Experimental Ehrlichia chaffeensis infection in beagles.
A canine model for human monocytic ehrlichiosis was used to assess persistent infection and antigenic variation of Ehrlichia chaffeensis. Two beagle dogs were infected subcutaneously with E. chaffeensis Arkansas strain. The dogs were observed for 6 months after inoculation for clinical signs, blood chemistry changes, antibodies to E. chaffeensis and presence of E. chaffeensis in the blood. Both dogs developed thrombocytopenia, but exhibited normal body temperatures during the entire course of infection. In one dog, E. chaffeensis was cultivated for up to 74 days post-inoculation and E. chaffeensis DNA was detected in the dog's blood for up to 81 days. In the other dog, E. chaffeensis was cultured for up to 102 days and E. chaffeensis DNA was detected in the blood for up to 117 days. PCR amplification and DNA sequence analysis indicated that there was no genetic variation in the 120 kDa outer-membrane glycoprotein gene of E. chaffeensis during infection of the dogs. The dogs developed antibodies to the immunodominant proteins of E. chaffeensis, including the 175, 140, 120, 80, 50 and 28 kDa proteins, starting in the fifth week post-inoculation. The dogs maintained high antibody titres throughout the 6-month study period. These results indicate that dogs become carriers of E. chaffeensis for 2-4 months after infection without exhibiting signs of clinical disease, suggesting that dogs may serve as a natural host for E. chaffeensis.


The structure of the core of the spiral wave in the belousov-zhabotinskii reaction.
The quantitative structure of the core of the spiral-shaped traveling wave of chemical activity appearing in a thin excitable layer of the Belousov-Zhabotinskii reaction, in which the oxidation and decarboxylation of malonic acid by bromate ions is catalyzed by ferroin, was analyzed experimentally. Light absorption by ferroin as the reduced reaction catalyst and indicator was measured by means of a video-and computer-based two-dimensional spectrophotometer with 10-micrometer spatial, 2-second temporal, and 256-digital units intensity resolution. The spiral core is a singular site (diameter, 30 micrometers or less) at which intensity modulations due to ferroin-ferriin distributions are at least ten times smaller than in the surrounding area of spiral propagation. Archimedian spirals were fitted to isoconcentration lines.


Evaluating the impact of a new pay system on nurses in the UK.
This study examines the impact of implementing a new pay system (Agenda for Change) on nursing staff in the National Health Service (NHS) in the UK. This new pay system covered approximately 400,000 nursing staff. Its objectives were to improve the delivery of patient care as well as staff recruitment, retention and motivation. The new system aimed to provide a simplified approach to pay determination, with a more systematic use of agreed job descriptions and job evaluation to 'price' individual jobs, linked to a new career development framework. Secondary analysis of survey data. Analysis of results of large-scale surveys of members of the Royal College of Nursing of the United Kingdom (RCN) to assess the response of nurses to questions about the implementation process itself and their attitude to pay levels. The results demonstrated that there was some positive change after implementation of Agenda for Change in 2006, mainly some time after implementation, and that the process of implementation itself raised expectations that were not fully met for all nurses. There were clear indications of differential impact and reported experiences, with some categories of nurse being less satisfied with the process of implementation. The overall message is that a national pay system has strengths and weaknesses compared to the local systems used in other countries and that these benefits can only be maximised by effective communication, adequate funding and consistent management of the system. How nurses' pay is determined and delivered can be a major satisfier and incentive to nurses if the process is well managed and can be a factor in supporting clinical practice, performance and innovation. This study highlights that a large-scale national exercise to reform the pay system for nurses is a major undertaking, carries risk and will take significant time to implement effectively.


Effects of a carrot juice intervention on plasma carotenoids, oxidative stress, and inflammation in overweight breast cancer survivors.
Evidence suggests that higher plasma carotenoid concentrations are protective in relation to breast cancer recurrence. This simple randomized carrot juice intervention study was designed to test the hypothesis that daily intake of 8 ounces of fresh BetaSweet (anthocyanin-rich) or Balero orange carrot juice would increase plasma total carotenoid concentrations to levels previously shown to be associated with reduced breast cancer recurrence. It was hypothesized that regular carrot juice intake would be associated with reductions in oxidative stress (8-iso-PGF2α) and inflammation (thromboxane B2, prostaglandin E2 metabolites, and hsC-reactive protein). Sixty-nine overweight breast cancer survivors consumed fresh carrot juice made from study-provided carrots for 3 wk. Total plasma carotenoids increased by 1.65 and 1.38 umol/L for the BetaSweet and Balero carrot juice, respectively. Rise in total plasma carotenoids for the overall sample was inversely associated with 8-iso-PGFα (OR: 0.13; 95% CI: 0.20 to 0.75; no differences were shown by carrot variety. These results suggest daily intake of fresh carrot juice is a simple and effective approach to increasing plasma total carotenoids and in turn reducing oxidative stress, but not inflammatory markers, in women previously treated for breast cancer.


The impact of COVID-19 on student experiences and expectations: Evidence from a survey.
In order to understand the impact of the COVID-19 pandemic on higher education, we surveyed approximately 1500 students at one of the largest public institutions in the United States using an instrument designed to recover the causal impact of the pandemic on students' current and expected outcomes. Results show large negative effects across many dimensions. Due to COVID-19: 13% of students have delayed graduation, 40% have lost a job, internship, or job offer, and 29% expect to earn less at age 35. Moreover, these effects have been highly heterogeneous. One quarter of students increased their study time by more than 4 hours per week due to COVID-19, while another quarter decreased their study time by more than 5 hours per week. This heterogeneity often followed existing socioeconomic divides. Lower-income students are 55% more likely than their higher-income peers to have delayed graduation due to COVID-19. Finally, we show that the economic and health related shocks induced by COVID-19 vary systematically by socioeconomic factors and constitute key mediators in explaining the large (and heterogeneous) effects of the pandemic.


Effects of a model treatment approach on adults with autism.
The study evaluated the effectiveness of a residential program, based on the TEACCH model, in improving the quality of the treatment program and the adaptation of individuals with autism with severe disabilities. The results indicated that participants in the Carolina Living and Learning Center experienced an increase in structure and individualized programming in the areas of communication, independence, socialization, developmental planning, and positive behavior management compared to participants in control settings. The experimental program was viewed as a more desirable place to live than the other settings, and the families were significantly more satisfied. Based on exploratory analyses, the use of the TEACCH methods over time were related to a decrease in behavior difficulties. There was no difference in the acquisition of skills.


Identification of a new North American hantavirus that causes acute pulmonary insufficiency.
In May 1993, a pulmonary disease syndrome with novel clinical and epidemiologic features was identified in the southwestern United States. Healthy young adults developed a febrile prodrome followed by the rapid onset of often lethal acute respiratory distress. Although an infectious disease was suspected, intensive investigations initially failed to identify the causative agent. Multiple specialized microbiology laboratories at the National Center for Infectious Diseases (Centers for Disease Control and Prevention) applied classic serologic and culture methods as well as recently developed molecular biological techniques to samples collected from field investigations of the patients. Serologic tests detected the presence of an active immune response to a hantavirus. Reverse transcription and polymerase chain reaction amplification of RNA extracted from human tissues used primers designed from sequences of known hantaviruses to demonstrate genomic sequences of a novel hantavirus. Immunohistochemistry showed the presence of hantavirus antigens in the endothelium of lung tissues from patients and provided the final pathogenetic link to this group of viruses. These methods were concordantly positive in virtually all samples available from 18 patients with compatible clinical histories identified between January and July 1993. Test results of control subjects and searches for other agents in identified cases were negative. This newly recognized hantavirus causes a novel syndrome of acute pulmonary edema and shock; the pathogenesis is related to the presence of virus antigens in the pulmonary capillaries. The virus may be an important cause of severe and fatal disease presenting as adult respiratory distress syndrome in otherwise healthy persons.


Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database.
Estimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates in patients undergoing prospective cancer surveillance. We undertook a multicentre study of patients carrying Lynch syndrome-associated mutations affecting MLH1, MSH2, MSH6 or PMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle relational database and analysed by age, sex and mutated gene. 1942 mutation carriers without previous cancer had follow-up including colonoscopic surveillance for 13 782 observation years. 314 patients developed cancer, mostly colorectal (n=151), endometrial (n=72) and ovarian (n=19). Cancers were detected from 25 years onwards in MLH1 and MSH2 mutation carriers, and from about 40 years in MSH6 and PMS2 carriers. Among first cancer detected in each patient the colorectal cancer cumulative incidences at 70 years by gene were 46%, 35%, 20% and 10% for MLH1, MSH2, MSH6 and PMS2 mutation carriers, respectively. The equivalent cumulative incidences for endometrial cancer were 34%, 51%, 49% and 24%; and for ovarian cancer 11%, 15%, 0% and 0%. Ten-year crude survival was 87% after any cancer, 91% if the first cancer was colorectal, 98% if endometrial and 89% if ovarian. The four Lynch syndrome-associated genes had different penetrance and expression. Colorectal cancer occurred frequently despite colonoscopic surveillance but resulted in few deaths. Using our data, a website has been established at http://LScarisk.org enabling calculation of cumulative cancer risks as an aid to genetic counselling in Lynch syndrome.


Caffeine: An Overview of Its Beneficial Effects in Experimental Models and Clinical Trials of Parkinson's Disease.
Parkinson's Disease (PD) is a neurological disease characterized by the progressive degeneration of the nigrostriatal dopaminergic pathway with consequent loss of neurons in the substantia nigra pars compacta and dopamine depletion. The cytoplasmic inclusions of α-synuclein (α-Syn), known as Lewy bodies, are the cytologic hallmark of PD. The presence of α-Syn aggregates causes mitochondrial degeneration, responsible for the increase in oxidative stress and consequent neurodegeneration. PD is a progressive disease that shows a complicated pathogenesis. The current therapies are used to alleviate the symptoms of the disease without changing its clinical course. Recently, phytocompounds with neuroprotective effects and antioxidant properties such as caffeine have aroused the interest of researchers. The purpose of this review is to summarize the preclinical studies present in the literature and clinical trials recorded in ClinicalTrial.gov, aimed at illustrating the effects of caffeine used as a nutraceutical compound combined with the current PD therapies. Therefore, the preventive effects of caffeine in the neurodegeneration of dopaminergic neurons encourage the use of this alkaloid as a supplement to reduce the progress of the PD.


