Is rheumatoid arthritis care more costly when provided by rheumatologists compared with generalists?
Controversy surrounds the cost-effectiveness of rheumatologist care compared with generalist care for patients with rheumatoid arthritis (RA). Rheumatologists can provide 2 distinct types of care for RA patients: primary care and specialist care. We sought to examine the relationship between cost and type of care in a population-based cohort of patients with RA. Data regarding specialty of care and use of health services (i.e., total direct medical costs, surgeries, radiographs, laboratory tests, hospital days) were collected from a community sample of 249 patients with RA (defined using the 1987 American College of Rheumatology diagnostic criteria) among Rochester, Minnesota residents > or =35 years of age. In a randomly selected subset of 99 of these RA patients, detailed information on all physician encounters was collected and categorized according to whether or not the care received constituted "primary care" according to the Institute of Medicine definition. Using these data, we evaluated the influence of type of care as well as specialty of provider on utilization. For these analyses, total direct costs included all inpatient and outpatient health care costs incurred by all local providers (excluding outpatient prescription drugs). The 249 patients with RA (mean age 64 years, 75% women) were followed up for a median of 5.4 years, while the subset of 99 RA patients (mean age 64 years, 77% women) were followed up for a median of 4.7 years. The overall median direct medical costs per person per year were $2,749 and $2,929 for the total cohort and for the subset of 99 patients, respectively. Generalized linear regression analyses (considering all visits of the 249 RA patients) revealed that after adjusting for demographics and disease characteristics, rheumatologist care (compared with nonrheumatologist care) was not associated with higher total direct medical costs (P = 0.85) or more hospital days (P = 0.35), but was associated with slightly more radiographs (P = 0.037) and significantly more laboratory tests (P < 0.0001). When considering only primary care, such care by rheumatologists was, again, not associated with higher total direct medical costs (P = 0.11) or more hospital days (P = 0.69) or more laboratory tests (P = 0.54), but was associated with slightly more radiographs (P = 0.035). Rheumatologist care is not more costly than generalist care for patients with RA. Important differences (especially in the use of laboratory tests) become apparent when the type of care provided as well as the specialty of the provider are considered in the analyses.


MALAT1 and HOTAIR Long Non-Coding RNAs Play Opposite Role in Estrogen-Mediated Transcriptional Regulation in Prostate Cancer Cells.
In the complex network of nuclear hormone receptors, the long non-coding RNAs (lncRNAs) are emerging as critical determinants of hormone action. Here we investigated the involvement of selected cancer-associated lncRNAs in Estrogen Receptor (ER) signaling. Prior studies by Chromatin Immunoprecipitation (ChIP) Sequencing showed that in prostate cancer cells ERs form a complex with the endothelial nitric oxide synthase (eNOS) and that in turn these complexes associate with chromatin in an estrogen-dependent fashion. Among these associations (peaks) we focused our attention on those proximal to the regulatory region of HOTAIR and MALAT1. These transcripts appeared regulated by estrogens and able to control ERs function by interacting with ERα/ERβ as indicated by RNA-ChIP. Further studies performed by ChIRP revealed that in unstimulated condition, HOTAIR and MALAT1 were present on pS2, hTERT and HOTAIR promoters at the ERE/eNOS peaks. Interestingly, upon treatment with17β-estradiol HOTAIR recruitment to chromatin increased significantly while that of MALAT1 was reduced, suggesting an opposite regulation and function for these lncRNAs. Similar results were obtained in cells and in an ex vivo prostate organotypic slice cultures. Overall, our data provide evidence of a crosstalk between lncRNAs, estrogens and estrogen receptors in prostate cancer with important consequences on gene expression regulation.


Rationale and design of the steroids in cardiac surgery trial.
Steroids may improve outcomes in high-risk patients undergoing cardiac surgery with the use of cardiopulmonary bypass (CBP). There is a need\ for a large randomized controlled trial to clarify the effect of steroids in such patients. We plan to randomize 7,500 patients with elevated European System for Cardiac Operative Risk Evaluation who are undergoing cardiac surgery with the use of CBP to methylprednisolone or placebo. The first coprimary outcome is 30-day all-cause mortality, and the most second coprimary outcome is a composite of death, MI, stroke, renal failure, or respiratory failure within 30 days. Other outcomes include a composite of MI or mortality at 30 days, new onset atrial fibrillation, bleeding and transfusion requirements, length of intensive care unit stay and hospital stay, infection, stroke, wound complications, gastrointestinal complications, delirium, postoperative insulin use and peak blood glucose, and all-cause mortality at 6 months. As of October 22, 2013, 7,034 patients have been recruited into SIRS in 82 centers from 18 countries. Patient's mean age is 67.3 years, and 60.4% are male. The average European System for Cardiac Operative Risk Evaluation is 7.0 with 22.1% having an isolated coronary artery bypass graft procedure, and 66.1% having a valve procedure. SIRS will lead to a better understanding of the safety and efficacy of prophylactic steroids for cardiac surgery requiring CBP.


Out of the silos: identifying cross-cutting features of health-related stigma to advance measurement and intervention.
Many health conditions perceived to be contagious, dangerous or incurable, or resulting in clearly visible signs, share a common attribute - an association with stigma and discrimination. While the etiology of stigma may differ between conditions and, sometimes, cultural settings, the manifestations and psychosocial consequences of stigma and discrimination are remarkably similar. However, the vast majority of studies measuring stigma or addressing stigma through interventions employ a disease-specific approach. The current paper opposes this siloed approach and advocates a generic concept of 'health-related stigma' in both stigma measurement and stigma interventions. Employing a conceptual model adapted from Weiss, the current paper demonstrates the commonalities among several major stigmatized conditions by examining how several stigma measurement instruments, such as the Social Distance Scale, Explanatory Model Interview Catalogue, Internalized Stigma of Mental Illness, and Berger stigma scale, and stigma reduction interventions, such as information-based approaches, contact with affected persons, (peer) counselling, and skills building and empowerment, were used successfully across a variety of conditions to measure or address stigma. The results demonstrate that 'health-related stigma' is a viable concept with clearly identifiable characteristics that are similar across a variety of stigmatized health conditions in very diverse cultures. A more generic approach to the study of health-related stigma opens up important practical opportunities - cross-cutting measurement and intervention tools are resource saving and easier to use for personnel working with multiple conditions, allow for comparison between conditions, and recognize the intersectionality of many types of stigma. Further research is needed to build additional evidence demonstrating the advantages and effectiveness of cross-condition approaches to stigma measurement and interventions.


The NACHT, LRR and PYD Domains-Containing Protein 3 (NLRP3) Inflammasome Mediates Inflammation and Voiding Dysfunction in a Lipopolysaccharide-Induced Rat Model of Cystitis.
NOD-like receptors (NLRs) sense sterile and non-sterile signals and form inflammasomes which trigger an inflammatory response through the activation of caspase-1 and release of IL-1β. Recently we have shown the presence of several NLRs in the bladder urothelia and demonstrated the importance of NLRP3 in bladder outlet obstruction and cyclophosphamide-induced cystitis, both models of sterile inflammation. In this study we explore a role for NLRP3 in mediating the response to LPS, a key antigen of uropathogenic bacteria. In order to bypass the protective glycosaminoglycan layer lining the urothelium, LPS was directly injected into the bladder wall of Sprague-Dawley rats. Glyburide (a NLRP3 inhibitor) or vehicle was administered orally prior to and after injection. Rats were analyzed 24 h later. Inflammasome activity (caspase-1 activity, IL-1β release) and inflammation (Evan's Blue extravasation, bladder weight) were assessed, as was physiological bladder function (urodynamics). Injection of LPS stimulated inflammasome activation (caspase-1 activity) and the release of IL-1β into the urine which was prevented by glyburide. Likewise, LPS increased inflammation, (bladder weight and the extravasation of Evan's blue dye), and this was reversed by glyburide. Functionally, animals injected with saline alone demonstrated decreased voiding volume as measured by urodynamics. In the presence of LPS, additional urinary dysfunction was evident with decreased voiding pressures and threshold pressures. The decrease in voiding pressure was blocked by glyburide but the decrease in threshold pressure was not, suggesting that LPS has significant effects mediated by inflammasome-dependent and -independent mechanisms. Overall, the results demonstrate the potential importance of inflammasomes in bacterial cystitis as well as the ability of the bladder wall injection technique to isolate the in vivo effects of specific inflammasome ligands to the physiological changes associated with cystitis.


Acute dehydroepiandrosterone (DHEA) effects on sexual arousal in postmenopausal women.
The age-related decline of dehydroepiandrosterone (DHEA) has prompted research on its experimental replacement in women. Although no relationship to sexual functioning in healthy women has been shown to date, DHEA replacement has potential for affecting sexual response. To investigate DHEA effects, 16 sexually functional postmenopausal women participated in a randomized, double-blind, crossover protocol in which oral administration of DHEA (300 mg) or placebo occurred 60 minutes before the presentation of an erotic video segment. Blood DHEA sulfate (DHEAS) changes, subjective and physiological sexual responses, as well as affective responses were measured in response to videotaped neutral and erotic video segments. The concentration of DHEAS increased 2-5-fold following DHEA administration in all 16 women. Subjective ratings across DHEA and placebo conditions showed significantly greater mental (p < 0.016) and physical (p < 0.036) sexual arousal to the erotic video with DHEA vs. placebo. Positive affect also increased during the erotic video across drug conditions. Vaginal pulse amplitude (VPA) and vaginal blood volume (VBV) demonstrated a significant increase (p < 0.001) between neutral and erotic film segments within both conditions (DHEA and placebo) but did not differentiate drug conditions. In sum, increases in mental and physical sexual arousal ratings significantly increased in response to an acute dose of DHEA in postmenopausal women.


