Bridging the gap between textbook and maternity patient: a nurse-developed teaching model for first-year medical students.
Providing more opportunities for first-year medical students to interact with patients in clinical settings is a current discussion topic in medical student education reform. Early clinical experience helps students bridge the gap between textbook and patient while observing patient-centered care, and serves as a first step for students to develop the skills needed to work cooperatively as members of a multidisciplinary health care team. The author developed a model to provide perinatal education to first-year medical students, consistent with the concept of interprofessional education. Primarily first-year medical students participated in the nurse-developed education model, a component of a noncredit extracurricular, student-run perinatal program at a Midwestern university medical center. Students were placed at the bedsides of hospitalized women to provide support and education to them during perinatal procedures, labor, childbirth, and cesarean delivery. A total of 350 students participated over a period of 13 school calendar years. Students remarked that participation in the program reinforced the importance of their concurrent anatomy and physiology classes. They observed interdependence and cooperation among the members of the health care team caring for women, and their evaluations of their experiences at the bedside were highly positive. Women consistently expressed appreciation for the additional individualized attention and education received from our student and nurse team. Nurses can enhance the learning of first-year medical students in the maternity care clinical setting. This nurse-developed education program provided students with a variety of vivid clinical experiences with maternity patients.


Integrating an evidence-based medicine rotation into an internal medicine residency program.
To measure the impact of a resident focused evidence-based medicine (EBM) educational intervention on EBM knowledge of residents and students, to assess its feasibility, and to evaluate residents' attitudes regarding this rotation. In 2002, based on the EBM user and EBM practitioner model, the authors designed the EBM elective rotation and conducted a controlled trial of its implementation in the internal medicine residency program in three teaching hospitals affiliated with the University at Buffalo, New York. The intervention group (one hospital, 17 medical students and residents) received a multifaceted intervention. In the control group (two hospitals, 23 medical students and residents), there was no curriculum change. The effectiveness in a pre- and post-test was assessed using the English version of the Berlin Questionnaire. A survey of all internal medicine residents (n = 119) was conducted to evaluate their attitudes toward the EBM elective rotation. In the intervention group, knowledge improved slightly, but not significantly (.71 on a scale ranging from 0-15 on the Berlin questionnaire, p =.3). The mean score in the control group decreased significantly (1.65, p =.005). The difference in change scores between the two groups was significant even after adjustment for covariates (2.52, p =.006). Residents (response rate 83%) had positive attitudes regarding the rotation. An EBM elective rotation was successfully integrated into a residency program. This multifaceted educational approach with an "on-the-ward" EBM resident, may improve the EBM knowledge and skills of targeted students and residents.


Abnormal cytokine production by bone marrow stromal cells of multiple myeloma patients in response to RPMI8226 myeloma cells.
Recent studies indicate that bone marrow stromal cells (BMSCs) derived from patients with multiple myeloma (MM) differ from those of healthy donors in their expression of extracellular matrix compounds and in cytokine production. It is not known whether these abnormalities are primary or are acquired by BMSCs on contact with MM cells. Interleukin (IL)-6, IL-11, IL-10, and tumor necrosis factor (TNF)-alpha production by CD166+ mesenchymal BMSCs and the CD38+/CD138+ RPMI8226 myeloma cell line cultivated in vitro in monocultures or co-cultivated under cell-to-cell contact or non-contact conditions in the presence of a tissue culture insert were measured. Intracellular cytokines were measured by flow cytometry analysis as the percentage of cytokine-producing cells or by mean fluorescence intensity as the level of cytokine expression in cells. Additionally, ELISA was used to measure IL-6, soluble IL-6 receptor (sIL-6R), IL-11, IL-10, TNF-alpha, B-cell-activating factor of the TNF family (BAFF), hepatocyte growth factor (HGF), and osteopontin (OPN) production in the supernatants of the cultures and co-cultures. A higher ability of the BMSCs of MM patients than in controls was detected to produce IL-6, IL-10, TNF-alpha, OPN, and especially HGF and BAFF in response to the RPMI8226 cells. Moreover, the BMSCs of the MM patients significantly enhanced the production of sIL-6R by the RPMI8226 cells. Cytokines over-expressed by BMSCs of MM patients can function as growth factors for myeloma cells (IL-6, IL-10, HGF), migration stimulatory factors for tumor plasma cells (TNF-alpha, HGF), adhesion stimulatory factors (HGF, BAFF and OPN), stimulators of osteoclastogenesis (IL-6, TNF-alpha), and angiogenic factors (TNF-alpha). The results of this experiment strongly suggest that the BMSCs from MM patients differed in spontaneous and myeloma cell-induced production of cytokines, especially of HGF and BAFF, and these abnormalities were both primary and acquired by the BMSCs on contact with the MM cells. This in turn suggests the presence of an undefined, autocrine stimulation pathway resulting in a prolonged production of cytokines even in long-term cultures in vitro and in vivo. These abnormalities might provide optimal conditions for the proliferation and differentiation of residual tumor cells or their precursors in the affected bone marrow.


Catatonia in Down syndrome: systematic approach to diagnosis, treatment and outcome assessment based on a case series of seven patients.
The goal is to expand our knowledge of catatonia occurring in adolescents and young adults with Down syndrome (DS) by describing the first prospective, consecutive, well-characterized cohort of seven young people with DS diagnosed with catatonia and treated between 2013 and 2018, and to assess each patient's treatment responses. Longitudinal assessment of each patient's response to treatment is intended to provide clinicians and psychiatrists a firm foundation from which assess treatment efficacy. Young adults with Down syndrome were consecutively enrolled in the study as they were diagnosed with catatonia. A comprehensive data set included medical, laboratory, developmental, demographic, family, social and genetic data, including query into disorders for which individuals with DS are at risk. Catatonia was diagnosed based on an unequivocal history of regression, positive Bush-Francis Catatonia Rating Scale and positive response to intravenous lorazepam. Patients' longitudinal progress was monitored using the Catatonia Impact Scale (CIS) developed for this purpose. Seven consecutive DS patients, who presented with unequivocal regression were diagnosed with catatonia and treated for 2.7-6 years using standard-of-care therapies; primarily GABA agonist, lorazepam, electroconvulsive therapy (ECT) and glutamate antagonists (dextromethorphan/quinidine, memantine, minocycline). Responses to each treatment modality were assessed at clinic visits and through weekly electronic CIS reports. Seven young adults with DS were diagnosed with catatonia; all responded to Lorazepam and/or ECT therapy with good to very good results. Though ECT most dramatically returned patients to baseline, symptoms often returned requiring additional ECT. Dextromethorphan/quinidine, not used until mid-2017, appeared to reduce the reoccurrence of symptoms following ECT. Though all seven patients improved significantly, each continues to require some form of treatment to maintain a good level of functioning. Findings of a significant number of autoimmune disorders and laboratory markers of immune activation in this population may guide new diagnostic and treatment opportunities.


Attitudes toward genetic testing and personalised nutrition in a representative sample of European consumers.
Negative consumer opinion poses a potential barrier to the application of nutrigenomic intervention. The present study has aimed to determine attitudes toward genetic testing and personalised nutrition among the European public. An omnibus opinion survey of a representative sample aged 14-55+ years (n 5967) took place in France, Italy, Great Britain, Portugal, Poland and Germany during June 2005 as part of the Lipgene project. A majority of respondents (66 %) reported that they would be willing to undergo genetic testing and 27 % to follow a personalised diet. Individuals who indicated a willingness to have a genetic test for the personalising of their diets were more likely to report a history of high blood cholesterol levels, central obesity and/or high levels of stress than those who would have a test only for general interest. Those who indicated that they would not have a genetic test were more likely to be male and less likely to report having central obesity. Individuals with a history of high blood cholesterol were less likely than those who did not to worry if intervention foods contained GM ingredients. Individuals who were aware that they had health problems associated with the metabolic syndrome appeared particularly favourable toward nutrigenomic intervention. These findings are encouraging for the future application of personalised nutrition provided that policies are put in place to address public concern about how genetic information is used and held.


Perception of Reproductive Health in Women with Inflammatory Bowel Disease.
As inflammatory bowel diseases [IBD] affect female patients almost exclusively during their reproductive age, issues related to fertility, fecundity, pregnancy, delivery, and lactation are of utmost importance. Lack of education and misconceptions regarding the effect of disease and/or treatment on reproductive outcome may lead to voluntary childlessness and/or development of unwanted cervical pathologies which may impact tremendously on patients' welfare and quality of life. The aims of this study were to assess the perspectives of IBD patients on fertility, pregnancy and its outcomes, and lactation, as well as their awareness of human papillomavirus [HPV]-related pathologies and screening for cervical cancer. This prospective study was performed across nine different Mediterranean IBD centres between 2014 and 2015 and included consecutive female IBD patients between the ages of 16 and 50 years. All patients responded to a questionnaire based on ECCO guidelines. A total of 348 IBD female patients with a mean age of 37.4 (standard deviation [SD] ± 2.1) years were recruited; 50% had a diagnosis of ulcerative colitis, 49.4% had Crohn`s disease, and 0.6% patients had a diagnosis of indeterminate colitis [IC]. A significant proportion of patients [ > 60%] were afraid that IBD may lead to a complicated pregnancy and that the disease itself and/or its medications can cause fetal harm. Patients had similar concerns that IBD can be transmitted to their offspring as well as with regard to breastfeeding. Counselling from health care professionals with regard to fertility, pregnancy, and lactation was associated positively with the highest number of pregnancies and inversely with the lowest number of patients who considered voluntary childlessness [p < 0.0001]. Patients with a higher level of education were more likely to get pregnant [p = 0.004]. There was a low uptake of the HPV vaccine. However, there was a reasonably good uptake of cervical cancer screening. Our study demonstrates that women with IBD have misperceptions about fertility, pregnancy, and health maintenance. We also show that education by physicians has a positive influence. We thus conclude that improved multidisciplinary approaches should be used to educate and implement European guidelines for women with IBD.