TreeDom: a graphical web tool for analysing domain architecture evolution.
We present TreeDom, a web tool for graphically analysing the evolutionary history of domains in multi-domain proteins. Individual domains on the same protein chain may have distinct evolutionary histories, which is important to grasp in order to understand protein function. For instance, it may be important to know whether a domain was duplicated recently or long ago, to know the origin of inserted domains, or to know the pattern of domain loss within a protein family. TreeDom uses the Pfam database as the source of domain annotations, and displays these on a sequence tree. An advantage of TreeDom is that the user can limit the analysis to N sequences that are most similar to a query, or provide a list of sequence IDs to include. Using the Pfam alignment of the selected sequences, a tree is built and displayed together with the domain architecture of each sequence.Availablility and implementation: http://TreeDom.sbc.su.se email@example.com.


Microfluidic filter device with nylon mesh membranes efficiently dissociates cell aggregates and digested tissue into single cells.
Tissues are increasingly being analyzed at the single cell level in order to characterize cellular diversity and identify rare cell types. Single cell analysis efforts are greatly limited, however, by the need to first break down tissues into single cell suspensions. Current dissociation methods are inefficient, leaving a significant portion of the tissue as aggregates that are filtered away or left to confound results. Here, we present a simple and inexpensive microfluidic device that simultaneously filters large tissue fragments and dissociates smaller aggregates into single cells, thereby improving single cell yield and purity. The device incorporates two nylon mesh membranes with well-defined, micron-sized pores that operate on aggregates of different size scales. We also designed the device so that the first filtration could be performed under tangential flow to minimize clogging. Using cancer cell lines, we demonstrated that aggregates were effectively dissociated using high flow rates and pore sizes that were smaller than a single cell. However, pore sizes that were less than half the cell size caused significant damage. We then improved results by passing the sample through two filter devices in series, with single cell yield and purity predominantly determined by the pore size of the second membrane. Next, we optimized performance using minced and digested murine kidney tissue samples, and determined that the combination of 50 and 15 μm membranes was optimal. Finally, we integrated these two membranes into a single filter device and performed validation experiments using minced and digested murine kidney, liver, and mammary tumor tissue samples. The dual membrane microfluidic filter device increased single cell numbers by at least 3-fold for each tissue type, and in some cases by more than 10-fold. These results were obtained in minutes without affecting cell viability, and additional filtering would not be required prior to downstream applications. In future work, we will create complete tissue analysis platforms by integrating the dual membrane microfluidic filter device with additional upstream tissue processing technologies, as well as downstream operations such as cell sorting and detection.


Self-deprecation and estimates of body size in women.
The subject of body image in women has received considerable attention particularly with concern about its relationship to behaviours such as dieting. This study investigated the reported tendency of women to see thinness as desirable and to perceive themselves as fatter than others do. This tendency is inconsistent with the general findings on self-enhancement that show that people (including women) generally overestimate the extent to which they possess desirable characteristics. Thus, the purpose of this study was to investigate whether the tendency for women to report themselves as fatter than others perceive them is part of a general tendency to deprecate themselves on socially desirable qualities or whether this deprecation is restricted to body size. To investigate this, 29 female undergraduates in psychology participated in a study comparing own and others' perceptions of body size, attractiveness, sexiness, intelligence, and friendliness. Compared with the ratings of them given by others, women tended to make self-enhancing judgements of their attractiveness, sexiness, intelligence, and friendliness. This was not found for body size, however, for which self-ratings tended to be the same as those made by others. The failure to find self-enhancing judgements of body size is discussed in terms of the relatively unvarying standards presented to women concerning ideal body size compared to the more subjective standards used to evaluate other qualities.


Platelet volume and plateletcrit in dogs with presumed primary immune-mediated thrombocytopenia.
Mean platelet volume (MPV) and plateletcrit (PCT) are indices used in evaluating immune-mediated thrombocytopenia (IMT) in humans and in dogs with congenital macrothrombocytopenia. These indices may provide clinically valuable information in acquired thrombocytopenia. Dogs with presumed primary IMT will have increased MPV, and therefore platelet mass (PCT) will increase faster than platelet count (PLT) during recovery. Forty-nine dogs with automated PLT < 30,000/μL because of presumed primary IMT and hematocrit (HCT), PCT, MPV, and platelet distribution width determined from the same complete blood count (CBC), and 46 healthy controls. Case-control retrospective study; PLT, PCT, MPV, and platelet distribution width (PDW) were recorded from CBCs from 49 dogs, with 45 having data collected on the day of presentation. Fifteen were confirmed to have attained a PLT ≥ 75,000/μL on at least 1 CBC within 15 days after admission. The PCT equivalent to a PLT of 75,000/μL (assuming an average MPV) was calculated for comparison with PLT in terms of time to achieve a threshold of platelet mass by the 2 measures. Mean platelet volume was higher in IMT dogs (17.3 fl) than the reference population (10.5 fl) (P < .0001). The PDW was not significantly different among the groups. The median time for PCT to reach threshold in confirmed responders was faster (3 days) compared with PLT (4 days). Immune-mediated thrombocytopenia is characterized by increased MPV. Time to achieve a threshold PCT tended to be shorter than PLT, suggesting that PCT may be a useful platelet parameter for monitoring dogs with IMT.


Dietary sodium restriction for mild hypertension in general practice.
Eighteen patients with stable mild hypertension (mean blood pressure 144/93 mm Hg) restricted their sodium intake for eight weeks while taking part in a double blind randomised crossover trial of slow sodium and placebo tablets. Mean 24 hour urinary sodium excretion was 143 mmol(mEq) during the period on slow sodium and 87 mmol during the period on placebo. Five patients were unable to reduce their sodium intake below 120 mmol, but the others had a mean 24 hour urinary sodium excretion of 59 mmol during the period on placebo. There was no significant difference in blood pressure between the slow sodium and placebo treatment periods, although the study had a power of 99% to detect a difference of 5 mm Hg in mean arterial pressure between the two periods. Moderate dietary sodium restriction does not lower blood pressure in patients with this degree of hypertension.


Androgen receptor-target genes in african american prostate cancer disparities.
The incidence and mortality rates of prostate cancer (PCa) are higher in African American (AA) compared to Caucasian American (CA) men. To elucidate the molecular mechanisms underlying PCa disparities, we employed an integrative approach combining gene expression profiling and pathway and promoter analyses to investigate differential transcriptomes and deregulated signaling pathways in AA versus CA cancers. A comparison of AA and CA PCa specimens identified 1,188 differentially expressed genes. Interestingly, these transcriptional differences were overrepresented in signaling pathways that converged on the androgen receptor (AR), suggesting that the AR may be a unifying oncogenic theme in AA PCa. Gene promoter analysis revealed that 382 out of 1,188 genes contained cis-acting AR-binding sequences. Chromatin immunoprecipitation confirmed STAT1, RHOA, ITGB5, MAPKAPK2, CSNK2A,1 and PIK3CB genes as novel AR targets in PCa disparities. Moreover, functional screens revealed that androgen-stimulated AR binding and upregulation of RHOA, ITGB5, and PIK3CB genes were associated with increased invasive activity of AA PCa cells, as siRNA-mediated knockdown of each gene caused a loss of androgen-stimulated invasion. In summation, our findings demonstrate that transcriptional changes have preferentially occurred in multiple signaling pathways converging ("transcriptional convergence") on AR signaling, thereby contributing to AR-target gene activation and PCa aggressiveness in AAs.


Environmental exposure of commuters in Mexico City to volatile organic compounds as assessed by blood concentrations, 1998.
To assess the extent of exposure for Volatile Organic Compounds (VOCs) among nonoccupationally exposed commuters in Mexico City. Blood concentrations of benzene, toluene, ethylbenzene, m-/p-xylene, o-xylene and methyl tert-butyl ether were determined on samples collected from participants after the morning commute. Median blood concentrations of benzene (0.11 microg/l), ethylbenzene (0.081 microg/l), m-/p-xylene (0.32 microg/l) and toluene (0.56 microg/l) in the Mexico City participants were all approximately two times higher than in a nonsmoking subset of the Third National Health and Nutrition Examination Survey population of the United States. On the other hand, median VOC blood levels were similar to medians observed in other studies involving commuters in specific U.S. cities, despite the fact that only half the Mexico City study participants commuted by personal vehicles compared with all U.S. commuters. These results reflect the extent of the air pollution problem in Mexico City. The surrounding topography exacerbates the problems caused by heavy vehicular traffic, poor emission-control devices on older vehicles, and poor maintenance practices. Elevated levels of gasoline components in the blood of nonoccupationally exposed commuters emphasize the need for regulatory initiatives and mass-transit options to reduce hydrocarbon emissions and thus reduce the risk for nonoccupational exposure for the residents of Mexico City.


AXSIS: Exploring the frontiers in attosecond X-ray science, imaging and spectroscopy.
X-ray crystallography is one of the main methods to determine atomic-resolution 3D images of the whole spectrum of molecules ranging from small inorganic clusters to large protein complexes consisting of hundred-thousands of atoms that constitute the macromolecular machinery of life. Life is not static, and unravelling the structure and dynamics of the most important reactions in chemistry and biology is essential to uncover their mechanism. Many of these reactions, including photosynthesis which drives our biosphere, are light induced and occur on ultrafast timescales. These have been studied with high time resolution primarily by optical spectroscopy, enabled by ultrafast laser technology, but they reduce the vast complexity of the process to a few reaction coordinates. In the AXSIS project at CFEL in Hamburg, funded by the European Research Council, we develop the new method of attosecond serial X-ray crystallography and spectroscopy, to give a full description of ultrafast processes atomically resolved in real space and on the electronic energy landscape, from co-measurement of X-ray and optical spectra, and X-ray diffraction. This technique will revolutionize our understanding of structure and function at the atomic and molecular level and thereby unravel fundamental processes in chemistry and biology like energy conversion processes. For that purpose, we develop a compact, fully coherent, THz-driven atto-second X-ray source based on coherent inverse Compton scattering off a free-electron crystal, to outrun radiation damage effects due to the necessary high X-ray irradiance required to acquire diffraction signals. This highly synergistic project starts from a completely clean slate rather than conforming to the specifications of a large free-electron laser (FEL) user facility, to optimize the entire instrumentation towards fundamental measurements of the mechanism of light absorption and excitation energy transfer. A multidisciplinary team formed by laser-, accelerator,- X-ray scientists as well as spectroscopists and biochemists optimizes X-ray pulse parameters, in tandem with sample delivery, crystal size, and advanced X-ray detectors. Ultimately, the new capability, attosecond serial X-ray crystallography and spectroscopy, will be applied to one of the most important problems in structural biology, which is to elucidate the dynamics of light reactions, electron transfer and protein structure in photosynthesis.