Long-term follow-up of collateral pathways established after lymphadenectomy in rats.
A collateral pathway established after lymphadenectomy could play an important role in long-term lymphedema treatment. The present study investigated alterations of lymph dynamics 1 year after lymphadenectomy using indocyanine green fluorescent lymphography to determine if a collateral pathway may be used for long-term lymphedema treatment. Wistar rats were anaesthetized and lymph nodes were excised at the inguinal and popliteal fossae. The treated hind limb was evaluated by fluorescent lymphography between 10 weeks and 6 months and between 6 months and 1 year postoperatively. Fluorescent lymphography demonstrated a lymphatic pathway to the ipsilateral axillary fossa in all rats 1 year after lymphadenectomy. Some capillary branches in the paths leading to the ipsilateral axillary fossa were dilated and tortuous. In addition, areas in which a fluorescent signal was not visible were increased in the thigh. In conclusion, the collateral pathway did not appear to be only for temporary use to compensate for drainage from the edematous limb but appears more stable as a component of a compensating lymphatic system. These new dilated vessels, although functional at this point, may still be susceptible to disturbance by further alteration to the lymph vessels.


Can (should) theories of crowding be unified?
Objects in clutter are difficult to recognize, a phenomenon known as crowding. There is little consensus on the underlying mechanisms of crowding, and a large number of models have been proposed. There have also been attempts at unifying the explanations of crowding under a single model, such as the weighted feature model of Harrison and Bex (2015) and the texture synthesis model of Rosenholtz and colleagues (Balas, Nakano, & Rosenholtz, 2009; Keshvari & Rosenholtz, 2016). The goal of this work was to test various models of crowding and to assess whether a unifying account can be developed. Adopting Harrison and Bex's (2015) experimental paradigm, we asked observers to report the orientation of two concentric C-stimuli. Contrary to the predictions of their model, observers' recognition accuracy was worse for the inner C-stimulus. In addition, we demonstrated that the stimulus paradigm used by Harrison and Bex has a crucial confounding factor, eccentricity, which limits its usage to a very narrow range of stimulus parameters. Nevertheless, reporting the orientations of both C-stimuli in this paradigm proved very useful in pitting different crowding models against each other. Specifically, we tested deterministic and probabilistic versions of averaging, substitution, and attentional resolution models as well as the texture synthesis model. None of the models alone was able to explain the entire set of data. Based on these findings, we discuss whether the explanations of crowding can (should) be unified.


Evidence for Oldenlandia diffusa-evoked cancer cell apoptosis through superoxide burst and caspase activation.
Oldenlandia diffusa (Bai Hua She She Cao) is one of the herbs most commonly used in traditional Chinese medicine for treating cancer. Various studies using the herb alone or in combination with other therapy plans have evidenced the effectiveness of the herb in the management of cancers of different tissue origin. However, the mechanisms underlying its anti-cancer activity are unknown. In the present study, we attempted to investigate the apoptotic activity of crude extracts of the herb as well as the possible molecular pathways. We incubated human promyelocytic leukemia cell line HL60 cells with ethanol or aqueous extracts of the herb, and determined the levels of intracellular superoxide at 2 and 4 hours as well as caspase activity at 3, 6 and 8 hours using photospectrometry. Cancer cell survival and apoptosis were quantified at 24 hours by using MTT and flow cytometry analyses respectively. We found that it dose-dependently inhibited the cancer cell growth in MTT assay. Flow cytometry analysis revealed that it elicited significant production of sub-G(1) population of the cells, indicating the extract-evoked cell apoptotic death. The LD(50) of the ethanol extract was estimated to be approximately 320 microg/ml. Moreover, treatment of the cancer cells with the ethanol component markedly increased the production of superoxide within few hours. Significant elevation in the protease activities of caspases-2 and -3 were detected at as early as 3 and 6 hours respectively. Our results show that the ethanol extract of the herb effectively evokes cancer cell apoptosis, possibly through burst-mediated caspase activation.


Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and alpha1-syntrophin mediated by PDZ domains.
Neuronal nitric oxide synthase (nNOS) is concentrated at synaptic junctions in brain and motor endplates in skeletal muscle. Here, we show that the N-terminus of nNOS, which contains a PDZ protein motif, interacts with similar motifs in postsynaptic density-95 protein (PSD-95) and a related novel protein, PSD-93.nNOS and PSD-95 are coexpressed in numerous neuronal populations, and a PSD-95/nNOS complex occurs in cerebellum. PDZ domain interactions also mediate binding of nNOS to skeletal muscle syntrophin, a dystrophin-associated protein. nNOS isoforms lacking a PDZ domain, identified in nNOSdelta/delta mutant mice, do not associate with PSD-95 in brain or with skeletal muscle sarcolemma. Interaction of PDZ-containing domains therefore mediates synaptic association of nNOS and may play a more general role in formation of macromolecular signaling complexes.


The Physiological Assessment and Analysis of the Physical Demand of Riding a Snowmobile.
Insufficient physical activity (PA) is associated with numerous chronic diseases and premature mortality, and the challenge of meeting recommended PA guidelines is exacerbated in the winter. Snowmobiling can potentially contribute to PA accumulation, but the objective metabolic and physical demands are unclear. The purpose of this study was to assess the physical demands of riding a snowmobile. Habitual snowmobile riders responded to a survey describing a typical ride (n = 4015). Using this data, terrain-specific testing courses were created, and recreational snowmobile riders (n = 40) participated in a scaled representative ride (21 [8] min) while aerobic metabolism (VO2) and muscular fatigue were quantified. The mean VO2 while riding, irrespective of terrain, was 18.5 (8.4) mL·kg-1·min-1, with significant differences based on geographic location (13.4 [5.2] vs 25.7 [6.6] mL·kg-1·min-1, P < .001). Muscular fatigue was apparent in maximal handgrip (-7% [8%], P < .001) across both riding terrains, but not lower body power, suggesting a greater influence of an upper body strength component. Snowmobiling is an activity that generally falls within the moderate-intensity activity range and involves both aerobic fitness and muscular strength. There were substantial differences in demand between terrains, suggesting that additional benefits may be conferred from mountain riding as it was more metabolically demanding.


Tablet-Based Intervention for Reducing Children's Preoperative Anxiety: A Pilot Study.
To examine the feasibility, acceptability, and effects of a novel tablet-based application, Story-Telling Medicine (STM), in reducing children's preoperative anxiety. Children (N = 100) aged 7 to 13 years who were undergoing outpatient surgery were recruited from a local children's hospital. This study comprised 3 waves: Waves 1 (n = 30) and 2 (n = 30) examined feasibility, and Wave 3 (n = 40) examined the acceptability of STM and compared its effect on preoperative anxiety to Usual Care (UC). In Wave 3, children were randomly allocated to receive STM+UC or UC. A change in preoperative anxiety was measured using the Children's Perioperative Multidimensional Anxiety Scale (CPMAS) 7 to 14 days before surgery (T1), on the day of surgery (T2), and 1 month postoperatively (T3). Wave 1 demonstrated the feasibility of participant recruitment and data collection procedures but identified challenges with attrition at T2 and T3. Wave 2 piloted a modified protocol that addressed attrition and increased the feasibility of follow-up. In Wave 3, children in the STM+UC demonstrated greater reductions in CPMAS compared with the UC group (ΔM = 119.90, SE = 46.36, t(27) = 2.59, p = .015; 95% confidence interval = 24.78-215.02). This pilot study provides preliminary evidence that STM is a feasible and acceptable intervention for reducing children's preoperative anxiety in a busy pediatric operative setting and supports the investigation of a full-scale randomized controlled trial.


In situ characterization of inflammatory responses in the rectal mucosae of patients with shigellosis.
Shigella species cause bacillary dysentery in humans by invading epithelial cells of the colonic mucosa leading to colonic epithelial cell destruction and inflammation. For further analysis of local gut inflammation, morphological changes and the potential involvement of mediators in regulatory mechanisms of cell activation and cell proliferation were studied immunohistochemically in rectal mucosal biopsies taken from patients during the acute phase of shigellosis and at convalescence. Rectal biopsies from 25 Shigella dysenteriae-1 and 10 Shigella flexneri-infected patients and from 40 controls were studied. The frequencies of proliferative cells (Ki67-positive cells), p53-immunostaining cells, and cells coexpressing Ki67 with CD3 or with p53 were analyzed. Immunostaining for the inducible nitric oxide synthase (iNOS) and the endothelial NOS was assessed. In addition, the frequencies of apoptotic cells and CD68+ cells that engulf apoptotic cells were assessed. By morphological grading, 20% of the patients had advanced inflammation (grade 3) in the acute phase; mild inflammation (grade 1) was seen in 37% of the patients at convalescence as well as in 10% of the controls. The findings in the present study suggest that in the acute phase of shigellosis inflammation is characterized by increased cell turnover in the lamina propria (LP) and the epithelium, increased iNOS expression in the surface epithelium, and apoptosis, which seems to be associated with LP macrophages. The findings also suggest that neither p53 nor iNOS are important factors for the induction of apoptosis in shigellosis. Expression of p53 may be related to early cell activation in crypt epithelium. Moreover, there is an indication of an active, low-level inflammatory process at convalescence. The results thus indicate that Shigella-induced inflammation is associated with a complex series of cellular reactions in the rectal gut mucosa which persist long after clinical symptoms have resolved.


Range of Normal Liver Stiffness and Factors Associated With Increased Stiffness Measurements in Apparently Healthy Individuals.
Transient elastography (TE) is a noninvasive technique used to measure liver stiffness to estimate the severity of fibrosis. The range of liver stiffness measurements (LSMs) in healthy individuals is unclear. We performed a systematic review to determine the range of LSMs, examined by TE, in healthy individuals and individuals who are susceptible to fibrosis. We collected data from 16,082 individuals, in 26 cohorts, identified from systematic searches of Embase, Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for studies of liver stiffness measurements. Studies analyzed included apparently healthy adults (normal levels of liver enzymes, low-risk alcohol use patterns, and negative for markers of viral hepatitis). The presence of diabetes, hypertension, dyslipidemia, or steatosis, based on ultrasound examination, was known for most participants. We performed a meta-analysis of data from individual participants. The cohort was divided into 4 groups; participants with a body mass index <30 kg/m2 were examined with the medium probe and those with a body mass index ≥30 kg/m2 were examined with the extra-large probe. Linear regression models were conducted after adjusting for potential confounding factors of LSMs. We performed several sensitivity analyses. We established LSM ranges for healthy individuals measured with both probes-these did not change significantly in sensitivity analyses of individuals with platelets ≥150,000/mm3 and levels of alanine aminotransferase ≤33 IU/L in men or ≤25 IU/L in women. In multivariate analysis, factors that modified LSMs with statistical significance included diabetes, dyslipidemia, waist circumference, level of aspartate aminotransferase, and systolic blood pressure at examination time. Significant increases in LSMs were associated with the metabolic syndrome in individuals examined by either probe. Diabetes in obese individuals increased the risk of LSMs in the range associated with advanced fibrosis. In a systematic review and meta-analysis of data from individual participants, we established a comprehensive set of LSM ranges, measured by TE in large cohorts of healthy individuals and persons susceptible to hepatic fibrosis. Regression analyses identified factors associated with increased LSMs obtained by TE with the medium and extra-large probes.


