (mean = 6, SD±2.28) at baseline compared with ventral (mean = 5, SD±3.07), although this was not significant (p=0.416). This highlights the possibility of using UTC to subcategories patients into ventral and dorsal which seems to correlate to increased clinical severity in the dorsal group. This is perhaps due to increased tension and stretching acting through this part of the tendon on loading and thus more nociceptive stimulation and greater dysfunction of the tendon. This could be used to help determine differing rehabilitation interventions in future with differing intensities for the two groups. It further highlights as previous studies1,2 have that there is no direct correlation between overall structure and clinical severity.


Linking structure and function: development of lateral spatial interactions in macaque monkeys.
Lateral spatial interactions among elements of a scene, which either enhance or degrade visual performance, are ubiquitous in vision. The neural mechanisms underlying lateral spatial interactions are a matter of debate, and various hypotheses have been proposed. Suppressive effects may be due to local inhibitory interactions, whereas facilitatory effects are typically ascribed either to the function of long-range horizontal projections in V1 or to uncertainty reduction. We investigated the development of lateral spatial interactions, facilitation and suppression, and compared their developmental profiles to those of potential underlying mechanisms in the visual system of infant macaques. Animals ranging in age from 10 weeks to 3 years were tested with a lateral masking paradigm. We found that suppressive interactions are present from very early in postnatal life, showing no change over the age range tested. However, facilitation develops slowly over the first year after birth. Our data suggest that the early maturation of suppressive interactions is related to the relatively mature receptive field properties of neurons in early visual cortical areas near birth in infant macaques, whereas the later maturation of facilitation is unlikely to be explained by development of local or long-range connectivity in primary visual cortex. Instead our data favor a late developing feedback or top-down cognitive process to explain the origin of facilitation.


RUNX/AML and C/EBP factors regulate CD11a integrin expression in myeloid cells through overlapping regulatory elements.
The CD11a/CD18 (leukocyte function-associated antigen 1 [LFA-1]) integrin mediates critical leukocyte adhesive interactions during immune and inflammatory responses. The CD11a promoter directs CD11a/CD18 integrin expression, and its activity in lymphoid cells depends on a functional RUNX1/AML-1-binding site (AML-110) within the MS7 sequence. We now report that MS7 contains a C/EBP-binding site (C/EBP-100), which overlaps with AML-110 and is bound by C/EBP factors in myeloid cells. C/EBP and RUNX/AML factors compete for binding to their respective cognate elements and bind to the CD11a promoter MS7 sequence in a cell lineage- and differentiation-dependent manner. In myeloid cells MS7 is primarily recognized by C/EBP factors in proliferating cells whereas RUNX/AML factors (especially RUNX3/AML-2) bind to MS7 in differentiated cells. RUNX3/AML-2 binding to the CD11a promoter correlates with increased RUNX3/AML-2 protein levels and enhanced CD11a/CD18 cell surface expression. The relevance of the AML-110 element is underscored by the ability of AML-1/ETO to inhibit CD11a promoter activity, thus explaining the low CD11a/CD18 expression in t(8;21)-containing myeloid leukemia cells. Therefore, the expression of the CD11a/CD18 integrin in myeloid cells is determined through the differential occupancy of the CD11a proximal promoter by transcription factors implicated in the pathogenesis of myeloid leukemia.


Current management of secondary hyperparathyroidism: a multicenter observational study (COSMOS).
To survey bone mineral disturbances in the hemodialysis (HD) population in Europe and current clinical practice in Europe for the prevention, diagnosis and treatment of secondary hyperparathyroidism (SHPT) in HD patients. First, to estimate the prevalence of Kidney Disease Outcomes Quality Initiative (K/DOQI) guideline achievement in a representative sample of European hemodialysis subjects. As part of this objective, we will investigate the prevalence of achievement by type of dialysis, type of center and time on dialysis (less than or greater than 1 year). Among new dialysis subjects (less than 1 year), we will evaluate prevalence of K/DOQI target achievement until the end of the study. The study will run for 3 years. Second, to estimate the association of bone mineral markers (parathyroid hormone [PTH], calcium [Ca], serum phosphorus [P] and calcium phosphate product [CaxP]) classified by achievement of K/DOQI targets with mortality and overall cardiovascular hospitalization. Third, to characterize the longitudinal changes in bone mineral markers. As part of this objective, we will describe the patterns and predictors of bone mineral markers and achievement, with K/DOQI targets, using repeated measurements on individuals over time. First, To estimate the association of bone mineral markers (PTH, Ca, P and CaxP) classified by achievement of K/DOQI targets with specific cardiovascular outcomes, parathyroidectomy, manifest bone disease (including incidence of symptomatic bone fractures), hospitalizations and vascular access. Second, to evaluate the additional value of albumin and hemoglobin levels in conjunction with bone mineral markers in the prediction of mortality and clinical events.