Identification of AB-FUBINACA metabolites in authentic urine samples suitable as urinary markers of drug intake using liquid chromatography quadrupole tandem time of flight mass spectrometry.
Synthetic cannabinoids are a group of psychoactive drugs presently widespread among drug users in Europe. Analytical methods to measure these compounds in urine are in demand as urine is a preferred matrix for drug testing. For most synthetic cannabinoids, the parent compounds are rarely detected in urine. Therefore urinary metabolites are needed as markers of drug intake. AB-FUBINACA was one of the top three synthetic cannabinoids most frequently found in seizures and toxicological drug screening in Sweden (2013-2014). Drug abuse is also reported from several other countries such as the USA and Japan. In this study, 28 authentic case samples were used to identify urinary markers of AB-FUBINACA intake using liquid chromatography quadrupole tandem time of flight mass spectrometry and human liver microsomes. Three metabolites suitable as markers of drug intake were identified and at least two of them were detected in all but one case. In total, 15 urinary metabolites of AB-FUBINACA were reported, including hydrolxylations on the indazole ring and the amino-oxobutane moiety, dealkylations and hydrolysis of the primary amide. No modifications on the fluorobenzyl side-chain were observed. The parent compound was detected in 54% of the case samples. Also, after three hours of incubation with human liver microsomes, 77% of the signal from the parent compound remained. Copyright © 2015 John Wiley & Sons, Ltd.


Sex Differences in Age of Diagnosis and First Concern among Children with Autism Spectrum Disorder.
Early identification of autism spectrum disorder (ASD) is an essential healthcare priority. Girls may be at risk for late diagnosis, although research is equivocal regarding how sex and other factors relate to ASD identification. The goals of the current investigation were to (1) identify how child sex, cognitive abilities, and demographic factors relate to age of first concern (AOC) and age of diagnosis (AOD), (2) evaluate trends in AOC/AOD over time, and (3) consider whether main effects of sex on AOC/AOD are moderated by cognitive abilities or time. Children (N = 365; 20% female; 85.6% identified as White) with ASD participated through the Province of Ontario Neurodevelopmental Disorders (POND) Network. Study records included AOD, date/timing of diagnosis (between 1996 and 2017), age of first parent concern, demographics, and standardized cognitive testing results (24.7% of children had IQ scores below standard scores of 70). Average AOC occurred before 2 years of age whereas average AOD occurred after 5 years of age. Girls did not differ on AOC but had a later AOD than boys. Higher verbal IQ was associated with later AOD more strongly in girls than boys. Regarding time-related changes, average AOC and AOD increased across the study period, more strongly for girls. Results support that sex is a key factor underlying delays in ASD identification and highlight the urgent need to improve diagnostic practices among girls. Limitations and implications for improving the diagnostic process are discussed. Abbreviations: ASD=autism spectrum disorder; IQ=intelligence quotient; AOC=parental report of age of first concern; AOD=age of diagnosis.


Impact of nanopore morphology on cell viability on mesoporous polymer and carbon surfaces.
Topography at the nanoscale can lead to dramatic changes in the adhesion of cells to surfaces and their subsequent viability. For biological applications, including tissue engineering and cell-based sensing, the large internal surface area of ordered mesoporous carbons provides an opportunity for enhanced sensitivity and performance, but the mesostructure also affects the topography of the material. In this work, we probe the viability and adhesion of osteoblasts on ordered mesoporous materials with different morphologies and matrix chemistries. FDU-15 (hexagonal) and FDU-16 (cubic) films were processed at either 350 degrees C (polymeric) or 800 degrees C (carbon) to provide these different materials. For the films processed at 350 degrees C, the cell adhesion was markedly improved on the mesoporous films in comparison to a dense film analog, consistent with many reports in the literature that nanostructuring of surfaces improves the viability and adhesion of osteoblasts. Conversely, osteoblast adhesion was reduced on the carbonized surfaces processed at 800 degrees C when ordered mesopores were introduced, particularly for the cubic mesostructure (FDU-16). We attribute the decrease in cell adhesion to the propensity of the ordered mesoporous carbon films to sorb organics from aqueous solution, which could lead to removal of adhesion-promoting compounds at the film surface. These results suggest that cell viability on mesoporous polymer and carbon films can be controlled through simple changes in the pyrolysis temperature.


Split course radiotherapy for bladder cancer in elderly unfit patients.
Between 1980 and 1987, 89 patients with T1-T4 carcinoma of the bladder were treated with a split course of external beam radiotherapy. All patients were felt to be unsuitable for a prolonged course of radical radiotherapy because of age and/or poor general health. The intention was to provide local control. The majority of patients were treated with 10-12 fractions, with a mean dose of 45 Gy (range 31.5-57.7), within a mean overall time of 48 days. Of the 89 patients only 62 were assessable with a median follow-up of 110 months (range 64-157). In the remainder, poor health, poor performance status, or early (< 3 months) death did not allow assessment of tumour control. Complete remission was achieved in 28/89 (31%) patients. This was highly dependent on T stage: 56% T1/T2, 30% T3a/T3b, 5% T4. Median survival for patients with Stage T1/T2, T3a/T3b and T4 disease was 22, 10 and 8 months respectively. Acute grade 1-2 radiation reactions occurred in 60% of these patients, and only 5/62 (8%) experienced grade 2-3 late complications, assessed according to the RTOG scoring system. No patient had more severe treatment related morbidity.


Limelight on two HIV/SIV accessory proteins in macrophage infection: is Vpx overshadowing Vpr?
HIV viruses encode a set of accessory proteins, which are important determinants of virulence due to their ability to manipulate the host cell physiology for the benefit of the virus. Although these viral proteins are dispensable for viral growth in many in vitro cell culture systems, they influence the efficiency of viral replication in certain cell types. Macrophages are early targets of HIV infection which play a major role in viral dissemination and persistence in the organism. This review focuses on two HIV accessory proteins whose functions might be more specifically related to macrophage infection: Vpr, which is conserved across primate lentiviruses including HIV-1 and HIV-2, and Vpx, a protein genetically related to Vpr, which is unique to HIV-2 and a subset of simian lentiviruses. Recent studies suggest that both Vpr and Vpx exploit the host ubiquitination machinery in order to inactivate specific cellular proteins. We review here why it remains difficult to decipher the role of Vpr in macrophage infection by HIV-1 and how recent data underscore the ability of Vpx to antagonize a restriction factor which counteracts synthesis of viral DNA in monocytic cells.


Social Support to Empower Parents (STEP): an intervention for parents of young children newly diagnosed with type 1 diabetes.
The purpose of this study was to test the efficacy of a social support intervention with parents of children <13 years old newly diagnosed with type 1 diabetes mellitus (T1DM). For this randomized, controlled clinical trial, 10 parent mentors of children diagnosed with T1DM >or=1 year and 60 parent participants were recruited from 2 pediatric diabetes centers. Mentors were trained to provide social support (home visits and phone calls) for 12 months to families in the experimental arm (32 mothers). Control group parents (28 mothers) received the phone number of an experienced parent (not trained to give social support) to call as needed. Findings Mothers in the experimental and control arms differed at baseline only in birth order of the child with T1DM. The 2 groups did not differ significantly at 3, 6, or 12 months in parent concern, confidence, worry, impact on the family, or perceived social support. Mothers in the experimental arm identified the parent mentor as someone they would seek for advice and issues regarding growth and development, sleep, eating habits, and identification of community agencies. Parent mentors consistently referred mothers to health care providers for advice on medications and treatments but helped them incorporate this advice into day-to-day management. Mothers in the experimental arm valued the mentors' help in adjusting to the diagnosis, but this value was not measured by the study instruments. Focus group research is under way to clarify the concept of parent mentor social support and to develop a social support measurement tool.


The Origin of Mutants Under Selection: How Natural Selection Mimics Mutagenesis (Adaptive Mutation).
Selection detects mutants but does not cause mutations. Contrary to this dictum, Cairns and Foster plated a leaky lac mutant of Escherichia coli on lactose medium and saw revertant (Lac(+)) colonies accumulate with time above a nongrowing lawn. This result suggested that bacteria might mutagenize their own genome when growth is blocked. However, this conclusion is suspect in the light of recent evidence that revertant colonies are initiated by preexisting cells with multiple copies the conjugative F'lac plasmid, which carries the lac mutation. Some plated cells have multiple copies of the simple F'lac plasmid. This provides sufficient LacZ activity to support plasmid replication but not cell division. In nongrowing cells, repeated plasmid replication increases the likelihood of a reversion event. Reversion to lac(+) triggers exponential cell growth leading to a stable Lac(+) revertant colony. In 10% of these plated cells, the high-copy plasmid includes an internal tandem lac duplication, which provides even more LacZ activity—sufficient to support slow growth and formation of an unstable Lac(+) colony. Cells with multiple copies of the F'lac plasmid have an increased mutation rate, because the plasmid encodes the error-prone (mutagenic) DNA polymerase, DinB. Without DinB, unstable and stable Lac(+) revertant types form in equal numbers and both types arise with no mutagenesis. Amplification and selection are central to behavior of the Cairns-Foster system, whereas mutagenesis is a system-specific side effect or artifact caused by coamplification of dinB with lac. Study of this system has revealed several broadly applicable principles. In all populations, gene duplications are frequent stable genetic polymorphisms, common near-neutral mutant alleles can gain a positive phenotype when amplified under selection, and natural selection can operate without cell division when variability is generated by overreplication of local genome subregions.


Trading carbon for food: global comparison of carbon stocks vs. crop yields on agricultural land.
Expanding croplands to meet the needs of a growing population, changing diets, and biofuel production comes at the cost of reduced carbon stocks in natural vegetation and soils. Here, we present a spatially explicit global analysis of tradeoffs between carbon stocks and current crop yields. The difference among regions is striking. For example, for each unit of land cleared, the tropics lose nearly two times as much carbon (∼120 tons·ha(-1) vs. ∼63 tons·ha(-1)) and produce less than one-half the annual crop yield compared with temperate regions (1.71 tons·ha(-1)·y(-1) vs. 3.84 tons·ha(-1)·y(-1)). Therefore, newly cleared land in the tropics releases nearly 3 tons of carbon for every 1 ton of annual crop yield compared with a similar area cleared in the temperate zone. By factoring crop yield into the analysis, we specify the tradeoff between carbon stocks and crops for all areas where crops are currently grown and thereby, substantially enhance the spatial resolution relative to previous regional estimates. Particularly in the tropics, emphasis should be placed on increasing yields on existing croplands rather than clearing new lands. Our high-resolution approach can be used to determine the net effect of local land use decisions.