Population structure of a whale shark Rhincodon typus aggregation in the Red Sea.
The presence of whale sharks Rhincodon typus were recorded around Shib Habil, a small, coastal reef off the Red Sea coast of Saudi Arabia, from 2010 to 2015. A total of 267 suitable photographs resulting in the identification of 136 individuals, were documented from 305 encounters. Sharks were divided evenly between the sexes with no evidence of temporal or spatial segregation. All individuals were immature based on size estimates and, for males, juvenile clasper morphology. Scars were reported for 57% of R. typus with 15% showing evidence of propeller trauma. Estimates of population size and patterns of residency were calculated by modelling the lagged identification rate. Multiple models were run simultaneously and compared using the Akaike information criterion. An open population model was found to best represent the data and estimates a daily abundance between 15 and 34 R. typus during the aggregation season, with local residence times ranging from 4 to 44 days. Residence times away from Shib Habil range from 15 to 156 days with a permanent emigration-death rate between 0·07 and 0·58 individuals year(-1) . These results are broadly similar to those from other aggregations of R. typus, although the observed sexual parity and integration found at this site is unique for the species and needs further study.


National estimates of predictors of outcomes for emergency general surgery.
Identifying predictors of mortality and surgical complications has led to outcome improvements for a variety of surgical conditions. However, similar work has yet to be done for factors affecting outcomes of emergency general surgery (EGS). The objective of this study was to determine the predictors of in-hospital complications and mortality among EGS patients. The Nationwide Inpatient Sample (2003-2011) was queried for patients with conditions encompassing EGS as determined by the American Association for Surgery of Trauma, categorizing them into predefined EGS groups using DRG International Classification of Diseases-9th Rev.-Clinical Modification codes. Primary outcomes considered included incidence of a major complication (pneumonia, pulmonary emboli, urinary tract infections, myocardial infarctions, sepsis, or septic shock) and in-hospital mortality. Separate multivariate logistic regression analyses for complications and mortality were performed to identify risk factors of either outcome from the following domains: patient demographics (age, sex, insurance type, race, and income quartile), comorbidities, and hospital characteristics (location, teaching status, and bed size). This study included 6,712,151 discharge records, weighted to represent 32,910,446 visits for EGS conditions. Mean age was 58.50 (19.74) years; slightly more than half (54.66%) were female. Uninsured patients were more likely to die (odds ratio,1.25; 95% confidence interval, 1.20-1.30), whereas patients in the highest income quartile had the least likelihood of mortality (odds ratio, 0.86; 95% confidence interval, 0.84-0.87). Old age was an independent predictor of mortality for all EGS subdiagnoses. The overall mortality rate was 1.76%; the overall complication rate was 10.03%. Of the patients who died, 62% experienced at least one major complication. Patients requiring resuscitation had the highest likelihood of mortality followed by patients with vascular disease and hepatic disease. Death patterns of EGS patients were discerned using an administrative data set. Understanding patterns of mortality and complications derived from studies such as this could improve hospital benchmarking for EGS, akin to trauma surgery's previous success. Prognostic and epidemiologic study, level III.


Laparoscopic Versus Open Cholecystectomy in Pediatric Patients: A Propensity Score-Matched Analysis.
Background: As minimally invasive pediatric surgery becomes standard approach to many surgical solutions, access has become an important point for improvement. Laparoscopic cholecystectomy (LC) is the gold standard for many conditions affecting the gallbladder; however, open cholecystectomy (OC) is offered as the initial approach in a surprisingly high percentage of cases. Materials and Methods: The Kids' Inpatient Database (1997-2012) was searched for International Classification of Disease, 9th revision, Clinical Modification procedure code (51.2x). LC and OC performed in patients <20 years old were identified. Propensity score-matched analyses using 39 variables were performed to isolate the effects of race, income group, location, gender, payer status, and hospital size on the percentage of LCs and OCs offered. Cases were weighted to provide national estimates. Results: A total of 78,578 cases were identified, comprising LC (88.1%) and OC (11.9%). Girls were 1.6 (CI: 1.4, 1.7) times more likely to undergo LC versus boys. Large facilities were 1.4 (1.3, 1.7) times more likely to perform LCs than small facilities. Children in lower income quartiles were 1.2 (1.1, 1.3) times more likely to undergo LC compared with those in higher income quartiles. Rates of LC were not affected by race, hospital location, or payer status. Conclusions: Risk-adjusted analysis of a large population-based data set demonstrated evidence that confirms, but also refutes, traditional disparities to minimally invasive surgery access. Despite laparoscopic gold standard, OC remains the initial approach in a surprisingly high percentage of pediatric cases independent of demographics or socioeconomic status. Additional research is required to identify factors affecting the distribution of LC and OC within the pediatric population.


Partial manual exchange reduces iron accumulation during chronic red cell transfusions for sickle cell disease.
Iron overload is an inevitable consequence of chronic red cell transfusions without erythrocytapheresis or chelation therapy. The effectiveness of partial manual exchange, a technique used to slow iron loading, has not been evaluated. We evaluated all children with sickle cell disease (SCD) receiving chronic transfusion to identify chelation-naive subjects who had quantitative liver iron concentration (LIC) studies. Seventeen chelation-naive children with SCD received a median of 29 transfusions before first LIC determination. Serum ferritin concentrations were assessed before each transfusion. The mean volume of blood phlebotomized before each transfusion was 5.1±1.8 mL/kg, which cumulatively resulted in a calculated median of 35.0 mg/kg iron removal. Using linear regression, pretransfusion phlebotomy resulted in a statistically significant reduction in ferritin (-8.8 ng/mL of ferritin for each mg/kg of iron phlebotomized, P=0.02). A reduction in LIC from pretransfusion phlebotomy could not be established (P=0.4). Partial manual exchanges appear to be an effective strategy for slowing the pace of iron loading in the setting of chronic transfusion for SCD.


Cocaine-induced locomotor activity is increased by prior handling in adolescent but not adult female rats.
Adolescence is a period of transition that is associated with increased levels of stress and a heightened propensity to initiate drug use. Neuronal development is still occurring during this transitional period, which includes the continued development of the dopamine system during the adolescent period. In the present study, the effects of pre-test handling on cocaine-induced locomotor activity were investigated among female adolescent and young adult rats upon presentation to a novel environment. On postnatal days (PND) 41-44 and 56-59 animals were handled (b.i.d.) in the colony room for 3 min. On PND 45 or PND 60, animals were removed from the colony room, weighed, and administered an acute injection of either cocaine or saline and presented to a novel environment where behavior was recorded for 30 min. Adolescent females (PND 45) that were handled prior to cocaine administration demonstrated elevated levels of cocaine-induced activity relative to their age-matched non-handled counterparts and also to their handled-adult counterparts. In contrast, among non-handled animals, young adults (PND 60) exhibited elevated drug-induced locomotion at several time points during the trial. Non-handled adolescent animals demonstrated the previously described "hyporesponsive" behavioral profile relative to their non-handled adult counterparts. The results from the present experiment indicate that adolescent animals may be more sensitive to basic laboratory manipulations such as pre-test handling, and care must be taken when utilizing adolescent animals in behavioral testing. Handling appears to be a sensitive manipulation in elucidating differences in cocaine-induced behavioral activation between ages.


Exploration of the imidazo[1,2-b]pyridazine scaffold as a protein kinase inhibitor.
3,6-Disubstituted imidazo[1,2-b]pyridazine derivatives were synthesized to identify new inhibitors of various eukaryotic kinases, including mammalian and protozoan kinases. Among the imidazo[1,2-b]pyridazines tested as kinase inhibitors, several derivatives were selective for DYRKs and CLKs, with IC50 < 100 nM. The characterization of the kinome of several parasites, such as Plasmodium and Leishmania, has pointed out profound divergences between protein kinases of the parasites and those of the host. This led us to investigate the activities of the prepared compounds against 11 parasitic kinases. 3,6-Disubstituted imidazo[1,2-b]pyridazines showed potent inhibition of Plasmodium falciparum CLK1 (PfCLK1). Compound 20a was found to be the most selective product against CLK1 (IC50 = 82 nM), CLK4 (IC50 = 44 nM), DYRK1A (IC50 = 50 nM), and PfCLK1 (IC50 = 32 nM). The compounds were also tested against Leishmania amazonensis. Several compounds showed anti-leishmanial activity at rather high (10 μM) concentration, but were not toxic at 1 μM or 10 μM, as judged by viability assays carried out using a neuroblastoma cell line.