Unusual complication of a pancreatic neuroendocrine tumor presenting with malignant hypercalcemia.
Hypersecretion of PTHrP is a relatively common cause of malignancy-related hypercalcemia but has only been described in a few cases of neuroendocrine tumors (NET). The aim of this case report is to describe the clinical syndrome, complex therapeutic interventions, and unusual complications caused by persistent PTHrP hypersecretion in a patient with a pancreatic NET. A 58-yr-old male patient presented with nonspecific abdominal pain and was found to have severe hypercalcemia secondary to a well-differentiated NET of the pancreas associated with extensive liver metastases. Elevated ionized calcium levels accompanied by low serum PTH and remarkably elevated PTHrP concentrations were consistent with PTHrP-related hypercalcemia that proved to be resistant to various chemotherapeutic regimens and supportive therapy. Partial control of the humoral syndrome was obtained only after the application of cytoreductive interventions and the introduction of various molecular targeted therapies. Due to persistent PTHrP action, bone disease emerged in the form of brown tumors. The manifestation of paraneoplastic syndrome due to PTHrP hypersecretion, despite its rareness in NET, should be considered in the differential diagnosis of hypercalcemia in such tumors. Moreover, the appearance of bone lesions in this setting may be in the context of metabolic bone disease and could be misdiagnosed as bone metastases.


Identification of genetic drivers of plasma lipoprotein size in the Diversity Outbred mouse population.
Despite great progress in understanding lipoprotein physiology, there is still much to be learned about the genetic drivers of lipoprotein abundance, composition, and function. We used ion mobility spectrometry to survey 16 plasma lipoprotein subfractions in 500 Diversity Outbred mice maintained on a Western-style diet. We identified 21 quantitative trait loci (QTL) affecting lipoprotein abundance. To refine the QTL and link them to disease risk in humans, we asked if the human homologs of genes located at each QTL were associated with lipid traits in human genome-wide association studies. Integration of mouse QTL with human genome-wide association studies yielded candidate gene drivers for 18 of the 21 QTL. This approach enabled us to nominate the gene encoding the neutral ceramidase, Asah2, as a novel candidate driver at a QTL on chromosome 19 for large HDL particles (HDL-2b). To experimentally validate Asah2, we surveyed lipoproteins in Asah2-/- mice. Compared to wild-type mice, female Asah2-/- mice showed an increase in several lipoproteins, including HDL. Our results provide insights into the genetic regulation of circulating lipoproteins, as well as mechanisms by which lipoprotein subfractions may affect cardiovascular disease risk in humans.


Oldest cave art found in Sulawesi.
Indonesia harbors some of the oldest known surviving cave art. Previously, the earliest dated rock art from this region was a figurative painting of a Sulawesi warty pig (Sus celebensis). This image from Leang Bulu' Sipong 4 in the limestone karsts of Maros-Pangkep, South Sulawesi, was created at least 43,900 years ago (43.9 ka) based on Uranium-series dating. Here, we report the Uranium-series dating of two figurative cave paintings of Sulawesi warty pigs recently discovered in the same karst area. The oldest, with a minimum age of 45.5 ka, is from Leang Tedongnge. The second image, from Leang Balangajia 1, dates to at least 32 ka. To our knowledge, the animal painting from Leang Tedongnge is the earliest known representational work of art in the world. There is no reason to suppose, however, that this early rock art is a unique example in Island Southeast Asia or the wider region.


The analysis of lidar signatures of cirrus clouds.
The terminology of light scattering pertinent to a simple form of the lidar equation and the approximate analytical solution of the lidar equation are reviewed without specific restriction on the nature of the cloud scatterers. A boundary value of the volume backscattering coefficient and the relationship between extinction and backscattering are required for the solution. Given the boundary value of the backscattering coefficient and the total transmittance through a cloud, it is possible to derive (by successive approximation) an extinction/ backscatter ratio empirically. Application of the method to the ruby lidar return from a cirrus cloud led to a ratio of 28 sr, and to reasonable profiles of the backscatter coefficient and the transmittance through the cloud.