Exosome purification based on PEG-coated Fe3O4 nanoparticles.
Cancer cells secrete many exosomes, which facilitate metastasis and the later growth of cancer. For early cancer diagnosis, the detection of exosomes is a crucial step. Exosomes exist in biological fluid, such as blood, which contains various proteins. It is necessary to remove the proteins in the biological fluid to avoid test interference. This paper presented a novel method for exosome isolation using Fe3O4 magnetic nanoparticles (MNPs), which were synthesized using the chemical co-precipitation method and then coated with polyethylene glycol (PEG). The experimental results showed that the diameter of the PEG-coated Fe3O4 nanoparticles was about 20 nm, while an agglomerate of MNPs reached hundreds of nanometers in size. In the protein removal experiments, fetal bovine serum (FBS) was adopted as the analyte for bioassays of exosome purification. PEG-coated Fe3O4 MNPs reduced the protein concentration in FBS to 39.89% of the original solution. By observing a particle size distribution of 30~200 nm (the size range of various exosomes), the exosome concentrations were kept the same before and after purification. In the gel electrophoresis experiments, the bands of CD63 (~53 kDa) and CD9 (~22 kDa) revealed that exosomes existed in FBS as well as in the purified solution. However, the bands of the serum albumins (~66 kDa) and the various immunoglobulins (around 160 ~ 188 kDa) in the purified solution's lane explained that most proteins in FBS were removed by PEG-coated Fe3O4 MNPs. When purifying exosomes from serum, protein removal is critical for further exosome investigation. The proposed technique provides a simple and effective method to remove proteins in the serum using the PEG-coated Fe3O4 MNPs.


[Evaluation of medicinal reasonableness and resource utilization of Dida (Zang Yin Cheng) commonly used in Tibetan medicine].
To evaluate the medicinal reasonableness and resource utilization of Dida from different species. With common characteristic absorption peaks of HPLC fingerprints and SPSS cluster, the composition similarity of Dida from different species was evaluated. The composition similarity of HPLC fingerprints of 33 Dida samples from 15 species and 1 variety originated from Swertia, Halenia, Gentianopsis, Lomatogonium was difference. The original species can be clustered into four groups by the relative area of 10 common characteristic peaks of HPLC fingerprints. The compositions of four different genera are quite different. Because of containing iridoids, xanthones, and triterpenes which have liver protection and cholagogue functions, all of species from Swertia, Halenia, Gentianopsis and Lomatogonium in Gentianaceae are classified as Dida in Tibetan medicine. According to the composition difference among different species, the HPLC fingerprints established for Dida from different source are an effective means to identify nd control the quality of Dida.


Extinction of an infectious disease: a large fluctuation in a nonequilibrium system.
We develop a theory of first passage processes in stochastic nonequilibrium systems of birth-death type using two closely related epidemiological models as examples. Our method employs the probability generating function technique in conjunction with the eikonal approximation. In this way the problem is reduced to finding the optimal path to extinction: a heteroclinic trajectory of an effective multidimensional classical Hamiltonian system. We compute this trajectory and mean extinction time of the disease numerically and uncover a nonmonotone, spiral path to extinction of a disease. We also obtain analytical results close to a bifurcation point, where the problem is described by a Hamiltonian previously identified in one-species population models.


Analysis of stranded information using an automated procedure for strand specific RNA sequencing.
Strand specific RNA sequencing is rapidly replacing conventional cDNA sequencing as an approach for assessing information about the transcriptome. Alongside improved laboratory protocols the development of bioinformatical tools is steadily progressing. In the current procedure the Illumina TruSeq library preparation kit is used, along with additional reagents, to make stranded libraries in an automated fashion which are then sequenced on Illumina HiSeq 2000. By the use of freely available bioinformatical tools we show, through quality metrics, that the protocol is robust and reproducible. We further highlight the practicality of strand specific libraries by comparing expression of strand specific libraries to non-stranded libraries, by looking at known antisense transcription of pseudogenes and by identifying novel transcription. Furthermore, two ribosomal depletion kits, RiboMinus and RiboZero, are compared and two sequence aligners, Tophat2 and STAR, are also compared. The, non-stranded, Illumina TruSeq kit can be adapted to generate strand specific libraries and can be used to access detailed information on the transcriptome. The RiboZero kit is very effective in removing ribosomal RNA from total RNA and the STAR aligner produces high mapping yield in a short time. Strand specific data gives more detailed and correct results than does non-stranded data as we show when estimating expression values and in assembling transcripts. Even well annotated genomes need improvements and corrections which can be achieved using strand specific data. Researchers in the field should strive to use strand specific data; it allows for more confidence in the data analysis and is less likely to lead to false conclusions. If faced with analysing non-stranded data, researchers should be well aware of the caveats of that approach.


Inflammatory profile of awake function-controlled craniotomy and craniotomy under general anesthesia.
Surgical stress triggers an inflammatory response and releases mediators into human plasma such as interleukins (ILs). Awake craniotomy and craniotomy performed under general anesthesia may be associated with different levels of stress. Our aim was to investigate whether those procedures cause different inflammatory responses. Twenty patients undergoing craniotomy under general anesthesia and 20 patients undergoing awake function-controlled craniotomy were included in this prospective, observational, two-armed study. Circulating levels of IL-6, IL-8, and IL-10 were determined pre-, peri-, and postoperatively in both patient groups. VAS scores for pain, anxiety, and stress were taken at four moments pre- and postoperatively to evaluate physical pain and mental duress. Plasma IL-6 level significantly increased with time similarly in both groups. No significant plasma IL-8 and IL-10 change was observed in both experimental groups. The VAS pain score was significantly lower in the awake group compared to the anesthesia group at 12 hours postoperative. Postoperative anxiety and stress declined similarly in both groups. This study suggests that awake function-controlled craniotomy does not cause a significantly different inflammatory response than craniotomy performed under general anesthesia. It is also likely that function-controlled craniotomy does not cause a greater emotional challenge than tumor resection under general anesthesia.


Videotape as a research tool.
In a study of the natural history of back pain presenting in general practice, video recordings of consultations were used in the analysis of observer variation in the examination of the back. Video provided information which could not have been obtained from other sources and stimulated the doctors involved in the study to be meticulous in their examination technique.


Buffering effects of general and medication-specific social support on the association between substance use and HIV medication adherence.
The success of highly active antiretroviral therapy (HAART) among persons living with HIV is largely dependent on strict medication adherence. Recent research suggests that alcohol and other drug use (AOD) may be an important barrier to HAART adherence. In this study, we examined the impact of AOD on HAART adherence as well as the moderating effects of general and medication-specific social support. The data were collected as part of a longitudinal randomized control trial with 224 HIV-positive patients at an HIV primary care clinic in the northwestern United States. Findings indicated that AOD use was negatively associated with HAART adherence and that medication-specific (but not general) social support moderated the AOD-adherence association at 3 (but not at 6 or 9) months. Results indicate the importance of medication-specific social support to treat comorbid AOD use and HIV; implications for future research and intervention programs for HIV-positive AOD users are discussed.


Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign database.
The Surviving Sepsis Campaign guidelines recommend obtaining a serum lactate measurement within 6 hours of presentation for all patients with suspected severe sepsis or septic shock. A lactate greater than 4 mmol/L qualifies for administration of early quantitative resuscitation therapy. We evaluated lactate elevation (with special attention to values > 4 mmol/L) and presence or absence of hypotension as a marker of clinical outcome. The Surviving Sepsis Campaign developed a database to assess the overall effect of the sepsis bundles as a performance improvement tool for clinical practice and patient outcome. This analysis focuses on one element of the Surviving Sepsis Campaign's resuscitation bundle, measuring serum lactate in adult severe sepsis or septic shock patients and its interaction with hypotension. This analysis was conducted on data submitted from January 2005 through March 2010. Data from 28,150 subjects at 218 sites were analyzed. None. Unadjusted analysis of the 28,150 observations from the Surviving Sepsis Campaign database demonstrated a significant mortality increase with the presence of hypotension in conjunction with serum lactate elevation greater than 2 mmol/L. On multivariable analysis, only lactate values greater than 4 mmol/L, in conjunction with hypotension, significantly increased mortality when compared with the referent group of lactate values less than 2 mmol/L and not hypotensive. Mortality was 44.5% in patients with combined lactate greater than 4 mmol/L and hypotension when compared with 29% mortality in patients not meeting either criteria. Serum lactate was commonly measured within 6 hours of presentation in the management of severe sepsis or septic shock in this subset analysis of the Surviving Sepsis Campaign database in accordance with the Surviving Sepsis Campaign guidelines. Our results demonstrate that elevated lactate levels are highly associated with in-hospital mortality. However, only patients who presented with lactate values greater than 4 mmol/L, with and without hypotension, are significantly associated with in-hospital mortality and is associated with a significantly higher risk than intermediate levels (2-3 and 3-4 mmol/L). This supports the use of the cutoff of greater than 4 mmol/L as a qualifier for future clinical trials in severe sepsis or septic shock in patient populations who use quantitative resuscitation and the Surviving Sepsis Campaign bundles as standard of care.


Nanomechanics of the substrate binding domain of Hsp70 determine its allosteric ATP-induced conformational change.
Owing to the cooperativity of protein structures, it is often almost impossible to identify independent subunits, flexible regions, or hinges simply by visual inspection of static snapshots. Here, we use single-molecule force experiments and simulations to apply tension across the substrate binding domain (SBD) of heat shock protein 70 (Hsp70) to pinpoint mechanical units and flexible hinges. The SBD consists of two nanomechanical units matching 3D structural parts, called the α- and β-subdomain. We identified a flexible region within the rigid β-subdomain that gives way under load, thus opening up the α/β interface. In exactly this region, structural changes occur in the ATP-induced opening of Hsp70 to allow substrate exchange. Our results show that the SBD's ability to undergo large conformational changes is already encoded by passive mechanics of the individual elements.