Impact of peer review on discussion of study limitations and strength of claims in randomized trial reports: a before and after study.
In their research reports, scientists are expected to discuss limitations that their studies have. Previous research showed that often, such discussion is absent. Also, many journals emphasize the importance of avoiding overstatement of claims. We wanted to see to what extent editorial handling and peer review affects self-acknowledgment of limitations and hedging of claims. Using software that automatically detects limitation-acknowledging sentences and calculates the level of hedging in sentences, we compared the submitted manuscripts and their ultimate publications of all randomized trials published in 2015 in 27 BioMed Central (BMC) journals and BMJ Open. We used mixed linear and logistic regression models, accounting for clustering of manuscript-publication pairs within journals, to quantify before-after changes in the mean numbers of limitation-acknowledging sentences, in the probability that a manuscript with zero self-acknowledged limitations ended up as a publication with at least one and in hedging scores. Four hundred forty-six manuscript-publication pairs were analyzed. The median number of manuscripts per journal was 10.5 (interquartile range 6-18). The average number of distinct limitation sentences increased by 1.39 (95% CI 1.09-1.76), from 2.48 in manuscripts to 3.87 in publications. Two hundred two manuscripts (45.3%) did not mention any limitations. Sixty-three (31%, 95% CI 25-38) of these mentioned at least one after peer review. Changes in mean hedging scores were negligible. Our findings support the idea that editorial handling and peer review lead to more self-acknowledgment of study limitations, but not to changes in linguistic nuance.


Macromolecular changes in nilotinib resistant K562 cells; an in vitro study by Fourier transform infrared spectroscopy.
Nilotinib is a second generation tyrosine kinase inhibitor which is used in both first and second line treatment of chronic myeloid leukemia (CML). In the present work, the effects of nilotinib resistance on K562 cells were investigated at the molecular level using Fourier transform infrared (FT-IR) spectroscopy. Human K562 CML cells were exposed to step-wise increasing concentrations of nilotinib, and sub-clones of K562 cells resistant to 50nM nilotinib were generated and referred to as K562/NIL-50 cells. Antiproliferative effects of nilotinib were determined by XTT cell proliferation assay. Changes in macromolecules in parental and resistant cells were studied by FT-IR spectroscopy. Nilotinib resistance caused significant changes which indicated increases in the level of glycogen and membrane/lipid order. The amount of unsaturated lipids increased in the nilotinib resistant cells indicating lipid peroxidation. The total amount of lipids did not change significantly but the relative proportion of cholesterol and triglycerides altered considerably. Moreover, the transcriptional status decreased but metabolic turn-over increased as revealed by the FT-IR spectra. In addition, changes in the proteome and structural changes in both proteins and the nucleus were observed in the K562/NIL-50 cells. Protein secondary structural analyses revealed that alpha helix structure and random coil structure decreased, however, anti-parallel beta sheet structure, beta sheet structure and turns structure increased. These results indicate that the FT-IR technique provides a method for analyzing drug resistance related structural changes in leukemia and other cancer types.


Ecology of Pseudallescheria and Scedosporium species in human-dominated and natural environments and their distribution in clinical samples.
This study aims to determine the occurrence of Pseudallescheria and Scedosporium species in natural and human-dominated environments. Habitats (136 sampling sites) in a transect with increasing human impact were investigated (natural areas, agricultural soils, urban playgrounds, industrial areas). Physico-chemical parameters were measured to characterize the different areas included in this investigation. Fungal identification was performed by morphology and sequence data analysis. Comparative description of virulence was largely based on the database of the ECMM/ISHAM Working Group on Pseudallescheria/Scedosporium Infections. Pseudallescheria and Scedosporium species were most abundant in industrial areas, followed by urban playgrounds and agricultural areas. None of the species were isolated from natural habitats. The abundance of Pseudallescheria and Scedosporium species could be correlated with increasing nitrogen concentrations (P<0.01) and decreasing pH (P<0.05) within a pH range of 6.1-7.5. In general, frequency of the different Pseudallescheria and Scedosporium species in the environment is strongly enhanced by human activities, and largely differs from species distribution in clinical settings, suggesting that these species have different degrees of virulence. Pseudallescheria boydii is relatively frequently found as agent of human disease, while Scedosporium dehoogii is found almost exclusively in the environment. Scedosporium apiospermum is responsible for the majority of infections and is found at comparable frequency in the environment; S. aurantiacum and P. minutispora showed similar spectra, but at much lower frequencies.


The detection of changes in mammographic densities.
We previously reported reductions in mammographic densities in women participating in a trial of a gonadotropin-releasing hormone agonist (GnRHA)-based regimen for breast cancer prevention. In our previous report, we compared (by simultaneous evaluation) three basic elements of mammographic densities. The purpose of the present study was to evaluate whether a standard (expert) method of measuring mammographic densities would detect such changes in densities and whether a novel nonexpert computer-based threshold method could do so. Mammograms were obtained from 19 women at baseline and 12 months after randomization to the GnRHA-based regimen. The extent of mammographic densities was determined by: (a) a standard expert outlining method developed by Wolfe and his colleagues (Am. J. Roentgenol., 148: 1087-1092, 1987); and (b) a new computer-based threshold method of determining densities. The results from both the expert outlining method and the computer-based threshold method were highly consistent with the results of our original (simultaneous evaluation) method. All three methods yielded statistically significant reductions in densities from baseline to the 12-month follow-up mammogram in women on the contraceptive regimen. The difference between the treated and the control group was statistically significant with the expert outlining method and was of borderline statistical significance with the computer-based threshold method. The computer-based results correlated highly (r > 0.85) with the results from the expert outlining method. Both the standard expert outlining method and the computer-based threshold method detected the reductions we had previously noted in mammographic densities induced by the GnRHA-based regimen.


Muscular force in running turkeys: the economy of minimizing work.
During running, muscles and tendons must absorb and release mechanical work to maintain the cyclic movements of the body and limbs, while also providing enough force to support the weight of the body. Direct measurements of force and fiber length in the lateral gastrocnemius muscle of running turkeys revealed that the stretch and recoil of tendon and muscle springs supply mechanical work while active muscle fibers produce high forces. During level running, the active muscle shortens little and performs little work but provides the force necessary to support body weight economically. Running economy is improved by muscles that act as active struts rather than working machines.


Mapping allostery through the covariance analysis of NMR chemical shifts.
Allostery is a fundamental mechanism of regulation in biology. The residues at the end points of long-range allosteric perturbations are commonly identified by the comparative analyses of structures and dynamics in apo and effector-bound states. However, the networks of interactions mediating the propagation of allosteric signals between the end points often remain elusive. Here we show that the covariance analysis of NMR chemical shift changes caused by a set of covalently modified analogs of the allosteric effector (i.e., agonists and antagonists) reveals extended networks of coupled residues. Unexpectedly, such networks reach not only sites subject to effector-dependent structural variations, but also regions that are controlled by dynamically driven allostery. In these regions the allosteric signal is propagated mainly by dynamic rather than structural modulations, which result in subtle but highly correlated chemical shift variations. The proposed chemical shift covariance analysis (CHESCA) identifies interresidue correlations based on the combination of agglomerative clustering (AC) and singular value decomposition (SVD). AC results in dendrograms that define functional clusters of coupled residues, while SVD generates score plots that provide a residue-specific dissection of the contributions to binding and allostery. The CHESCA approach was validated by applying it to the cAMP-binding domain of the exchange protein directly activated by cAMP (EPAC) and the CHESCA results are in full agreement with independent mutational data on EPAC activation. Overall, CHESCA is a generally applicable method that utilizes a selected chemical library of effector analogs to quantitatively decode the binding and allosteric information content embedded in chemical shift changes.


The role of education in explaining and forecasting trends in functional limitations among older Americans.
Using the Survey of Income and Program Participation, we document the importance of education in accounting for declines in functional limitations among older Americans from 1984 to 1993. Of the eight demographic and socioeconomic variables considered, education is most important in accounting for recent trends. The relationship between educational attainment and functioning has not changed measurably, but educational attainment has increased greatly during this period. Our analysis suggests, all else being equal, that future changes in education will continue to contribute to improvements in functioning, although at a reduced rate.


Medical negligence and wrongful birth actions: Australian developments.
Wrongful birth actions aim to compensate litigants who are negligently deprived by health professionals of their right to reproductive choice. Access to safe and legal abortion is integral to the action and wrongful birth claims in the United Kingdom have been facilitated by the Abortion Act 1967 (as amended). The recent Australian case CES v Superclinics (1995) 38 NSWLR 47 shows how judicial confusion about the legality of abortion can result in judges condoning medical negligence. The Superclinics case also suggests that doctors are not required to provide pregnant women with the same standard of care as other patients. These developments show that law can become incoherent and health professionals can act negligently with impunity when reproductive choice does not have a secure legal foundation.