Antibacterial suture vs silk for the surgical removal of impacted lower third molars. A randomized clinical study.
The aim of this study was to evaluate the clinical and microbiological impact of an antibacterial suture (Monocryl® Plus) in the surgical removal of I3M. A "split-mouth", prospective pilot clinical study was designed involving 20 patients programmed for the surgical removal of I3M. Each side was randomly sutured with Monocryl® Plus or silk suture and removed for microbiological study 72 hours and 7 days after surgery. Presence of SSI, wound bleeding and the degree of discomfort associated with each type of suture material (scored by means of a visual analog scale) were evaluated. The level of contamination of each material was observed under the scanning electron microscope. Wound bleeding upon suture removing was slightly greater after 72 hours and 7 days with black silk suture, though the differences were not statistically significant (p=0.752 and p=0.113, respectively). Patient discomfort was very similar with both types of suture material (p=0.861). Only one case of SSI was recorded with black silk suture after 72 hours. Microbiologically, the antibacterial suture showed a lesser presence of microorganisms (p<0.001, at 72h and p=0.033 at 7th day, respectively). The most common bacterial species included grampositive cocci (Streptococcus viridans group, Neisseria spp., Coagulasenegative Staphylococcus and Peptostreptococcus), gramnegative cocci (Veillonella), grampositive Bacilli (Lactobacillus), and gramnegative Bacilli (Prevotella). The greatest antibacterial effect of Monocryl Plus suture was observed after 72 hours. According to most authors, there is no doubt that this antibacterial suture can provide little safety in the control of SSI.


A Combined ULBP2 and SEMA5A Expression Signature as a Prognostic and Predictive Biomarker for Colon Cancer.
Background: Prognostic biomarkers for cancer have the power to change the course of disease if they add value beyond known prognostic factors, if they can help shape treatment protocols, and if they are reliable. The aim of this study was to identify such biomarkers for colon cancer and to understand the molecular mechanisms leading to prognostic stratifications based on these biomarkers. Methods and Findings: We used an in house R based script (SSAT) for the in silico discovery of stage-independent prognostic biomarkers using two cohorts, GSE17536 and GSE17537, that include 177 and 55 colon cancer patients, respectively. This identified 2 genes, ULBP2 and SEMA5A, which when used jointly, could distinguish patients with distinct prognosis. We validated our findings using a third cohort of 48 patients ex vivo. We find that in all cohorts, a combined ULBP2/SEMA5A classification (SU-GIB) can stratify distinct prognostic sub-groups with hazard ratios that range from 2.4 to 4.5 (p≤0.01) when overall- or cancer-specific survival is used as an end-measure, independent of confounding prognostic parameters. In addition, our preliminary analyses suggest SU-GIB is comparable to Oncotype DX colon(®) in predicting recurrence in two different cohorts (HR: 1.5-2; p≤0.02). SU-GIB has potential as a companion diagnostic for several drugs including the PI3K/mTOR inhibitor BEZ235, which are suitable for the treatment of patients within the bad prognosis group. We show that tumors from patients with worse prognosis have low EGFR autophosphorylation rates, but high caspase 7 activity, and show upregulation of pro-inflammatory cytokines that relate to a relatively mesenchymal phenotype. Conclusions: We describe two novel genes that can be used to prognosticate colon cancer and suggest approaches by which such tumors can be treated. We also describe molecular characteristics of tumors stratified by the SU-GIB signature.


The utility of S100B level in detecting mild traumatic brain injury in intoxicated patients.
S100B is a serum protein known to elevate in patients with brain injury, but it is unknown whether it can predict intracranial pathology in intoxicated patients following mild traumatic brain injury (MTBI). We performed a systematic review and meta-analysis of the English language literature to address this question. Four prospective cohort trials of serum S100B levels on acutely intoxicated patients with MTBI were included in this meta-analysis. Prevalence of intracranial pathology in the pooled cohort of the intoxicated MTBI patients was 10%, lower than the 15-30% reported in the literature for the general MTBI population. Standard mean difference of serum S100B levels between patients with and without intracranial pathology on CT was 0.73 μg/L (Z = 18.33, P < 0.001). Following sensitivity analysis and hierarchical summary receiver-operating characteristic models, three remaining articles were used for pooled estimates that found that S100B had a sensitivity of 0.96 (95% CI: 0.84-1.00, I2 = 0%) and specificity of 0.63 (95% CI: 0.58-0.68, I2 = 86.8%) with a high negative predictive value (100%, 95% CI: 95.14-100, I2 = 0%) and a negative LR of 0.06 (95% CI: 0.01-0.31). Serum S100B levels may have utility in ruling out intracranial pathology in intoxicated patients, however more study and comparison with other serum biomarkers of brain injury are necessary before this becomes the accepted standard of care.


