Vitamin D receptor polymorphism FokI and cancer risk: a comprehensive meta-analysis.
Numerous studies investigated the associations of VDR polymorphisms with various types of cancer, suggesting an influence on cancer risk. FokI is one of the most frequently analysed polymorphisms but the results from single studies are contradictory. We performed a meta-analysis looking at the association between the FokI and all cancer sites and investigating sources of heterogeneity. We identified 77 independent studies up to April 2014. We presented the summary odds ratios (SORs) by cancer sites, ethnicity and study features. We found a significant association between FokI and ovarian cancer for ff genotype versus FF with no heterogeneity: SOR = 1.20 (95% CI: 1.02-1.41, I (2) = 0%). Moreover, we found a significant increased risk of any cancer: SOR = 1.08 (95% CI: 1.01-1.16, I (2) = 58%). A significant increased risk of any cancer is confirmed among Caucasian, among studies in Hardy-Weinberg equilibrium and nested case-control studies. Furthermore, among studies in Hardy-Weinberg equilibrium, skin cancer was found significantly associated with FokI: SOR = 1.24 (95% CI: 1.01-1.54; I (2) = 24%) for ff versus FF. The estimated number of cases attributable to ff genotype is 4221 for ovarian cancer and 52858 for skin cancer worldwide each year. No indication for publication bias was found for any cancer site. In conclusion, we found an overall significant association of FokI polymorphism with any cancer, with differential effect by ethnicity. In particular, the summary estimates indicate an increase risk for ovarian and skin cancer for ff versus FF. However, other factors may act modifying the association, and further studies are needed to clarify the impact on cancer risk.


Emissions of CO2 and CH4 from sludge treatment reed beds depend on system management and sludge loading.
Sludge treatment reed beds (STRB) are considered as eco-friendly and sustainable alternatives to conventional sludge treatment methods, although little is known about greenhouse gas emissions from such systems. We measured CO2 and CH4 emissions and substrate characteristics in a STRB, an occasionally loaded sludge depot (SD) and a natural reed wetland (NW). The aim was to compare (i) emissions among the sites in relation to substrate characteristics and (ii) emissions before and after sludge loading in the STRB. The STRB emitted twice as much CO2 (1200 mg m(-2) h(-1)) as the SD, whereas the SD emitted four times more CH4 (2 mg m(-2) h(-1)) than the STRB. The NW had the lowest emissions of both gases. The differences in gas emissions among the sites were primarily explained by differences in the availability of oxygen in the substrate. As a consequence of overloading and poor management, the SD had no vegetation and a poor dewatering capacity, which resulted in anaerobic conditions favoring CH4 emission. In contrast, the well-managed STRB had more aerobic conditions in the sludge residue resulting in low CH4 emission rates. We conclude that well-designed and well-managed STRBs have a low climate impact relative to conventional treatment alternatives, but that overloading and poor sludge management enhances the emissions of CH4.


EEG signature of grouping strategies in numerosity perception.
The moment we see a group of objects, we can appreciate its numerosity. Our numerical estimates can be imprecise for large sets (>4 items), but they become much faster and more accurate if items are clustered into groups compared to when they are randomly displaced. This phenomenon, termed groupitizing, is thought to leverage on the capacity to quickly identify groups from 1 to 4 items (subitizing) within larger sets, however evidence in support for this hypothesis is scarce. The present study searched for an electrophysiological signature of subitizing while participants estimated grouped numerosities exceeding this range by measuring event-related potential (ERP) responses to visual arrays of different numerosities and spatial configurations. The EEG signal was recorded while 22 participants performed a numerosity estimation task on arrays with numerosities in the subitizing (3 or 4) or estimation (6 or 8) ranges. In the latter case, items could be spatially arranged into subgroups (3 or 4) or randomly scattered. In both ranges, we observed a decrease in N1 peak latency as the number of items increased. Importantly, when items were arranged to form subgroups, we showed that the N1 peak latency reflected both changes in total numerosity and changes in the number of subgroups. However, this result was mainly driven by the number of subgroups to suggest that clustered elements might trigger the recruitment of the subitizing system at a relatively early stage. At a later stage, we found that P2p was mostly modulated by the total numerosity in the set, with much less sensitivity for the number of subgroups these might be segregated in. Overall, this experiment suggests that the N1 component is sensitive to both local and global parcelling of elements in a scene suggesting that it could be crucially involved in the emergence of the groupitizing advantage. On the other hand, the later P2p component seems to be much more bounded to the global aspects of the scene coding the total number of elements while being mostly blind to the number of subgroups in which elements are parsed.


Delayed habituation in Behcet's disease.
The autonomic nervous system in Behcet's patients may be affected due to various reasons. This entity may be detected with the measurement of the electrodermal activities, heart rate variability and pupillometric methods. Habituation is one of the implicit forms of learning and memory and the loss of habituation can reveal pathological changes in the synaptic regions. To determine whether there is a functional decrease in the synaptic effectiveness (habituation) of the pathways to sympathetic neurons that had been repeatedly activated in Behcet's. Twelve patients with Behcet's disease and 12 healthy controls were included in the study. Sympathetic skin potential (SSP) records were taken at normal room temperature in a quiet place within a Faraday cage. Sixteen square wave single shock impulses (duration: 1200 ms, strength: 5 mA) were applied on each case. After the 1st stimulus, the SSP amplitudes were lower in the patients compared to the controls (P<0.001, t value=7.69). There was no significant differences among the SSP amplitudes after the 13th impulse in the patients (P>0.05). Whereas there was no significant differences among the SSP amplitudes after the 9th impulse in the controls (P>0.05). The habituation rate of the SSP after consecutive impulses was slowest in the patients compared to controls (P<0.001, t value=12.39). There is a delayed habituation in Behcet's disease and that may due to pathologic changes with vasculitis through their peripheral nerves.


Primary testicular mucinous neoplasms: case report and literature review.
Testicular epithelial mucinous tumours are an extremely rare, but interesting form of testicular neoplasm. We reviewed the medical literature using PubMed search terms: testis, mucinous cystadenoma, mucinous cystadenocarcinoma, neoplasms and testicular neoplasms. We describe a case from our institution and provide a review of the literature. Only 11 previously reported cases of mucinous testicular tumours have been reported in the English literature. The natural history of these tumours is poorly understood, due to their rarity, but it appears that, like their ovarian counterparts, they have an excellent prognosis. Exclusion of metastasis is an important point for the urologist when encountering a mucinous testicular tumour, as metastatic cystic lesions may mimic a primary mucinous tumour. We describe a case of ossified testicular mucinous tumour of low malignant potential. Such tumours are common in the ovary, but arise very rarely in the testicle. The clinical and histological features of this tumour are presented, and previously reported cases are reviewed to highlight important clinical features.


Effects of isokinetic strength training on concentric and eccentric torque development in the ankle dorsiflexors of older adults.
This study quantifies concentric and eccentric dorsiflexor muscle torque at various movement velocities and determines the neuromuscular effects from short-term practice of repeated maximal voluntary contractions using an isokinetic resisted exercise program in older adults. Twenty-eight subjects (76.3+/-4.6 years) trained concentric and eccentric dorsiflexion 3 days per week for 2 weeks at 30 degrees, 90 degrees, and 180 degrees/s through 40 degrees of dorsiflexion range of motion. Peak torque, rate of torque development, surface electromyography, and strength curves at each velocity were compared before and after training. Increases were found for concentric (27%) and eccentric (20%) dorsiflexor peak torque and concentric rate of torque production (20%-53%) across all movement velocities (p < .01). Training also significantly increased dorsiflexor concentric (64%) and eccentric (55%) surface electromyography; taken together, this is evidence of apparent adaptation of neural factors in older adults with short-term training. These findings support that eccentric and concentric strength training enhances the control and production of ankle muscle dorsiflexor torque in older adults, with implications for improving functional mobility of the ankle joint.


[Endoprosthetic repair of abdominal aortic aneurysm complicated by rupture into the vena cava inferior with formation of an aortocaval fistula].
The article deals with is a case report of successful endovascular treatment of a patient with a saccular aneurysm of the infrarenal portion of the abdominal aorta complicated by its rupture into the inferior vena cava with formation of an aortocaval fistula. The patient underwent endoprosthetic repair of the abdominal aorta with the unilateral stent graft Endurant II 32x14-117 mm ("Medtronic") and cross-over femorofemoral bypass. The postoperative period was complicated by acute cardiac insufficiency and pulmonary oedema. After the appropriate intensive therapy lung oedema subsided, the events of cardiac insufficiency disappeared, and haemodynamics stabilized. According to the findings of the control multispiral computed tomography, the fistula does not function, there are no signs of the stent graft's dislocation or endoleak, with the cross-over femorofemoral bypass patent. The patient was discharged in a satisfactory condition.


Tumor markers in pancreatic cancer. Sensitivity and specificity of CA 19-9.
The tumor marker CA 19-9 is based on monoclonal antibody to colonic carcinoma cell lines. In this study, the utility of the tumor marker in the diagnosis of pancreatic carcinoma was evaluated. CA 19-9 is strongly expressed in most tissue specimens obtained from pancreatic carcinomas. However, this antigen is also found in normal pancreas and specimens from chronic pancreatitis. The CA 19-9 is released into the circulation, and was found at increased concentrations (greater than 37 U/ml) in 87% of the patients with pancreatic carcinoma n = 145, as compared with only 13% in the group of patients with benign diseases n = 1,081 and 29% of those with extrapancreatic malignancies n = 691 (P less than 0.0001). The preoperatively raised CA 19-9 concentration in patients with stage I pancreatic carcinoma decreases after curative resection of the carcinoma to values within the normal range. However, in no CA 19-9 estimation following palliative surgical intervention of stage III and IV patients or in cases of inoperable carcinomas was a serum concentration of less than 37 U/ml recorded. Accordingly, the median survival of stage I patients was 29 months, and of stage III, IV and patients with inoperable carcinomas 6 months only.