Crizotinib and PARP inhibitors act synergistically by triggering apoptosis in high-grade serous ovarian cancer.
High-grade serous ovarian cancer (HGSOC) is the predominant and most lethal histological type of epithelial ovarian cancer. During the last few years, several new treatment options with PARP inhibitors have emerged. The FDA has approved the PARP inhibitor olaparib (Lynparza™) as maintenance treatment after first-line platinum-containing chemotherapy and olaparib, niraparib (Zejula™) and rucaparib (Rubraca™) are approved as maintenance therapies in the recurrent, platinum-sensitive setting; nevertheless, development of resistance limits their efficacy. In this study, new combinatorial treatment strategies targeting key signaling pathways were explored to enhance the activity of PARP inhibitors in HGSOC. Carboplatin, olaparib, niraparib, the PI3K inhibitor LY294002 and the c-Met inhibitor crizotinib were used for this investigation. PARP inhibitors and carboplatin alone and in combination caused accumulation of DNA double-strand breaks and G2/M cell cycle arrest. In contrast, crizotinib alone or in combination with PARP inhibitors induced accumulation of cells in sub-G1. Crizotinib together with either of the PARP inhibitors was more strongly synergistic than combinations with a PARP inhibitor and carboplatin or the PI3K inhibitor. Sequential combination of crizotinib and a PARP inhibitor resulted in activation of ATM/CHK2 and inhibition of c-Met pathways, contributing to a decrease in RAD51 levels and induction of caspase-3 dependent apoptotic cell death and suggesting that the combination of crizotinib with a PARP inhibitor may be considered and further explored as a new therapeutic strategy in HGSOC.


[Suicide - background, epidemiology, risk factors].
Suicide research, in particular epidemiology, comprises a huge amount of data. However, the theoretical understanding clearly lags behind the empirical knowledge. Suicide, suicide attempts and other suicidal behaviors are more heterogeneous than most explanatory approaches would assume. The most important recent contributions to a better understanding have come from selected epidemiological findings and, interestingly, prevention. This article provides an overview of epidemiological findings, the most relevant risk factors and conclusions related to successful preventive efforts.


Chlorovirus: a genus of Phycodnaviridae that infects certain chlorella-like green algae.
SUMMARY Taxonomy: Chlorella viruses are assigned to the family Phycodnaviridae, genus Chlorovirus, and are divided into three species: Chlorella NC64A viruses, Chlorella Pbi viruses and Hydra viridis Chlorella viruses. Chlorella viruses are large, icosahedral, plaque-forming, dsDNA viruses that infect certain unicellular, chlorella-like green algae. The type member is Paramecium bursaria chlorella virus 1 (PBCV-1). Physical properties: Chlorella virus particles are large (molecular weight approximately 1 x 10(9) Da) and complex. The virion of PBCV-1 contains more than 100 different proteins; the major capsid protein, Vp54, comprises approximately 40% of the virus protein. Cryoelectron microscopy and three-dimensional image reconstruction of PBCV-1 virions indicate that the outer glycoprotein-containing capsid shell is icosahedral and surrounds a lipid bilayered membrane. The diameter of the viral capsid ranges from 1650 A along the two- and three-fold axes to 1900 A along the five-fold axis. The virus contains 5040 copies of Vp54, and the triangulation number is 169. The PBCV-1 genome is a linear, 330 744-bp, non-permuted dsDNA with covalently closed hairpin ends. The PBCV-1 genome contains approximately 375 protein-encoding genes and 11 tRNA genes. About 50% of the protein-encoding genes match proteins in the databases. Hosts: Chlorella NC64A and Chlorella Pbi, the hosts for NC64A viruses and Pbi viruses, respectively, are endosymbionts of the protozoan Paramecium bursaria. However, they can be grown in the laboratory free of both the paramecium and the virus. These two chlorella species are hosts to viruses that have been isolated from fresh water collected around the world. The host for hydra chlorella virus, a symbiotic chlorella from Hydra viridis, has not been grown independently of its host; thus the virus can only be obtained from chlorella cells freshly released from hydra.


The functional neuroanatomy of the evolving parent-infant relationship.
Infant survival and the development of secure and cooperative relationships are central to the future of the species. In humans, this relies heavily on the evolving early parent-infant social and affective relationship. While much is known about the behavioural and psychological components of this relationship, relatively little is known about the underlying functional neuroanatomy. Affective and social neuroscience has helped to describe the main adult brain networks involved, but has so far engaged very little with developmental findings. In this review, we seek to highlight future avenues for research by providing a coherent framework for describing the parent-infant relationship over the first 18 months. We provide an outline of the evolving nature of the relationship, starting with basic orienting and recognition processes, and culminating in the infant's attainment of higher socio-emotional and cognitive capacities. Key social and affective interactions, such as communication, cooperative play and the establishment of specific attachments propel the development of the parent-infant relationship. We summarise our current knowledge of the developing infant brain in terms of structure and function, and how these relate to the emergent abilities necessary for the formation of a secure and cooperative relationship with parents or other caregivers. Important roles have been found for brain regions including the orbitofrontal, cingulate, and insular cortices in parent-infant interactions, but it has become clear that much more information is needed about the developmental time course and connectivity of these regions.


Control of Saccharomyces cerevisiae filamentous growth by cyclin-dependent kinase Cdc28.
The ascomycete Saccharomyces cerevisiae exhibits alternative vegetative growth states referred to as the yeast form and the filamentous form, and it switches between the two morphologies depending on specific environmental signals. To identify molecules involved in control of morphologic differentiation, this study characterized mutant S. cerevisiae strains that exhibit filamentous growth in the absence of the normal external signals. A specific amino acid substitution in the cyclin-dependent protein kinase Cdc28 was found to cause constitutive expression of most filamentous growth characteristics. These effects include specifically modified cell polarity characteristics in addition to the defined shape and division cycle alterations typical of the filamentous form. Several other mutations affecting Cdc28 function also had specific effects on filamentous growth. Constitutive filamentous growth resulting from deletion of the protein kinase Elm1 was prevented by modification of Cdc28 such that it could not be phosphorylated on tyrosine residue 19. In addition, various mutations affecting Hsl1 or Swe1, known or presumed components of a protein kinase cascade that mediates Cdc28 phosphorylation on Y19, either prevented or enhanced filamentous growth. The data suggest that a protein kinase cascade involving Elm1, Hsl1, and Swe1 can modulate Cdc28 activity and that Cdc28 in turn exerts global effects that cause filamentous growth.


A Global Scale Scenario for Prebiotic Chemistry: Silica-Based Self-Assembled Mineral Structures and Formamide.
The pathway from simple abiotically made organic compounds to the molecular bricks of life, as we know it, is unknown. The most efficient geological abiotic route to organic compounds results from the aqueous dissolution of olivine, a reaction known as serpentinization (Sleep, N.H., et al. (2004) Proc. Natl. Acad. Sci. USA 101, 12818-12822). In addition to molecular hydrogen and a reducing environment, serpentinization reactions lead to high-pH alkaline brines that can become easily enriched in silica. Under these chemical conditions, the formation of self-assembled nanocrystalline mineral composites, namely silica/carbonate biomorphs and metal silicate hydrate (MSH) tubular membranes (silica gardens), is unavoidable (Kellermeier, M., et al. In Methods in Enzymology, Research Methods in Biomineralization Science (De Yoreo, J., Ed.) Vol. 532, pp 225-256, Academic Press, Burlington, MA). The osmotically driven membranous structures have remarkable catalytic properties that could be operating in the reducing organic-rich chemical pot in which they form. Among one-carbon compounds, formamide (NH2CHO) has been shown to trigger the formation of complex prebiotic molecules under mineral-driven catalytic conditions (Saladino, R., et al. (2001) Biorganic & Medicinal Chemistry, 9, 1249-1253), proton irradiation (Saladino, R., et al. (2015) Proc. Natl. Acad. Sci. USA, 112, 2746-2755), and laser-induced dielectric breakdown (Ferus, M., et al. (2015) Proc Natl Acad Sci USA, 112, 657-662). Here, we show that MSH membranes are catalysts for the condensation of NH2CHO, yielding prebiotically relevant compounds, including carboxylic acids, amino acids, and nucleobases. Membranes formed by the reaction of alkaline (pH 12) sodium silicate solutions with MgSO4 and Fe2(SO4)3·9H2O show the highest efficiency, while reactions with CuCl2·2H2O, ZnCl2, FeCl2·4H2O, and MnCl2·4H2O showed lower reactivities. The collections of compounds forming inside and outside the tubular membrane are clearly specific, demonstrating that the mineral self-assembled membranes at the same time create space compartmentalization and selective catalysis of the synthesis of relevant compounds. Rather than requiring odd local conditions, the prebiotic organic chemistry scenario for the origin of life appears to be common at a universal scale and, most probably, earlier than ever thought for our planet.


Anion-exchange capillary electrochromatography with indirect UV and direct contactless conductivity detection.
Conductivity detection is applied to ion-exchange capillary electrochromatography (IE-CEC) with a packed stationary phase, using a capacitively coupled contactless conductivity detector with detection occurring through the packed bed. Columns were packed with a polymeric latex-agglomerate anion-exchanger (Dionex AS9-SC). A systematic approach was used to determine suitable eluants for IE-CEC separations using simultaneous indirect UV and direct conductivity detection. Salicylate and p-toluenesulfonate were identified as potential eluant competing anions having sufficient eluotropic strength to induce changes in separation selectivity, but salicylate was found to be unsuitable with regard to baseline stability. It was also found for both indirect UV and direct conductivity detection that homogenous column packing was imperative, and monitoring of the baseline could be used to assess the homogeneity of the packed bed. Using a p-toluenesulfonate eluant, the separation of eight common anions was achieved in 2.5 min. Direct conductivity detection was found to be superior to indirect UV detection with regard to both baseline stability and detection sensitivity with detection limits of 4-25 microg/L being obtained. However, the calibration for each anion was not linear over more than one order of magnitude. When using conductivity detection, the concentration of the eluant could be varied over a wider range (2.5-50 mM p-toluenesulfonate) than was the case with indirect UV detection (2.5-10 mM), thereby allowing greater changes in separation selectivity to be achieved. By varying the concentration of p-toluenesulfonate in the eluant, the separation selectivity could be manipulated from being predominantly ion-exchange in nature (2.5 mM) to predominantly electrophoretic in nature (50 mM).