Population-specific risk of type 2 diabetes conferred by HNF4A P2 promoter variants: a lesson for replication studies.
Single nucleotide polymorphisms (SNPs) in the P2 promoter region of HNF4A were originally shown to be associated with predisposition for type 2 diabetes in Finnish, Ashkenazi, and, more recently, Scandinavian populations, but they generated conflicting results in additional populations. We aimed to investigate whether data from a large-scale mapping approach would replicate this association in novel Ashkenazi samples and in U.K. populations and whether these data would allow us to refine the association signal. Using a dense linkage disequilibrium map of 20q, we selected SNPs from a 10-Mb interval centered on HNF4A. In a staged approach, we first typed 4,608 SNPs in case-control populations from four U.K. populations and an Ashkenazi population (n = 2,516). In phase 2, a subset of 763 SNPs was genotyped in 2,513 additional samples from the same populations. Combined analysis of both phases demonstrated association between HNF4A P2 SNPs (rs1884613 and rs2144908) and type 2 diabetes in the Ashkenazim (n = 991; P < 1.6 x 10(-6)). Importantly, these associations are significant in a subset of Ashkenazi samples (n = 531) not previously tested for association with P2 SNPs (odds ratio [OR] approximately 1.7; P < 0.002), thus providing replication within the Ashkenazim. In the U.K. populations, this association was not significant (n = 4,022; P > 0.5), and the estimate for the OR was much smaller (OR 1.04; [95%CI 0.91-1.19]). These data indicate that the risk conferred by HNF4A P2 is significantly different between U.K. and Ashkenazi populations (P < 0.00007), suggesting that the underlying causal variant remains unidentified. Interactions with other genetic or environmental factors may also contribute to this difference in risk between populations.


The sFlt1/PlGF ratio predicts faster fetal deterioration in early fetal growth restriction: A historical cohort study.
The velocity of fetal deterioration in fetal growth restriction is extremely variable, which makes monitoring and counseling very challenging. The soluble fms-like tyrosine kinase to placental growth factor (sFlt1/PlGF) ratio provides a readout of the vasoactive environment that correlates with preeclampsia and fetal growth restriction and that could be useful to predict fetal deterioration. Previous studies showed a correlation between higher sFlt1/PlGF ratios and lower gestational ages at birth, although it is unclear whether this is due to the increased incidence of preeclampsia. Our goal was to evaluate whether the sFlt1/PlGF ratio predicts faster fetal deterioration in early fetal growth restriction. This was a historical cohort study in a tertiary maternity hospital. Data from singleton pregnancies with early fetal growth restriction (diagnosed before 32 gestational weeks) confirmed after birth monitored between January 2016 and December 2020 were retrieved from clinical files. Cases of chromosomal/fetal abnormalities, infection and medical terminations of pregnancy were excluded. The sFlt1/PlGF ratio was acquired at diagnosis of early fetal growth restriction in our unit. The correlation of log10 sFlt1/PlGF with latency to delivery/fetal demise was assessed with linear, logistic (positive sFlt1/PlGF if >85) and Cox regression excluding deliveries for maternal conditions and controlling for preeclampsia, gestational age at time of ratio test, maternal age and smoking during pregnancy. Receiver-operating characteristic (ROC) analysis tested the performance of sFlt1/PlGF ratio in predicting delivery for fetal reasons in the following week. 125 patients were included. Mean sFlt1/PlGF ratio was 91.2 (SD 148.7) and 28% of patients had a positive ratio. A higher log10 sFlt1/PlGF ratio predicted shorter latency for delivery/fetal demise in linear regression after controlling for confounders, β = -3.001, (-3.713 to -2.288). Logistic regression with ratio positivity confirmed these findings (latency for delivery 5.7 ± 3.32 weeks for ratios ≤85 vs 1.9 ± 1.52 weeks for ratios >85); β = -0.698 (-1.064 to -0.332). Adjusted Cox regression showed that a positive ratio confers a significantly positive hazard ratio (HR) for earlier delivery/fetal demise, HR 9.869 (5.061-19.243). ROC analysis showed an area under the curve of 0.847 (SE ± 0.06). sFlt1/PlGF ratio is correlated with faster fetal deterioration in early fetal growth restriction, independently of preeclampsia.