Acute exposure to hair bleach causes airway hyperresponsiveness in a rabbit model.
Ammonium persulphate (APS) and hydrogen peroxide (H2O2) are used as oxidants in many industrial processes and are the main constituents of standard hair bleaching products. In a previous study, it was demonstrated that aerosols of APS induce alterations in airway responsiveness. The present study examined whether exposure for 4 h to a hair bleach composition (containing APS, potassium persulphate and H2O2) or H2O2 could induce airway hyperresponsiveness and/or an obstructive ventilation pattern in a rabbit model. Exposure to the aerosols altered neither baseline airway resistance, dynamic elastance, slope of inspiratory pressure generation nor arterial blood pressure and blood gas measurements. Similarly to APS, hair bleach aerosols containing > or =10.9 mg x m(-3) persulphate (ammonium and potassium salt) in air and > or =1.36 mg x m(-3) H2O2 in air caused airway hyperresponsiveness to acetylcholine after 4 h of exposure. Aerosolized H2O2 (> or =37 mg x m(-3) in air) did not influence airway responsiveness to acetylcholine. The results demonstrate that hair bleaching products containing persulphates dissolved in H2O2 cause airway hyperresponsiveness to acetylcholine in rabbits.


Heterogeneous antibody repertoire of marginal zone B cells specific for virus-like particles.
Marginal zone (MZ) B cells differ from follicular (FO) B cells in their functional, phenotypic and localization properties. It is still unclear whether B cells from the MZ compartment also have distinct or biased BCR specificities, recognizing only a limited number of conserved antigenic structures. To address the complexity of the immune response mounted by marginal zone B cells, we compared the antibody repertoire of murine MZ and FO B cells induced by immunization with two different virus-like particles (VLPs). Antibody sequences isolated from sorted VLP-specific MZ and FO B cells were similar in heavy chain V, D and J gene segment usage. Sequence analysis of CDR3 regions of antibodies from MZ and FO B cells also revealed no consistent difference in N nucleotide additions or CDR3 length. In contrast, somatic hypermutations were reduced in CDR regions of antibodies from MZ B cells compared to those from FO B cells. These results indicate that the response of MZ B cells to VLPs is clonotypically heterogeneous and suggest that the MZ B cell compartment is capable of generating variable and diverse antibody responses.


Feasibility and cardiac safety of trastuzumab emtansine after anthracycline-based chemotherapy as (neo)adjuvant therapy for human epidermal growth factor receptor 2-positive early-stage breast cancer.
Trastuzumab emtansine (T-DM1), an antibody-drug conjugate comprising the cytotoxic agent DM1, a stable linker, and trastuzumab, has demonstrated substantial activity in human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer, raising interest in evaluating the feasibility and cardiac safety of T-DM1 in early-stage breast cancer (EBC). Patients (N = 153) with HER2-positive EBC and prechemotherapy left ventricular ejection fraction (LVEF) ≥ 55% received (neo)adjuvant doxorubicin plus cyclophosphamide or fluorouracil plus epirubicin plus cyclophosphamide followed by T-DM1 for four cycles. Patients could then receive three to four cycles of optional docetaxel with or without trastuzumab. T-DM1 was then resumed with optional radiotherapy (sequential or concurrent) for 1 year (planned) of HER2-directed therapy. The coprimary end points were rate of prespecified cardiac events and safety. Median follow-up was 24.6 months. No prespecified cardiac events or symptomatic congestive heart failures were reported. Four patients (2.7%) had asymptomatic LVEF declines (≥ 10 percentage points from baseline to LVEF < 50%), leading to T-DM1 discontinuation in one patient. Of 148 patients who received ≥ one cycle of T-DM1, 82.4% completed the planned 1-year duration of HER2-directed therapy. During T-DM1 treatment, 38.5% and 2.7% of patients experienced grade 3 and 4 adverse events, respectively. Approximately 95% of patients receiving T-DM1 plus radiotherapy completed ≥ 95% of the planned radiation dose with delay ≤ 5 days. Use of T-DM1 for approximately 1 year after anthracycline-based chemotherapy was feasible and generally well tolerated by patients with HER2-positive EBC, providing support for phase III trials of T-DM1 in this setting.


[Treatment tactics by frostbites].
317 patients with frostbitten limb injuries of various severity were healed. A differential treatment tactics were worked out, basing on localization, area, time of frost exposure and concurrent vascular disease. Surgical treatment of IV stage congelation stipulates early necrectomy by lower limbs affection, whereas, congelation of the upper limbs requires delayed necrectomy; both should be followed by appropriate wound healing and early reconstructive operations. Indications for primary amputations by deep congelation were formulated.


Cost-effectiveness analysis of anastrozole versus tamoxifen in adjuvant therapy for early-stage breast cancer - a health-economic analysis based on the 100-month analysis of the ATAC trial and the German health system.
In the 'Arimidex', Tamoxifen Alone or in Combination (ATAC) trial, the aromatase inhibitor (AI) anastrozole had a significantly better efficacy and safety profile than tamoxifen as initial adjuvant therapy for hormone receptor-positive (HR+) early breast cancer (EBC) in postmenopausal patients. To compare the combined long-term clinical and economic benefits, we carried out a cost-effectiveness analysis (CEA) of anastrozole versus tamoxifen based on the data of the 100month analysis of the ATAC trial from the perspective of the German public health insurance. A Markov model with a 25-year time horizon was developed using the 100-month analysis of the ATAC trial as well as data obtained from published literature and expert opinion. Adjuvant treatment of EBC with anastrozole achieved an additional 0.32 quality-adjusted life-years (QALYs) gained per patient compared with tamoxifen, at an additional cost of D 6819 per patient. Thus, the incremental cost effectiveness of anastrozole versus tamoxifen at 25 years was D 21,069 ($30,717) per QALY gained. This is the first CEA of an AI that is based on extended follow-up data, taking into account the carryover effect of anastrozole, which maintains the efficacy benefits beyond therapy completion after 5 years. Adjuvant treatment with anastrozole for postmenopausal women with HR+ EBC is a cost-effective alternative to tamoxifen.


How Systemic Sclerosis Affects Healthcare Use and Complication Rates after Total Hip Arthroplasty.
To assess whether outcomes after primary total hip arthroplasty (THA) differ in systemic sclerosis (SSc). We used the 1998-2014 US National Inpatient Sample. THA and SSc were identified using procedure and diagnostic codes, respectively. Multivariable-adjusted logistic regression analyses assessed the association of SSc with in-hospital complications (implant infection, revision, transfusion, mortality) post-THA and associated healthcare use (hospital charges, hospital stay, discharge to non-home setting), adjusting for age, sex, race, Deyo-Charlson comorbidity index, primary diagnosis for THA, household income, and insurance payer. Of the 4,116,485 primary THA performed in the United States in 1998-2014, SSc patients made up 0.06% (n = 2672). In multivariable-adjusted analyses, compared to people without SSc, people with SSc had higher adjusted OR (95% CI) of the following post-primary THA: (1) non-home discharge, 1.25 (95% CI 1.03-1.50); (2) hospital stay > 3 days, 1.61 (95% CI 1.35-1.92); (3) transfusion, 1.54 (95% CI 1.28-1.84); and (4) in-hospital revision, 9.53 (95% CI 6.75-13.46). Differences in in-hospital mortality had a nonsignificant trend [2.19 (95% CI 0.99-4.86)]. There were no differences in total hospital charges or implant infection rates. SSc was associated with a higher rate of in-hospital complications and healthcare use after primary THA. Future studies should examine whether pre- or postoperative interventions can reduce the risk of post-THA complications in people with SSc.


Recombinant-DNA-derived bovine growth hormone from Escherichia coli. 1. Demonstration that the hormone is expressed in reduced form, and isolation of the hormone in oxidized, native form.
The isolation of bacterially synthesized, recombinant-DNA-derived, bovine growth hormone (r-bGH) with native structure is described. The r-bGH is found in insoluble form, in a pellet fraction, after cell breakage and centrifugation. Cell envelope components (protein, lipid, endotoxin) and nucleic acids are selectively removed from the pellet fraction by an EDTA/lysozyme/deoxycholate extraction. We demonstrate that the r-bGH is largely reduced until solubilized using 6 M guanidine/HCl. Air oxidation is then carried out, in the presence of the guanidine/HCl. The oxidation results in a mixture of about one-third disulfide-linked oligomers and two-thirds oxidized monomer. The latter may include some incorrectly oxidized material, but appears to be mostly correctly oxidized. The oxidized monomer is isolated by gel filtration in the presence of guanidine/HCl. Subsequent guanidine/HCl removal leads to refolded, oxidized r-bGH. All steps in the procedure, in particular the oxidation and refolding steps, can be carried out at relatively high protein concentrations.


Sex comparison of familial predisposition to anterior cruciate ligament injury.
In an effort to identify risk factors for anterior cruciate ligament (ACL) injury, many potential risk factors have been proposed, including familial predisposition. However, no study has evaluated familial predisposition in male or females separately. The purpose of this study was to determine whether a familial predisposition to ACL injury exists in both males and females. One hundred and twenty (78 males and 42 females) patients who had undergone surgical ACL reconstruction were recruited as the ACL group, and 107 patients (67 males and 40 females) that had undergone arthroscopic partial menisectomy, with no previous history of ACL injury, were recruited as the referent control group. A familial ACL injury and subject particulars questionnaire was completed. When all subjects were combined, the ACL group (20.0 %, 24 of 120) did not demonstrate a higher familial (first-degree relative) prevalence (n.s.) of ACL injury compared to the referent control group (15.0 %; 16 of 107 patients). When the data were stratified by sex, the male ACL group (19.2 %, 15 of 78) demonstrated a significantly higher familial (first-degree relative) prevalence (P = 0.02) of ACL injury compared to the male referent control group (7.5 %; 5 of 67 patients). There were no differences among the females (n.s.). The results of this study show that male patients with ACL tears are more likely to have a first-degree relative with an ACL tear compared to male referent control subjects. Future research is warranted to better delineate sex-specific risk factors for ACL injuries could help guide intervention programs aimed at preventative treatment strategies, especially in high-risk families.


Biological functions of thyroid hormone in placenta.
The thyroid hormone, 3,3,5-triiodo-L-thyronine (T3), modulates several physiological processes, including cellular growth, differentiation, metabolism, inflammation and proliferation, via interactions with thyroid hormone response elements (TREs) in the regulatory regions of target genes. Infection and inflammation are critical processes in placental development and pregnancy-related diseases. In particular, infection is the leading cause of neonatal mortality and morbidity worldwide. However, to date, no successful approach has been developed for the effective diagnosis of infection in preterm infants. Pre-eclampsia (PE) is a serious disorder that adversely affects ~5% of human pregnancies. Recent studies identified a multiprotein complex, the inflammasome, including the Nod-like receptor (NLR) family of cytosolic pattern recognition receptors, the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase-1, which plays a vital role in the placenta. The thyroid hormone modulates inflammation processes and is additionally implicated in placental development and disease. Therefore, elucidation of thyroid hormone receptor-regulated inflammation-related molecules, and their underlying mechanisms in placenta, should facilitate the identification of novel predictive and therapeutic targets for placental disorders. This review provides a detailed summary of current knowledge with respect to identification of useful biomarkers and their physiological significance in placenta.


