Quantification of NO A-X (0, 2) laser-induced fluorescence: investigation of calibration and collisional influences in high-pressure flames.
Laser-induced-fluorescence techniques have been used successfully for quantitative two-dimensional measurements of nitric oxide. NO A-X(0, 2) excitation at 248 nm recently found applications in internal-combustion engines. We assess the collisional processes that influence quantification of signal intensities in terms of saturation, rotational energy transfer, and line broadening, using laminar high-pressure methane/air and n-heptane/air flames at pressures as high as 80 bars (8 x 10(6) Pa). A calibration method that is applicable in technical combustion systems based on addition of NO to the burning flame is investigated for various air/fuel ratios and pressures and yields information about the influence of NO reburn processes.


Identification of quantitative trait loci influencing wood specific gravity in an outbred pedigree of loblolly pine.
We report the identification of quantitative trait loci (QTL) influencing wood specific gravity (WSG) in an outbred pedigree of loblolly pine (Pinus taeda L.). QTL mapping in an outcrossing species is complicated by the presence of multiple alleles (> 2) at QTL and marker loci. Multiple alleles at QTL allow the examination of interaction among alleles at QTL (deviation from additive gene action). Restriction fragment length polymorphism (RFLP) marker genotypes and wood specific gravity phenotypes were determined for 177 progeny. Two RFLP linkage maps were constructed, representing maternal and paternal parent gamete segregations as inferred from diploid progeny RFLP genotypes. RFLP loci segregating for multiple alleles were vital for aligning the two maps. Each RFLP locus was assayed for cosegregation with WSG QTL using analysis of variance (ANOVA). Five regions of the genome contained one or more RFLP loci showing differences in mean WSG at or below the P = 0.05 level for progeny as grouped by RFLP genotype. One region contained a marker locus (S6a) whose QTL-associated effects were highly significant (P > 0.0002). Marker S6a segregated for multiple alleles, a prerequisite for determining the number of alleles segregating at the linked QTL and analyzing the interactions among QTL alleles. The QTL associated with marker S6a appeared to be segregating for multiple alleles which interacted with each other and with environments. No evidence for digenic epistasis was found among the five QTL.


Advances in the Sensing and Treatment of Wound Biofilms.
Wound biofilms represent a particularly challenging problem in modern medicine. They are increasingly antibiotic resistant and can prevent the healing of chronic wounds. However, current treatment and diagnostic options are hampered by the complexity of the biofilm environment. In this review, we present new chemical avenues in biofilm sensors and new materials to treat wound biofilms, offering promise for better detection, chemical specificity, and biocompatibility. We briefly discuss existing methods for biofilm detection and focus on novel, sensor-based approaches that show promise for early, accurate detection of biofilm formation on wound sites and that can be translated to point-of-care settings. We then discuss technologies inspired by new materials for efficient biofilm eradication. We focus on ultrasound-induced microbubbles and nanomaterials that can both penetrate the biofilm and simultaneously carry active antimicrobials and discuss the benefits of those approaches in comparison to conventional methods.


Histological Aspects of a Hypersensitive Response in Poplar to Melampsora larici-populina.
ABSTRACT The course of the infection and development of the biotrophic fungus Melampsora larici-populina on leaf tissue from the hybrid poplar Populus deltoides x P. nigra 'Ogy' was monitored at the histological level. Leaf disks were inoculated with one of two rust physiological races (E1 and E2), resulting in interactions that were either incompatible (race E1) or compatible (race E2). In the compatible interaction, the fungus rapidly colonized the leaf without inducing any apparent host response. Symptoms appeared on the leaf several days after inoculation just prior to spore dissemination. The incompatible interaction was characterized by the early collapse and disorganization of cytoplasm of infected cells 17 h after inoculation and within 2 h after the appearance of the first haustoria. Resistance to M. larici-populina was mediated through a hypersensitive response, since it was extremely localized and involved only the few cells that were in the immediate vicinity of each infected cell.