Sialobiology of influenza: molecular mechanism of host range variation of influenza viruses.
The gene pool of influenza A viruses in aquatic birds provides all of the genetic diversity required for human and lower animals. Host range selection of the receptor binding specificity of the influenza virus hemagglutinin occurs during maintenance of the virus in different host cells that express different receptor sialo-sugar chains. In this paper, functional roles of the hemagglutinin and neuraminidase spikes of influenza viruses are described in the relation to 1) host range of influenza viruses, 2) receptor binding specificity of human and other animal influenza viruses, 3) recognition of sialyl sugar chains by Spanish influenza virus hemagglutinin, 4) highly pathogenic and potentially pandemic H5N1, H9N2, and H7N7 avian influenza viruses and molecular mechanism of host range variation of influenza viruses, 5) role of the neuraminidase spike for the host range of influenza viruses, and 6) Development of anti-influenza drugs.


The structure of the yrdC gene product from Escherichia coli reveals a new fold and suggests a role in RNA binding.
The yrdC family of genes codes for proteins that occur both independently and as a domain in proteins that have been implicated in regulation. An example for the latter case is the sua5 gene from yeast. SuaS was identified as a suppressor of a translation initiation defect in cytochrome c and is required for normal growth in yeast (Na JG, Pinto I, Hampsey M, 1992, Genetics 11:791-801). However, the function of the Sua5 protein remains unknown; Sua5 could act either at the transcriptional or the posttranscriptional levels to compensate for an aberrant translation start codon in the cyc gene. To potentially learn more about the function of YrdC and proteins featuring this domain, the crystal structure of the YrdC protein from Escherichia coli was determined at a resolution of 2.0 A. YrdC adopts a new fold with no obvious similarity to those of other proteins with known three-dimensional (3D) structure. The protein features a large concave surface on one side that exhibits a positive electrostatic potential. The dimensions of this depression, its curvature, and the fact that conserved basic amino acids are located at its floor suggest that YrdC may be a nucleic acid binding protein. An investigation of YrdC's binding affinities for single- and double-stranded RNA and DNA fragments as well as tRNAs demonstrates that YrdC binds preferentially to double-stranded RNA. Our work provides evidence that 3D structures of functionally uncharacterized gene products with unique sequences can yield novel folds and functional insights.


Elevation of serum transaminases with norovirus infection.
From November to December in 2006, we experienced 4 pediatric cases with an elevation of the serum transaminase levels accompanied by acute gastroenteritis. All examined stool specimens were norovirus positive according to the Reverse Transcription-Polymerase Chain Reaction (RT-PCR) assay. The clinical courses of these cases were the same as those of common gastroenteritis. Blood examinations showed only a slight elevation of the transaminase levels at the onset of gastroenteritis, while the symptoms were severe. Interestingly, the transaminase levels significantly increased after gastroenteritis disappeared. The average period between the onset of gastroenteritis and the peak of transaminase levels was 13.8 days. In all cases, the patients were treated with the administration of glycyrrhizin, and the transaminase levels returned to normal approximately 4 weeks (average 26.8 days) after the onset of gastroenteritis, thus suggesting that an elevation of the transaminase levels in association with norovirus gastroenteritis may therefore be a self-limited process which may demonstrate a relatively good natural prognosis. Norovirus is one of the important pathogens which cause an elevation in the serum transaminase levels in young children. When an elevation in the transaminase levels in association with gastroenteritis is observed in young children, it is important to continuously follow up such patients even after the gastroenteritis has disappeared and to perform a virus search based on examinations of stool specimens using an RT-PCR assay in order to detect the presence of norovirus infections.


Systems Biomedicine of Rabies Delineates the Affected Signaling Pathways.
The prototypical neurotropic virus, rabies, is a member of the Rhabdoviridae family that causes lethal encephalomyelitis. Although there have been a plethora of studies investigating the etiological mechanism of the rabies virus and many precautionary methods have been implemented to avert the disease outbreak over the last century, the disease has surprisingly no definite remedy at its late stages. The psychological symptoms and the underlying etiology, as well as the rare survival rate from rabies encephalitis, has still remained a mystery. We, therefore, undertook a systems biomedicine approach to identify the network of gene products implicated in rabies. This was done by meta-analyzing whole-transcriptome microarray datasets of the CNS infected by strain CVS-11, and integrating them with interactome data using computational and statistical methods. We first determined the differentially expressed genes (DEGs) in each study and horizontally integrated the results at the mRNA and microRNA levels separately. A total of 61 seed genes involved in signal propagation system were obtained by means of unifying mRNA and microRNA detected integrated DEGs. We then reconstructed a refined protein-protein interaction network (PPIN) of infected cells to elucidate the rabies-implicated signal transduction network (RISN). To validate our findings, we confirmed differential expression of randomly selected genes in the network using Real-time PCR. In conclusion, the identification of seed genes and their network neighborhood within the refined PPIN can be useful for demonstrating signaling pathways including interferon circumvent, toward proliferation and survival, and neuropathological clue, explaining the intricate underlying molecular neuropathology of rabies infection and thus rendered a molecular framework for predicting potential drug targets.


Childhood deaths in Africa: uses and limitations of verbal autopsies.
The verbal autopsy (VA) is an epidemiological tool that is widely used to ascribe causes of death by interviewing bereaved relatives of children who were not under medical supervision at the time of death. This technique was assessed by comparison with a prospective survey of 303 childhood deaths at a district hospital in Kenya where medically confirmed diagnoses were available. Common causes of death were detected by VA with specificities greater than 80%. Sensitivity of the VA technique was greater than 75% for measles, neonatal tetanus, malnutrition, and trauma-related deaths; however, malaria, anaemia, acute respiratory-tract infection, gastroenteritis, and meningitis were detected with sensitivities of less than 50%. There may have been unwarranted optimism in the ability of VAs to detect some of the major causes of death, such as malaria, in African children. VA used in malaria-specific intervention trials should be interpreted with caution and only in the light of known sensitivities and specificities.


Clicking 3'-azidothymidine into novel potent inhibitors of human immunodeficiency virus.
3'-Azidothymidine (AZT) was the first approved antiviral for the treatment of human immunodeficiency virus (HIV). Reported efforts in clicking the 3'-azido group of AZT have not yielded 1,2,3-triazoles active against HIV or any other viruses. We report herein the first AZT-derived 1,2,3-triazoles with submicromolar potencies against HIV-1. The observed antiviral activities from the cytopathic effect (CPE) based assay were confirmed through a single replication cycle assay. Structure-activity-relationship (SAR) studies revealed two structural features key to antiviral activity: a bulky aromatic ring and the 1,5-substitution pattern on the triazole. Biochemical analysis of the corresponding triphosphates showed lower ATP-mediated nucleotide excision efficiency compared to AZT, which along with molecular modeling suggests a mechanism of preferred translocation of triazoles into the P-site of HIV reverse transcriptase (RT). This mechanism is corroborated with the observed reduction of fold resistance of the triazole analogue to an AZT-resistant HIV variant (9-fold compared to 56-fold with AZT).


Mechanisms of Myocardial Ischemia in Hypertrophic Cardiomyopathy: Insights From Wave Intensity Analysis and Magnetic Resonance.
Angina is common in hypertrophic cardiomyopathy (HCM) and is associated with abnormal myocardial perfusion. Wave intensity analysis improves the understanding of the mechanics of myocardial ischemia. Wave intensity analysis was used to describe the mechanisms underlying perfusion abnormalities in patients with HCM. Simultaneous pressure and flow were measured in the proximal left anterior descending artery in 33 patients with HCM and 20 control patients at rest and during hyperemia, allowing calculation of wave intensity. Patients also underwent quantitative first-pass perfusion cardiac magnetic resonance to measure myocardial perfusion reserve. Patients with HCM had a lower coronary flow reserve than control subjects (1.9 ± 0.8 vs. 2.7 ± 0.9; p = 0.01). Coronary hemodynamics in HCM were characterized by a very large backward compression wave during systole (38 ± 11% vs. 21 ± 6%; p < 0.001) and a proportionately smaller backward expansion wave (27% ± 8% vs. 33 ± 6%; p = 0.006) compared with control subjects. Patients with severe left ventricular outflow tract obstruction had a bisferiens pressure waveform resulting in an additional proximally originating deceleration wave during systole. The proportion of waves acting to accelerate coronary flow increased with hyperemia, and the magnitude of change was proportional to the myocardial perfusion reserve (rho = 0.53; p < 0.01). Coronary flow in patients with HCM is deranged. Distally, compressive deformation of intramyocardial blood vessels during systole results in an abnormally large backward compression wave, whereas proximally, severe left ventricular outflow tract obstruction is associated with an additional deceleration wave. Perfusion abnormalities in HCM are not simply a consequence of supply/demand mismatch or remodeling of the intramyocardial blood vessels; they represent a dynamic interaction with the mechanics of myocardial ischemia that may be amenable to treatment.


Gestational exposure to an epidemiologically defined mixture of phthalates leads to gonadal dysfunction in mouse offspring of both sexes.
The increasing concern for the reproductive toxicity of abundantly used phthalates requires reliable tools for exposure risk assessment to mixtures of chemicals, based on real life human exposure and disorder-associated epidemiological evidence. We herein used a mixture of four phthalate monoesters (33% mono-butyl phthalate, 16% mono-benzyl phthalate, 21% mono-ethyl hexyl phthalate, and 30% mono-isononyl phthalate), detected in 1st trimester urine of 194 pregnant women and identified as bad actors for a shorter anogenital distance (AGD) in their baby boys. Mice were treated with 0, 0.26, 2.6 and 13 mg/kg/d of the mixture, corresponding to 0x, 10x, 100x, 500x levels detected in the pregnant women. Adverse outcomes detected in the reproductive system of the offspring in pre-puberty and adulthood included reduced AGD index and gonadal weight, changes in gonadal histology and altered expression of key regulators of gonadal growth and steroidogenesis. Most aberrations were apparent in both sexes, though more pronounced in males, and exhibited a non-monotonic pattern. The phthalate mixture directly affected expression of steroidogenesis as demonstrated in a relevant in vitro model. The detected adversities at exposures close to the levels detected in pregnant women, raise concern on the existing safety limits for early-life human exposures and emphasizes the need for re-evaluation of the exposure risk.