Nonclonal Emergence of Colistin Resistance Associated with Mutations in the BasRS Two-Component System in Escherichia coli Bloodstream Isolates.
Infections by multidrug-resistant Gram-negative bacteria are increasingly common, prompting the renewed interest in the use of colistin. Colistin specifically targets Gram-negative bacteria by interacting with the anionic lipid A moieties of lipopolysaccharides, leading to membrane destabilization and cell death. Here, we aimed to uncover the mechanisms of colistin resistance in nine colistin-resistant Escherichia coli strains and one Escherichia albertii strain. These were the only colistin-resistant strains of 1,140 bloodstream Escherichia isolates collected in a tertiary hospital over a 10-year period (2006 to 2015). Core-genome phylogenetic analysis showed that each patient was colonized by a unique strain, suggesting that colistin resistance was acquired independently in each strain. All colistin-resistant strains had lipid A that was modified with phosphoethanolamine. In addition, two E. coli strains had hepta-acylated lipid A species, containing an additional palmitate compared to the canonical hexa-acylated E. coli lipid A. One E. coli strain carried the mobile colistin resistance (mcr) gene mcr-1.1 on an IncX4-type plasmid. Through construction of chromosomal transgene integration mutants, we experimentally determined that mutations in basRS, encoding a two-component signal transduction system, contributed to colistin resistance in four strains. We confirmed these observations by reversing the mutations in basRS to the sequences found in reference strains, resulting in loss of colistin resistance. While the mcr genes have become a widely studied mechanism of colistin resistance in E. coli, sequence variation in basRS is another, potentially more prevalent but relatively underexplored, cause of colistin resistance in this important nosocomial pathogen.IMPORTANCE Multidrug resistance among Gram-negative bacteria has led to the use of colistin as a last-resort drug. The cationic colistin kills Gram-negative bacteria through electrostatic interaction with the anionic lipid A moiety of lipopolysaccharides. Due to increased use in clinical and agricultural settings, colistin resistance has recently started to emerge. In this study, we used a combination of whole-genome sequence analysis and experimental validation to characterize the mechanisms through which Escherichia coli strains from bloodstream infections can develop colistin resistance. We found no evidence of direct transfer of colistin-resistant isolates between patients. The lipid A of all isolates was modified by the addition of phosphoethanolamine. In four isolates, colistin resistance was experimentally verified to be caused by mutations in the basRS genes, encoding a two-component regulatory system. Our data show that chromosomal mutations are an important cause of colistin resistance among clinical E. coli isolates.


Serological responses and biomarker evaluation in mice and pigs exposed to tsetse fly bites.
Tsetse flies are obligate blood-feeding insects that transmit African trypanosomes responsible for human sleeping sickness and nagana in livestock. The tsetse salivary proteome contains a highly immunogenic family of the endonuclease-like Tsal proteins. In this study, a recombinant version of Tsal1 (rTsal1) was evaluated in an indirect ELISA to quantify the contact with total Glossina morsitans morsitans saliva, and thus the tsetse fly bite exposure. Mice and pigs were experimentally exposed to different G. m. morsitans exposure regimens, followed by a long-term follow-up of the specific antibody responses against total tsetse fly saliva and rTsal1. In mice, a single tsetse fly bite was sufficient to induce detectable IgG antibody responses with an estimated half-life of 36-40 days. Specific antibody responses could be detected for more than a year after initial exposure, and a single bite was sufficient to boost anti-saliva immunity. Also, plasmas collected from tsetse-exposed pigs displayed increased anti-rTsal1 and anti-saliva IgG levels that correlated with the exposure intensity. A strong correlation between the detection of anti-rTsal1 and anti-saliva responses was recorded. The ELISA test performance and intra-laboratory repeatability was adequate in the two tested animal models. Cross-reactivity of the mouse IgGs induced by exposure to different Glossina species (G. m. morsitans, G. pallidipes, G. palpalis gambiensis and G. fuscipes) and other hematophagous insects (Stomoxys calcitrans and Tabanus yao) was evaluated. This study illustrates the potential use of rTsal1 from G. m. morsitans as a sensitive biomarker of exposure to a broad range of Glossina species. We propose that the detection of anti-rTsal1 IgGs could be a promising serological indicator of tsetse fly presence that will be a valuable tool to monitor the impact of tsetse control efforts on the African continent.


Purpurin as a specific inhibitor of spermidine-induced autoactivation of the protease plasma hyaluronan-binding protein.
Plasma hyaluronan-binding protein (PHBP), a serine protease that can activate coagulation factor VII and prourokinase, circulates as a single-chain form (pro-PHBP), and is autoproteolytically converted to an active two-chain form with the aid of an effector such as spermidine and heparin. In this study, we screened natural sources for inhibitors of spermidine-induced pro-PHBP autoactivation. As an active agent, we purified bikaverin from a culture of a fungus. Bikaverin inhibited spermidine-induced autoactivation with an IC(50) of 0.45 microM, while it also inhibited the active form of PHBP (IC(50)=0.8 microM). Additional screening of related compounds led to the identification of purpurin, a plant anthraquinone, as a specific inhibitor: IC(50)=6.6 microM for spermidine-induced autoactivation; no inhibition of heparin-induced autoactivation and active PHBP. Alizarin and emodin, which structurally differed from purpurin in the position or the number of the hydroxyl groups, were less active and nonspecific. Thus, the position and/or the number of the hydroxyl group affect both the potency and selectivity of the anthraquinone inhibitors.


In Vitro and in Silico Studies of Lichen Compounds Atranorin and Salazinic Acid as Potential Antioxidant, Antibacterial and Anticancer Agents.
Lichens are symbiotic organisms made up of alga/cyanobacterium and fungus. We investigated antioxidant, antibacterial and anticancer properties of two lichen compounds, atranorin and salazinic acid, and five lichen species: Heterodermia boryi, Heterodermia diademata, Heterodermia hypocaesia, Parmotrema reticulatum, and Stereocaulon foliolosum. Free radical scavenging, Ferric reducing potential, Nitric oxide scavenging, and Trolox equivalent capacity were used to measure antioxidant activity. Strong radical scavenging action was demonstrated by atranorin and salazinic acid, with IC50 values of 39.31 μM and 12.14 μM, respectively. The Minimum Inhibitory Concentration (MIC) assay based on resazurin, was used to measure antibacterial activity. Parmotrema reticulatum demonstrated significant antibacterial activity against Raoultella planticola with MIC of 7.8 μg/mL. Cytotoxicity assay on breast cancer cell line was used to assess anticancer activity. To further understand the binding locations on the target proteins Er (Estrogen Receptor alpha), EGFR (Epidermal Growth Factor Receptor), mTOR (Mammalian Target of Rapamycin), and PgR (Progesterone Receptor), molecular docking experiments were conducted. Docking study showed that the binding energies of atranorin and salazinic acid with mTOR were -5.31 kcal/mol and -3.43 kcal/mol, respectively. The results suggest that atranorin has the potential to be a multitargeted molecule with natural antioxidant, antibacterial, and anticancer properties.


How children with facial differences are perceived by non-affected children and adolescents: perceiver effects on stereotypical attitudes.
Children with a facial difference are presumed to be at risk of social stigmatization. The purposes of this study were twofold: (1) to assess the effect of facial differences on social perceptions by unaffected children and adolescents; and (2) to identify perceiver characteristics that predict stereotypical attitudes toward facial differences. Participants were 344 non-affected children and adolescents, ages 8-17 years. Participants rated digitally altered images of 12 children depicted either with or without a facial difference. Results show that participants attributed less favorable characteristics to children with a facial difference than to those without. Moreover, participants reported less willingness to interact with or befriend a child with a facial difference. Significant predictors of low discriminative attitudes were older participant age and previous contact with someone with a facial difference. Our data call attention to the need for public education programs targeted at reducing negative attitudes toward facial differences.


What Will We Expect From Novel Therapies to Esophageal and Gastric Malignancies?
Esophageal cancer and gastric cancer are aggressive diseases for which treatment approaches are facing a new era. Some molecular pathways, such as VEGF, EGFR, fibroblast growth factor receptor, PIK3CA, and PARP-1, have been studied, and novel targeted drugs are presumed to be developed in the near future. From The Cancer Genome Atlas report, 80% of Epstein-Barr virus tumors and 42% of tumors with microsatellite instability have PIK3CA mutations, suggesting that this pathway could be reevaluated as a possible target for new systemic treatment of gastric cancer. Notably, higher PARP-1 expression can be found in gastric cancer, which might be related to more advanced disease and worse prognosis. In addition, PD-L1 expression, high microsatellite instability, and mismatch repair deficiency can be found in gastric cancer, thus suggesting that immunotherapy may also play a role in those patients. We discuss trends related to the potential of novel therapies for patients with esophageal and gastric cancers in the near future.


Periosteal PTHrP regulates cortical bone modeling during linear growth in mice.
The modeling of long bone surfaces during linear growth is a key developmental process, but its regulation is poorly understood. We report here that parathyroid hormone-related peptide (PTHrP) expressed in the fibrous layer of the periosteum (PO) drives the osteoclastic (OC) resorption that models the metaphyseal-diaphyseal junction (MDJ) in the proximal tibia and fibula during linear growth. PTHrP was conditionally deleted (cKO) in the PO via Scleraxis gene targeting (Scx-Cre). In the lateral tibia, cKO of PTHrP led to a failure of modeling, such that the normal concave MDJ was replaced by a mound-like deformity. This was accompanied by a failure to induce receptor activator of NF-kB ligand (RANKL) and a 75% reduction in OC number (P ≤ 0.001) on the cortical surface. The MDJ also displayed a curious threefold increase in endocortical osteoblast mineral apposition rate (P ≤ 0.001) and a thickened cortex, suggesting some form of coupling of endocortical bone formation to events on the PO surface. Because it fuses distally, the fibula is modeled only proximally and does so at an extraordinary rate, with an anteromedial cortex in CD-1 mice that was so moth-eaten that a clear PO surface could not be identified. The cKO fibula displayed a remarkable phenotype, with a misshapen club-like metaphysis and an enlargement in the 3D size of the entire bone, manifest as a 40-45% increase in the PO circumference at the MDJ (P ≤ 0.001) as well as the mid-diaphysis (P ≤ 0.001). These tibial and fibular phenotypes were reproduced in a Scx-Cre-driven RANKL cKO mouse. We conclude that PTHrP in the fibrous PO mediates the modeling of the MDJ of long bones during linear growth, and that in a highly susceptible system such as the fibula this surface modeling defines the size and shape of the entire bone.