MicroRNA biogenesis is required for Myc-induced B-cell lymphoma development and survival.
Many tumor cells express globally reduced levels of microRNAs (miRNA), suggesting that decreased miRNA expression in premalignant cells contributes to their tumorigenic phenotype. In support of this, Dicer, an RNase III-like enzyme that controls the maturation of miRNA, was recently shown to function as a haploinsufficient tumor suppressor in nonhematopoietic cells. Because the Myc oncoprotein, a critical inducer of B-cell lymphomas, was reported to suppress the expression of multiple miRNAs in lymphoma cells, it was presumed that a deficiency of Dicer and subsequent loss of miRNA maturation would accelerate Myc-induced lymphoma development. We report here that, surprisingly, a haploinsufficiency of Dicer in B cells failed to promote B-cell malignancy or accelerate Myc-induced B-cell lymphomagenesis in mice. Moreover, deletion of Dicer in B cells of CD19-cre(+)/Emicro-myc mice significantly inhibited lymphomagenesis, and all lymphomas that did arise in these mice lacked functional Cre expression and retained at least one functional Dicer allele. Uncharacteristically, the lymphomas that frequently developed in the CD19-cre(+)/Dicer(fl/fl)/Emicro-myc mice were of very early precursor B-cell origin, a stage of B-cell development prior to Cre expression. Therefore, loss of Dicer function was not advantageous for lymphomagenesis, but rather, Dicer ablation was strongly selected against during Myc-induced B-cell lymphoma development. Moreover, deletion of Dicer in established B-cell lymphomas resulted in apoptosis, revealing that Dicer is required for B-cell lymphoma survival. Thus, Dicer does not function as a haploinsufficient tumor suppressor in B cells and is required for B-cell lymphoma development and survival.


Identifying Patients With Inflammatory Bowel Diseases at High vs Low Risk of Complications.
People with Crohn's disease and ulcerative colitis have varying presentations and clinical consequences of their disease. Patients commonly ask about their prognosis, and what this diagnosis means for them. They are asking their clinicians to predict the future. The importance of predicting the course of any disease is to guide patient expectations and to guide treatment decisions. In the past decade the strategy of inflammatory bowel disease (IBD) treatment has shifted to treat patients earlier in the course of their disease, before irreversible damage occurs. Treatment approaches for disease categorized as mild, moderate or severe has most often been based on a current assessment of symptoms or disease activity without including a longitudinal assessment of a patient's disease course including past disease complications and surgeries. While a patient's current disease activity most typically drives these treatment decisions, optimally, treatment decisions would be made accounting for past disease activity and complications and the predicted future disease course. When developing a treatment plan for an individual patient, the immediate goal is to treat the current disease activity for relief of symptoms, and the long-term goal is to prevent progression of their disease due to complications. Since not all patients will progress to a complicated disease course, it is important to be able to select the right patients for the right therapy. Therefore, developing methods of stratifying patients into low-risk versus high-risk of complications will be an important aspect of treating IBD now and in the future.


cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection.
Interferon γ-inducible protein 16 (IFI16) and cGMP-AMP synthase (cGAS) have both been proposed to detect herpesviral DNA directly in herpes simplex virus (HSV)-infected cells and initiate interferon regulatory factor-3 signaling, but it has been unclear how two DNA sensors could both be required for this response. We therefore investigated their relative roles in human foreskin fibroblasts (HFFs) infected with HSV or transfected with plasmid DNA. siRNA depletion studies showed that both are required for the production of IFN in infected HFFs. We found that cGAS shows low production of cGMP-AMP in infected cells, but instead cGAS is partially nuclear in normal human fibroblasts and keratinocytes, interacts with IFI16 in fibroblasts, and promotes the stability of IFI16. IFI16 is associated with viral DNA and targets to viral genome complexes, consistent with it interacting directly with viral DNA. Our results demonstrate that IFI16 and cGAS cooperate in a novel way to sense nuclear herpesviral DNA and initiate innate signaling.


Tracking progress towards the Millennium Development Goals: reaching consensus on child mortality levels and trends.
The increased attention to tracking progress towards the Millennium Development Goals (MDG), including Goal 4 of reducing child mortality, has drawn attention to a number of interrelated technical, operational and political challenges and to the underlying weaknesses of country health information systems upon which reliable monitoring depends. Assessments of child mortality published in 2005, for almost all low-income countries, are based on an extrapolation of the trends observed during the 1990s, rather than on the empirical data for more recent years. The validity of the extrapolation depends on the quality and quantity of the data used, and many countries lack suitable data. In the long run, it is hoped that vital registration or sample registration systems will be established to monitor vital events in a sustainable way. However, in the short run, tracking child mortality in high-mortality countries will continue to rely on household surveys and extrapolations of historical trends. This will require more collaborative efforts both to collect data through initiatives to strengthen health information systems at the country level, and to harmonize the estimation process. The latter objective requires the continued activity of a coordinating group of international agencies and academics that aims to produce transparent estimates -- through the consistent application of an agreed-upon methodology --for monitoring at the international level.


Metachronous skeletal osteosarcoma in patients treated with adjuvant and neoadjuvant chemotherapy for nonmetastatic osteosarcoma.
The prognosis for patients who develop metachronous skeletal osteosarcoma (OS) has been considered grave compared with that for patients with relapse limited to the lungs. We investigated the incidence and outcome of metachronous skeletal OS after initial treatment of the primary tumor. Twenty-three (median age 18.7 years) of 426 patients with nonmetastatic, high-grade primary OS treated at Memorial Sloan-Kettering Cancer Center (New York, NY) between February 1973 and May 2000 developed metachronous skeletal OS. Initial therapy included combination chemotherapy and surgery. Treatment of subsequent relapses consisted of chemotherapy or radiation alone or surgery with or without additional individualized chemotherapy. The median time from the diagnosis of primary OS to the development of metachronous OS was 1.4 years (range, 0.2 to 11.3 years). Median survival was 1.5 years (95% confidence interval [CI], 0.8 to 6.9 years). Two- and 5-year postmetachronous overall survival was 43.5% (95% CI, 23.2% to 63.7%) and 33% (95% CI, 13% to 53%), respectively. At last follow-up (range, 0.1 to 12.8 years), five (30.4%) patients were alive with no evidence of disease (range, 1.7 to 12.8 years; median, 4.4 years). For 11 patients who developed metachronous OS 24 months or more from initial diagnosis, 5-year postmetachronous survival rate for patients receiving combined modality versus monotherapy was 83% (95% CI, 54% to 100%) and 40% (95% CI, 0% to 83%), respectively. In a small subset of patients who developed late metachronous OS, combined-modality therapy with surgery and aggressive chemotherapy may result in long-term postmetachronous survival. This implies that principles used in treatment of primary OS may be applied to patients with late metachronous skeletal OS.


Two prophylactic medication approaches in addition to a pain control regimen for early medical abortion < 63 days' gestation with mifepristone and misoprostol: study protocol for a randomized, controlled trial.
Pain is often cited as one of the worst features of medical abortion. Further, inadequate pain management may motivate some women to seek unnecessary clinical care. There is a need to identify effective methods for pain control in this setting. We propose a randomized, placebo-controlled trial. 576 participants (288 nulliparous; 288 parous) from study sites in Nepal, South Africa and Vietnam will be randomly allocated to one of three treatments: (1) ibuprofen 400 mg PO and metoclopramide 10 mg PO; (2) tramadol 50 mg PO and a placebo; or (3) two placebo pills, to be taken immediately before misoprostol and repeated once four hours later. All women will be provided with supplementary analgesia for use as needed during the medical abortion. We hypothesize that women receiving prophylactic analgesia will report lower maximal pain scores in the first 8 h following misoprostol administration compared to women receiving placebos for medical abortion through 63 days' gestation. Our primary objective is to determine whether prophylactic administration of ibuprofen and metoclopramide or tramadol provides superior pain relief compared to analgesia administration after pain begins, measured during the first eight hours after misoprostol administration. Secondary objectives include identifying covariates associated with higher reported pain scores; determining any impact of the study medicines on medical abortion success; and, qualitatively exploring women's physical experiences of medical abortion, especially related to pain, and how can they be improved. Data sources include medical records, participant symptom diaries and interview data obtained on the day of enrollment, during the medical abortion, and at follow-up. Participants will be contacted via telephone on day 3 and return for follow-up will occur approximately 14 days after mifepristone, concluding study participation. A subset of 42 women will also be invited to undergo in-depth qualitative interviews following study completion. Although pain is one of the most common side effects encountered with medical abortion, little is known about optimal pain management for this process. This multi-arm trial design offers an efficient approach to evaluating two prophylactic pain management regimens compared to use of pain medication as needed. ACTRN12613000017729 (Prospectively registered 8/1/2013).


Production and characterization of monoclonal antibodies specific to lactotriaosylceramide.
We have established hybridoma cell lines producing monoclonal antibodies (mAbs) directed to N-acetylglucosaminylβ1-3galactose (GlcNAcβ1-3Gal) residue by immunizing BALB/c mice with lactotriaosylceramide (Lc(3)Cer). These obtained hybridoma cells, specific to Lc(3)Cer, were dual immunoglobulin (Ig)-producing cells which secreted both IgM and IgG molecules as antibodies. The established mAbs are able to react with not only Lc(3)Cer but also GlcNAcβ1-3-terminal glycosphingolipids (GSLs) despite branching or lactosamine chain lengths and human transferrin with terminal GlcNAc residues. Comparison of the variable regions of the cloned IgM and IgG by reversed transcription-polymerase chain reaction analysis confirmed that the variable regions determine the specificity, the other amino acids are conserved, and these mAbs are encoded by J558 and Vκ-21family genes. Furthermore, we have analyzed the expression of GSLs with GlcNAcβ1-3 epitope in acute leukemia cell lines and mouse fetal tissues using these mAbs, in which antigens were distributed comparatively. These mAbs are useful for studying the precise distribution of GlcNAcβ1-3Gal-terminating GSL expression in tissues as well as for detecting GSLs carrying terminal GlcNAcβ1-3Gal carbohydrate structure.


The Glasgow Norms: Ratings of 5,500 words on nine scales.
The Glasgow Norms are a set of normative ratings for 5,553 English words on nine psycholinguistic dimensions: arousal, valence, dominance, concreteness, imageability, familiarity, age of acquisition, semantic size, and gender association. The Glasgow Norms are unique in several respects. First, the corpus itself is relatively large, while simultaneously providing norms across a substantial number of lexical dimensions. Second, for any given subset of words, the same participants provided ratings across all nine dimensions (33 participants/word, on average). Third, two novel dimensions-semantic size and gender association-are included. Finally, the corpus contains a set of 379 ambiguous words that are presented either alone (e.g., toast) or with information that selects an alternative sense (e.g., toast (bread), toast (speech)). The relationships between the dimensions of the Glasgow Norms were initially investigated by assessing their correlations. In addition, a principal component analysis revealed four main factors, accounting for 82% of the variance (Visualization, Emotion, Salience, and Exposure). The validity of the Glasgow Norms was established via comparisons of our ratings to 18 different sets of current psycholinguistic norms. The dimension of size was tested with megastudy data, confirming findings from past studies that have explicitly examined this variable. Alternative senses of ambiguous words (i.e., disambiguated forms), when discordant on a given dimension, seemingly led to appropriately distinct ratings. Informal comparisons between the ratings of ambiguous words and of their alternative senses showed different patterns that likely depended on several factors (the number of senses, their relative strengths, and the rating scales themselves). Overall, the Glasgow Norms provide a valuable resource-in particular, for researchers investigating the role of word recognition in language comprehension.