Hospital fall prevention: a systematic review of implementation, components, adherence, and effectiveness.
To systematically document the implementation, components, comparators, adherence, and effectiveness of published fall prevention approaches in U.S. acute care hospitals. Systematic review. Studies were identified through existing reviews, searching five electronic databases, screening reference lists, and contacting topic experts for studies published through August 2011. U.S. acute care hospitals. Studies reporting in-hospital falls for intervention groups and concurrent (e.g., controlled trials) or historic comparators (e.g., before-after studies). Fall prevention interventions. Incidence rate ratios (IRR, ratio of fall rate postintervention or treatment group to the fall rate preintervention or control group) and ratings of study details. Fifty-nine studies met inclusion criteria. Implementation strategies were sparsely documented (17% not at all) and included staff education, establishing committees, seeking leadership support, and occasionally continuous quality improvement techniques. Most interventions (81%) included multiple components (e.g., risk assessments (often not validated), visual risk alerts, patient education, care rounds, bed-exit alarms, and postfall evaluations). Fifty-four percent did not report on fall prevention measures applied in the comparison group, and 39% neither reported fidelity data nor described adherence strategies such as regular audits and feedback to ensure completion of care processes. Only 45% of concurrent and 15% of historic control studies reported sufficient data to compare fall rates. The pooled postintervention incidence rate ratio (IRR) was 0.77 (95% confidence interval = 0.52-1.12, P = .17; eight studies; I(2) : 94%). Meta-regressions showed no systematic association between implementation intensity, intervention complexity, comparator information, or adherence levels and IRR. Promising approaches exist, but better reporting of outcomes, implementation, adherence, intervention components, and comparison group information is necessary to establish evidence on how hospitals can successfully prevent falls.


Purification and characterization by fast-atom-bombardment mass spectrometry of the polymorphonuclear-leucocyte-elastase-generated A alpha (1-21) fragment of fibrinogen from human blood after incubation with calcium ionophore A23187.
The stimulation of human blood with a Ca2+ ionophore, A23187, leads to activation of polymorphonuclear leucocytes (PMN) with release of small amounts of catalyticaly active elastase, as demonstrated by the formation of a characteristic product, the N-terminal A alpha (1-21) peptide of the Aa subunit of fibrinogen. The identity of the peptide was initially established by radioimmunoassay (r.i.a.) with an antibody raised to A alpha (1-21). We now provide independent confirmation of the formation of A alpha (1-21) by fast-atom-bombardment-m.s. analysis of the fractions separated chromatographically after spiking of plasma samples with peptide labelled with [2H8]Phe at position 8. Identity of the peptides was established on the basis of their chromatographic retention time and by the distinct peaks in the mass spectra of these fractions. The relative intensities of the molecular ions of natural and labelled peptides were measured. On the basis of a comparison of the peaks of similar intensities, the concentration of the natural peptide at the time of spiking was close (79%) to the amount obtained by r.i.a. An additional peptide, des-alanyl-A alpha (2-21), was also seen. The total amount of material measured by r.i.a. could be accounted for by the sum of these two provides. The addition of label and assay by m.s. has provided an independent physical-chemical method for identifying A alpha (1-21) as a characteristic product of PMN elastase release in whole blood, but which is absent in freshly drawn blood.


Cervical cancer: a meta-analysis, therapy and future of nanomedicine.
Cervical cancer is one of the leading causes of female death, with an annual mortality rate exceeding 200,000 in developing communities. Despite the past decade bearing witness to a reduction in cervical cancer cases throughout developed countries, the prevalence in developing countries continues to rapidly rise. The increase in cervical cancer cases is attributed to the lack of financial resources and the unavoidable risk factors of the disease. Traditional means of anticancer therapy are compromised by reduced drug potency, non-specificity, negative side effects and the development of multiple drug resistance (MDR), which leads to a decrease in the long-term anticancer therapeutic efficacy. Recent advances in nanomedicine have elucidated the potential of nanoparticles to reduce the side effects and improve the survival rate of patients, by enhancing selective delivery and uptake of photosensitive, therapeutic and genetic material to cervical cancer cells, thereby enhancing antitumour efficiency. This review paper analyses the risk factors and epidemiology of cervical cancer globally, especially in developing communities, whilst demonstrating the enhanced anticancer treatment using selected nanoparticles.


Fruit and vegetable intakes are associated with lower risk of colorectal adenomas.
Many phytochemicals in fruits and vegetables have been shown to have cancer-inhibitory effects in animal studies. These effects on cancer, however, have not been clearly demonstrated in human studies. This study investigated the association between fruit and vegetable intakes and the risk of adenomatous polyps. Participants were part of the Tennessee Colorectal Polyp Study. Eligible participants aged 40-75 y were recruited from patients undergoing colonoscopy at 2 medical centers in Nashville, Tennessee from 2003 to 2005. Cases had at least one adenoma and controls were polyp free. Dietary intake was assessed using a self-administered FFQ. Associations between dietary intakes and adenoma risk were evaluated using unconditional logistic regression with restricted cubic function spline. In multivariate analyses of 764 cases and 1517 controls, increased intakes of total fruits, berries, fruit juice, and green leafy vegetables were associated with reduced adenoma risk. The odds ratio for upper tertile intake compared with lower was 0.66 (95% CI = 0.51-0.86) for total fruits, 0.64 (95% CI = 0.47-0.87) for berries, 0.72 (95% CI = 0.56-0.92) for fruit juice, and 0.74 (95% CI = 0.58-0.96) for green vegetables. This study provides additional evidence that high total fruit intake and certain fruit and vegetable intakes may be associated with a reduced risk of colorectal adenomas.


Congenital Heart Disease and Risk of Suicide and Self-Harm: A Danish Nationwide Cohort Study.
Background In this nationwide study, we used the unique Danish registries to estimate the risk of suicide and deliberate self-harm in patients with congenital heart disease (CHD). Methods and Results We identified all Danish citizens receiving a diagnosis of CHD between 1977 and 2007. As a reference cohort, we randomly selected 10 citizens for each patient, matched by sex and birth year. Using the Fine and Gray competing risk regression, we estimated the cumulative incidences of suicide and self-harm, and Cox proportional regression analysis was used to compare the risk of suicide and deliberate self-harm in patients with CHD with the reference cohort. We identified 14 433 patients with CHD. Mean follow-up was 21.3 years, with a maximum follow-up of 42 years. Since the time of diagnosis, 2659 patients had died, with a median age of death of 23 years. A total of 15 patients had died by suicide, compared with 232 suicides in the reference cohort. Patients with CHD had a low and similar risk of dying by suicide when compared with the reference cohort (cause-specific hazard ratio, 0.81; 95% CI, 0.48-1.37; and subhazard ratio, 0.68; 95% CI, 0.41-1.16). We identified 336 events of self-harm among patients with CHD, and 3484 events in the reference group. The overall risk of deliberate self-harm was not increased in patients with CHD when compared with the reference group (subhazard ratio, 0.95; 95% CI, 0.85-1.06). Conclusions This is the first study to estimate the risk of suicide and deliberate self-harm in patients with CHD. We found that patients with CHD do not have an increased risk of suicide or deliberate self-harm when compared with a large reference cohort.


The diagnostic value of the diatom test for drowning, II. Validity: analysis of diatoms in bone marrow and drowning medium.
In part two of this series, we investigated the characteristics of diatom frustules recovered from bone marrow and samples of putative drowning medium in case of freshwater drownings. A total of 52 cases of freshwater drowning with diatoms in the femoral bone marrow in which a sample of the putative drowning medium was also collected were available for analysis. The same types of diatoms were found in the bone marrow and putative drowning medium in 47 cases (90%) indicating that the water samples were representative of the site of drowning in at least 90% of freshwater drownings. In the remaining 5 cases (10%), the diatoms in the water samples did not match those in the bone marrow indicating that the site of body and water sample recovery were likely geographically remote from the site of drowning. In cases with matching diatoms in the bone marrow and drowning medium, the diatoms were consistently the smallest and most abundant types represented in the water samples. In addition, there were highly stereotyped physical characteristics of typical "drowning-associated" diatoms with small pennate diatoms representing the most common type of frustule found in the bone marrow. In an additional 34 cases of putative drowning in water that lacked detectable diatoms, 29 cases (85%) lacked diatoms in the bone marrow. Analysis of the diatom content of samples of putative drowning medium by month revealed that winter months had the highest frequency of samples devoid of diatoms. These data indicate that the true positive rate of the diatom test for drowning is at least 90% and that small pennate frustules are most commonly associated with drowning, particular in non winter months.


[Endovascular treatment of ischemic heart disease in patients with multivessel coronary artery disease: immediate and long-term results].
Immediate and long-term results of endovascular treatment of multivessel coronary artery disease by using different revascularization strategies were analyzed in 171 patients. Duration of follow up ranged from 12 to 18 months. Complete myocardium revascularization was performed in 63 patients, culprit vessel revascularization--in 86 pts and incomplete revascularization--in 22 pts. Results of this study showed that strategy of complete and culprit vessel revascularization in patients with multivessel coronary artery disease has comparable immediate and long-term results. Strategy of incomplete revascularization reduce immediate clinical success and lead to increased number of myocardial infarctions and needs of coronary artery bypass surgery in long-term follow-up period.


ESS: A Tool for Genome-Scale Quantification of Essentiality Score for Reaction/Genes in Constraint-Based Modeling.
Genome-scale metabolic models (GEMs) are comprehensive descriptions of cell metabolism and have been extensively used to understand biological responses in health and disease. One such application is in determining metabolic adaptation to the absence of a gene or reaction, i.e., essentiality analysis. However, current methods do not permit efficiently and accurately quantifying reaction/gene essentiality. Here, we present Essentiality Score Simulator (ESS), a tool for quantification of gene/reaction essentialities in GEMs. ESS quantifies and scores essentiality of each reaction/gene and their combinations based on the stoichiometric balance using synthetic lethal analysis. This method provides an option to weight metabolic models which currently rely mostly on topologic parameters, and is potentially useful to investigate the metabolic pathway differences between different organisms, cells, tissues, and/or diseases. We benchmarked the proposed method against multiple network topology parameters, and observed that our method displayed higher accuracy based on experimental evidence. In addition, we demonstrated its application in the wild-type and ldh knock-out E. coli core model, as well as two human cell lines, and revealed the changes of essentiality in metabolic pathways based on the reactions essentiality score. ESS is available without any limitation at https://sourceforge.net/projects/essentiality-score-simulator.