GPR54 (KISS1R) transactivates EGFR to promote breast cancer cell invasiveness.
Kisspeptins (Kp), peptide products of the Kisspeptin-1 (KISS1) gene are endogenous ligands for a G protein-coupled receptor 54 (GPR54). Previous findings have shown that KISS1 acts as a metastasis suppressor in numerous cancers in humans. However, recent studies have demonstrated that an increase in KISS1 and GPR54 expression in human breast tumors correlates with higher tumor grade and metastatic potential. At present, whether or not Kp signaling promotes breast cancer cell invasiveness, required for metastasis and the underlying mechanisms, is unknown. We have found that kisspeptin-10 (Kp-10), the most potent Kp, stimulates the invasion of human breast cancer MDA-MB-231 and Hs578T cells using Matrigel-coated Transwell chamber assays and induces the formation of invasive stellate structures in three-dimensional invasion assays. Furthermore, Kp-10 stimulated an increase in matrix metalloprotease (MMP)-9 activity. We also found that Kp-10 induced the transactivation of epidermal growth factor receptor (EGFR). Knockdown of the GPCR scaffolding protein, β-arrestin 2, inhibited Kp-10-induced EGFR transactivation as well as Kp-10 induced invasion of breast cancer cells via modulation of MMP-9 secretion and activity. Finally, we found that the two receptors associate with each other under basal conditions, and FRET analysis revealed that GPR54 interacts directly with EGFR. The stability of the receptor complex formation was increased upon treatment of cells by Kp-10. Taken together, our findings suggest a novel mechanism by which Kp signaling via GPR54 stimulates breast cancer cell invasiveness.


A guaB mutant strain of Rhizobium tropici CIAT899 pleiotropically defective in thermal tolerance and symbiosis.
Rhizobium tropici strain CIAT899 displays a high intrinsic thermal tolerance, and had been used in this work to study the molecular basis of bacterial responses to high temperature. We generated a collection of R. tropici CIAT899 mutants affected in thermal tolerance using TnS-luxAB mutagenesis and described the characterization of a mutant strain, CIAT899-10T, that fails to grow under conditions of high temperature. Strain CIAT899-10T carries a single transposon insertion in a gene showing a high degree of similarity with the guaB gene of Escherichia coli and other organisms, encoding the enzyme inosine monophosphate dehydrogenase. The guaB strain CIAT899-10T does not require guanine for growth due to an alternative pathway via xanthine dehydrogenase and, phenotypically, in addition to the thermal sensitivity, the mutant is also defective in symbiosis with beans, forming nodules that lack rhizobial content. Guanine and its precursors restore wild-type tolerance to grow at high temperature. Our data show that, in R. tropici, the production of guanine via inosine monophosphate dehydrogenase is essential for growth at extreme temperatures and for effective nodulation.


Homology model of dihydropyridine receptor: implications for L-type Ca(2+) channel modulation by agonists and antagonists.
L-type calcium channels (LCCs) are transmembrane (TM) proteins that respond to membrane depolarization by selectively permeating Ca(2+) ions. Dihydropyridine (DHP) agonists and antagonist modulate Ca(2+) permeation by stabilizing, respectively, the open and closed states of the channel. The mechanism of action of these drugs remains unclear. Using, as a template, the crystal structure of the KcsA K(+) channel (Doyle et al. (1998) Science 280, 69-77), we have built several homology models of LCC with alternative alignments of TM segments between the proteins. In each model, nifedipine was docked in the pore region and in the interface between repeats III and IV. Several starting structures were generated by constraining the ligand to residues whose mutations reportedly affect DHP binding (DHP-sensing residues). These structures were Monte Carlo-minimized with and without constraints. In the complex with the maximum number of contacts between the ligand and DHP-sensing residues and the lowest ligand-receptor energy, the drug fits snugly in the "water-lake" cavity between segments S6s, which were aligned with M2 segment of KcsA as proposed for Na(+) channel (Lipkind and Fozzard (2000) Biochemistry 39, 8161-8170). In the flattened-boat conformation of DHP ring, the NH group at the stern approaches the DHP-sensing tyrosines in segments IIIS6 and IVS6. Stacking interactions of IVS6 Tyr with the bowsprit aromatic ring stabilize the ligand's orientation in which the starboard COOMe group coordinates Ca(2+) ion chelated by two conserved glutamates in the selectivity filter. In the inverted teepee structure of LCC, the portside COOMe group approaches a bracelet of conserved hydrophobic residues at the helical-bundle crossing, which may function as the activation gate. The dimensions of the gate may readily change upon small rotation of the pore-forming TM segments. The end of the portside group is hydrophobic in nifedipine, (R)-Bay K 8644, and other antagonists. Favorable interactions of this group with the hydrophobic bracelet would stabilize its closed conformation. In contrast, (S)-Bay K 8644 and several other agonists have hydrophilic groups at the portside. Unfavorable interactions of the hydrophilic group with the hydrophobic bracelet would destabilize its closed conformation thereby stabilizing the open conformation. In the agonist-bound channel, Ca(2+) ions would permeate between the hydrophilic face of the ligand and conserved hydrophilic residues in segments IS6 and IIS6. Our model suggests mutational experiments that could further our understanding of the pharmacological modulation of voltage-gated ion channels.