Merlin, a "magic" linker between extracellular cues and intracellular signaling pathways that regulate cell motility, proliferation, and survival.
Genetic alterations of neurofibromatosis type 2 (NF2) gene lead to the development of schwannomas, meningiomas, and ependymomas. Mutations of NF2 gene were also found in thyroid cancer, mesothelioma, and melanoma, suggesting that it functions as a tumor suppressor in a wide spectrum of cells. The product of NF2 gene is merlin (moesin-ezrin-radixin-like protein), a member of the Band 4.1 superfamily proteins. Merlin shares significant sequence homology with the ERM (Ezrin-Radixin-Moesin) family proteins and serves as a linker between transmembrane proteins and the actin-cytoskeleton. Merlin is a multifunctional protein and involved in integrating and regulating the extracellular cues and intracellular signaling pathways that control cell fate, shape, proliferation, survival, and motility. Recent studies showed that merlin regulates the cell-cell and cell-matrix adhesions and functions of the cell surface adhesion/extracellular matrix receptors including CD44 and that merlin and CD44 antagonize each other's function and work upstream of the mammalian Hippo signaling pathway. Furthermore, merlin plays important roles in stabilizing the contact inhibition of proliferation and in regulating activities of several receptor tyrosine kinases. Accumulating data also suggested an emerging role of merlin as a negative regulator of growth and progression of several non-NF2 associated cancer types. Together, these recent advances have improved our basic understanding about merlin function, its regulation, and the major signaling pathways regulated by merlin and provided the foundation for future translation of these findings into the clinic for patients bearing the cancers in which merlin function and/or its downstream signaling pathways are impaired or altered.


Group belongingness and procedural justice: social inclusion and exclusion by peers affects the psychology of voice.
The authors focus on the relation between group membership and procedural justice. They argue that whether people are socially included or excluded by their peers influences their reactions to unrelated experiences of procedural justice. Findings from 2 experiments corroborate the prediction that reactions to voice as opposed to no-voice procedures are affected more strongly when people are included in a group than when they are excluded from a group. These findings are extended with a 3rd experiment that shows that people who generally experience higher levels of inclusion in their lives respond more strongly to voice as opposed to no-voice procedures. It is concluded that people's reactions to procedural justice are moderated by people's level of inclusion in social groups.


Effects of recombinant human hemoglobin on motor functions of the opossum esophagus.
Chemically altered hemoglobins are being investigated as blood substitutes. They may affect numerous biological processes since free hemoglobin binds nitric oxide (NO). Nitric oxide is a neural mediator of relaxation of the lower esophageal sphincter (LES) and esophageal peristalsis. We hypothesize that recombinant human hemoglobin (rHb1.1) alters esophageal motor function by scavenging NO. Contraction of transverse muscle strips from the opossum esophagus and LES was monitored. Transmembrane potential differences of circular smooth muscle from the esophagus were recorded using glass microelectrodes. Intrinsic esophageal nerves were stimulated electrically. Esophageal manometries were performed with a low-compliance perfused-catheter system. The activity of the enzyme NO synthase was determined with the citrulline assay. Recombinant hemoglobin diminished nerve-induced relaxation of LES muscle but did not alter LES tone. Circular esophageal muscle responded to nerve stimulation with an inhibitory junction potential and a mechanical off response. Recombinant hemoglobin diminished the inhibitory junction potential and shortened the latency of the off response. It increased the velocity of esophageal peristalsis, decreased the amplitudes of these contractions and diminished LES relaxation. Cyanomethemoglobin had little effect on nerve- or swallow-induced responses. Hemoglobin did not inhibit the activity of NO synthase. Recombinant human hemoglobin appears to alter esophageal motor function by scavenging NO.


Increased Velocity Storage in Subjects with Meniere's Disease.
Velocity storage mechanism is a multisensory rotation estimator; it compensates for errors in the information provided by the peripheral vestibular organs by means of an adjustment in the duration of the vestibular signal. The aim of this study was to determine the activity of the velocity storage mechanism in the presence of a labyrinthine disorder, using galvanic vestibular stimulation to cause direct activation of the vestibular afferent neurons. Forty-one subjects with definite Meniere's disease (MD) and 36 healthy volunteers were evaluated using a 20-s galvanic vestibular stimulation. We found a post-stimulus nystagmus overshoot exclusively in subjects with MD (47% in subjects with unilateral disease and 82% in subjects with bilateral disease), but no overshoot in healthy subjects. Because post-stimulus nystagmus overshoot is caused by the velocity storage mechanism, this finding suggests an increase in the velocity storage in subjects with a labyrinthine disease.


Protein trans-splicing and characterization of a split family B-type DNA polymerase from the hyperthermophilic archaeal parasite Nanoarchaeum equitans.
Nanoarchaeum equitans family B-type DNA polymerase (Neq DNA polymerase) is encoded by two separate genes, the large gene coding for the N-terminal part (Neq L) of Neq DNA polymerase and the small gene coding for the C-terminal part (Neq S), including a split mini-intein sequence. The two Neq DNA polymerase genes were cloned and expressed in Escherichia coli individually, together (for the Neq C), and as a genetically protein splicing-processed form (Neq P). The protein trans-spliced Neq C was obtained using the heating step at 80 degrees C after the co-expression of the two genes. The protein trans-splicing of the N-terminal and C-terminal parts of Neq DNA polymerase was examined in vitro using the purified Neq L and Neq S. The trans-splicing was influenced mainly by temperature, and occurred only at temperatures above 50 degrees C. The trans-splicing reaction was inhibited in the presence of zinc. Neq S has no catalytic activity and Neq L has lower 3'-->5' exonuclease activity; whereas Neq C and Neq P have polymerase and 3'-->5' exonuclease activities, indicating that both Neq L and Neq S are needed to form the active DNA polymerase that possesses higher proofreading activity. The genetically protein splicing-processed Neq P showed the same properties as the protein trans-spliced Neq C. Our results are the first evidence to show experimentally that natural protein trans-splicing occurs in an archaeal protein, a thermostable protein, and a family B-type DNA polymerase.


Selective processing of eating-, shape-, and weight-related words in persons with bulimia nervosa.
The Stroop color-naming task was used to investigate selective information processing in people with bulimia nervosa. Three cards were used: a target card consisting of words related to eating, weight, and shape; a control word card; and the standard conflicting-color card. Thirty-six patients with bulimia nervosa were compared with a group of age-matched female controls. It was found that the amount of disruption caused to color naming by the target card was significantly greater in the bulimia nervosa group than in the female control group, whereas that caused by the color card was similar in the two groups. The Stroop color-naming task may be a useful objective measure of one aspect of the cognitive disturbance of patients with bulimia nervosa.


Spirituality and spiritual caring: nurses' perspectives and practice in palliative and acute care environments.
Identify and compare spiritual caring practice by palliative care and acute care registered nurses (RNs), determine any correlation between nurses' spiritual perspective and their spiritual caring, and to investigate perceived barriers to spiritual caring. Over the past decade there has been growing interest in spiritual caring in nursing. Professional nursing bodies have proposed spirituality and spiritual caring as an integral component of holistic nursing. Cross sectional study. Palliative care RNs (n = 42) from one community palliative care service and three hospices, and acute care RNs (n = 50) from three major acute care hospitals all in metropolitan Sydney, Australia completed a research questionnaire. Two validated tools and a demographic survey were used to collect data. These tools measured spiritual perspectives including saliency of personal spirituality, spiritual views and engagement in spiritually-related activities; and spiritual practice including assessment, interventions and barriers to spiritual caring. Data were collected over a six-month period and interpreted with both descriptive and analytical statistics. Significant differences were seen between the two RN groups. Palliative care RNs' spiritual caring practice was more advanced and their spiritual perspective stronger; this relationship was positive. Both RN groups identified 'insufficient time' as the most common barrier to spiritual caring practice; 'patient privacy' was also common for acute care RNs. Palliative care RNs' spiritual perspectives influenced their spiritual caring. These nurses were older and more career-advanced than the acute care RNs, which may explain the differences observed. Acute care RNs may benefit from additional support for their spiritual caring and to address perceived barriers. The development of nurses' spiritual perspective early in their preparation for practice, and the articulation and documentation of spiritual caring may enhance their spiritual caring practice. Further research on barriers to spiritual caring in acute care nursing environments is recommended.


Responsiveness of visual analogue and McGill pain scale measures.
To compare the responsiveness of the McGill Pain Questionnaire with the Visual Analogue Scale (VAS). A repeated measures 2-group design was used, with subjects divided into "improved" and "non-improved" groups. The external criterion to identify improved and non-improved patients was a 7-point global perceived effect scale. Seventy-five patients with low back pain who had participated in a randomized controlled trial of postsurgical rehabilitation were included in the study. All patients completed both a VAS and McGill pain scale to describe their pain over the last 24 hours and a separate VAS to describe their current pain. Responsiveness was evaluated by using receiver-operating characteristic curves, with the analysis repeated for a range of cut-off points on the global perceived effect scale. Secondary analyses of responsiveness were provided by the t value for independent change scores and Spearman's rank correlation coefficient (rho). The study confirmed the results of earlier studies in finding that the VAS was less responsive to clinical change when used to rate current pain in comparison with pain over the last 24 hours. The study found that the VAS was more responsive than the McGill Pain Questionnaire when both instruments were used to rate pain over the last 24 hours. The results of this study suggest that the VAS may be a better tool than the McGill Pain Questionnaire for measuring pain in clinical trials and clinical practice.