Does socioeconomic status affect lengthy wait time in Canada? Evidence from Canadian Community Health Surveys.
Reasonable access to health services without financial or other barriers is a primary objective of the Canadian health system. Notwithstanding such concern about accessibility of services, long waiting times for health services have been a prominent health policy issue in recent years. Using pooled data from four nationally representative Canadian Community Health Surveys (CCHSs, 2000/01, 2003, 2005 and 2010; n = 266,962) we examine socioeconomic inequality in lengthy wait time (LWT) to health care among adults (aged 18-65) in Canada. The relative and absolute concentration indices (RC and AC, respectively) are used to quantify income-related inequality in LWT in Canada and for its provinces. Additionally, we decompose the RC and AC indices to identify factors affecting income-related inequality in LWT. Our descriptive results show that, on average, 5% of Canadian adults experienced LWT to access health services in the past 12 months. While 3% of the residents of British Columbia and Saskatchewan reported LWT to access health care services, this figure was 7% in Quebec. Our findings also demonstrated that LWT was mainly concentrated among the poor in Canada [RC = -0.039; 95% confidence interval (CI) -0.049 to -0.028 and AC = -0.067; CI -0.086 to -0.049]. The RC and AC suggested statistically significant pro-rich inequality of LWT in Nova Scotia, New Brunswick, Quebec, Manitoba, Saskatchewan and British Columbia. Decomposition analyses indicate that, besides income itself, health status (measured by a set of 15 chronic condition indicators), immigration status and geographical factors were the most important factors contributing to the concentration of LWT among the poor in Canada. These results provide some evidence that low-income individuals tend to have lengthier wait times for publicly-funded health care in Canada in comparison to their high-income counterparts. The observed negative gradient between income and long waiting time may be interpreted as evidence of socioeconomic inequity within Canadian health care system. Thus, further work is required to understand the mechanisms explaining the concentration of long wait time among the poor in Canada.


Protective Effects of Maclurin against Benzo[a]pyrene via Aryl Hydrocarbon Receptor and Nuclear Factor Erythroid 2-Related Factor 2 Targeting.
Benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon formed during the incomplete combustion of organic matter, has harmful effects. Therefore, much research is ongoing to develop agents that can mitigate the effects of B[a]P. The aim of this study was to examine the effect of maclurin, one component of the branches of Morus alba L., on the B[a]P-induced effects in HaCaT cells, a human keratinocyte cell line. Maclurin treatment inhibited aryl hydrocarbon receptor (AHR) signaling as evidenced by reduced xenobiotic response element (XRE) reporter activity, decreased expression of cytochrome P450 1A1 (CYP1A1), and reduced nuclear translocation of AHR. The B[a]P-induced dissociation of AHR from AHR-interacting protein (AIP) was suppressed by maclurin. Maclurin also inhibited the production of intracellular reactive oxygen species (ROS) induced by B[a]P. In addition, the antioxidant property of maclurin itself was demonstrated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Furthermore, maclurin activated antioxidant response element (ARE) signaling through enhancement of ARE luciferase reporter activity and the expression of ARE-dependent genes including nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1). Nrf2 activation and its nuclear translocation were promoted by maclurin through p38 MAPK activation. These data indicate that maclurin had antagonistic activity against B[a]P effects through activation of Nrf2-mediated signaling and inhibition of AHR signaling and, suggesting its potential in protecting from harmful B[a]P-containing pollutants.


[Diagnosis and therapy of vertebrogenic vertigo].
Functional disorders of the cervical spine may lead to vertigenous symptoms. The typical pathological finding in these patients is a hyperlordotic position of the cervical spine. This causes functional problems of the C0/C1 and C1/C2 joints. X-rays show morphological changes of the vertebrae and may also point to functional disorders. Physiotherapy is the most important treatment modality and preventative measure in static dysbalance of the cervical spine. sometimes chiropractic therapy by an experienced manual therapist or carefully directed infiltration therapy is necessary.


Development, validity and reliability of the short multidimensional positive mental health instrument.
The 47-item positive mental health (PMH) instrument measures the level of PMH in multiethnic adult Asian populations. This study aimed to (1) develop a short PMH instrument and (2) establish its validity and reliability among the adult Singapore population. Two separate studies were conducted among adult community-dwelling Singapore residents of Chinese, Malay or Indian ethnicity where participants completed self-administered questionnaires. In the first study, secondary data analysis was conducted using confirmatory factor analysis (CFA) to shorten the PMH instrument. In the second study, the newly developed short PMH instrument and other scales were administered to 201 residents to establish its factor structure, validity and reliability. A 20-item short PMH instrument fulfilling a higher-order six-factor structure was developed following secondary analysis. The mean age of the participants in the second study was 41 years and about 53% were women. One item with poor factor loading was further removed to generate a 19-item version of the PMH instrument. CFA demonstrated a first-order six-factor model of the short PMH instrument. The PMH-19 instrument and its subscales fulfilled criterion validity hypotheses. Internal consistency and test-retest reliability of the PMH-19 instrument were high (Cronbach's α coefficient = 0.87; intraclass correlation coefficient = 0.93, respectively). The 19-item PMH instrument is multidimensional, valid and reliable, and most importantly, with its reduced administration time, the short PMH instrument can be used to measure and evaluate PMH in Asian communities.


Pro-oxidant status and matrix metalloproteinases in apical lesions and gingival crevicular fluid as potential biomarkers for asymptomatic apical periodontitis and endodontic treatment response.
Oxidative stress and matrix metalloproteinases -9 and -2 are involved in periodontal breakdown, whereas gingival crevicular fluid has been reported to reflect apical status. The aim of this study was to characterize oxidant balance and activity levels of MMP -2 and -9 in apical lesions and healthy periodontal ligament; and second, to determine whether potential changes in oxidant balance were reflected in gingival crevicular fluid from asymptomatic apical periodontitis (AAP)-affected teeth at baseline and after endodontic treatment. Patients with clinical diagnosis of AAP and healthy volunteers having indication of tooth extraction were recruited. Apical lesions and healthy periodontal ligaments, respectively, were homogenized or processed to obtain histological tissue sections. Matrix metalloproteinase -9 and -2 levels and/or activity were analyzed by Immunowestern blot, zymography and consecutive densitometric analysis, and their tissue localization was confirmed by immunohistochemistry. A second group of patients with AAP and indication of endodontic treatment was recruited. Gingival crevicular fluid was extracted from AAP-affected teeth at baseline, after endodontic treatment and healthy contralateral teeth. Total oxidant and antioxidant status were determined in homogenized tissue and GCF samples. Statistical analysis was performed using STATA v10 software with unpaired t test, Mann-Whitney test and Spearman's correlation. Activity of MMP-2 and MMP-9 along with oxidant status were higher in apical lesions (p < 0.05). Total oxidant status correlated positively with matrix metalloproteinase-2 and lesion size (p < 0.05). Gingival crevicular fluid showed significantly lower levels of total antioxidant status in diseased teeth at baseline compared to controls and endodontically-treated groups. Apical lesions display an oxidant imbalance along with increased activity of matrix metalloproteinase-2 and -9 and might contribute to AAP progression. Oxidant imbalance can also be reflected in GCF from AAP-affected teeth and was restored to normal levels after conservative endodontic treatment. These mediators might be useful as potential biomarkers for chair-side complementary diagnostic of apical status in GCF.


Effects of three PTSD treatments on anger and guilt: exposure therapy, eye movement desensitization and reprocessing, and relaxation training.
This study sought to investigate the efficacy of prolonged exposure, eye movement desensitization and reprocessing, and relaxation training on trait anger and guilt and on trauma-related anger and guilt within the context of posttraumatic stress disorder (PTSD) treatment. Fifteen PTSD patients completed each treatment and were assessed at posttreatment and at 3-month follow-up. All three treatments were associated with significant reductions in all measures of anger and guilt, with gains maintained at follow-up. There were no significant treatment differences in efficacy or in the proportion of patients who worsened on anger or guilt measures over the course of treatment. Between-treatment effect sizes were generally very small. Results suggest that all three treatments are associated with reductions in anger and guilt, even for patients who initially have high levels of these emotions. However, these PTSD therapies may not be sufficient for treating anger and guilt; additional interventions may be required.


Fully quantum state-resolved inelastic scattering between He and NO(X (2)Pi).
Quantum mechanical close-coupling calculations have been used to obtain fully quantum state-resolved differential cross sections and opacity functions for the rotationally inelastic collisions of NO(X (2)Pi) with He at collision energies of 63 and 147 meV using the most recent ab initio potential energy surfaces of Kłos et al. [J. Chem. Phys. 112, 2195 (2000)]. Double peaks observed in the Lambda-doublet resolved differential cross sections are shown to be related to the presence of analogous peaks in the corresponding opacity functions. These structures can be linked directly to a specific expansion term in the potential, and reflect the fact that NO is not quite homonuclear.


Multi-factor climate change effects on insect herbivore performance.
The impact of climate change on herbivorous insects can have far-reaching consequences for ecosystem processes. However, experiments investigating the combined effects of multiple climate change drivers on herbivorous insects are scarce. We independently manipulated three climate change drivers (CO2, warming, drought) in a Danish heathland ecosystem. The experiment was established in 2005 as a full factorial split-plot with 6 blocks × 2 levels of CO2 × 2 levels of warming × 2 levels of drought = 48 plots. In 2008, we exposed 432 larvae (n = 9 per plot) of the heather beetle (Lochmaea suturalis Thomson), an important herbivore on heather, to ambient versus elevated drought, temperature, and CO2 (plus all combinations) for 5 weeks. Larval weight and survival were highest under ambient conditions and decreased significantly with the number of climate change drivers. Weight was lowest under the drought treatment, and there was a three-way interaction between time, CO2, and drought. Survival was lowest when drought, warming, and elevated CO2 were combined. Effects of climate change drivers depended on other co-acting factors and were mediated by changes in plant secondary compounds, nitrogen, and water content. Overall, drought was the most important factor for this insect herbivore. Our study shows that weight and survival of insect herbivores may decline under future climate. The complexity of insect herbivore responses increases with the number of combined climate change drivers.