Appropriate end-points for right results in the age of antiangiogenic agents: future options for phase II trials in patients with recurrent glioblastoma.
The progression-free survival rate at 6 months (PFS-6) has long been considered the best end-point for assessing the efficacy of new agents in phase II trials in patients with recurrent glioblastoma. However, due to the introduction of antiangiogenic agents in this setting, and their intrinsic propensity to alter neuroradiological disease assessment by producing pseudoregression, any end-point based on neuroradiological modifications should be reconsidered. Further, statistically significant effects on progression-free survival (PFS) only should not automatically be considered reliable evidence of meaningful clinical benefit. In this context, because of its direct and unquestionable clinical relevance, overall survival (OS) represents the gold standard end-point for measuring clinical efficacy, despite the disadvantage that it is influenced by subsequent therapies and usually takes longer time to be evaluated. Therefore, while awaiting novel imaging criteria for response evaluation and/or new imaging tools to distinguish between 'true' and 'pseudo'-responses to antiangiogenic agents, the measurement of OS or OS rates should be considered primary end-points, also in phase II trials with these agents.


Use of a zinc-finger consensus sequence framework and specificity rules to design specific DNA binding proteins.
We have designed three zinc-finger proteins with different DNA binding specificities. The design strategy combines a consensus zinc-finger framework sequence with previously characterized recognition regions such that the specificity of each protein is predictable. The first protein consists of three identical zinc fingers, each of which was expected to recognize the subsite GCG. This protein binds specifically to the sequence 5'-GCG-GCG-GCG-3' with a dissociation constant of approximately 11 microM. The second protein has three zinc fingers with different predicted preferred subsites. This protein binds to the predicted recognition site 5'-GGG-GCG-GCT-3' with a dissociation constant of 2 nM. Furthermore, selection experiments indicate that this is the optimal binding site. A permuted version of the second protein was also constructed and shown to preferentially recognize the corresponding permuted site 5'-GGG-GCT-GCG-3' over the non-permuted site. These results indicate that earlier observations on the specificity of zinc fingers can be extended to generalized zinc-finger structures and realize the use of zinc fingers for the design of site-specific DNA binding proteins. This consensus-based design system provides a useful model system with which to study details of zinc-finger-DNA specificity.


An updated patent review: xanthine oxidase inhibitors for the treatment of hyperuricemia and gout (2011-2015).
Xanthine oxidase (XO) is a versatile molybdoflavoprotein, widely distributed, occurring in milk, kidney, lung, heart, and vascular endothelium. Catalysis by XO to produce uric acid and reactive oxygen species leads to many diseases. Anti hyperuricemic therapy by xanthine oxidase inhibitors has been mainly employed for the treatment of gout. Area covered: This review covers the patent literature (2011-2015) and also presents the interesting strategies/rational approaches employed for the design of xanthine oxidase inhibitors reported recently. Expert opinion: Recent literature indicates that various non purine scaffolds have been extensively investigated for xanthine oxidase inhibition. The significant potential endowed by heteroaryl based compounds, in particularly fused heterocycles clearly highlights their clinical promise and the need for detailed investigation. Studies by various research groups have also revealed that the flavone framework is open for isosteric replacements and structural modifications for yielding potent non purine xanthine oxidase inhibitors. In addition, various plant extracts recently reported to possess significant xanthine oxidase inhibitory potential presents enough promise to initiate a screening program for the identification of other plant extracts and phytoconstituents possessing inhibitory potential towards the enzyme.


Effect of frequency and amplitude of vibration and role of a surfactant on void formation in models poured from polyvinyl siloxane impressions.
To determine whether the frequency and amplitude of vibration and the use of surfactant has any effect on the formation of voids on the cast surface, poured from a polyvinyl siloxane impression material, using a mechanical model vibrator. A total of 100 impressions of a master die were made using Reprosil, Type 1, Medium Viscosity, Regular body, and Dentsply Caulk. The test group was subdivided into a surfactant and non-surfactant group, 50 impressions each. The impressions were poured in a dental stone with a mechanical model vibrator that was set at a vibration frequency of 3000 cycles / minute (low) and 6000 cycles / minute (high) with the help of a knob. The resultant casts were examined with a Stereomicroscope (LABOMED CZM4) under ×10 magnifications. For the low and high frequencies, when surfactant and non-surfactant groups were compared, for all the amplitudes and for both the material groups, the surfactant groups resulted in fewer void formations and showed very high statistical significance (P-value = 0.001). The lowest mean voids were obtained for high frequency surfactant groups. Reprosil: High frequency amplitude 2 being the most prominent, produced the least mean voids (mean = 23.2000, P = 0.001, very highly significant). In comparison, the surfactant groups produced the least voids for both frequencies.


Focus issue: signals to neurodegeneration.
Neurodegenerative diseases exact a tremendous toll on afflicted individuals and their families. Understanding the underlying signaling cascades that are perturbed by or contribute to neurodegeneration may identify new therapeutic targets or improve current therapies. The pieces in this Focus Issue of Science Signaling discuss molecular mechanisms and signaling pathways implicated in the pathologies of Parkinson's, Alzheimer's, and Huntington's diseases.


Racial and geographic disparities in the utilization of surgical therapy for hepatocellular carcinoma.
The incidence of hepatocellular carcinoma (HCC) continues to increase, a trend that will likely continue because of the rising prevalence of chronic hepatitis C infection. This study sought to determine the recent patterns of utilization of surgical therapy (hepatectomy, ablation, or liver transplantation) for HCC from the Surveillance, Epidemiology, and End Results national cancer registry. Data were extracted for 16,121 patients with HCC diagnosed between 1998 and 2004. Twenty-three percent of patients underwent surgical therapy (9.5% resection, 7.8% ablation, 6% transplant); the proportion of patients treated with surgical therapy increased approximately 9% over the study period. On multivariate analysis, female sex, younger age, and smaller solitary tumors were associated with increased utilization of surgical therapy. Blacks and Hispanics were 24-27% less likely to receive surgical therapy than white individuals (P<0.001). Racial and geographic disparities persisted despite the adjustment for Health Service Area and limitation of the cohort to small localized HCC. Blacks were especially disadvantaged in the utilization of liver transplant for small HCC (OR=0.42, P<0.001). Further investigation to understand the etiology of these profound racial and geographic disparities is essential to ensure equitable provision of surgical therapies, which provide the only potentially curative treatments for HCC.


Alternative RNA splicing of the hyaluronic acid receptor CD44 in the normal human brain and in brain tumors.
The cell-surface receptor for hyaluronic acid, CD44, is expressed by both normal and malignant cells. Numerous CD44 isoforms have recently been identified that are derived by alternative ribonucleic acid splicing. The expression of some CD44 isoforms has been shown to be involved in tumor progression and metastatic spread in a rat carcinoma model and in human carcinomas. In the present study, CD44 isoform expression was evaluated by reverse transcriptase-polymerase chain reaction (PCR) analysis in frozen sections derived from three samples of normal brain tissue and from 40 brain tumors, including samples of glioblastoma multiforme, anaplastic astrocytoma, low-grade astrocytoma, cerebral primitive neuroectodermal tumor, medulloblastoma, metastatic colon carcinoma, and metastatic melanoma. Normal brain tissue adjacent to the tumors was also examined in 14 of 18 glioblastomas. In all normal brain and tumor samples, with the exception of metastases from colon carcinoma, PCR analysis demonstrated one prominent product that corresponded to the CD44H hematopoietic form of CD44. Metastases from colon carcinoma demonstrated two prominent PCR amplification products corresponding to CD44H and CD44R1. These results suggest that CD44H is the predominant isoform of this protein in normal human brain tissue and in human neuroectodermal tumors of varying degrees of malignancy. The ability of CD44H to mediate tumor cell motility and invasiveness (in contrast to CD44R1) suggests that the CD44 alternative splicing pattern of neuroectoderm-derived tumors may enhance their local biological aggressiveness and intracerebral spread. The lack of expression of larger molecular weight CD44 variants by primary brain tumors may also partially explain why these tumors rarely metastasize to distant sites.


Toward the genetics of mammalian reproduction: induction and mapping of gametogenesis mutants in mice.
The genetic control of mammalian gametogenesis is inadequately characterized because of a lack of mutations causing infertility. To further the discovery of genes required for mammalian gametogenesis, phenotype-driven screens were performed in mice using random chemical mutagenesis of whole animals and embryonic stem cells. Eleven initial mutations are reported here that affect proliferation of germ cells, meiosis, spermiogenesis, and spermiation. Nine of the mutations have been mapped genetically. These preliminary studies provide baselines for estimating the number of genes required for gametogenesis and offer guidance in conducting new genetic screens that will accelerate and optimize mutant discovery. This report demonstrates the efficacy and expediency of mutagenesis to identify new genes required for mammalian gamete development.


The genetic prehistory of the Andean highlands 7000 years BP though European contact.
The peopling of the Andean highlands above 2500 m in elevation was a complex process that included cultural, biological, and genetic adaptations. Here, we present a time series of ancient whole genomes from the Andes of Peru, dating back to 7000 calendar years before the present (BP), and compare them to 42 new genome-wide genetic variation datasets from both highland and lowland populations. We infer three significant features: a split between low- and high-elevation populations that occurred between 9200 and 8200 BP; a population collapse after European contact that is significantly more severe in South American lowlanders than in highland populations; and evidence for positive selection at genetic loci related to starch digestion and plausibly pathogen resistance after European contact. We do not find selective sweep signals related to known components of the human hypoxia response, which may suggest more complex modes of genetic adaptation to high altitude.


Association of residential dampness and mold with respiratory tract infections and bronchitis: a meta-analysis.
Dampness and mold have been shown in qualitative reviews to be associated with a variety of adverse respiratory health effects, including respiratory tract infections. Several published meta-analyses have provided quantitative summaries for some of these associations, but not for respiratory infections. Demonstrating a causal relationship between dampness-related agents, which are preventable exposures, and respiratory tract infections would suggest important new public health strategies. We report the results of quantitative meta-analyses of published studies that examined the association of dampness or mold in homes with respiratory infections and bronchitis. For primary studies meeting eligibility criteria, we transformed reported odds ratios (ORs) and confidence intervals (CIs) to the log scale. Both fixed and random effects models were applied to the log ORs and their variances. Most studies contained multiple estimated ORs. Models accounted for the correlation between multiple results within the studies analyzed. One set of analyses was performed with all eligible studies, and another set restricted to studies that controlled for age, gender, smoking, and socioeconomic status. Subgroups of studies were assessed to explore heterogeneity. Funnel plots were used to assess publication bias. The resulting summary estimates of ORs from random effects models based on all studies ranged from 1.38 to 1.50, with 95% CIs excluding the null in all cases. Use of different analysis models and restricting analyses based on control of multiple confounding variables changed findings only slightly. ORs (95% CIs) from random effects models using studies adjusting for major confounding variables were, for bronchitis, 1.45 (1.32-1.59); for respiratory infections, 1.44 (1.31-1.59); for respiratory infections excluding nonspecific upper respiratory infections, 1.50 (1.32-1.70), and for respiratory infections in children or infants, 1.48 (1.33-1.65). Little effect of publication bias was evident. Estimated attributable risk proportions ranged from 8% to 20%. Residential dampness and mold are associated with substantial and statistically significant increases in both respiratory infections and bronchitis. If these associations were confirmed as causal, effective control of dampness and mold in buildings would prevent a substantial proportion of respiratory infections.