Evolution of acute infections and the invasion-persistence trade-off.
We seek to understand the conditions favoring the evolution of acute, highly transmissible infections. Most work on the life-history evolution of pathogens has focused on the transmission-virulence trade-off. Here we focus on a distinct trade-off that operates, even among avirulent pathogens, between a pathogen's speed of invasion and its ability to persist in a finite host population. Other authors have shown how this invasion-persistence trade-off can lead to intermediate pathogen attack rates but have done so only by imposing trade-offs between the pathogen's transmissibility and the duration of the infectious period. Here we delve deeper, by linking a model of within-host pathogen dynamics-in which pathogen life-history parameters figure directly-to an epidemiological model at the population level. We find that a key determinant of the evolutionary trajectory is the shape of the dose-response curve that relates within-host pathogen load to between-host transmission. In particular, under the usual assumption of proportionality we find that pathogens tend to evolve to the edge of their own extinction. Under more realistic assumptions, a critical host population size exists, above which highly acute pathogens are buffered from extinction. Our study is motivated by the emergence of acuteness in two human pathogens, Bordetella pertussis and Bordetella parapertussis, which independently evolved from an ancestor, Bordetella bronchiseptica, characterized by chronic (nonacute) infection of wildlife. In contrast to the plethora of models that predict evolution of more aggressive pathogens in larger or denser populations, the invasion-persistence trade-off also operates for frequency-dependent pathogens.


Is pharmacologic treatment better than neural mobilization for cervicobrachial pain? A randomized clinical trial.
Purpose: This study aim was to compare the effectiveness of the median nerve neural mobilization (MNNM) and cervical lateral glide (CLG) intervention versus oral ibuprofen (OI) in subjects who suffer cervicobrachial pain (CP). Methods: This investigation was a, multicenter, blinded, randomized controlled clinical trial (NCT02595294; NCT02593721). A number of 105 individuals diagnosed with CP were enrolled in the study and treated in 2 different medical facilities from July to November 2015. Participants were recruited and randomly assigned into 3 groups of 35 subjects. Intervention groups received MNNM or CLG neurodynamic treatments, and the (active treatment) control group received an OI treatment for 6 weeks. Primary outcome was pain intensity reported through the Numeric Rating Scale for Pain (NRSP). Secondary outcomes were physical function involving the affected upper limb using the Quick DASH scale, and ipsilateral cervical rotation (ICR) using a cervical range of motion (CROM) device. Assessments were performed before and 1 hour after treatment for NRSP (baseline, 3 and 6 weeks) and CROM (baseline and 6 weeks), as well as only 1 assessment for Quick DASH (baseline and 6 weeks). Results: Repeated-measures ANOVA intergroup statistically significant differences were shown for CP intensity (F(2,72) = 22.343; P < .001; Eta2 = 0.383) and Quick DASH (F(2,72) = 15.338; P < .001; Eta2 = 0.299), although not for CROM (F(2,72) = 1.434; P = .245; Eta2 = 0.038). Indeed, Bonferroni´s correction showed statistically significant differences for CP intensity (P < .01; 95% CI = 0.22 - 3.26) and Quick DASH reduction (P < .01; 95% CI = 8.48 - 24.67) in favor of the OI treatment at all measurement moments after baseline. Conclusions: OI pharmacologic treatment may reduce pain intensity and disability with respect to neural mobilization (MNNM and CLG) in patients with CP during six weeks. Nevertheless, the non-existence of between-groups ROM differences and possible OI adverse effects should be considered.