Immobilization of selenite via two parallel pathways during in situ bioremediation.
It is widely understood that selenite can be biologically reduced to elemental selenium. Limited studies have shown that selenite can also be immobilized through abiotic precipitation with sulfide, a product of biological sulfate reduction. We demonstrate that both pathways significantly contribute to selenite immobilization in a microfluidic flow cell having a transverse mixing zone between propionate and selenite that mimics the reaction zone along the margins of a selenite plume undergoing bioremediation in the presence of background sulfate. The experiment showed that red particles of amorphous elemental selenium precipitate on the selenite-rich side of the mixing zone, while long crystals of selenium sulfides precipitate on the propionate-rich side of the mixing zone. We developed a continuum-scale reactive transport model that includes both pathways. The simulated results are consistent with the experimental results, and indicate that spatial segregation of the two selenium precipitates is due to the segregation of the more thermodynamic favorable selenite reduction and the less thermodynamically favorable sulfate reduction. The improved understanding of selenite immobilization and the improved model can help to better design in situ bioremediation processes for groundwater contaminated by selenite or other contaminants (e.g., uranium(IV)) that can be immobilized via similar pathways.


Practice patterns and predictors of followup imaging after a negative bone scan in men with castration resistant prostate cancer: results from the SEARCH database.
We investigated imaging practice patterns in men with nonmetastatic (M0) castration resistant prostate cancer. We analyzed data on 247 patients with documented M0 CRPC from the SEARCH database. Patients were selected regardless of primary treatment modality and all had a negative bone scan after a castration resistant prostate cancer diagnosis. Cox models were used to test associations of time to a second imaging test with several demographic and clinical factors. During a median followup of 29.0 months (IQR 12.9-43.5) after a post-castration resistant prostate cancer bone scan was negative, 190 patients (77%) underwent a second imaging test. On univariable analysis patients with higher prostate specific antigen (HR 1.13, p = 0.016), shorter prostate specific antigen doubling time (HR 0.79, p < 0.001) and faster prostate specific antigen velocity (HR 1.01, p < 0.001) were more likely to undergo a second imaging test. Treatment center was also a significant predictor of a second imaging test (p = 0.010). No other factor was a significant predictor. Results were similar on multivariable analysis. It was estimated that approximately 20% of men with a prostate specific antigen doubling time of less than 3 months did not undergo an imaging test in the first year after a post-castration resistant prostate cancer negative bone scan. However, 50% of patients with prostate specific antigen doubling time 15 months or greater underwent a second imaging test in the first year. Clinicians use some known predictors of positive imaging tests to determine which patients with M0 castration resistant prostate cancer undergo a second imaging test . However, there may be under imaging in those at high risk and over imaging in those at low risk. Further studies are needed to identify risk factors for metastasis and form clear imaging guidelines in patients with M0 castration resistant prostate cancer.


Pulsating Tonsil Due to Medial Displacement of the Internal Carotid Artery.
BACKGROUND The internal carotid artery (ICA) is about 2.5 cm away from the tonsils. It has no branches in the cervical portion. ICA anomalies of the neck zone may result in a massive arterial bleeding during pharynx and neck surgery. Due to these anomalies, the surgeon must be aware of this risk during tonsillectomy, adenoidectomy, and pharyngeal operations. CASE REPORT A 23-year-old woman who was discovered to have an acute S curling-type anomaly of the ICA in contact with the lateral border of the right tonsil during a work-up for a tonsillectomy. This anomaly was incidentally discovered via computed tomography (CT) with contrast. In re-evaluating the course of treatment, we found a severe S-shape kink on the right side, bringing it close to the right tonsil by approximately 2 mm, and putting it at severe risk of injury during a simple tonsillectomy, possibly exposing the patient to serious bleeding. Partial tonsillectomy was performed for this patient with the aim to preserve and not expose the internal carotid artery. Pulsation of right tonsil was recorded. The patient made an uneventful postoperative recovery. CONCLUSIONS Undetected ICA anomaly variation can lead to fatal bleeding during a simple procedure, like tonsillectomy. We recommend vigilance during tonsillectomy if one is using a hot dissection method versus a cold dissection method, which may allow for detection of a perioperative ICA anomaly. Tonsillectomy performed by a junior resident should be under direct supervision, particularly if the hot dissection method is used.


The chiropractic profession in Denmark 2010-2014: a descriptive report.
The chiropractic profession has been well established in Denmark for several decades with state authorization, partial reimbursement by the state and a formal academic education. Biennial systematic data collections among all chiropractors and clinics have been performed since 2010 in order to provide exact information on the profession to The Danish Chiropractic Association (DCA). It is the aim of this study to outline the major characteristics and developments of the chiropractic profession in Denmark to make this information accessible to other stakeholders, domestic as well as foreign. Using contact information from the DCA, two questionnaires were distributed electronically to all individual members of the association actively working as chiropractors and all clinics respectively in 2010, 2012 and 2014. The questions asked were developed for this specific survey. Response rates varied between 59 and 78 % for the clinic questionnaires and 75 to 86 % for the individual questionnaires. Almost half the Danish chiropractors were educated in Denmark and a small majority was female. The average Danish chiropractor of 2014 was 44 years old, graduated 17 years earlier, and worked full time in a primary care clinic with at least one colleague. Half the chiropractors spent more than 20 h a year on continued professional development. Danish chiropractic clinics had a median of 3 treatment rooms, most had digital X-ray equipment, around 6 out of 10 had exercise facilities, and 1 out of 4 employed a physiotherapist. Three out of 4 clinics employed a secretary, too. The average duration of a consultation was 40 min for a new patient and 13 min for a follow-up consultation. Virtually all Danish chiropractors working in the primary sector made use of manipulation as one of their treatment modalities. This is the first study to describe the state and latest development of the chiropractic profession in Denmark using repeated surveys. Displaying various characteristics of both clinics and individual chiropractors, the image emerging is one of a stable profession where rapid or drastic changes are not taking place over short intervals of time.


Acid-induced esophageal shortening in humans: a cause of hiatus hernia?
Hiatus hernia and gastroesophageal reflux disease commonly coexist, and there is pathophysiological evidence that the presence of a hiatus hernia contributes to abnormal acid reflux. However, the cause of hiatus hernia remains unclear. In an animal model, it has been shown that acute acid injury to the esophagus results in esophageal shortening, raising the possibility that reflux esophagitis per se can contribute to the formation of hiatus hernia by inducing esophageal shortening. To determine whether luminal acid produces esophageal shortening in humans. Twelve volunteers were each studied on two occasions, one week apart, in a double-blind, crossover trial. The location of the lower esophageal sphincter (LES), as well as the LES resting pressure and axial length were determined at baseline and then again after 20 min of either acid or saline perfusion. Acid perfusion did not induce significant changes in resting LES pressure but resulted in proximal migration of the LES (ie, esophageal shortening) by an average of 0.5 cm, with the largest proximal migration being 1.8 cm. In contrast, saline perfusion resulted in slight distal migration of the LES (ie, esophageal lengthening). Intraluminal acid perfusion causes longitudinal axis shortening of the esophagus and suggests that gastroesophageal acid reflux may contribute to the cause of hiatus hernia.


Caspase-independent cell death is involved in the negative effect of EGF receptor inhibitors on cisplatin in non-small cell lung cancer cells.
Results of multiple clinical trials suggest that EGF receptor (EGFR) tyrosine kinase inhibitors (TKI) exhibit negative effects on platinum-based chemotherapy in patients with lung cancer with wild-type (WT) EGFR, but the underlying molecular mechanisms are still uncertain. Studies that identify the mechanism of how TKIs negatively affect patients with WT EGFR are important for future development of effective strategies to target lung cancer. Thus, we returned to in vitro study to investigate and determine a possible explanation for this phenomenon. We investigated the effects of TKIs and cisplatin on caspase-independent cell death (CID) and the role of CID in the efficacy of each drug and the combination. Furthermore, we studied the mechanism by which EGFR signaling pathway is involved in CID. Finally, on the basis of the identified mechanism, we tested the combinational effects of cisplatin plus suberoylanilide hydroxamic acid (SAHA) or erastin on CID. We found that gefitinib inhibited cisplatin-induced CID but not caspase-dependent apoptotic cell death. In WT EGFR cells, gefitinib not only inhibited CID but also failed to induce apoptosis, therefore compromising the efficacy of cisplatin. Inhibition of EGFR-ERK/AKT by gefitinib activates FOXO3a, which in turn reduces reactive oxygen species (ROS) and ROS-mediated CID. To overcome this, we showed that SAHA and erastin, the inducers of ROS-mediated CID, strongly enhanced the effect of cisplatin in WT EGFR cells. TKI-mediated inhibition of CID plays an important role in the efficacy of chemotherapy. Moreover, FOXO3a is a key factor in the negative effects of TKI by eliminating cisplatin-induced ROS.


Enhanced avidity from a multivalent fluorescent antimicrobial peptide enables pathogen detection in a human lung model.
Rapid in situ detection of pathogens coupled with high resolution imaging in the distal human lung has the potential to provide new insights and diagnostic utility in patients in whom pneumonia is suspected. We have previously described an antimicrobial peptide (AMP) Ubiquicidin (fragment UBI29-41) labelled with an environmentally sensitive fluorophore that optically detected bacteria in vitro but not ex vivo. Here, we describe further chemical development of this compound and demonstrate that altering the secondary structure of the AMP to generate a tri-branched dendrimeric scaffold provides enhanced signal in vitro and ex vivo and consequently allows the rapid detection of pathogens in situ in an explanted human lung. This compound (NBD-UBIdend) demonstrates bacterial labelling specificity for a broad panel of pathogenic bacteria and Aspergillus fumigatus. NBD-UBIdend demonstrated high signal-to-noise fluorescence amplification upon target engagement, did not label host mammalian cells and was non-toxic and chemically robust within the inflamed biological environment. Intrapulmonary delivery of NBD-UBIdend, coupled with optical endomicroscopy demonstrated real-time, in situ detection of bacteria in explanted whole human Cystic Fibrosis lungs.