Genetic characterization of Vietnamese Yellow cattle using mitochondrial DNA and Y-chromosomal haplotypes and genes associated with economical traits.
Vietnamese Yellow cattle are native cattle well adapted to local tropical environment. The aim of this study was to investigate genetic characteristics of the Yellow cattle using molecular markers. We investigated the nucleotide sequences of mitochondrial DNA and SRY gene on Y chromosome, and genotyped SREBP-1, SCD1, EDG1, NCAPG, DGAT1, MC1R, and HSP70 genes in the Yellow cattle population. The sequence analysis of the mitochondrial DNA showed that most of the cattle possesses zebu (Bos indicus) type I1 haplotype, suggesting relatively low genetic diversity in maternal lineage. The sequence analysis of the SRY gene indicates that while most of the males possess zebu type haplotype, taurine (Bos taurus) type haplotype was also observed, suggesting gene-flow from taurine cattle. The results of the genotyping of the functional genes showed that the NCAPG, SCD, MC1R, and HsSP70 genes are polymorphic in the population, whereas the SREBP-1, EDG1, and DGAT1 genes are monomorphic. Particularly, the presence of the desirable and undesirable alleles of the NCAPG and HSP70 genes, respectively, will be important for the selection of animals by potential performances in meat productivity and fertility. The present findings will be informative for future conservation and breeding of the Vietnamese Yellow cattle.


Efficacy and safety of electromagnetic navigation bronchoscopy with or without radial endobronchial ultrasound for peripheral lung lesions.
Electromagnetic navigation bronchoscopy (ENB) is a promising new technology to increase the diagnostic yield of peripheral lung and mediastinal lesions. Conventional flexible bronchoscopy has a limited yield in peripheral pulmonary lesions, even in experienced hands. Radial endobronchial ultrasound (r-EBUS) with its real-time imaging capability can help to diagnose peripheral pulmonary lesions. In the present study, we aimed to investigate the diagnostic yield and safety of ENB with or without r-EBUS for peripheral lung lesions. This study was conducted in a tertiary medical center, and 56 consecutive patients who were thought to be the best candidates for bronchoscopic biopsies at a multidisciplinary meeting were enrolled. ENB was performed under conscious sedation by using an electromagnetic tracking system with multiplanar reconstruction of previously acquired computed tomography (CT) data. Sampling was performed by biopsy forceps, endobronchial brush, and bronchoalveolar lavage. Fifty-six patients (50 men and 6 women; mean age, 60 ± 9 years) were studied. While an electromagnetic navigation system was used in all patients, r-EBUS was used in 26 of 56 patients. The median diameter of the lesions was 30 mm (interquartile range: 23-44 mm). Mean distance of the lesions from the pleura was 14.9 ± 14.6 mm. Mean procedure time was 20 ± 11.5 min. Mean registration error was 5.8 ± 1.5 mm. Mean navigation error was 1.2 ± 0.5 mm. The diagnostic yield of the procedure was 71.4% for peripheral lesions (non-small cell lung cancer = 23, small cell lung cancer = 3, benign diseases = 14). Pneumothorax occurred in only 1 patient (1.7%). ENB with or without r-EBUS is a safe, efficient, and easily applied method for sampling of peripheral lung lesions, with high diagnostic yield independent of lesion size and location.


Not Otherwise Specified-Type Sarcoma of Breast with CD10 Expression: Case Report.
Primary breast sarcomas are very rare and account less than 1% of invasive breast carcinomas. Primary sarcomas of breast are leiomyosarcoma, angiosarcoma, liposarcoma, fibrosarcoma, rhabdomyosarcoma, malignant peripheral nerve sheath tumor and pleomorphic sarcoma. Recently, a new CD10 positive group of sarcoma was identified. These tumors cannot be classified as a soft tissue sarcoma and show diffuse strong positive staining pattern with CD10 (NSCD10). Herein we report clinical and morphological characteristics of two cases diagnosed with not otherwise specified-type sarcoma with CD10 expression by histologically and immunohistochemical findings with the literature. NSCD10 shows similarity with leiomyosarcoma and sarcomatoid-type metaplastic carcinoma histomorphologically among specific sarcomas of breast. CD10 expression should be taken into consideration in the presence of not diagnosed and not specified tumors and CD10 should be added to the immunohistochemical panel.


Doing better than your best: loud auditory stimulation yields improvements in maximal voluntary force.
Could task performance be constrained by our ability to fully engage necessary neural processing through effort of will? The StartReact phenomenon suggests that this might be the case, as voluntary reaction times are substantially reduced by loud sounds. Here, we show that loud auditory stimulation can also be associated with an improvement in the force and speed of force development when 18 healthy subjects are repeatedly asked to make a maximal grip as fast and as strongly as possible. Peak grip force was increased by 7.2 ± 1.4% (SEM) (P < 0.0001), and the rate of force development was increased by 17.6 ± 2.0% (P < 0.00001), when imperative visual cues were accompanied by a loud auditory stimulus rather than delivered alone. This implies that loud auditory stimuli may allow motor pathways to be optimised beyond what can be achieved by effort of will alone.


Whole genome resequencing reveals genomic regions associated with thermal adaptation in redband trout.
Adaptation to local environments involves evolution of ecologically important traits and underlying physiological processes. Here, we used low coverage whole-genome resequencing (lcWGR) on individuals to identify genome regions involved in thermal adaptation in wild redband trout Oncorhynchus mykiss gairdneri, a subspecies of rainbow trout that inhabits ecosystems ranging from cold montane forests to high elevation deserts. This study includes allele frequency-based analyses for selective sweeps among populations, followed by multiple association tests for specific sets of phenotypes measured under thermal stress (acute and chronic survival/mortality; high or low cardiac performance groups). Depending on the groups in each set of analyses, sequencing reads covered 43%-75% of the genome at ≥15× and each analysis included millions of SNPs across the genome. In tests for selective sweeps among populations, a total of six chromosomal regions were significant. The further association tests for specific phenotypes revealed that the region on chromosome 4 was consistently the most significant and contains the cerk gene (ceramide kinase). This study provides insight into a potential genetic mechanism of local thermal adaptation and suggests cerk may be an important candidate gene. However, further validation of this cerk gene is necessary to determine if the association with cardiac performance results in a functional role to influence thermal performance when exposed to high water temperatures and hypoxic conditions.


The use of adenosine to inhibit oocyte meiotic resumption in Bos taurus during pre-IVM and its potential to improve oocyte competence.
One of the major challenges of artificial reproductive technologies is to develop new methods for producing greater numbers of embryos. An oocyte fosters the ability to develop into an embryo before oocyte meiotic resumption. The aim of the present study was to assess the effect of adenosine (ADO), a purine nucleoside found in follicular fluid, on the inhibition of oocyte meiotic resumption and the production of blastocysts. The results showed the efficacy of ADO to inhibit oocyte meiotic resumption. The use of ADO (3 mM) during a pre-in vitro maturation (pre-IVM) culture period of 6 h resulted in a significant increase (p < 0.05) of blastocysts compared to control conditions with no pre-IVM culture period. No effect on the percentage of cleavage was observed. The effect of adenosine on blastocyst yield was time- and concentration-dependent with an optimum effect at 3 mM for 6 h. Supplementing the ADO pre-IVM culture medium with estradiol, follicle-stimulating hormone, progesterone, epidermal growth factor, insulin-like growth factor-2 or reelin did not improve the blastocyst yield. Transcriptional analyses of ADO-treated cumulus cells revealed that NRP1, RELN, MAN1A1, THRA and GATM were up-regulated. Finally, bioinformatic analysis identified mitochondrial function as the top canonical pathway affected by ADO. This opens up new opportunities for further investigations.


Extended Venous Thromboembolism Prophylaxis in Medically Ill Patients.
Prophylaxis for venous thromboembolism (VTE) in hospitalized acutely ill medical patients is a well-established practice. Despite the increased use of inpatient prophylaxis, the duration of hospitalization is typically shorter than the duration of VTE prophylaxis provided in clinical trials. In addition, VTE events after hospitalization are not unusual, with most events occurring within 30 days of hospital discharge. Therefore, the 30-day time period postdischarge has been identified as a stage in which patients are still at high risk of developing VTE. Attempts to provide extended prophylaxis with enoxaparin, rivaroxaban, or apixaban in patients with acute medical illness have been met with mixed results. Although some of these agents have reduced the incidence of VTE with extended prophylaxis, all of these agents have also demonstrated a significant increase in major bleeding that seems to offset any potential benefit. A recent trial of a new direct factor Xa inhibitor, betrixaban, demonstrated a reduction in VTE events with extended prophylaxis without significantly increasing the risk of major bleeding. Understanding appropriate patient selection, dosing, and outcomes associated with betrixaban will be important to potentially reducing the continued risk of VTE in patients with acute medical illness.