Biological treatments in Behçet's disease: beyond anti-TNF therapy.
Behçet's disease (BD) is universally recognized as a multisystemic inflammatory disease of unknown etiology with chronic course and unpredictable exacerbations: its clinical spectrum varies from pure vasculitic manifestations with thrombotic complications to protean inflammatory involvement of multiple organs and tissues. Treatment has been revolutionized by the progressed knowledge in the pathogenetic mechanisms of BD, involving dysfunction and oversecretion of multiple proinflammatory molecules, chiefly tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, and IL-6. However, although biological treatment with anti-TNF-α agents has been largely demonstrated to be effective in BD, not all patients are definite responders, and this beneficial response might drop off over time. Therefore, additional therapies for a subset of refractory patients with BD are inevitably needed. Different agents targeting various cytokines and their receptors or cell surface molecules have been studied: the IL-1 receptor has been targeted by anakinra, the IL-1 by canakinumab and gevokizumab, the IL-6 receptor by tocilizumab, the IL12/23 receptor by ustekinumab, and the B-lymphocyte antigen CD-20 by rituximab. The aim of this review is to summarize all current experiences and the most recent evidence regarding these novel approaches with biological drugs other than TNF-α blockers in BD, providing a valuable addition to the actually available therapeutic armamentarium.


Effects of dietary inclusion and NaOH treatment of dried distillers grains with solubles on ruminal metabolism of feedlot cattle.
Dried distillers grains with solubles (DDGS) can decrease rumen pH because of their inherent acidity. Two replicated 4 × 4 Latin square experiments were conducted with ruminally fistulated heifers to determine the effects of dietary inclusion and NaOH treatment of DDGS on rumen metabolism. In Exp. 1, dietary treatments were 0%, 20%, 40%, or 60% DDGS on a DM basis. The remainder of the diet was 15% corn silage, 20% vitamin-mineral supplement, and corn (to replace DDGS) on a DM basis. Dry matter intake decreased (linear; P < 0.01) with increasing dietary inclusion of DDGS. Rumen pH was less than 5.3 from 1.5 to 12 h after feeding regardless of dietary DDGS inclusion, and mean rumen pH tended to decrease (linear; P = 0.08) with increasing DDGS. Rumen fluid S(2-) and rumen H(2)S gas concentrations increased (P < 0.01) with increasing DDGS inclusion at all time points postfeeding. At 3 h after feeding, ruminal concentrations of acetate, propionate, and total VFA increased linearly (P < 0.04) with increasing dietary inclusion of DDGS. Acetate to propionate ratio (A:P) ranged from 0.97 to 1.25 and was not affected (P = 0.88) by diet over time. In Exp. 2, dietary treatments were 1) 25% DDGS inclusion, untreated, 2) 60% DDGS inclusion, untreated, 3) 25% DDGS inclusion, treated with 2% NaOH, and 4) 60% DDGS inclusion, treated with 2% NaOH. Dry matter intake decreased (P < 0.01) when 60% DDGS was included in the diet regardless of NaOH treatment. Mean rumen pH was greater (P < 0.01) when NaOH-treated DDGS was fed regardless of dietary inclusion level. There were interactions (P ≤ 0.06) of NaOH treatment by DDGS inclusion by time for mean H(2)S and S(2-) concentrations. These interactions occurred because the magnitude of the response to NaOH treatment was greater for the 60% DDGS diets than for the 25% DDGS diets only from 1.5 to 9 h postfeeding. There were no interactions (P > 0.05) of NaOH treatment by DDGS inclusion on VFA concentrations. Acetate concentration decreased (P = 0.04) in cattle fed 60% DDGS diets at 0 h, but at 3 h postfeeding it tended to increase (P = 0.06). Total lactate was less than 1.30 for all dietary treatments at all time points. Treating DDGS with 2% NaOH may increase rumen pH and decrease H(2)S, thereby alleviating polioencephalomalacia.


Cytogenetics and clinical features of pediatric myelodysplastic syndrome in Japan.
We analyzed the cytogenetics and clinical features of pediatric myelodysplastic syndrome (MDS) in Japan. Data on patients (<16 years) diagnosed with MDS from 1990 to 2000 were retrospectively collected from pediatric hematologists in 234 institutions. Chromosome analysis was successfully performed in 255 of 277 MDS patients. The numbers of patients with refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess of blasts (RAEB), refractory anemia with excess of blasts in transformation (RAEBt), chronic myelomonocytic leukemia, and juvenile myelomonocytic leukemia were 67 (24%), 51 (18%), 51 (18%), 20 (7%), and 65 (23%), respectively. The other 23 patients (8%) could not be classified specifically. The distribution of childhood MDS in Japan according to the French-American-British subclassification was similar to that in other countries. However, we identified a higher incidence of therapy-related cases. As for relationship between cytogenetics and prognoses, abnormal karyotypes were related to poorer prognoses than normal karyotype (P < 0.01). However, patients with trisomy 8 had prognoses comparable to those with normal karyotypes. Complex karyotypes were associated with poorer prognoses among RAEB and RAEBt patients. In conclusion, prognosis of pediatric MDS is related to cytogenetics. A more precise diagnosis and classification system is needed for childhood MDS.


Use of amifostine, a novel cytoprotective, in alpha-amanitin poisoning.
Mortality from ingestions of the mushroom Amanita phalloides remains as high as 20-40% with many surviving patients requiring liver transplantation. A variety of treatments for Amanita ingestion have been evaluated, yet other than supportive measures, no effective therapy has been identified. In addition, an antidote for Amanita toxicity may not be practical due to delayed patient presentation. The drug amifostine was proposed to potentially improve survival from alpha-amanitin toxicity by conferring cytoprotective effects on hepatocytes at risk for cell death. Amifostine is used as a radio--and chemo-protective agent. It protects against lipoperoxidation, interferes with the cross-linking of DNA, and may act by other mechanisms yet to be identified, making it attractive for potentially attenuating ongoing hepatic necrosis. It has not previously been studied in a toxicologic model. To determine whether amifostine is an effective postexposure therapy for alpha-amanitin, the primary lethal toxin in Amanita phalloides. Swiss mice (n = 30 in all groups) were given an approximate LD75 dose of intraperitoneal (i.p.) alpha-amanitin. Amifostine was administered i.p. 6 h after poisoning in three cumulative dosing groups: 250 mg/kg; 500 mg/kg; and 1600 mg/kg. Controls received equal volumes of i.p. sterile 0.9% saline. Mice were monitored and time of death recorded. At day 7, survival was assumed and the remaining mice were euthanized. Qualitative histologic comparisons of hepatic and renal toxicity were performed. At day 7, only 10% of the control mice survived. Survival in the amifostine 250, 500, and 1600 mg/kg groups was 20%, 20%, and 3%, respectively. No statistically significant differences were detected in Kaplan-Meier survival between the control group and those receiving 250 or 500 mg/kg; however, there was a statistically significant decrease in survival for the group receiving 1600 mg/kg (p = 0.0002). No survival benefit was seen with cumulative doses between 250 and 500 mg/kg; however, higher doses may result in subsequent toxicity and decreased survival.


Bone marrow stromal cells from myeloma patients support the growth of myeloma stem cells.
It has been well documented that bone marrow stromal cells (BMSCs) of multiple myeloma patients play a pivotal role in supporting the growth of mature myeloma cells. With evolving concepts concerning the presence of myeloma stem (initiating) cells, we aimed this investigation to specifically address the supportive role of BMSCs for myeloma stem cell growth in vitro and in vivo. BMSC lines were derived from myeloma or control patients (myeloma or control BMSCs). Myeloma stem cells of the RPMI 8226 myeloma cell line were recognized through the identification of "side populations" (SP) with Hoechst dye staining. SP cells formed more colonies when grown on myeloma BMSC than on control BMSC. Additionally, higher percentages of SP cells were observed when grown on myeloma BMSCs than on control BMSCs. In the mouse model, SP cells inoculated with myeloma BMSCs grew faster than those inoculated with control BMSCs. Of note, SP cells demonstrated an increased expression of CD184 (CXCR4) compared with non-SP cells. The expression of CD184 in SP cells was further increased when they were cultured with myeloma BMSCs. CD184(+) SP cells formed more colonies than CD184(-) SP cells. Treatment with AMD 3100, an inhibitor of CD184, reduced colony formation by CD184(+) SP cells when co-cultured with myeloma BMSCs. This was associated with the decreased activation of ERK, a downstream target of activated CD184, in myeloma cells. These findings indicate that the myeloma BMSCs create a microenvironment supportive of myeloma stem cells via, at least partially, the CXCR4 signaling pathway.


Metabolic syndrome and nutrition in a Granada's tropical coast population.
The metabolic syndrome (MS) is described as an association of health problems that a given person may simultaneously or successively develop, and it is considered a serious condition because it is related to a significantly increased risk of suffering diabetes, coronary disease and brain damage. Nutrition, along with other factors such as physical activity and genetic inheritance, has an influence on preventing MS. The aim of this research is to demonstrate important aspects concerning the diagnosis, the prevalence, and the prevention of metabolic syndrome among the population of the tropical coast of Granada. 119 individuals from the tropical coast of Granada were studied to collect personal data such as their body mass index, body fat percentage, glycaemia, total cholesterol, HDL cholesterol, LDL cholesterol, and food intake (through nutritional survey). As a result of this research, a metabolic syndrome prevalence of 20,2% was obtained, 58,3% of which was related to women. The results obtained show significant statistical differences between individuals having metabolic syndrome and the control group. Particularly, these differences can be noted in parameters such as the BMI or the % of body fat. Nevertheless, there are no significant differences between the two groups concerning parameters related to nutrition such as % of fat, carbohydrates, proteins and kcal/day. As a conclusion from the research, we can state that the metabolic syndrome prevalence among the population of the tropical coast of Granada is similar to the figure obtained for the population in the US and in other areas of Spain. In addition, this research shows that metabolic syndrome is more frequent among individuals whose BMI and % of body fat is higher than 30.