Vaccination coverage in healthcare workers: a multicenter cross-sectional study in Italy.
In recent years, a phenomenon known as "vaccine hesitancy" has spread throughout the world, even among health workers, determining a reduction in vaccination coverage (VC).A study aimed at evaluating VC among healthcare workers (HCWs) in 10 Italian cities (L'Aquila, Genoa, Milan, Palermo, Sassari, Catanzaro, Ferrara, Catania, Naples, Messina) was performed. Annex 3 of the Presidential Decree n. 445 of 28 December 2000 was used to collect information on the vaccination status of HCWs. The mean and standard deviation (SD) were calculated with regard to the quantitative variable (age), while absolute and relative frequencies were obtained for categorical data (sex, professional profile, working sector, vaccination status). The connection between VC and the categorical variables was evaluated by chi-square method (statistical significance at p < 0.05). The statistical analyses were performed by SPSS and Stata software. A total of 3,454 HCWs participated in the project: 1,236 males and 2,218 females.The sample comprised: physicians (26.9%), trainee physicians (16.1%), nurses (17.2%) and other professional categories (9.8%). Low VC was generally recorded. Higher VC was found with regard to polio, hepatitis B, tetanus and diphtheria, while coverage was very low for measles, mumps, rubella, pertussis, chickenpox and influenza (20-30%). This study revealed low VC rates among HCWs for all the vaccinations. Measures to increase VC are therefore necessary in order to prevent HCWs from becoming a source of transmission of infections with high morbidity and/or mortality both within hospitals and outside.


A systematic review of the behaviours associated with depression in people with severe-profound intellectual disability.
The assessment of depression in people with severe to profound intellectual disability (severe-profound ID) is challenging, primarily due to inability to report internal states such as mood, feelings of worthlessness and suicidal ideation. This group also commonly presents with challenging behaviours (e.g. aggression and self-injury) with debate about whether these behaviours should be considered 'depressive equivalents' or are sensitive for, but not specific to, depression in severe-profound ID. We conducted a systematic review exploring behaviours associated with depression and low mood in individuals with severe-profound ID. The review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (2009) guidelines. Three electronic databases were searched (Embase, PsycINFO and Ovid MEDLINE), and 13 studies were included and rated for quality. Few studies were rated as having high methodological quality. Behaviours captured by standard diagnostic schemes for depression (e.g. Diagnostic and Statistical Manual of Mental Disorders and International Classification of Diseases) showed a relationship with depression in severe-profound ID, including the two core symptoms (depressed affect and anhedonia), as well as irritability, sleep disturbance, psychomotor agitation, reduced appetite and fatigue. Challenging behaviours such as aggression, self-injury, temper tantrums, screaming and disruptive behaviour were associated with depression. Challenging behaviours show a robust relationship with depression. Whilst these behaviours may suggest an underlying depression, study limitations warrant caution in labelling them as 'depressive equivalents'. These limitations include not controlling for potential confounds (autism, other affective disorders and pain) and bias associated with comparing depressed/non-depressed groups on the same behavioural criteria used to initially diagnose and separate these groups. Future studies that use depressive measures designed for ID populations, which control for confounds and which explore low mood irrespective of psychiatric diagnosis, are warranted to better delineate the behaviours associated with depression in this population (PROSPERO 2018: CRD42018103244).


Prevalence and characteristics of fetal alcohol spectrum disorders.
To determine the prevalence and characteristics of fetal alcohol spectrum disorders (FASD) among first grade students (6- to 7-year-olds) in a representative Midwestern US community. From a consented sample of 70.5% of all first graders enrolled in public and private schools, an oversample of small children (≤ 25th percentile on height, weight, and head circumference) and randomly selected control candidates were examined for physical growth, development, dysmorphology, cognition, and behavior. The children's mothers were interviewed for maternal risk. Total dysmorphology scores differentiate significantly fetal alcohol syndrome (FAS) and partial FAS (PFAS) from one another and from unexposed controls. Alcohol-related neurodevelopmental disorder (ARND) is not as clearly differentiated from controls. Children who had FASD performed, on average, significantly worse on 7 cognitive and behavioral tests and measures. The most predictive maternal risk variables in this community are late recognition of pregnancy, quantity of alcoholic drinks consumed 3 months before pregnancy, and quantity of drinking reported for the index child's father. From the final multidisciplinary case findings, 3 techniques were used to estimate prevalence. FAS in this community likely ranges from 6 to 9 per 1000 children (midpoint, 7.5), PFAS from 11 to 17 per 1000 children (midpoint, 14), and the total rate of FASD is estimated at 24 to 48 per 1000 children, or 2.4% to 4.8% (midpoint, 3.6%). Children who have FASD are more prevalent among first graders in this Midwestern city than predicted by previous, popular estimates.


TSLP promotes influenza-specific CD8+ T-cell responses by augmenting local inflammatory dendritic cell function.
Thymic stromal lymphopoietin (TSLP) is a mucosal tissue-associated cytokine that has been widely studied in the context of T helper type 2 (Th2)-driven inflammatory disorders. Although TSLP is also produced upon viral infection in vitro, the role of TSLP in antiviral immunity is unknown. In this study we report a novel role for TSLP in promoting viral clearance and virus-specific CD8+ T-cell responses during influenza A infection. Comparing the immune responses of wild-type and TSLP receptor (TSLPR)-deficient mice, we show that TSLP was required for the expansion and activation of virus-specific effector CD8+ T cells in the lung, but not the lymph node. The mechanism involved TSLPR signaling on newly recruited CD11b+ inflammatory dendritic cells (DCs) that acted to enhance interleukin-15 production and expression of the costimulatory molecule CD70. Taken together, these data highlight the pleiotropic activities of TSLP and provide evidence for its beneficial role in antiviral immunity.


Thermal, physiological and perceptual strain mediate alterations in match-play tennis under heat stress.
This study compared the thermal, physiological and perceptual responses associated with match-play tennis in HOT (∼34°C wet-bulb-globe temperature (WBGT)) and COOL (∼19°C WBGT) conditions, along with the accompanying alterations in match characteristics. 12 male tennis players undertook two matches for an effective playing time (ie, ball in play) of 20 min, corresponding to ∼119 and ∼102 min of play in HOT and COOL conditions, respectively. Rectal and skin temperatures, heart rate, subjective ratings of thermal comfort, thermal sensation and perceived exertion were recorded, along with match characteristics. End-match rectal temperature increased to a greater extent in the HOT (∼39.4°C) compared with the COOL (∼38.7°C) condition (p<0.05). Thigh skin temperature was higher throughout the HOT match (p<0.001). Heart rate, thermal comfort, thermal sensation and perceived exertion were also higher during the HOT match (p<0.001). Total playing time was longer in the HOT compared with the COOL match (p<0.05). Point duration (∼7.1 s) was similar between conditions, while the time between points was ∼10 s longer in the HOT relative to the COOL match (p<0.05). This led to a ∼3.4% lower effective playing percentage in the heat (p<0.05). Although several thermal, physiological and perceptual variables were individually correlated to the adjustments in time between points and effective playing percentage, thermal sensation was the only predictor variable associated with both adjustments (p<0.005). These adjustments in match-play tennis characteristics under severe heat stress appear to represent a behavioural strategy adopted to minimise or offset the sensation of environmental conditions being rated as difficult.


Squamous Cell Tumors Recruit γδ T Cells Producing either IL17 or IFNγ Depending on the Tumor Stage.
The identification of reciprocal interactions between tumor-infiltrating immune cells and the microenviroment may help us understand mechanisms of tumor growth inhibition or progression. We have assessed the frequencies of tumor-infiltrating and circulating γδ T cells and regulatory T cells (Treg) from 47 patients with squamous cell carcinoma (SCC), to determine if they correlated with progression or survival. Vδ1 T cells infiltrated SSC tissue to a greater extent than normal skin, but SCC patients and healthy subjects had similar amounts circulating. However, Vδ2 T cells were present at higher frequencies in circulation than in the tissue of either cancer patients or healthy donors. Tregs were decreased in the peripheral blood of SCC patients, but were significantly increased in the tumor compartment of these patients. Tumor-infiltrating γδ T cells preferentially showed an effector memory phenotype and made either IL17 or IFNγ depending on the tumor stage, whereas circulating γδ T cells of SCC patients preferentially made IFNγ. Different cell types in the tumor microenvironment produced chemokines that could recruit circulating γδ T cells to the tumor site and other cytokines that could reprogram γδ T cells to produce IL17. These findings suggest the possibility that γδ T cells in SCC are recruited from the periphery and their features are then affected by the tumor microenvironment. Elevated frequencies of infiltrating Vδ2 T cells and Tregs differently correlated with early and advanced tumor stages, respectively. Our results provide insights into the functions of tumor-infiltrating γδ T cells and define potential tools for tumor immunotherapy. Cancer Immunol Res; 5(5); 397-407. ©2017 AACR.


Analytical methods for the geometric optics of thermal vision illustrated with four species of pitvipers.
The pitviper facial pit is a pinhole camera-like sensory organ consisting of a flask-shaped cavity divided into two chambers by a suspended membrane. Neurophysiological studies and simplified optical models suggest that facial pits detect thermal radiation and form an image that is combined with visual input in the optic tectum to form a single multispectral image. External pit anatomy varies markedly among taxonomic groups. However, optical function depends on unknown internal anatomy. Therefore, we developed methods for relating anatomy to optical performance. To illustrate, we constructed detailed anatomical models of the internal anatomy of the facial pits of four individuals of four pitviper species using X-ray tomography sections of fresh material. We used these models to define the point spread function, i.e. the distribution of radiation from a point source over the pit membrane, for each species. We then used optical physics, heat transfer physics and computational image processing to define the thermal image formed on the pit membrane for each species. Our computed pit membrane images are consistent with behavioral observations if the sensitivity of membrane receptors equals the most sensitive (ca. 0.001°C) laboratory estimates. Vignetting (variation in optical aperture size with view angle) and differences between body and environmental temperatures can create temperature variation across the membrane that greatly exceeds image temperature contrasts, potentially impairing imaging. Spread functions plotted versus source point azimuth and elevation show distinct patterns that suggest new research directions into the relationships among the optical anatomy, ecology, behavior and sensory neurophysiology of pitvipers.