Pf155/RESA protein influences the dynamic microcirculatory behavior of ring-stage Plasmodium falciparum infected red blood cells.
Proteins exported by Plasmodium falciparum to the red blood cell (RBC) membrane modify the structural properties of the parasitized RBC (Pf-RBC). Although quasi-static single cell assays show reduced ring-stage Pf-RBCs deformability, the parameters influencing their microcirculatory behavior remain unexplored. Here, we study the dynamic properties of ring-stage Pf-RBCs and the role of the parasite protein Pf155/Ring-Infected Erythrocyte Surface Antigen (RESA). Diffraction phase microscopy revealed RESA-driven decreased Pf-RBCs membrane fluctuations. Microfluidic experiments showed a RESA-dependent reduction in the Pf-RBCs transit velocity, which was potentiated at febrile temperature. In a microspheres filtration system, incubation at febrile temperature impaired traversal of RESA-expressing Pf-RBCs. These results show that RESA influences ring-stage Pf-RBCs microcirculation, an effect that is fever-enhanced. This is the first identification of a parasite factor influencing the dynamic circulation of young asexual Pf-RBCs in physiologically relevant conditions, offering novel possibilities for interventions to reduce parasite survival and pathogenesis in its human host.


Pregnancy outcome following maternal exposure to pregabalin may call for concern.
To investigate pregnancy outcomes following maternal use of pregabalin. This multicenter, observational prospective cohort study compared pregnancy outcomes in women exposed to pregabalin with those of matched controls (not exposed to any medications known to be teratogenic or to any antiepileptic drugs). Teratology Information Services systematically collected data between 2004 and 2013. Data were collected from 164 exposed pregnancies and 656 controls. A significantly higher major birth defect rate in the pregabalin group was observed after exclusion of chromosomal aberration syndromes, and when cases with exposure during first trimester of pregnancy were analyzed separately (7/116 [6.0%] vs 12/580 [2.1%]; odds ratio 3.0, 95% confidence interval 1.2-7.9, p = 0.03). The rate of live births was lower in the pregabalin group (71.9% vs 85.2%, p < 0.001), primarily due to a higher rate of both elective (9.8% vs 5.0%, p = 0.02) and medically indicated (5.5% vs 1.8%, p = 0.008) pregnancy terminations. In the Cox proportional cause specific hazards model, pregabalin exposure was not associated with a significantly higher risk of spontaneous abortion. This study demonstrated a signal for increased risk of major birth defects after first trimester exposure to pregabalin. However, several limitations such as the small sample size, differences across groups in maternal conditions, and concomitant medication exposure exclude definitive conclusions, so these results call for confirmation through independent studies.


Lanthanides in molecular magnetism: so fascinating, so challenging.
Due to their usual large magnetic moments and large magnetic anisotropy lanthanide ions are investigated for the search of Single Molecule Magnets with high blocking temperature. However, the low symmetry crystal environment, the complexity of the electronic states or the non-collinearity of the magnetic anisotropy easy-axes in polynuclear systems make the rationalization of the magnetic behaviour of lanthanide based molecular systems difficult. In this perspective article we expose a methodology in which the use of additional characterization techniques, like single crystal magnetic measurements or luminescence experiments, complemented by relativistic ab initio calculations and a suitable choice of spin Hamiltonian models, can be of great help in order to overcome such difficulties, representing an essential step for the rational design of lanthanide based Single Molecule Magnets with enhanced physical properties.


Optical properties, spectral, and lifetime measurements of central nervous system tumors in humans.
A key challenge of central nervous system tumor surgery is to discriminate between brain regions infiltrated by tumor cells and surrounding healthy tissue. Although monitoring of autofluorescence could potentially be an efficient way to provide reliable information for these regions, we found little information on this subject, and thus we conducted studies of brain tissue optical properties. This particular study focuses on the different optical quantitative responses of human central nervous system tumors and their corresponding controls. Measurements were performed on different fixed human tumoral and healthy brain samples. Four groups of central nervous system tumors (glioblastoma, diffuse glioma, meningioma and metastasis) were discriminated from healthy brain and meninx control tissues. A threshold value was found for the scattering and absorption coefficient between tumoral and healthy groups. Emission Spectra of healthy tissue had a significant higher intensity than tumoral groups. The redox and optical index ratio were thenn calculated and these also showed significant discrimination. Two fluorescent molecules, NADH and porphyrins, showed distinct lifetim values among the different groups of samples. This study defines several optical indexes that can act as combinated indicators to discriminate healthy from tumoral tissues.


Ultrasonography of borderline and asymmetric infant hips - a challenge in the management of developmental dysplasia of the hip.
Developmental dysplasia of the hip (DDH) is a potentially disabling disease. There are many diagnostic approaches, Graf method ultrasonography being the most popular imaging method. Although considered as a healthy condition, the existence of hips at the 60 degree limit or the asymmetries higher than 4 degrees between left and right side may be a source of unfavorable evolution and consequently of late diagnosed dysplasia cases. The retrospective study was conducted in the Radiology Department of the Emergency Clinical County Hospital Cluj-Napoca, by retrospective analysis of the database containing 3013 records of the subjects presented for DDH assessment between January 2008 and December 2014. The study focuses on investigating two possible sources of missed cases by clinical-ultrasound management of DDH: borderline and asymmetric hips. Two conditions were studied in patients considered healthy according to Graf method: borderline hips (those with α angle value of 60° and 61°) and asymmetric hips (left to right difference between the α angle values exceeds 4°). Three study groups were formed: healthy subjects, asymmetric/borderline subjects and patients with immature or mild dysplasia. The incidence of risk factors, clinical suspicion and the success of therapy were evaluated. There were no significant differences between the three groups regarding the role of the risk factors in DDH pathogenesis. Data reveal a high suspicion rate after the clinical examination, in groups II and III, compared to the healthy population. This means that from this point of view, Group II might be considered having at least a dysplastic prognosis. An increased correlation in the therapeutic results was observed between Group II patients and those from mild delayed maturation subgroups from Group III (IIa-, IIa+). Asymmetric and borderline hips should be approached similarly to immature hips, clinical suspicion and the therapeutic outcome being similar.


Characterization of the effects of ryanodine, TTX, E-4031 and 4-AP on the sinoatrial and atrioventricular nodes.
To characterize the effects of inhibition of Ryanodine receptor (RyR), TTX-sensitive neuronal Na+ current (iNa), "rapidly activating" delayed rectifier K+ current (iKr) and ultrarapid delayed rectifier potassium current (IKur) on the pacemaker activity of the sinoatrial node (SAN) and the atrioventricular node (AVN) in the mouse. The structure of mouse AVN was studied by histology and immunolabelling of Cx43 and hyperpolarization-activated, cyclic nucleotide-binding channels (HCN). The effects of Ryanodine, TTX, E-4031 and 4-AP on pacemaker activities recorded from mouse intact SAN and AVN preparations have been investigated. Immuno-histological characterization delineated the structure of the AVN showing the similar molecular phenotype of the SAN. The effects of these inhibitors on the cycle length (CL) of the spontaneous pacemaker activity of the SAN and the AVN were characterized. Inhibition of RyR by 0.2 and 2 microM Ryanodine prolonged CL by 42+/-12.3% and 64+/-18.1% in SAN preparations by 163+/-72.3% and 241+/-91.2% in AVN preparations. Inhibition of TTX-sensitive iNa by 100 nM TTX prolonged CL by 22+/-6.0% in SAN preparations and 53+/-13.6% in the AVN preparations. Block of iKr by E-4031 prolonged CL by 68+/-12.5% in SAN preparations and 28+/-3.4% in AVN preparations. Inhibition of iKur by 50 microM 4-AP prolonged CL by 20+/-3.4% in SAN preparations and 18+/-3.0% in AVN preparations. Mouse SAN and AVN showed distinct different response to the inhibition of RyR, TTX-sensitive INa, IKr and iKur, which reflects the variation in contribution of these currents to the pacemaker function of the cardiac nodes in the mouse. Our data provide valuable information for developing virtual tissue models of mouse SAN and AVN.


Endopolygalacturonase is essential for citrus black rot caused by Alternaria citri but not brown spot caused by Alternaria alternata.
Alternaria citri, the cause of Alternaria black rot, and Alternaria alternata rough lemon pathotype, the cause of Alternaria brown spot, are morphologically indistinguishable pathogens of citrus: one causes rot by macerating tissues and the other causes necrotic spots by producing a host-selective toxin. To evaluate the role of endopolygalacturonase (endoPG) in pathogenicity of these two Alternaria spp. pathogens, their genes for endoPG were mutated by gene targeting. The endoPGs produced by these fungi have similar biochemical properties, and the genes are highly similar (99.6% nucleotide identity). The phenotypes of the mutants, however, are completely different. An endoPG mutant of A. citri was significantly reduced in its ability to cause black rot symptoms on citrus as well as in the maceration of potato tissue and could not colonize citrus peel segments. In contrast, an endoPG mutant of A. alternata was unchanged in pathogenicity. The results indicate that a cell wall-degrading enzyme can play different roles in the pathogenicity of fungal pathogens. The role of a cell wall-degrading enzyme depends upon the type of disease but not the taxonomy of the fungus.


Online Discovery of Search Objectives for Test-Based Problems.
In test-based problems, commonly approached with competitive coevolutionary algorithms, the fitness of a candidate solution is determined by the outcomes of its interactions with multiple tests. Usually, fitness is a scalar aggregate of interaction outcomes, and as such imposes a complete order on the candidate solutions. However, passing different tests may require unrelated "skills," and candidate solutions may vary with respect to such capabilities. In this study, we provide theoretical evidence that scalar fitness, inherently incapable of capturing such differences, is likely to lead to premature convergence. To mitigate this problem, we propose disco, a method that automatically identifies the groups of tests for which the candidate solutions behave similarly and define the above skills. Each such group gives rise to a derived objective, and these objectives together guide the search algorithm in multi-objective fashion. When applied to several well-known test-based problems, the proposed approach significantly outperforms the conventional two-population coevolution. This opens the door to efficient and generic countermeasures to premature convergence for both coevolutionary and evolutionary algorithms applied to problems featuring aggregating fitness functions.