Empagliflozin in the elderly.
Glucose and sodium tubular reabsorption inhibitors, or gliflozins, are a new therapeutic class. Their novel mechanism of action involves inhibition of a glucose and Na+ reabsorption co-transporter in the renal proximal tubule. They reduce blood glucose levels by reducing renal glucose reabsorption. They therefore cause glycosuria, which constitutes an energy loss and ultimately leads to a weight loss of around 2 to 3 kg. They reduce sodium load and lower blood pressure. This class improves HbA1c by about 0.7%. Empagliflozin has been shown to reduce all-cause mortality in type 2 diabetic patients at high cardiovascular risk and to reduce episodes of cardiac decompensation and is nephroprotective in diabetic and non-diabetic subjects. Empagliflozin, like other gliflozins, does not induce hypoglycaemia as it does not directly stimulate insulin secretion. Due to the high prevalence of type 2 diabetes, heart failure and renal failure in the elderly, gliflozins will become part of geriatric prescriptions. Their advantages and use must be known, especially as their role will be extended to numerous indications in the field of chronic diseases.


Mkks-null mice have a phenotype resembling Bardet-Biedl syndrome.
McKusick-Kaufman syndrome (MKS) is an autosomal recessive disorder characterized by post-axial polydactyly, congenital heart defects and hydrometrocolpos, a congenital structural abnormality of female genitalia. Mutations in the MKKS gene have also been shown to cause some cases of Bardet-Biedl syndrome (BBS) which is characterized by obesity, pigmentary retinopathy, polydactyly, renal abnormalities and hypogenitalism with secondary features of hypertension and diabetes. Although there is overlap in clinical features between MKS and BBS, MKS patients are not obese and do not develop retinopathy or have learning disabilities. To further explore the pathophysiology of BBS and the related disorder MKS, we have developed an Mkks(-/-) mouse model. This model shows that the absence of Mkks leads to retinal degeneration through apoptosis, failure of spermatozoa flagella formation, elevated blood pressure and obesity. The obesity is associated with hyperphagia and decreased activity. In addition, neurological screening reveals deficits in olfaction and social dominance. The mice do not have polydactyly or vaginal abnormalities. The phenotype of the Mkks(-/-) mice closely resembles the phenotype of other mouse models of BBS (Bbs2(-/-) and Bbs4(-/-)). These observations suggest that the complete absence of MKKS leads to BBS while the MKS phenotype is likely to be due to specific mutations.


Combining Protein Ligation Systems to Expand the Functionality of Semi-Synthetic Outer Membrane Vesicle Nanoparticles.
Bacterial outer membrane vesicles (OMVs) attract increasing interest as immunostimulatory nanoparticles for the development of vaccines and therapeutic agents. We previously engineered the autotransporter protein Hemoglobin protease (Hbp) into a surface display carrier that can be expressed to high density on the surface of Salmonella OMVs. Moreover, we implemented Tag-Catcher protein ligation technology, to obtain dense display of single heterologous antigens and nanobodies on the OMVs through coupling to the distal end of the Hbp passenger domain. Here, we aimed to further expand the versatility of the Hbp platform by enabling the coupling of heterologous proteins to internal sites of the Hbp passenger. Inserted SpyTags were shown to be accessible at the Salmonella OMV surface and to efficiently couple SpyCatcher-equipped fusion proteins. Next, we combined distally placed SnoopCatcher or SnoopTag sequences with internal SpyTags in a single Hbp molecule. This allowed the coupling of two heterologous proteins to a single Hbp carrier molecule without obvious steric hindrance effects. Since coupling occurs to Hbp that is already exposed on the OMVs, there are no limitations to the size and complexity of the partner proteins. In conclusion, we constructed a versatile modular platform for the development of bivalent recombinant OMV-based vaccines and therapeutics.


Temporary migrants in Shanghai households, 1984.
In China, temporary migration is defined as a change in place of residence without a concomitant change in household registration; such mobility therefore encompasses a more heterogeneous set of movements than is usually subsumed under this heading in other nations. Because of China's strict control of permanent migration to large cities, temporary migration has become an important strategy for adjusting to economic changes and to effecting family reunification. The Shanghai Temporary Migration Survey of 1984 focused on one segment of temporary migrants, the 58% living in the households of permanent residents. Multinomial logistic regression suggests the heightened probability that close relatives of the household heads come to Shanghai to visit or to live, and nonrelatives to work. Regression on current and expected duration shows that many intended to stay for a year or more, some for up to 20 years. Their presence in the city places added strains on infrastructure and raises questions about the continued efficacy of China's migration policies.


Morbidity after tonsillectomy in children with autism spectrum disorders.
As the incidence of autism spectrum disorder (ASD) increases, otolaryngologists are more likely to encounter patients from this population during tonsillectomy. The purpose of this study was to examine whether outcomes differ between pediatric patients with and without ASD in a national cohort of children undergoing tonsillectomy. Understanding these differences may be used to inform future approaches to improve clinical outcomes and healthcare costs. Data for this study were obtained from the Kids Inpatient Database (KID) of the Healthcare Cost Utilization Project. We studied pediatric patients who underwent tonsillectomy during 2003, 2006, 2009, and 2012. Tonsillectomy was identified using ICD-9-CM diagnosis codes 28.2 (tonsillectomy without adenoidectomy) and 28.3 (tonsillectomy with adenoidectomy). ASD was identified using ICD-9-CM diagnosis code 299 (autism). Outcomes including complications, length of hospital stay, and total hospitalization costs. Analyses were performed using multivariable models. Propensity score matching was used to control for covariate imbalance between patients with and without ASD. In our sample of 27,040 patients, 322 (1.2%) had a diagnosis of ASD. After controlling for potential confounders, multivariable modeling suggested patients with ASD had a shorter LOS of 0.50 days (p < 0.0001), were less likely to experience complications (odds ratio 0.57, p = 0.001), and had lower associated costs of $1308 less (p < 0.0001). Propensity score matching confirmed the findings of the multivariable modeling. Although ASD alone does not appear to confer additional costs or morbidity, differences between children with and without ASD suggest the need for providers to address patients with ASD uniquely.


Endothelial dysfunction, subclinical atherosclerosis and LDL cholesterol are the independent predictors of left atrial functions in hypertension.
Left atrial function has an important role in determining optimal performance of the heart. Increase of left atrial dysfunction and volume are poor prognostic factors. In this study, we investigated independent determinants of left atrial function in non-diabetic patients with de novo hypertension. The study included 124 consecutive non-diabetic patients with de novo hypertension. Brachial artery flow-mediated dilatation, carotid intima-media thickness, transthoracic echocardiography, 24-h rhythm holter, and aortic stiffness measurements were recorded. In echocardiography, left atrial maximum (LAMaV) and minimum (LAMiV) volumes were calculated. Left atrium total emptying fraction (LATEF) and total emptying volume (LATEV) were divided into two groups according to the mean levels. Multivariate analysis was performed after correlation analysis for LATEV and LATEF mean levels. By logistic regression analysis, systolic blood pressure (OR 0.882, 95% CI 0.784-0.992, p = 0.036), percent of flow-mediated dilation (OR 0.747, 95% CI 0.595-0.938, p = 0.012), and presence of carotid plaque (OR 0.014, 95% CI 0.001-0.188, p = 0.001) were found as independent variables that determine LATEF. Age (OR 0.879, 95% CI 0.795-0.972, p = 0.012), smoking (OR 23.739, 95% CI 2.699-208.810, p = 0.004), left ventricular mass index (OR 1.052, 95% CI 1.012-1.094, p = 0.011), mitrale E-wave velocity (OR 1.108, 95% CI 1.031-1.191, p = 0.005) and LDL (low-density lipoprotein) cholesterol (OR 0.942, 95% CI 0.911-0.974, p = 0.001) were independent predictors of LATEV. In non-diabetic patients with de novo hypertension endothelial dysfunction, subclinical atherosclerosis and LDL cholesterol levels independently affect left atrial function.


Gastric necrosis after fundoplication: a novel approach for esophageal preservation.
An 11-year-old boy presented moribund, with massive abdominal distension. A Nissen fundoplication and gastrostomy tube had been established at age 2 years. After attempts to pass a nasogastric tube were unsuccessful, the old gastrostomy site was used to gain percutaneous access to the stomach resulting in release of gastric contents and stabilization of blood pressure and perfusion. During operation, massive gastric distention with gastric necrosis was found. Subtotal gastrectomy was performed with stapled closure of the distal intraabdominal esophagus and prepyloric region. Sump suction was placed in the proximal esophagus and the abdomen was drained widely. A distal esophageal perforation was apparent on postoperative day 19 confirmed by imaging and endoscopy. A nasoesophageal tube was passed into the abdomen, tied to a Jackson-Pratt drain, and the composite tube repositioned in the midesophagus allowing controlled proximal and distal drainage. Six months later, a Hunt-Laurence esophagojejunal pouch was created. At age 13, the child is clinically well, and enjoys 50% of his nutritional needs orally, with the remainder delivered overnight via tube feedings. This case describes gastric necrosis after gas bloat syndrome as a late complication of Nissen fundoplication. A novel approach to the management of distal esophageal perforation allowed preservation of a functional, intact native esophagus.


Kinematic analysis of Drosophila larval locomotion in response to intermittent light pulses.
We report a quantitative analysis of the modulation of locomotion by light in the Drosophila larva. The photobehavior of wild type larvae and of larvae carrying mutations altering various aspects of locomotion was evaluated in an assay that exposes individual animals to intermittent pulses of dark and light (ON/OFF assay). The application of the Dynamic Image Analysis System for the analysis of larval movement in the ON/OFF assay allowed a detailed description of the behavioral repertoire underlying the modulation of larval motion by light. We established that the larval response to light is characterized by decreased frequency of peristaltic contractions in addition to increased direction change and pausing. Moreover, using various mutant strains we show that this approach allows the detection of a response to light in mutant larvae whose locomotion is severely reduced and uncoordinated, mutants that would otherwise have been considered non-responders in this assay.