Metabolizable energy content of wheat distillers' dried grains with solubles supplemented with or without a mixture of carbohydrases and protease for broilers and turkeys.
In this study, 2 experiments were conducted to determine the AME and AMEn of wheat distillers' dried grains with solubles (DDGS) without or with supplementation of an enzyme mixture containing xylanase, amylase, and protease (XAP) in broilers and turkeys. One hundred twenty-six male Ross 308 broilers (Experiment 1) or 126 male BUT 10 turkeys (Experiment 2) were offered a nutrient-adequate diet from d 1 to 14. On d 14, birds in each experiment were allocated to 6 treatments consisting of 3 levels of wheat-DDGS (0, 300, or 600 g/kg) and 2 levels of XAP (0 or 250 mg/kg diet) in a randomized complete block design. The AME or AMEn content of wheat-DDGS was determined from the slope of regression of wheat-DDGS-associated energy intake (kilocalories) against wheat-DDGS intake (kilograms). In Experiment 1, wheat-DDGS inclusion in the diets linearly decreased (P<0.05) DM retention, AME, and AMEn, irrespective of XAP supplementation. The AME of wheat-DDGS without or with XAP for broilers was 3,587 or 3,700 kcal/kg DM, respectively, and AMEn was 3,356 and 3,459 kcal/kg DM for wheat-DDGS without and with XAP, respectively. In Experiment 2, wheat-DDGS inclusion in the diet linearly decreased (P<0.05) DM retention irrespective of XAP supplementation. Diet AME and AMEn linearly decreased (P<0.05) as the level of wheat-DDGS increased in the diets without added XAP, whereas there was no effect of increasing wheat-DDGS level on dietary AME or AMEn in the XAP-supplemented diets. The AME of wheat-DDGS without and with supplemental XAP for turkeys were 3,355 and 3,558 kcal/kg DM, respectively, and AMEn was 3,109 and 3,294 kcal/kg DM, respectively, for wheat-DDGS without and with XAP. Supplemental XAP increased (P>0.05) the AME and AMEn of wheat-DDGS for broilers and turkeys by up to 6%. It was concluded that wheat-DDGS is a valuable source of AME for broilers and turkeys.


Do grandparents influence parents' decision to vaccinate their children? A systematic review.
The global reduction in childhood infectious diseases since the 1960s is primarily due to the success of extensive worldwide immunisation campaigns. However, the universal vaccination coverage program appears to have lost momentum in the wake of negative, unfounded claims about the safety of vaccines. While parents of the 21st century have little first-hand knowledge of devastating childhood diseases, grandparents are more likely to remember family and community members who were afflicted. In the current age of vaccine hesitancy and science scepticism, where research-informed arguments are not always persuasive, grandparents, through their experience of the diseases, may positively influence paediatric vaccine uptake. This paper reviews the literature investigating potential direct or indirect influences of grandparents on parents' decisions to vaccinate their children. A database search using the keywords immunisation, vaccination, children and grandparents resulted in 1988 articles. Titles were screened for relevance and seventy-seven results were retained. After the abstracts were read, only five articles that either explored paediatric vaccines, factors promoting and/or inhibiting paediatric vaccine use and decision-making strategies were reviewed. One paper located through Google Scholar, which failed to show up on database searches, was also retained for a total of six papers. While none of the six papers set out to explore the impact of grandparents on vaccine uptake, they found that grandparents were involved to varying degrees in paediatric vaccine uptake within young families. The research clearly showing that grandparents, and older people more generally, promote vaccination uptake is not currently available. The dearth of literature shows the need for research exploring the perceived and real influences of grandparents on childhood vaccination. This will establish whether grandparents' memory and knowledge of preventable childhood infectious diseases could be harnessed as a public health measure to counteract the current, ill-informed, negative attention on paediatric vaccines.


L-Arginine attenuates xanthine oxidase and myeloperoxidase activities in hearts of rats during exhaustive exercise.
The present study was to investigate the effects of l-arginine (l-Arg) supplementation on cardiac oxidative stress and the inflammatory response in rats following acute exhaustive exercise on a treadmill. Rats were randomly divided into four groups: sedentary control (SC); SC with l-Arg treatment (SC+Arg); exhaustive exercise (E); exhaustive exercise with l-Arg treatment (E+Arg). Rats in groups SC+Arg and E+Arg received a 2 % l-Arg diet. Rats in groups E and E+Arg performed an exhaustive running test on a treadmill at a final speed of 30 m/min, 10 % grade, at approximately 70-75 % VO2max. The results showed a significant increase in cardiac xanthine oxidase (XO) and myeloperoxidase activities and membrane lipid peroxidation endproduct (malondialdehyde; MDA) levels of exercised rats compared with SC rats. The increased cardiac XO activity and MDA levels in exercised rats were significantly decreased in exercised rats supplemented with l-Arg. Myocardial GSSG content increased whereas the GSH:GSSG ratio was depressed in exercised rats compared with SC rats. Cardiac GSSG levels significantly decreased, whereas total glutathione, GSH and the GSH:GSSG ratio increased in exercised rats supplemented with l-Arg compared with exercised rats. The activities of creatinine kinase (CK) and lactate dehydrogenase (LDH), and lactate, uric acid, and nitrite and nitrate levels in the plasma significantly increased in exercised rats compared with SC rats. The activities of plasma CK and LDH were significantly decreased in l-Arg-supplemented plus exercised rats compared with exercised rats. These findings suggest that l-Arg supplementation reduces the oxidative damage and inflammatory response on the myocardium caused by exhaustive exercise in rats.