NH4+ transport in acid-secreting insect epithelium.
The relationship between ammonia secretion (JAmm), hydrogen ion secretion (JH), and intracellular pH (pHi) was investigated in isolated locust (Schistocerca gregaria) rectal epithelia mounted as flat sheets in specially designed Ussing chambers. In the absence of exogenous CO2 and ammonia, the rectum is capable of net acid and ammonia secretion into the lumen against pH gradients of up to 1.8 U. JAmm was dependent on the presence of luminal amino acids and Na+ and it was relatively unaffected by K+ removal or changes in membrane potential. JAmm and pHi remained fairly constant over a luminal pH range of 7-5, whereas JH decreased linearly to zero over the same pH range. Mucosal addition of 1 mM amiloride reduced JAmm by 60%. This study demonstrates that the locust rectum secretes significant quantities of endogenously produced ammonia preferentially into the lumen as NH+4 rather than NH3. Moreover, the results suggest that the ammonia crosses the apical membrane via an amiloride-inhibitable Na+-NH+4 exchange mechanism.


LK6, a short lived protein kinase in Drosophila that can associate with microtubules and centrosomes.
A number of polyclonal mouse sera were raised against Drosophila proteins that bound to microtubules in vitro (Kellogg et al. (1989) J. Cell Biol. 109, 2977-2991). Some of these sera recognised centrosomes in vivo, and we have been using these to screen expression libraries to isolate cDNAs encoding these putative centrosomal microtubule-associated proteins. Here we report the cloning of one such cDNA that encodes a novel serine/threonine protein kinase called LK6. The protein appears to exist in two forms: an abundant 185 kDa form and a rarer approximately 220 kDa form that interacts with microtubules. At least some of the LK6 protein is located in centrosomes at all stages of the cell cycle in fly embryos. Interestingly, the protein contains a PEST-like sequence and is rapidly turned over in vivo. Constitutive overexpression of LK6 is deleterious to flies and causes defects in microtubule organisation in both eggs and early embryos, whereas constitutive overexpression of a mutant form containing a point mutation that severely impairs the kinase activity is without effect. These findings suggest that LK6 may play a role in regulating microtubule function.


Soft Tissue and Bone Defect Management in Total Sacrectomy for Primary Sacral Tumors: A Systematic Review With Expert Recommendations.
Systematic review and expert consensus. To address the following two questions: (A) Is there a difference in outcomes after spino-pelvic reconstruction of total sacrectomy defects compared with no reconstruction? (B) What constitutes best surgical technique for soft tissue and bony reconstruction after total sacrectomy? The management of the soft tissue and bony defect after total sacrectomy for primary sacral tumors remains a challenge due to the complex anatomical relationships and biomechanical requirements. The scarcity of evidence-based literature in this specialized field makes it difficult for the treating surgeon to make an informed choice. A systematic literature review was performed (1950-2015), followed by a meeting of an international expert panel. Medline, Embase, and CINAHL databases and Cochrane Libraries were searched. Using the GRADE guidelines, the panel of experts formulated recommendations based on the available evidence. Three hundred fifty-three studies were identified. Of these, 17 studies were included and were case series. Seven were evaluated as high quality of evidence and nine were of low quality. There were a total of 116 participants. Three studies included patients (n = 24) with no spino-pelvic reconstruction. One study included patients (n = 3) with vascularized bone reconstruction. Twelve studies included patients (n = 80) with no soft tissue reconstruction, three studies described patients with a local flap (n = 20), and four studies with patients having regional flap reconstruction (n = 16). Patients with or without spino-pelvic reconstruction had similar outcomes with regards to walking; however, most patients in the nonreconstructed group had some ilio-lumbar ligamentous stability preserved. The wound dehiscence and return to theater rates were higher in patients with no soft tissue reconstruction. We recommend spino-pelvic reconstruction be undertaken with soft tissue reconstruction after total sacrectomy. N/A.


Effects of Stem Cell Factor on Cell Homing During Functional Pulp Regeneration in Human Immature Teeth.
Conventional root canal treatment in immature permanent teeth can lead to early tooth loss in children because root formation is discontinued. We investigated whether the stem cell factor (SCF) could facilitate cell homing in the pulpless immature root canal and promote regeneration of a functional pulp. In vitro, human mesenchymal stem cells (hMSCs) were exposed to SCF at various concentrations for assessing cell migration, proliferation, and differentiation toward odonto/osteoblasts by 3D-chemotaxis slides, WST-1 assay, and alkaline phosphatase activity, respectively. Fibrin gels were used to deliver 15 μg/mL SCF for in vivo experiments. The release kinetic of SCF was assessed in vitro. Two corresponding human immature premolars, with or without SCF, were placed at rat calvariae for 6 and 12 weeks. All tooth specimens were either analyzed histologically and the percentage of tissue ingrowth determined or the cells were extracted from the pulp space, and the mRNA level of DMP1, DSPP, Col1, NGF, and VEGF were assessed by quantitative polymerase chain reaction. In the presence of SCF, we saw an increase in hMSCs directional migration, proliferation, and odonto/osteogenic differentiation. SCF also increased the extent of tissue ingrowth at 6 weeks but not at 12 weeks. However, at this time point, the formed tissue appeared more mature in samples with SCF. In terms of gene transcription, DMP1, Col1, and VEGF were the significantly upregulated genes, while DSPP and NGF were not affected. Our results suggest that SCF can accelerate cell homing and the maturation of the pulp-dentin complex in human immature teeth.


Effects of imipramine hydrochloride on the EEG of children with Attention-Deficit/Hyperactivity Disorder who are non-responsive to stimulants.
Although stimulant medications are the most commonly-used treatments for Attention-Deficit/Hyperactivity Disorder (AD/HD), as many as 20% of treated children do not respond clinically to stimulants. One non-stimulant medication that has been widely used when the stimulants fail is a tricyclic antidepressant, imipramine hydrochloride. This study investigated the effects of imipramine on the EEG of children with AD/HD who were poor responders to dexamphetamine and ritalin, but who showed clinical improvement on a six month trial of imipramine. An initial pre-medication EEG was recorded during an eyes-closed resting condition, with data Fourier transformed to provide absolute and relative power estimates for the delta, theta, alpha and beta bands. A second EEG was recorded at the end of the imipramine trial. Compared to controls, the unmedicated AD/HD children had significant global increases in absolute and relative theta, with decreased global absolute and relative alpha, increased posterior relative delta, and decreased posterior absolute beta. No change in the EEG was found as a result of administering the medication. These results suggest that good responders to imipramine have an underlying EEG abnormality different from that in children who respond to the stimulants, and that an initial pre-treatment EEG may be useful in selecting a trial medication. However, as no change in the EEG was found with imipramine, it is unlikely that the EEG will be useful in evaluating responsivity to this medication.


Comment on "Proton transport in barium stannate: classical, semi-classical and quantum regimes" by G. Geneste, A. Ottochian, J. Hermet and G. Dezanneau, Phys. Chem. Chem. Phys., 2015, 17, 19104.
In a recent paper in this journal, proton transport in oxides was considered in terms of density functional theory and the non-adiabatic Flynn-Stoneham approach of small polaron type proposed much earlier for metals. Also, regimes of hydrogen diffusion relevant to oxides were reviewed, but the straightforwardly observable channel of low-temperature over-barrier jumps has passed unnoticed. We offer this latter possibility, together with some additional arguments, to make our objection more compelling. There are two major contentious findings in the article. First, in discussing the phonon-assisted quantum regime and the adiabatic coincidence configuration in barium stannate, the article claimed that the models based on a fully non-adiabatic picture for metals cannot be generalized to proton-conducting oxides. It is difficult to agree with such a viewpoint because such generalizations are being published. By means of a counterexample, this comment illustrates the real efficacy of using Flynn-Stoneham-like models in studying these oxides. Second, we have strong grounds for supposing that the main claim of the paper being commented on about the adiabatic nature of the proton transfer is in conflict with general interpretation of small polaron hopping. The exact knowledge of energy barriers for proton transfer is needed to confirm the validity of assuming an adiabatic regime. Since the most likely influence of the functional on the adiabaticity criterion formulation is certainly evident, comparison of the results of Geneste et al. to results obtained with higher functionals may check the validity of the present GGA-PBE scheme.


Screening for Atrial Fibrillation During Automatic Blood Pressure Measurements.
Atrial fibrillation (Afib) contributes significantly to overall cardiovascular risk. Widespread screening for Afib in primary care is sometimes performed by palpation, but suffers from low accuracy and is dependent on clinician experience. Algorithms implemented on oscillometric blood pressure devices can detect Afib with high sensitivity and specificity, but information on factors affecting accuracy is scant. Concurrent diagnostic electrocardiogram (ECG) and oscillometry were measured in participants in ECG clinics at two sites. Root mean squared successive difference (RMSSD) and irregularity index (Irrx) were calculated from oscillometric data and used to train logistic regression classifiers. Monte Carlo cross validation with 20 splits was performed to estimate confidence intervals for mean sensitivity and specificity, with various weightings, in the absence or presence of ectopics, and with or without repeated measurements. 707 measurements, including 168 Afib, were collected from 569 participants with mean (standard deviation) age of 63 (16) years. Sensitivity/specificity of RMSSD and Irrx were 0.982/0.908 and 0.986/0.960 respectively when ectopics were included. Excluding ectopics from the data improved specificity by up to 5%. Nevertheless, based on this performance and after accounting for prevalence of Afib in the population aged over 60 years, and estimated costs of healthcare, oscillometric screening for Afib in this age group could return a positive net health-economic benefit.


Preoperative Controlling Nutritional Status Score Predicts Mortality after Hepatectomy for Hepatocellular Carcinoma.
Preoperative nutritional status is reportedly associated with postoperative outcomes in patients with hepatocellular carcinoma. This study aimed to investigate the significance of the controlling nutritional status (CONUT) score and the prognostic nutritional index (PNI) as predictors of postoperative outcomes. We retrospectively reviewed data from 331 patients who underwent hepatectomy for hepatocellular carcinoma between January 2007 and December 2015. Patients were divided into 2 groups based on their CONUT score and the PNI. We evaluated the effect of the CONUT score and PNI on perioperative outcomes. Multivariate analysis was performed to identify independent predictors of in-hospital mortality after hepatectomy. -Results: The high CONUT group had a significantly higher -incidence of 30-day mortality (p < 0.001), in-hospital mortality (p = 0.002), ascites (p = 0.006), liver failure (p = 0.02), sepsis (p = 0.01), and enteritis (p < 0.001). The low PNI group was also significantly associated with 30-day mortality (p < 0.001), in-hospital mortality (p = 0.003), liver failure (p < 0.001), sepsis (p = 0.02), enteritis (p = 0.02), and hospital stay (p = 0.01). In multivariate analyses, a high CONUT score was an independent predictor of in-hospital mortality after hepatectomy (hazard ratio [HR] 9.41, p = 0.038), but the PNI was not (HR 5.86, p = 0.08). Preoperative assessment of the CONUT score is helpful for evaluating patients' nutritional status and mortality risk after liver surgery.