Protective Effects of Sinomenine Against Ankylosing Spondylitis and the Underlying Molecular Mechanisms.
BACKGROUND This study aimed to investigate the effect and underlying molecular mechanism of sinomenine (SIN) on ankylosing spondylitis (AS). MATERIAL AND METHODS To study the potential role of SIN in the pathogenesis of AS, an AS mouse model was established and mice were treated with different concentrations of SIN (10, 30, and 50 mg/kg, administered intraperitoneally). Markers of inflammation and oxidative stress were determined by ELISA assay. Western blot analysis and qRT-PCR were used to quantify the levels of related proteins and gene mRNA expression. RESULTS The results suggest that AS mice has higher levels of TNF-α, IL-1β, and IL-6 (p<0.01 for all), and lower levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX) (p<0.01 for all). SIN treatment reduced the level of TNF-α, IL-1β, and IL-6 in a dose-dependent manner, and the levels of SOD, CAT, and GSH-PX were dose-dependently increased (p<0.05 for all). The results also revealed that NF-κBp65 expression decreased, while the level of IkB increased, in a dose-dependent manner, after SIN treatment in AS mice (p<0.05 for all). The level of p-p38 was dose-dependently reduced in AS mice by SIN treatment (p<0.05). Moreover, SIN inhibited Cox-2 expression in AS mice in a dose-dependent manner (p<0.05). CONCLUSIONS SIN has a beneficial role in AS through suppressing inflammatory mediators and by down-regulating oxidative stress via inhibiting the MAPKp38/NF-kB pathway and Cox-2 expression.


An Analysis on Promoting Prefabrication Implementation in Construction Industry towards Sustainability.
As a game-changing technology with significant environmental, economic, and social benefits, prefabricated technology has attracted attention and has been increasingly adopted in the construction industry. Although multitudinous studies have investigated various aspects of prefabrication in construction, a thorough review of its current development state that synthesized environmental, economic, and social sustainability dimensions remains overdue. Therefore, this study aims to fill this research gap by constructing a systematic framework, analyzing the research status quos, and providing recommendations for future research. This study first conducted a holistic review of 768 references with NVivo. A research foci framework that represented the body of knowledge in prefabrication in construction was developed with five levels, which were advantages, hindrances, stakeholders, promotion policies, and strategy spectrum. Following the framework, the in-depth analyses from the perspectives of environmental, economic, social sustainability, technologies development, and promotion strategies were performed. The current research domains were further linked with potential research directions for promoting prefabricated construction towards sustainability. The study is of value in both offering references for policy formulation and stakeholder practice and providing recommendations for future research.


Effects of osmolality on phosphoinositide hydrolysis in renal medulla.
We have reported previously that carbachol stimulates hydrolysis of phosphoinositides (PIs) in the renomedullary slices when incubated in a buffer of 300 mOsm/kg of H2O. However, the mammalian renal medulla has a hypertonic environment that changes with the state of hydration of the animal. In order to determine if the change in renal osmolality produces a change in the response of the inner medulla to hormones and neurotransmitters, we determined the effects of osmolality on carbachol-stimulated hydrolysis of PIs in the inner medullary slices of the rabbit kidney. The hydrolysis was determined by incorporation of [3H]inositol into PIs and the release of [3H]inositol phosphates in the presence and absence of 1 mM carbachol. The osmolality of the incubation media was increased from 300 to 1200 mOsm/kg of H2O in increments of 300 mOsm/kg of H2O by addition of either urea, NaCl, mannitol or an equiosmolar mixture of urea and NaCl. Increasing the osmolality of the incubation media by any one of these solutes decreased carbachol-stimulated release of inositol phosphates in the inner medullary slices of the rabbit kidney. Our results suggest that the effect of carbachol on PI messenger system in the renal medulla in vivo will depend on the tissue osmolality that itself depends on the state of hydration of the animal.


P2Y12 inhibitors: do they increase cancer risk?
Treatment with dual antiplatelet therapy (DAPT), typically combining a P2Y12 inhibitor with aspirin, is the standard of care for the prevention of coronary stent thrombosis, especially post revascularization and in the setting of acute coronary syndromes (ACS). Determining the appropriate duration has been debated as prolonged courses have been associated with reduced thrombotic complications. Despite proven benefit, there have been reports of a potential cancer risk associated with DAPT following the FDA's review of the TRITON-TIMI 38 trial and the DAPT trial. The latter revealed an increased risk of non-cardiovascular death, which was driven by more bleeding and cancer-related deaths. This further clouds the decision if longer courses of DAPT should be recommended. Several trials and meta-analyses have been conducted to further review this cancer risk with P2Y12 inhibitors. This manuscript intends to evaluate current literature to determine if there is a risk of cancer for patients on DAPT and its consequences in the management of cardiovascular disease.


Endovascular beta-radiation to reduce restenosis after coronary balloon angioplasty: results of the beta energy restenosis trial (BERT).
In the porcine overstretch injury model of restenosis, endovascular beta-radiation reduces neointima formation. To determine whether this therapy could be applied to patients with coronary artery disease, a special device was developed to allow delivery of 12 encapsulated 90Sr/Y sources, measuring a total of 30 mm, to various sites within the coronary arterial tree. This study was designed to evaluate the feasibility of the delivery of 12, 14, or 16 Gy at 2 mm after balloon angioplasty of stenoses of native coronary vessels. Delivery of beta-radiation was attempted in 23 patients after successful balloon angioplasty. Source delivery was successful in 21 of the 23 patients (91%). There was no in-hospital or 30-day morbidity or mortality. Follow-up quantitative coronary arteriography in 20 patients demonstrated a late loss of 0.05 mm, a late loss index of 4%, and a restenosis rate of 15%. The use of the beta-emitter 90Sr/Y significantly reduced treatment time and operator exposure compared with previous trials with the gamma-emitter 192Ir. In this study, the administration of endovascular beta-radiation after angioplasty was safe and feasible and substantially altered the postangioplasty late lumen loss, resulting in a lower-than-expected rate of restenosis. On the basis of these encouraging results, a multicenter, randomized trial with operators and patients blinded to treatment assignment is planned.


Multi-omics investigation of Clostridioides difficile-colonized patients reveals pathogen and commensal correlates of C. difficile pathogenesis.
Clostridioides difficile infection (CDI) imposes a substantial burden on the health care system in the United States. Understanding the biological basis for the spectrum of C. difficile-related disease manifestations is imperative to improving treatment and prevention of CDI. Here, we investigate the correlates of asymptomatic C. difficile colonization using a multi-omics approach. We compared the fecal microbiome and metabolome profiles of patients with CDI versus asymptomatically colonized patients, integrating clinical and pathogen factors into our analysis. We found that CDI patients were more likely to be colonized by strains with the binary toxin (CDT) locus or strains of ribotype 027, which are often hypervirulent. We find that microbiomes of asymptomatically colonized patients are significantly enriched for species in the class Clostridia relative to those of symptomatic patients. Relative to CDI microbiomes, asymptomatically colonized patient microbiomes were enriched with sucrose degradation pathways encoded by commensal Clostridia, in addition to glycoside hydrolases putatively involved in starch and sucrose degradation. Fecal metabolomics corroborates the carbohydrate degradation signature: we identify carbohydrate compounds enriched in asymptomatically colonized patients relative to CDI patients. Further, we reveal that across C. difficile isolates, the carbohydrates sucrose, rhamnose, and lactulose do not serve as robust growth substrates in vitro, consistent with their enriched detection in our metagenomic and metabolite profiling of asymptomatically colonized individuals. We conclude that pathogen genetic variation may be strongly related to disease outcome. More interestingly, we hypothesize that in asymptomatically colonized individuals, carbohydrate metabolism by other commensal Clostridia may prevent CDI by inhibiting C. difficile proliferation. These insights into C. difficile colonization and putative commensal competition suggest novel avenues to develop probiotic or prebiotic therapeutics against CDI.


Effect of adenoviral transduction of the fragile histidine triad gene into esophageal cancer cells.
Reintroduction of a tumor suppressor gene product in cancer cells is a promising strategy for cancer gene therapy. The fragile histidine triad (FHIT) gene has been identified in a region at chromosome 3p14.2, which is deleted in many tumors, including esophageal cancer. Previous studies have shown frequent biallelic alterations of the FHIT gene in numerous tumors, and have demonstrated a tumor suppressor function of Fhit. We have studied the biological effects of adenoviral-FHIT transduction in esophageal cancer cell lines. Results showed suppression of cell growth in vitro in three of seven esophageal cancer cell lines, all seven of which showed abundant expression of the transgene. Adenoviral-FHIT expression, but not control adenoviral infections, induced caspase-dependent apoptosis in two esophageal cancer cell lines, TE14 and TE4, which express no or very little Fhit, respectively. Treatment of TE14 cells with adenoviral-FHIT vectors resulted in abrogation of tumorigenicity in nude mice. A third esophageal cancer cell line, TE12, without detectable endogenous Fhit, showed accumulation of cells at S to G2-M and a small apoptotic cell fraction after adenoviral-FHIT transduction. Thus, adenoviral-FHIT expression can inhibit the growth of esophageal cancer cells, at least in part through caspase-dependent apoptosis, suggesting that adenoviral-FHIT infection should be explored as a therapeutic strategy.


The role of living vaccines in prophylaxis.
Although strain 19 vaccine has been widely recognized as the most effective vaccine for the control of bovine brucellosis, its use in the United States has declined in the last ten years. When the national level of infection was reduced to 1%, it was believed possible to move towards complete eradication of bovine brucellosis. The continued use of strain 19 vaccine was thought to interfere with the goal of complete eradication because: 1. persistence of serum agglutination titers in some animals caused confusion in the serological diagnosis, 2. occasional persistence of strain 19 infection in adult animals caused reactions in surveillance tests which required follow-up herd tests, 3. vaccination was reported to "mask" virulent infection in a herd by prolonging the incubation period. These perceived disadvantages of strain 19 are discussed in relation to the benefits derived from its use in infected areas. In the last ten years the number of calves vaccinated with strain 19 has steadily declined, whereas the national average of infected cattle has remained stationary. The level of infection in some areas has increased however. The date for complete eradication of bovine brucellosis in the United States has had to be postponed. A retrospective examination of the brucellosis eradication program shows that in general those states which vaccinated 40% or more of their eligible calves with strain 19 were able to eradicate brucellosis. States which still have a bovine brucellosis problem, in general, have never employed wide-scale vaccination. Other factors contributing to these differences in the progress of eradication will be discussed. The important role of strain 19 in the successful eradication of bovine brucellosis in some areas of the United States has been the reduction in the level of infection to the point where eradication was economically feasible.