Arterial stiffness and pulse wave reflection are increased in patients suffering from severe periodontitis.
This single blind cross-sectional study compared the vascular health of subjects suffering from severe chronic periodontitis, severe aggressive periodontitis and periodontal healthy controls by evaluating pulse wave velocity (PWV), augmentation index (AIx) and pulse pressure amplification (PPA). In a total of 158 subjects, 92 suffering from severe periodontitis and 66 matched periodontal healthy controls, PWV, AIx, central and peripheral blood pressure were recorded using an oscillometric device (Arteriograph). Subjects suffering from severe chronic or aggressive periodontitis exhibited significantly higher PWV (p = 0.00004), higher AIx (p = 0.0049) and lower PPA (p = 0.028) than matched periodontal healthy controls. The results of this study confirm the association between periodontal inflammation and increased cardiovascular risk shown by impaired vascular health in case of severe periodontitis. As impaired vascular health is a common finding in patients suffering from severe periodontal disease a concomitant routine cardiovascular evaluation may be advised.


Modulatory effects of propolis samples from Latin America (Brazil, Cuba and Mexico) on cytokine production by human monocytes.
Propolis has been used in folk medicine in different regions of the world including Latin America. Propolis is a resinous mixture of substances collected by honey bees from several botanical sources, and its composition contains a rich chemical variety, depending on the geographical area and plant sources. Our aim was to compare the modulatory effect of propolis samples from three different countries of Latin America (Brazil, Cuba and Mexico) on pro- and anti-inflammatory cytokine production (tumor necrosis factor (TNF)-α and interleukin (IL)-10, respectively) by human monocytes. Cells were incubated with propolis for 18 h at 37°C. Cell viability was assessed by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide method, and cytokine production was determined by ELISA. All samples did not affect monocyte viability. Brazilian propolis stimulated both TNF-α and IL-10 production by monocytes. Cuban propolis stimulated TNF-α and inhibited IL-10 production, while Mexican sample exerted the opposite effect, inhibiting TNF-α and stimulating IL-10 production. The major compounds found in Brazilian, Cuban and Mexican propolis samples were artepillin C, isoflavonoids and pinocembrin, respectively. Brazilian, Cuban and Mexican propolis contained different components that may exert pro- and anti-inflammatory activity depending on concentration, what may provide a novel approach to the development of immunomodulatory drugs containing propolis.


The Management of Staphylococcal Toxic Shock Syndrome. A Case Report.
Staphylococcal toxic shock syndrome (TSS) is most frequently produced by TSS toxin-1 (TSST-1) and Staphylococcal enterotoxin B (SEB), and only rarely by enterotoxins A, C, D, E, and H. Various clinical pictures can occur depending on severity, patient age and immune status of the host. Severe forms, complicated by sepsis, are associated with a death rate of 50-60%. The case of a Caucasian female infant, aged seven weeks, hospitalized with a diffuse skin rash, characterized as allergodermia, who initially developed TSS with axillary intertrigo, is reported. TSS was confirmed according to 2011 CDC criteria, and blood cultures positive for Methicillin-sensitive Staphylococcus aureus (MSSA). Severe development occurred initial, including acidosis, consumption coagulopathy, multiple organ failures (MOF), including impaired liver and kidney function. Central nervous system damage was manifest by seizures. Clinical management included medical supervision by a multidisciplinary team of infectious diseases specialist and intensive care specialist, as well as the initiation of a complex treatment plan to correct hydro electrolytic imbalances and acidosis. This treatment included antibiotic and antifungal therapy, diuretic therapy, immunoglobulins, and local treatment similar to a patient with burns to prevent superinfection of skin and mucous membranes lesions. There was a favourable response to the treatment with resolution of the illness.


Endoplasmic reticulum stress disrupts lysosomal homeostasis and induces blockade of autophagic flux in human trophoblasts.
Pregnancy is a stress factor culminating into mild endoplasmic reticulum (ER) stress, which is necessary for placental development. However, excessive or chronic ER stress in pre-eclamptic placentas leads to placental dysfunction. The precise mechanisms through which excessive ER stress impacts trophoblasts are not well understood. Here, we showed that ER stress reduces the number of lysosomes, resulting in inhibition of autophagic flux in trophoblast cells. ER stress also disrupted the translocation of lysosomes to the surface of trophoblast cells, and inhibited lysosomal exocytosis, whereby the secretion of lysosomal-associated membrane protein 1 (LAMP1) into culture media was significantly attenuated. In addition, we found that serum LAMP1 and beta-galactosidase levels were significantly decreased in pre-eclampsia patients compared to normal pregnant women, potentially indicating lysosomal dysfunction through ER stress in pre-eclamptic placentas. Thus, we demonstrated that excessive ER stress essentially disrupts homeostasis in trophoblasts in conjunction with autophagy inhibition by lysosomal impairment.


Local variation in endoparasite intensities of bank voles (Clethrionomys glareolus) from ecologically similar sites: morphometric and endocrine correlates.
Much interest has centred recently on the role of adaptive trade-offs between the immune system and other components of life history in determining resistance and parasite intensities among hosts. Steroid hormones, particularly glucocorticoids and sex steroids, provide a plausible mechanism for mediating such trade-offs. A basic assumption behind the hypothesis, however, is that steroid activity will generally correlate with reduced resistance and thus greater parasite intensities. Here, we present some findings from a field study of bank voles (Clethrionomys glareolus) in which we have looked at associations between parasite intensities, anatomical and morphometric measures relating to endocrine function and life history variation in three local populations inhabiting similar but mutually isolated woodland habitats. In general, sites with greater parasite intensities were those in which male C. glareolus had significantly larger adrenal glands, testes and seminal vesicles for their age and body size. Females also showed a site difference in adrenal gland weight. Some aspects of site-related parasite intensity were associated with asymmetry in adrenal gland weight and hind foot length, which may have reflected developmental effects on glucocorticoid activity.


Geo-spatial analysis of individual-level needle and syringe coverage in Melbourne, Australia.
Distance to health services is known to be negatively associated with usage and needle and syringe programs (NSPs) for people who inject drugs (PWID) are no different. Australia has a mixture of NSP modalities (primary or secondary fixed-site NSPs), which may present unique barriers to access. In this study, we explore 1) the effect of distance to NSPs on individual-level needle and syringe coverage, and 2) differences in coverage dependent on NSP modality. Using data from 219 PWID in an ongoing cohort study in Melbourne, Australia, we measured the straight-line distance from participants' residence to their nearest primary or secondary fixed-site NSP. We analysed the relationship between geographical distance and coverage via regression analysis. The median distance to any type of NSP was 1872 metres. Regardless of service type, 52% of participants lived within 2 kms of a fixed-site NSP and 87% lived within 5 kms. We found no association between distance to NSPs and syringe coverage or a significant difference in coverage by nearest service type. Our findings suggest that the number and distribution of NSPs in Melbourne, Australia caters adequately for the population of PWID.


Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence.
To evaluate dorsolateral prefrontal cortex (DLPFC) physiology and function simultaneously, 20 medication-free patients with chronic schizophrenia and 25 normal controls underwent three separate xenon Xe 133 inhalation procedures for determination of regional cerebral blood flow (rCBF): first at rest, then while performing an automated version of the Wisconsin Card Sort (WCS), a DLPFC-specific cognitive test, and while performing a simple number-matching (NM) test. During rest, patients had significantly reduced relative, but not absolute, rCBF to DLPFC. During NM, no specific region differentiated patients from controls. During WCS, however, both absolute and relative rCBF to DLPFC significantly distinguished patients from controls. While controls showed a clear increase in DLPFC rCBF, patients did not. The changes were regionally specific, involving only DLPFC. Furthermore, in patients, DLPFC rCBF correlated positively with WCS cognitive performance, suggesting that the better DLPFC was able to function, the better patients could perform. Autonomic arousal measures, the pattern of WCS errors, and results of complementary studies suggest that the DLPFC finding is linked to regionally specific cognitive function and is not a nonspecific epiphenomenon.


Environmental and complexation effects on the structures and spectroscopic signatures of organic pigments relevant to cultural heritage: the case of alizarin and alizarin-Mg(II)/Al(III) complexes.
An integrated computational approach allowed an unbiased analysis of optical and structural properties of alizarin-based pigments, which can be directly compared with experimental results. Madder lake pigments have been modeled by Mg(II)- and Al(III)-coordinated alizarin taking into account solvation and metal-linkage effects, responsible for colour modifications. Moreover, different environmental conditions have been analyzed for free alizarin, showing in all cases semi-quantitative agreement with experimental spectroscopic data (UV-VIS). Our results point out the ability of in silico approaches to unravel the subtle interplay of stereo-electronic, dynamic, and environmental effects in tuning the physico-chemical properties of pigments relevant to cultural heritage.


Positional apoptosis during vertebrate CNS development in the absence of endogenous retinoids.
We have previously shown that quail embryos that develop in the absence of vitamin A have severe defects in their central nervous system. One defect is a completely missing posterior hindbrain. Here we have studied how this comes about by examining cell death using a wholemount technique. In these A- embryos we observe two narrow bands of ectopic apoptosis. One is in the mesenchyme in the region of the first somite and occurs at the 4-6 somite stage, before neural tube closure. The second band follows immediately afterwards and occurs in the neuroepithelium of the presumptive posterior hindbrain at the 6-8 somite stage. Electron microscopy shows that the dying neuroepithelial cells exhibit the characteristics of apoptosis. Rescuing the embryos by injecting retinol before gastrulation completely prevents these apoptotic events. In an effort to identify some of the genes that may be involved in the apoptotic pathway we show that Msx-2 is upregulated in the apoptotic neuroepithelium and thus may be involved, whereas Bmp-4 is not altered and thus presumably not involved. Since these apoptotic event take place at the time of specification of axial identity and segmentation in the mesenchyme and neuroepithelium we conclude that these cells die because they are wrongly specified in terms of their rostrocaudal position, a novel phenomenon which we refer to as positional apoptosis.