Reconstruction of the Genetic History and the Current Spread of HIV-1 Subtype A in Germany.
HIV-1 non-B infections have been increasing in Europe for several years. In Germany, subtype A belongs to the most abundant non-B subtypes showing an increasing prevalence of 8.3% among new infections in 2016. Here we trace the origin and examine the current spread of the German HIV-1 subtype A epidemic. Bayesian coalescence and birth-death analyses were performed with 180 German HIV-1 pol sequences and 528 related and publicly available sequences to reconstruct the population dynamics and fluctuations for each of the transmission groups. Our reconstructions indicate two distinct sources of the German subtype A epidemic, with an Eastern European and an Eastern African lineage both cocirculating in the country. A total of 13 German-origin clusters were identified; among these, 6 clusters showed recent activity. Introductions leading to further countrywide spread originated predominantly from Eastern Africa when introduced before 2005. Since 2005, however, spreading introductions have occurred exclusively within the Eastern European clade. Moreover, we observed changes in the main route of subtype A transmission. The beginning of the German epidemic (1985 to 1995) was dominated by heterosexual transmission of the Eastern African lineage. Since 2005, transmissions among German men who have sex with men (MSM) have been increasing and have been associated with the Eastern European lineage. Infections among people who inject drugs dominated between 1998 and 2005. Our findings on HIV-1 subtype A infections provide new insights into the spread of this virus and extend the understanding of the HIV epidemic in Germany.IMPORTANCE HIV-1 subtype A is the second most prevalent subtype worldwide, with a high prevalence in Eastern Africa and Eastern Europe. However, an increase of non-B infections, including subtype A infections, has been observed in Germany and other European countries. There has simultaneously been an increased flow of refugees into Europe and especially into Germany, raising the question of whether the surge in non-B infections resulted from this increased immigration or whether German transmission chains are mainly involved. This study is the first comprehensive subtype A study from a western European country analyzing in detail its phylogenetic origin, the impact of various transmission routes, and its current spread. The results and conclusions presented provide new and substantial insights for virologists, epidemiologists, and the general public health sector. In this regard, they should be useful to those authorities responsible for developing public health intervention strategies to combat the further spread of HIV/AIDS.


The impact of cigarette deprivation and cigarette availability on cue-reactivity in smokers.
This experiment was conducted to determine the impact of cigarette deprivation and cigarette availability on reactivity measures to cigarette cues. Smokers were recruited who were 18 years of age or older, not attempting to quit or cut down on their smoking, smoked at least 20 cigarettes daily, had been smoking regularly for past year and had an expired carbon monoxide level of at least 10 parts per million. Smokers were assigned randomly to abstain from smoking for 24 hours (n = 51) or continue smoking their regular amount (n = 50). Twenty-four hours later, they were exposed to trials of either a lit cigarette or a glass of water with a 0, 50 or 100% probability of being able to sample the cue on each trial. Craving, mood, heart rate, skin conductance, puff topography and latency to access door to sample the cue were measured. Both exposure to cigarette cues and increasing availability of those cues produced higher levels of craving to smoke. Deprivation produced a generalized increase in craving. There was no consistent evidence, however, that even under conditions of high cigarette availability, deprived smokers were sensitized selectively to presentations of cigarette cues. The data suggest that, even under conditions of immediate cigarette availability, deprivation and cue presentations have independent, additive effects on self-reported craving levels in smokers.


Molecular determinants involved in differential behaviour between soluble tissue factor and full-length tissue factor towards factor VIIa.
During blood-coagulation, the transmembrane protein tissue factor (TF) binds to its ligand, factor (F)VII, activating and allosterically modifying it to form a mature active binary complex (TF-FVIIa). Although the extracellular domain of TF (sTF) can bind to FVII, it fails to activate it. Binding of TF with FVIIa only partially enhances FVIIa proteolytic activity. Our previous kinetic study revealed that sTF has a lower binding capacity with FVIIa compared to membrane bound full-length (fl)TF. The reason behind this incapability of FVII activation and reduced catalytic activity remains unexplored due to the lack of an flTF crystal structure. Here we employed a comparative dynamic study between sTF-FVIIa in solution and flTF-FVIIa in a membrane system to give probable explanations for the differential behaviour of these complexes. Based on potential of mean force and interaction energy calculations, the binding affinities between sTF and FVIIa are weaker than those of the flTF-FVIIa complex. We further observed domain-wise less stability, reduced height, and thus less inter and intra-domain interaction between the sTF and FVIIa complexes. We detected higher fluctuation among the inter-atomic distances of the catalytic triad (CT) residues in sTF-FVIIa over the flTF-FVIIa complex. The flTF-FVIIa complex forms two major interactions between EGF2 and TF. We showed the enhanced activity of the flTF-FVIIa complex over the sTF-FVIIa complex, which is guided by mainly two interactions between EGF2 and TF. Due to the lack of these interactions, sTF-FVIIa somehow forms a less stable binary complex and could not react upon binding its substrates (FIX, FX). Our study, for the first time, provides a possible explanation of the distinct behaviour of the two forms of TF (sTF and flTF) towards its only ligand FVII/FVIIa.


Safety and effectiveness of placement of pacemaker and defibrillator leads in the axillary vein guided by contrast venography.
Despite evidence of an increased incidence of lead fracture, the infraclavicular subclavian approach remains the dominant approach for placement of pacemaker and implantable defibrillator leads. Although this complication can be prevented by lead placement in the cephalic vein or by recently described approaches for lead placement in the axillary vein, these approaches have not gained widespread acceptance. The purpose of this study was to evaluate the safety and efficacy of an alternative technique for lead placement that uses contrast-guided venipuncture of the axillary vein with a 5Fr micropuncture introducer set. A total of 50 patients underwent an attempt at placement of pacemaker or implantable defibrillator leads via the axillary vein using this new technique. Patients were randomized into 2 groups based on whether the initial attempt at axillary vein access was performed medial or lateral to the rib cage margin. Lead placement was successfully accomplished in 49 of the 50 patients using this technique. Initial success was achieved in each of 25 patients randomized to the medial approach compared with 18 of 24 patients randomized to the lateral approach to the axillary vein (75%). In each of the 6 patients in whom the initial technique failed, lead placement was subsequently achieved with the medial approach. In addition to a higher initial success rate, the medial approach was determined to be preferable as evidenced by a shorter lead placement time, a smaller number of contrast injections, and a reduced requirement for additional micropuncture guidewires. There were no major complications associated with either approach. Contrast-guided venipuncture of the axillary vein is a safe and effective approach to placement of endocardial leads.


[Pseudomonas aeruginosa: spread of antimicrobial resistance in hospital effluent and surface water].
The aim of this study was to compare sewage samples from Hospital São Vicente de Paulo with water samples from the Passo Fundo river, with regard to the susceptibility profile of Pseudomonas aeruginosa isolates, in order to make inferences about the presence of strains of hospital origin in surface water samples. The statistical significance between the susceptibility profiles of the samples was tested using analysis of variance, and the samples were compared by means of contrasts of interest. One hundred and ninety-eight isolates of Pseudomonas aeruginosa were recovered from the samples analyzed. No phenotype for multiresistance was found in the samples from the Passo Fundo river, although some carbapenem-resistant isolates were identified, thereby indicating the presence of contamination with bacteria derived from an environment under strong selection pressure. Significant differences between the water and hospital effluent samples were observed, based on the analysis of variance by means of contrasts of interest.


Treatments for traumatic brain injury with emphasis on transcranial near-infrared laser phototherapy.
Traumatic brain injury (TBI) is a growing health concern affecting civilians and military personnel. In this review, treatments for the chronic TBI patient are discussed, including pharmaceuticals, nutraceuticals, cognitive therapy, and hyperbaric oxygen therapy. All available literature suggests a marginal benefit with prolonged treatment courses. An emerging modality of treatment is near-infrared (NIR) light, which has benefit in animal models of stroke, spinal cord injury, optic nerve injury, and TBI, and in human trials for stroke and TBI. The extant literature is confounded by variable degrees of efficacy and a bewildering array of treatment parameters. Some data indicate that diodes emitting low-level NIR energy often have failed to demonstrate therapeutic efficacy, perhaps due to failing to deliver sufficient radiant energy to the necessary depth. As part of this review, we present a retrospective case series using high-power NIR laser phototherapy with a Class IV laser to treat TBI. We demonstrate greater clinical efficacy with higher fluence, in contrast to the bimodal model of efficacy previously proposed. In ten patients with chronic TBI (average time since injury 9.3 years) given ten treatments over the course of 2 months using a high-power NIR laser (13.2 W/0.89 cm(2) at 810 nm or 9 W/0.89 cm(2) at 810 nm and 980 nm), symptoms of headache, sleep disturbance, cognition, mood dysregulation, anxiety, and irritability improved. Symptoms were monitored by depression scales and a novel patient diary system specifically designed for this study. NIR light in the power range of 10-15 W at 810 nm and 980 nm can safely and effectively treat chronic symptoms of TBI. The clinical benefit and effects of infrared phototherapy on mitochondrial function and secondary molecular events are discussed in the context of adequate radiant energy penetration.