Association of left ventricular strain with 30-day mortality and readmission in patients with heart failure.
Heart failure (HF) readmissions are a common and serious problem of heterogeneous etiology. Left ventricular (LV) ejection fraction has not been found to be a consistent risk marker. However, LV strain has been shown to predict outcomes in other settings, so the aim of this study was to determine the association of LV strain with 30-day HF readmission, independent of and incremental to clinical and basic echocardiographic parameters. A total of 468 patients who underwent echocardiography at the time of the first admission for HF from July 2009 to June 2012 were retrospectively studied. Clinical parameters were comprehensively assessed, and standard echocardiographic parameters and two strain parameters (global longitudinal strain [GLS] and global circumferential strain) were measured using speckle-tracking. Patients were followed for all-cause 30-day hospital readmission or death after discharge, and the associations of parameters with outcome were assessed using Cox proportional hazards models. Readmission within 30 days (n = 92 patients [20%]) was associated with greater impairment of LV GLS (-8.6% [interquartile range, -10.9% to -5.9%] vs -11.1% [interquartile range, -14.6% to -7.7%], P < .01). The association of GLS with readmission (hazard ratio, 1.13; 95% confidence interval, 1.07-1.19; P < .01) was independent of age, male gender, systolic blood pressure, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use, and comorbidity, as well as renal function, sodium, hematocrit, LV mass, left atrial size, and mitral regurgitation. Global circumferential strain was associated with outcome but not was independent after adjustment with echocardiographic parameters. In sequential models for 30-day outcome, GLS added incremental information to clinical parameters and LV ejection fraction and significantly improved reclassification (categorical net reclassification improvement, 0.34; P = .04) when LV ejection fraction was >50%. GLS is associated with HF readmission, independent of and incremental to clinical and basic echocardiographic parameters.


Transplantation of pituitary grafts fail to restore immune function and to reconstitute the thymus glands of aged mice.
There is evidence to indicate that the neuroendocrine and immune systems can interact. Thus, neuroendocrine hormones can modulate a variety of immune functions and there have been attempts to manipulate the neuroendocrine system of aged animals to enhance immune function. We have previously shown that the transplantation of a syngeneic pituitary gland under the kidney capsule of young adult mice elevates serum prolactin and enhances immune responsiveness. In the present study pituitary glands were transplanted under the kidney capsule of 22-month-old mice to determine if this maneuver can enhance a number of immunologic parameters. The results demonstrate that aged animals bearing transplanted pituitary grafts for 10 days did not exhibit any enhancement in their primary antibody response to sheep red blood cells, splenic T or B-cell mitogen responsiveness or restoration of thymic architecture. When these immunologic assessments are performed on animals bearing pituitary grafts for 28 days, the IgM and IgG primary antibody responses and splenic T-cell responsiveness are enhanced but repopulation of the thymus still does not occur. Importantly, this enhancement does not restore immunocompetence to levels observed in young mice.


The pediatric emergency department: a substitute for primary care?
Pediatric emergency department (PED) patients often present with non-urgent complaints. We attempted to estimate the perceived degree of urgency of the visit and to identify reasons for seeking non-urgent care in the PED by patients and parents. A prospective survey was completed by parents (for children 17 and younger) and patients (18-21) presenting to a suburban academic PED that sees approximately 15,000 patients per year. A convenience sample of participants was enrolled. Three hundred and five of 334 surveys were completed (91% response rate) over a 3-month period. Twenty-four percent of the chief complaints were perceived by those surveyed as emergent or possibly life-threatening, 23% were felt to be very urgent, and 52% were deemed somewhat urgent or minor. Twenty-five percent of those with minor or somewhat urgent complaints arrived by ambulance. Weekend visits and minority race correlated with a lower degree of perceived urgency. Overall, 79% of those surveyed identified a primary care provider (PCP) for themselves or their child. Of those, 54% had attempted to contact the PCP prior to coming to the PED. Six percent of those who attempted to reach their primary care providers were able to contact them and 52% were told to come to the PED. More than half of patients and parents presenting to the PED believed they had minor or somewhat urgent complaints. While the majority of patients have a regular provider, limited access to timely primary care and convenience may make the PED a more attractive care option than primary care for many parents and patients.


Perspectives on incorporating human neurobehavioral end points in risk assessments.
Three topics are addressed: (1) measurement issues (e.g., the reliability and validity of neurobehavioral test scores), (2) general principles of assessment, including test selection, and (3) interpretation of scores. Psychological tests generally perform as well as medical tests in terms of reliability and validity. Test manuals, assessment textbooks, and psychologists are useful resources to the risk assessor. The variety of different tests employed in neurobehavioral studies complicates interstudy comparisons. In addition, tests that ostensibly assess the same general domain of function might assess somewhat different abilities within that domain. Although a uniform battery for use in all studies seems desirable, the battery appropriate for a specific study depends on study goals, knowledge about the mechanism(s) of neurotoxicity, nature of the study population, and pattern of exposure. Exposure-related neurobehavioral deficits are generally indicators of "altered function" rather than of "clinical disease." Limiting concern to end points corresponding to clinical disease might not be appropriate. Many neurobehavioral diagnoses are phenomenological and a neurotoxicant might cause a unique pattern of deficits for which no label has been created. The concern that a small shift in the central tendency of a distribution of test scores has no significance for the individual should be reexamined in light of the prevention paradox, formulated on the basis of epidemiologic studies of chronic disease. Poor performance on a neurobehavioral test does not necessarily map clearly onto underlying behavioral or neural substrate. The absence of such linkages, given current knowledge about brain-behavior relationships, should not reduce confidence in neurobehavioral end points. Use of neurobehavioral test scores involves considerations that differ little from those that the risk assessor routinely addresses in using end points commonly used in research on other topics in environmental epidemiology.


An antimicrobial peptidomimetic induces Mucorales cell death through mitochondria-mediated apoptosis.
The incidence of mucormycosis has dramatically increased in immunocompromised patients. Moreover, the array of cellular targets whose inhibition results in fungal cell death is rather limited. Mitochondria have been mechanistically identified as central regulators of detoxification and virulence in fungi. Our group has previously designed and developed a proteolytically-resistant peptidomimetic motif D(KLAKLAK)2 with pleiotropic action ranging from targeted (i.e., ligand-directed) activity against cancer and obesity to non-targeted activity against antibiotic resistant gram-negative rods. Here we evaluated whether this non-targeted peptidomimetic motif is active against Mucorales. We show that D(KLAKLAK)2 has marked fungicidal action, inhibits germination, and reduces hyphal viability. We have also observed cellular changes characteristic of apoptosis in D(KLAKLAK)2-treated Mucorales cells. Moreover, the fungicidal activity was directly correlated with vacuolar injury, mitochondrial swelling and mitochondrial membrane depolarization, intracellular reactive oxygen species accumulation (ROS), and increased caspase-like enzymatic activity. Finally, these apoptotic features were prevented by the addition of the ROS scavenger N-acetyl-cysteine indicating mechanistic pathway specificity. Together, these findings indicate that D(KLAKLAK)2 makes Mucorales exquisitely susceptible via mitochondrial injury-induced apoptosis. This prototype may serve as a candidate drug for the development of translational applications against mucormycosis and perhaps other fungal infections.


Differences in the outcomes of adjuvant chemotherapy for colon cancer prescribed by physicians in different disciplines: a population-based study in Taiwan.
One feature unique to the Taiwanese healthcare system is the ability of physicians other than oncologists to prescribe systemic chemotherapy. This study investigated whether the care paths implemented by oncologists and non-oncologists differ with regard to patient outcomes. Data from the Taiwan Cancer Registry and National Health Insurance Database were linked to identify patients with colon cancer who underwent colectomy as first treatment within 3 months of diagnosis and adjuvant chemotherapy between 2005 and 2009. Postoperative patients who underwent adjuvant chemotherapy were included in this study. The exclusion criteria included patients with stage IV disease, a positive surgical margin and early disease recurrence. Among the patients presenting with multiple primary cancers, we also excluded patients who were diagnosed with colon cancer but for whom this was not the first primary cancer. The variables included sex, age, comorbidities, disease stage, chemotherapy cycle and changes in treatment regimen as well as the specialty of treatment providers and their case volume. Cox regression models and Kaplan-Meier analysis were used to examine differences in outcomes in the matched cohorts. We examined 3534 patients who were prescribed adjuvant chemotherapy by physicians from different disciplines. In terms of 5-year disease-free survival, no significant difference was observed between the groups of oncologists or surgeons among patients with stage II (90.02%vs88.99%) or stage III (77.64%vs79.99%) diseases. Patients who were subjected to changes in their chemotherapy regimens presented recurrence rates higher than those who were not. The discipline of practitioners is seldom taken into account in most series. This is the first study to provide empirical evidence demonstrating that the outcomes of patients with colon cancer do not depend on the treatment path, as long as the selection criteria for adjuvant chemotherapy is appropriate. Further study will be required before making any further conclusions.


Metabolic regulation of leaf senescence: interactions of sugar signalling with biotic and abiotic stress responses.
Sugars are important signals in the regulation of plant metabolism and development. During stress and in senescing leaves, sugars often accumulate. In addition, both sugar accumulation and stress can induce leaf senescence. Infection by bacterial and fungal pathogens and attack by herbivores and gall-forming insects may influence leaf senescence via modulation of the sugar status, either by directly affecting primary carbon metabolism or by regulating steady state levels of plant hormones. Many types of biotic interactions involve the induction of extracellular invertase as the key enzyme of an apoplasmic phloem unloading pathway, resulting in a source-sink transition and an increased hexose/sucrose ratio. Induction of the levels of the phytohormones ethylene and jasmonate in biotic interactions results in accelerated senescence, whereas an increase in plant- or pathogen-derived cytokinins delays senescence and results in the formation of green islands within senescing leaves. Interactions between sugar and hormone signalling also play a role in response to abiotic stress. For example, interactions between sugar and abscisic acid (ABA) signalling may be responsible for the induction of senescence during drought stress. Cold treatment, on the other hand, can result in delayed senescence, despite sugar and ABA accumulation. Moreover, natural variation can be found in senescence regulation by sugars and in response to stress: in response to drought stress, both drought escape and dehydration avoidance strategies have been described in different Arabidopsis accessions. The regulation of senescence by sugars may be key to these different strategies in response to stress.