Calcitonin gene-related peptide promotes angiogenesis via AMP-activated protein kinase.
Ischemia induces angiogenesis as a compensatory response. Although ischemia is known to causes synthesis and release of calcitonin gene-related peptide (CGRP), it is not clear whether CGRP regulates angiogenesis under ischemia and how does it function. Thus we investigated the role of CGRP in angiogenesis and the involved mechanisms. We found that CGRP level was increased in the rat hindlimb ischemic tissue. The expression of exogenous CGRP by adenovirus vectors enhanced blood flow recovery and increased capillary density in ischemic hindlimbs. In vitro, CGRP promoted human umbilical vein endothelial cell (HUVEC) tube formation and migration. Further more, CGRP activated AMP-activated protein kinase (AMPK) both in vivo and in vitro, and pharmacological inhibition of CGRP and cAMP attenuated the CGRP-activated AMPK in vitro. CGRP also induced endothelial nitric oxide synthase (eNOS) phosphorylation in HUVECs at Ser1177 and Ser633 in a time-dependent manner, and such effects were abolished by AMPK inhibitor Compound C. As well, Compound C blocked CGRP-enhanced HUVEC tube formation and migration. These findings indicate that CGRP promotes angiogenesis by activating the AMPK-eNOS pathway in endothelial cells.


The development of the pattern of retinal ganglion cells in the chick retina: mechanisms that control differentiation.
Neurons in both vertebrate and invertebrate eyes are organized in regular arrays. Although much is known about the mechanisms involved in the formation of the regular arrays of neurons found in invertebrate eyes, much less is known about the mechanisms of formation of neuronal mosaics in the vertebrate eye. The purpose of these studies was to determine the cellular mechanisms that pattern the first neurons in vertebrate retina, the retinal ganglion cells. We have found that the ganglion cells in the chick retina develop as a patterned array that spreads from the central to peripheral retina as a wave front of differentiation. The onset of ganglion cell differentiation keeps pace with overall retinal growth; however, there is no clear cell cycle synchronization at the front of differentiation of the first ganglion cells. The differentiation of ganglion cells is not dependent on signals from previously formed ganglion cells, since isolation of the peripheral retina by as much as 400 microm from the front of ganglion cell differentiation does not prevent new ganglion cells from developing. Consistent with previous studies, blocking FGF receptor activation with a specific inhibitor to the FGFRs retards the movement of the front of ganglion cell differentiation, while application of exogenous FGF1 causes the precocious development of ganglion cells in peripheral retina. Our observations, taken together with those of previous studies, support a role for FGFs and FGF receptor activation in the initial development of retinal ganglion cells from the undifferentiated neuroepithelium peripheral to the expanding wave front of differentiation.


Zone 2 flexor digitorum profundus and superficialis rupture treated with single-stage tendon reconstruction using an Active Hunter Rod Implant.
To our knowledge, no report has been published of a flexor tendon rupture as a result of a closed phalangeal fracture.A 58-year-old woman with multiple medical comorbidities presented with a closed, apex volar fracture of her long finger proximal phalynx with clinically intact flexor digitorum profundus and superficialis tendons in zone 2 of the flexor tendon sheath. After 5 weeks of nonoperative treatment, the patient reported hearing a pop in her finger, and clinical findings suggested rupture of the flexor digitorum profundus and superficialis tendons. Intraoperatively, the nonreparable attritional rupture was underneath the A2 pulley. A bony prominence in the tendon sheath floor from the healed phalynx fracture made rerupture a concern with a tendon graft. A Hunter Active Tendon Implant (Wright Medical Technology, Inc, Arlington, Tennessee) was used to reconstruct the flexor digitorum profundus tendon to avoid a second procedure. The patient progressed well and had regained a functional arc of active finger range of motion by 2 months postoperatively.The Hunter Active Tendon Implant provided a suitable alternative to a 2-staged procedure, with the added benefit that a good tendon bed was developed in the event that a second procedure was needed.