Ictal SPECT statistical parametric mapping in temporal lobe epilepsy surgery.
Although subtraction ictal SPECT coregistered to MRI (SISCOM) is clinically useful in epilepsy surgery evaluation, it does not determine whether the ictal-interictal subtraction difference is statistically different from the expected random variation between 2 SPECT studies. We developed a statistical parametric mapping and MRI voxel-based method of analyzing ictal-interictal SPECT difference data (statistical ictal SPECT coregistered to MRI [STATISCOM]) and compared it with SISCOM. Two serial SPECT studies were performed in 11 healthy volunteers without epilepsy (control subjects) to measure random variation between serial studies from individuals. STATISCOM and SISCOM images from 87 consecutive patients who had ictal SPECT studies and subsequent temporal lobectomy were assessed by reviewers blinded to clinical data and outcome. Interobserver agreement between blinded reviewers was higher for STATISCOM images than for SISCOM images (kappa = 0.81 vs kappa = 0.36). STATISCOM identified a hyperperfusion focus in 84% of patients, SISCOM in 66% (p < 0.05). STATISCOM correctly localized the temporal lobe epilepsy (TLE) subtypes (mesial vs lateral neocortical) in 68% of patients compared with 24% by SISCOM (p = 0.02); subgroup analysis of patients without lesions (as determined by MRI) showed superiority of STATISCOM (80% vs 47%; p = 0.04). Moreover, the probability of seizure-free outcome was higher when STATISCOM correctly localized the TLE subtype than when it was indeterminate (81% vs 53%; p = 0.03). Statistical ictal SPECT coregistered to MRI (STATISCOM) was superior to subtraction ictal SPECT coregistered to MRI for seizure localization before temporal lobe epilepsy (TLE) surgery. STATISCOM localization to the correct TLE subtype was prognostically important for postsurgical seizure freedom.


Evaluation of health benefits and harms of the breast cancer screening programme in the Basque Country using discrete event simulation.
Since the breast cancer screening programme in the Basque Country (BCSPBC) was started in 1996, more than 400,000 women aged 50 to 69 years have been invited to participate. Based on epidemiological observations and simulation techniques it is possible to extend observed short term data into anticipated long term results. The aim of this study was to assess the effectiveness of the programme through 2011 by quantifying the outcomes in breast cancer mortality, life-years gained, false positive results, and overdiagnosis. A discrete event simulation model was constructed to reproduce the natural history of breast cancer (disease-free, pre-clinical, symptomatic, and disease-specific death) and the actual observed characteristics of the screening programme during the evaluated period in the Basque women population. Goodness-of-fit statistics were applied for model validation. The screening effects were measured as differences in benefits and harms between the screened and unscreened populations. Breast cancer mortality reduction and life-years gained were considered as screening benefits, whereas, overdiagnosis and false positive results were assessed as harms. Results for a single cohort were also obtained. The screening programme yielded a 16 % reduction in breast cancer mortality and a 10 % increase in the incidence of breast cancer through 2011. Almost 2 % of all the women in the programme had a false positive result during the evaluation period. When a single cohort was analysed, the number of deaths decreased by 13 %, and 4 % of screen-detected cancers were overdiagnosed. Each woman with BC detected by the screening programme gained 2.5 life years due to early detection corrected by lead time. Fifteen years after the screening programme started, this study supports an important decrease in breast cancer mortality due to the screening programme, with reasonable risk of overdiagnosis and false positive results, and sustains the continuation of the breast cancer screening programme in the Basque population.


Early vaccinations are not risk factors for celiac disease.
To investigate if changes in the national Swedish vaccination program coincided with changes in the celiac disease (CD) incidence rate in infants (ie, the Swedish CD Epidemic), and to assess the potential association between these vaccinations and CD risk. All studies were based on the National Swedish Childhood Celiac Disease Register. Using an ecological approach, we plotted changes over time in the national vaccination program in the graph displaying CD incidence rate. A population-based incident case-referent study of invited infants was performed. Exposure information was received through a questionnaire and child health clinic records. Vaccines explored were diphtheria/tetanus, pertussis (acellular), polio (inactivated), Haemophilus influenzae type b (conjugated), measles/mumps/rubella, and live attenuated bacillus Calmette-Guérin (BCG) in children with increased tuberculosis risk. Findings were subjected to a birth cohort analysis. Introduction of pertussis vaccine coincided in time with decreasing CD incidence rates. In the infant case-referent study, however, neither vaccination against pertussis (odds ratio 0.91; 95% confidence interval 0.60-1.4), nor against Haemophilus influenzae type b or measles/mumps/rubella was associated with CD. Coverage for the diphtheria/tetanus and polio vaccines was 99%. BCG was associated with reduced risk for CD (adjusted odds ratio 0.54; 95% confidence interval 0.31-0.94). Discontinuation of general BCG vaccination did not affect the cumulative incidence of CD at age 15 years. Early vaccinations within the national Swedish program were not associated with CD risk, nor could changes in the program explain the Swedish epidemic. A protective effect by BCG was suggested, which could be subject to further studies.


HIV, infant feeding and more perils for poor people: new WHO guidelines encourage review of formula milk policies.
The release of the new WHO guidelines on HIV and infant feeding, in a global context of widespread impoverishment, requires countries to re-examine their infant-feeding policies in relation to broader socioeconomic issues. This widening scope is necessitated by compelling new reports on the scale of global underdevelopment in developing countries. This paper explores these issues by addressing feeding choices made by HIV-infected mothers and programmes supplying free formula milks within a global environment of persistent poverty. Accumulating evidence on the increase in malnutrition, morbidity and mortality associated with the avoidance or early cessation of breastfeeding by HIV-infected mothers, and the unanticipated hazards of formula feeding, demand a deeper assessment of the measures necessary for optimum policies on infant and child nutrition and for the amelioration of poverty. Piecemeal interventions that increase resources directed at only a fraction of a family's impoverishment, such as basic materials for preparation of hygienic formula feeds and making flawed decisions on choice of infant feeding, are bound to fail. These are not alternatives to taking fundamental steps to alleviate poverty. The economic opportunity costs of such programmes, the equity costs of providing resources to some and not others, and the leakages due to temptation to sell capital goods require careful evaluation. Providing formula to poor populations with high HIV prevalence cannot be justified by the evidence, by humanitarian considerations, by respect for local traditions or by economic outcomes. Exclusive breastfeeding, which is threatened by the HIV epidemic, remains an unfailing anchor of child survival.


Distribution of myocardial blood flow in the exercising dog with restricted coronary artery inflow.
The effect of a proximal coronary artery stenosis on transmural myocardial blood flow during exercise was studied in nine dogs with electromagnetic flowmeter probes and hydraulic occluders on the left circumflex coronary artery. Regional myocardial blood flow at rest and during treadmill exercise was estimated with radioactive microspheres 7-10 mum in diameter. Exercise studies were performed during unrestricted coronary artery inflow (control exercise) and during partial inflation of the occluder to a level which did not reduce flow at rest but which limited the increase in flow during exercise to 66 +/- 6% (mild restriction) or 44 +/- 3% (severe restriction) of the value during control exercise. Mean myocardial blood flow at rest was 0.94 +/- 0.06 ml/min per g of myocardium and increased to 2.45 +/- 0.15 ml/min per g during control exercise, with uniform distribution across the wall of the left ventricle. Flow to the subepicardial myocardium was significantly greater during exercise in the presence of a mild restriction than during control exercise, whereas flow to deeper layers of myocardium was progressively decreased below the control level. A similar pattern of redistribution of flow occurred during exercise in the presence of a severe restriction, but flow to all transmural layers was below that during mild restriction, resulting in more marked subendocardial underperfusion. Thus, exercise in the presence of stenosis resulted in transmural redistribution of myocardial blood flow with subendocardial underperfusion in proportion to the degree of restriction of coronary artery inflow.


Complications of syndesmotic screw removal.
Currently, the metallic syndesmotic screw is the gold standard in the treatment of syndesmotic disruption. Whether or not this screw needs to be removed remains debatable. The aim of the current study was to determine the complications which occur following routine removal of the syndesmotic screw following operative treatment of unstable ankle fractures. This was a retrospective study with consecutive cases in a Level-2 Trauma center. All patients with routine removal of a syndesmotic screw, following the treatment of an unstable ankle fracture, between January 1, 2004 and November 30, 2010 were included. Complications recorded were: 1) minor or major wound infection following removal of the syndesmotic screw, 2) recurrent syndesmotic diastasis, and 3) unnecessary removal of a broken screw, not recognized during preoperative planning prior to surgery. A total of 76 patients were included. A wound infection occurred in 9.2% (N = 7) of which 2.6% (N = 2) were deep infections requiring reoperation. Recurrent syndesmotic diastasis was found in 6.6% (N = 5) of patients, and in 6.6% (N = 5) screws were broken at the time of implant removal. In the group with recurrent diastasis the screws were removed significantly earlier compared with the group without recurrent diastasis (Mann-Whitney U-test; p = 0.011) and the group with screw breakage had their screws significantly longer in place compared with the group without breakage (p = 0.038). A total of 22.4% complications occurred upon routine removal of the syndesmotic screw. Removal might therefore be considered only in selected cases with complaints, after a minimum of eight to twelve weeks and using antibiotic prophylaxis during removal.


International partnerships and the development of a Sister Hospital Programme.
Despite some progress in meeting the Millennium Development Goals, there are still major discrepancies in health service provision between developed and developing countries. Nurses are key players to improving the quality of health services. Increasingly, partnerships are being initiated between nurses of different countries to enable those working in developing countries to improve standards of clinical care. This paper describes a partnership between two major teaching hospitals: one in Indonesia and one in Australia, designed to assist in improving standards of clinical care within the Indonesian hospital. The nature of the partnership, conceptualized as a Sister Hospital Program, is described. The processes and outcomes of the pilot programme conducted in 2011 are outlined. A brief description of the methods used to gain financial support from the Northern Territory Government is provided. The programme offered a skills development programme for selected staff from Sanglah General Hospital in Bali at Royal Darwin Hospital in northern Australia. The paper uses Green's PROCEED-PRECEDE framework both to describe and evaluate the pilot programme. The skills development programme was enthusiastically evaluated by staff from both hospitals and has led to major changes in the management of patients within the Emergency Department of Sanglah General Hospital. The success of the pilot has resulted in longer-term funding by the Australian government. WIDER POLICY OUTCOMES: The partnership model described in the paper is submitted as a possible framework for others wishing to build long-term and collaborative relationships between nurses of different nations.