Translational research on reserve against neurodegenerative disease: consensus report of the International Conference on Cognitive Reserve in the Dementias and the Alzheimer's Association Reserve, Resilience and Protective Factors Professional Interest Area working groups.
The concept of reserve was established to account for the observation that a given degree of neurodegenerative pathology may result in varying degrees of symptoms in different individuals. There is a large amount of evidence on epidemiological risk and protective factors for neurodegenerative diseases and dementia, yet the biological mechanisms that underpin the protective effects of certain lifestyle and physiological variables remain poorly understood, limiting the development of more effective preventive and treatment strategies. Additionally, different definitions and concepts of reserve exist, which hampers the coordination of research and comparison of results across studies. This paper represents the consensus of a multidisciplinary group of experts from different areas of research related to reserve, including clinical, epidemiological and basic sciences. The consensus was developed during meetings of the working groups of the first International Conference on Cognitive Reserve in the Dementias (24-25 November 2017, Munich, Germany) and the Alzheimer's Association Reserve and Resilience Professional Interest Area (25 July 2018, Chicago, USA). The main objective of the present paper is to develop a translational perspective on putative mechanisms underlying reserve against neurodegenerative disease, combining evidence from epidemiological and clinical studies with knowledge from animal and basic research. The potential brain functional and structural basis of reserve in Alzheimer's disease and other brain disorders are discussed, as well as relevant lifestyle and genetic factors assessed in both humans and animal models. There is an urgent need to advance our concept of reserve from a hypothetical model to a more concrete approach that can be used to improve the development of effective interventions aimed at preventing dementia. Our group recommends agreement on a common dictionary of terms referring to different aspects of reserve, the improvement of opportunities for data sharing across individual cohorts, harmonising research approaches across laboratories and groups to reduce heterogeneity associated with human data, global coordination of clinical trials to more effectively explore whether reducing epidemiological risk factors leads to a reduced burden of neurodegenerative diseases in the population, and an increase in our understanding of the appropriateness of animal models for reserve research.


Possible radiation injury at Koeberg Nuclear Power Station. Organization of medical care.
Any injured patient from Koeberg Nuclear Power Station will be treated in the conventional manner as an acute surgical emergency; this has priority over decontamination. The ideal situation is decontamination at Koeberg before ambulance transferral to the Tygerberg Radiation Casualty Facility, but if this is not possible or complete, decontamination can be accomplished by a trained team in the unit. Teamwork is the essence at the place of injury, during transfer, in the decontamination area, in the operating theatre and during the postoperative phase. No surgical management is appropriate or complete without the very necessary guidance and advice from a physicist and the Advisory Group for Radiation Casualties.


Differentiating suicide attempters from suicide ideators: a critical frontier for suicidology research.
Most individuals who consider suicide do not make suicide attempts. It is therefore critical to identify which suicide ideators are at greatest risk of acting on their thoughts. However, few seminal theories of suicide address which ideators go on to make attempts. In addition, perhaps surprisingly, most oft-cited risk factors for suicide-such as psychiatric disorders, depression, hopelessness, and even impulsivity-distinguish poorly between those who attempt suicide and those who only consider suicide. This special section of Suicide and Life-Threatening Behavior serves to highlight this knowledge gap and provide new data on differences (and similarities) between suicide attempters and suicide ideators.


The burden of illness of osteoporosis in Canada.
To update the 1993 burden of illness of osteoporosis in Canada, administrative and community data were used to calculate the 2010 costs of osteoporosis at $2.3 billion in Canada or 1.3% of Canada's healthcare expenditures. Prevention of fractures in high-risk individuals is key to decrease the financial burden of osteoporosis. Since the 1996 publication of the burden of osteoporosis in 1993 in Canada, the population has aged and the management of osteoporosis has changed. The study purpose was to estimate the current burden of illness due to osteoporosis in Canadians aged 50 and over. Analyses were conducted using five national administrative databases from the Canadian Institute for Health Information for the fiscal-year ending March 31 2008 (FY 2007/2008). Gaps in national data were supplemented by provincial and community data extrapolated to national levels. Osteoporosis-related fractures were identified using a combination of most responsible diagnosis at discharge and intervention codes. Fractures associated with severe trauma codes were excluded. Costs, expressed in 2010 dollars, were calculated for osteoporosis-related hospitalizations, emergency care, same day surgeries, rehabilitation, continuing care, homecare, long-term care, prescription drugs, physician visits, and productivity losses. Sensitivity analyses were conducted to measure the impact on the results of key assumptions. Osteoporosis-related fractures were responsible for 57,413 acute care admissions and 832,594 hospitalized days in FY 2007/2008. Acute care costs were estimated at $1.2 billion. When outpatient care, prescription drugs, and indirect costs were added, the overall yearly cost of osteoporosis was over $2.3 billion for the base case analysis and as much as $3.9 billion if a proportion of Canadians were assumed to be living in long-term care facilities due to osteoporosis. Osteoporosis is a chronic disease that affects a large segment of the adult population and results in a substantial economic burden to the Canadian society.


Correlation analysis of intracellular and secreted cytokines via the generalized integrated mean fluorescence intensity.
The immune response in humans is usually assessed using immunogenicity assays to provide biomarkers as correlates of protection (CoP). Flow cytometry is the assay of choice to measure intracellular cytokine staining (ICS) of cell-mediated immune (CMI) biomarkers. For CMI analysis, the integrated mean fluorescence intensity (iMFI) was introduced as a metric to represent the total functional CMI response as a CoP. iMFI is computed by multiplying the relative frequency (percent positive) of cells expressing a particular cytokine with the MFI of that population, and correlates better with protection in challenge models than either the percentage or the MFI of the cytokine-positive population. While determination of the iMFI as a CoP can readily be accomplished in animal models that allow challenge/protection experiments, this is not feasible in humans for ethical reasons. As a first step toward extending the iMFI concept to humans, we investigated the correlation of the iMFI derived from a human innate immune response ICS assay with functional cytokine release into the culture supernatant, as innate cytokines need to be released to have a functional impact. Next, we developed a quantitatively more correlative mathematical approach for calculating the functional response of cytokine-producing cells by incorporating the assignment of different weights to the magnitude (frequency of cytokine-positive cells) and the quality (the MFI) of the observed innate immune response. We refer to this model as generalized iMFI.


Extended-spectrum beta-lactamases in Ireland, including a novel enzyme, TEM-102.
Organisms producing extended-spectrum beta-lactamases (ESBLs) have been reported in many countries, but there is no information on the prevalence of ESBL-producing members of the family Enterobacteriaceae in Ireland. A total of 925 isolates of ampicillin-resistant members of the Enterobacteriaceae were received from six hospitals in Ireland over a 3-year period from September 1996 to September 1999. Isolates were screened for ESBL production by the double-disk diffusion (DDD) method. DDD-positive isolates that were (i) confirmed as ESBL producers by National Committee for Clinical Laboratory Standards (NCCLS) confirmatory testing and (ii) susceptible to cefoxitin by disk diffusion were considered ESBL producers. By these criteria, 27 (3%) of the ampicillin-resistant members of the Enterobacteriaceae studied were categorized as ESBL producers. Molecular typing suggested that some intra- and interhospital spread of ESBL-producing isolates had occurred. DNA sequencing of amplified bla(TEM) and bla(SHV) genes resulted in the detection of a novel bla(TEM) ESBL gene, bla(TEM-102) in two isolates (Klebsiella pneumoniae and Enterobacter cloacae) received from the same hospital but isolated from different patients. The study suggests dissemination of ESBL-producing bacteria within the health care system in Ireland and emphasizes the need for measures to control such spread.


Bone-Targeting Prodrug Mesoporous Silica-Based Nanoreactor with Reactive Oxygen Species Burst for Enhanced Chemotherapy.
Cancer remains a primary threat to human lives. Recently, amplification of tumor-associated reactive oxygen species (ROS) has been used as a boosting strategy to improve tumor therapy. Here, we report on a bone-targeting prodrug mesoporous silica-based nanoreactor for combined photodynamic therapy (PDT) and enhanced chemotherapy for osteosarcoma. Because of surface modification of a bone-targeting biphosphate moiety and the enhanced permeability and retention effect, the formed nanoreactor shows efficient accumulation in osteosarcoma and exhibits long-term retention in the tumor microenvironment. Upon laser irradiation, the loaded photosensitizer chlorin e6 (Ce6) produces in situ ROS, which not only works for PDT but also functions as a trigger for controlled release of doxorubicin (DOX) and doxycycline (DOXY) from the prodrugs based on a thioketal (TK) linkage. The released DOXY further promotes ROS production, thus perpetuating subsequent DOX/DOXY release and ROS burst. The ROS amplification induces long-term high oxidative stress, which increases the sensitivity of the osteosarcoma to chemotherapy, therefore resulting in enhanced tumor cell inhibition and apoptosis. The as-developed nanoreactor with combined PDT and enhanced chemotherapy based on ROS amplification shows significant promise as a potential platform for cancer treatment.


Pain relief during hysterosalpingography: a national survey.
Hysterosalpingography is a part of the infertility workup and can be painful. We conducted a postal survey of Obstetric and Gynaecology departments in the UK to evaluate the current clinical practice regarding the methods used to provide pain relief during hysterosalpingography. A total of 166 questionnaires were sent and 104 responses were received. Hysterosalpingography was offered by 93.3% of respondents. Respondents reported a wide variation in clinical practice with regards to the timing and the nature of analgesia used. Interestingly, 38% of respondents did not use analgesia at all. This variation in clinical practice may reflect the sparsity of evidence contained within the literature.


Living with mesothelioma: A qualitative study of the experiences of male military veterans in the UK.
The UK has the highest incidence of mesothelioma in the world. Evidence in the United States suggests that mesothelioma may disproportionately affect military veterans. However, there has been no investigation of the experience of UK veterans living with mesothelioma. The Military Mesothelioma Experience Study (MiMES) aimed to understand the experience and health/support needs of British Armed Forces personnel/veterans with mesothelioma. Semi-structured interviews were conducted with 13 veterans living with mesothelioma, and nine family members of veterans living with mesothelioma. Participants were recruited via charities and asbestos support groups. Data were analysed using thematic analysis. Participants' experiences are presented using three themes, i) exposure to asbestos and awareness of asbestos related diseases, ii) using military strategies to cope with mesothelioma and iii) preferences for information and support. MiMES indicates that the nature and range of UK military veterans' asbestos exposure is varied and not limited to high risk occupations. Participants' knowledge of asbestos and experience of mesothelioma influenced their experiences of diagnosis. Participants had coping strategies influenced by their military experiences. Assistance in navigating health and military systems was considered beneficial, especially if support was provided by professionals with knowledge or experience of the military. Attributes which may inhibit veterans from seeking professional support are discussed. MiMES provides insight into how UK military veterans experience and cope with mesothelioma. Key implications focus on the role that Mesothelioma Nurse Specialists, Asbestos Support Groups and veterans groups play in providing acceptable support for UK veterans.