Principles of Child Health Care Financing.
After passage of the Patient Protection and Affordable Care Act, more children and young adults have become insured and have benefited from health care coverage than at any time since the creation of the Medicaid program in 1965. From 2009 to 2015, the uninsurance rate for children younger than 19 years fell from 9.7% to 5.3%, whereas the uninsurance rate for young adults 19 to 25 years of age declined from 31.7% to 14.5%. Nonetheless, much work remains to be done. The American Academy of Pediatrics (AAP) believes that the United States can and should ensure that all children, adolescents, and young adults from birth through the age of 26 years who reside within its borders have affordable access to high-quality and comprehensive health care, regardless of their or their families' incomes. Public and private health insurance should safeguard existing benefits for children and take further steps to cover the full array of essential health care services recommended by the AAP. Each family should be able to afford the premiums, deductibles, and other cost-sharing provisions of the plan. Health plans providing these benefits should ensure, insofar as possible, that families have a choice of professionals and facilities with expertise in the care of children within a reasonable distance of their residence. Traditional and innovative payment methodologies by public and private payers should be structured to guarantee the economic viability of the pediatric medical home and of other pediatric specialty and subspecialty practices to address developing shortages in the pediatric specialty and subspecialty workforce, to promote the use of health information technology, to improve population health and the experience of care, and to encourage the delivery of evidence-based and quality health care in the medical home, as well as in other outpatient, inpatient, and home settings. All current and future health care insurance plans should incorporate the principles for child health financing outlined in this statement. Espousing the core principle to do no harm, the AAP believes that the United States must not sacrifice any of the hard-won gains for our children. Medicaid, as the largest single payer of health care for children and young adults, should remain true to its origins as an entitlement program; in other words, future fiscal or regulatory reforms of Medicaid should not reduce the eligibility and scope of benefits for children and young adults below current levels nor jeopardize children's access to care. Proposed Medicaid funding "reforms" (eg, institution of block grant, capped allotment, or per-capita capitation payments to states) will achieve their goal of securing cost savings but will inevitably compel states to reduce enrollee eligibility, trim existing benefits (such as Early and Periodic Screening, Diagnostic, and Treatment), and/or compromise children's access to necessary and timely care through cuts in payments to providers and delivery systems. In fact, the AAP advocates for increased Medicaid funding to improve access to essential care for existing enrollees, fund care for eligible but uninsured children once they enroll, and accommodate enrollment growth that will occur in states that choose to expand Medicaid eligibility. The AAP also calls for Congress to extend funding for the Children's Health Insurance Program, a plan vital to the 8.9 million children it covered in fiscal year 2016, for a minimum of 5 years.


Optical mesosensors for monitoring and removal of ultra-trace concentration of Zn(II) and Cu(II) ions from water.
Optical captor design is necessary for the controlled development of a technique for detecting and removing heavy and toxic metals from drinking water with high flexibility and low capital cost. We designed chemical mesocaptors for optical separation/extraction and monitoring/detection of Cu(II) and Zn(II) ions from water even at trace concentration levels without a preconcentration process. The mesoporous aluminosilica carriers with three-dimensional (3D) structures, high aluminum content, natural surfaces, and active acid sites strongly induced H-bonding and dispersive interactions with organic moieties, thereby leading to the formation of stable captors without chromophore leaching during the removal assays of Cu(II) and Zn(II) ions. Using such a tailored mesocaptor design, the direct immobilization of these hydrophobic ligands (4,5-diamino-6-hydroxy-2-mercaptopyrimidine and diphenylthiocarbazone) into ordered pore-based aluminasilica monoliths enabled the easy generation and transduction of optical colour signals as a response to metal-to-ligand binding events, even at ultra-trace concentrations (~10(-9) mol dm(-3)) of Cu(II) and Zn(II) ions in drinking water, without the need for sophisticated instruments. Theoretical models have been developed to provide insights into the effect of active site surfaces on the enhancement of the optical removal process in terms of long-term stability, reversibility, and selectivity, hence allowing us to understand the role of mesoscopic geometry and nanoscale pore orientation of mesocaptors better. Generally, this ion-capture model enables the development of a simple and effective technique for effective wastewater treatment and management.


PROMIS Pain Interference and Physical Function Scores Correlate With the Foot and Ankle Ability Measure (FAAM) in Patients With Hallux Valgus.
Traditional patient-reported outcome instruments like the Foot and Ankle Ability Measure (FAAM) quantify patient disability but often are limited by responder burden and incomplete questionnaires. The Patient-Reported Outcome Measurement Information System (PROMIS) overcomes such obstacles through computer-adaptive technology and can capture outcome data from various domains including physical and psychosocial function. Prior work has compared the FAAM with PROMIS physical function; however, there is little evidence comparing the association between foot and ankle-specific tools like the FAAM with more general outcomes measures of PROMIS pain interference and depression in foot and ankle conditions. (1) We asked whether there was a relationship between FAAM Activities of Daily Living (ADL) scores with PROMIS physical function, pain interference, and depression in patients with hallux valgus. (2) Additionally, we asked if we could identify specific factors that are associated with variance in FAAM and PROMIS physical function scores in patients with hallux valgus. Eighty-five new patients with either a primary or secondary diagnosis of hallux valgus based on clinic billing codes from July 2015 to February 2016 were retrospectively identified. Patients completed FAAM ADL paper-based surveys and electronic PROMIS questionnaires for physical function, pain interference, and depression from new patient visits at a single time. Spearman rho correlations were performed between FAAM ADL and PROMIS scores. Analyses then were used to identify differences in FAAM ADL and PROMIS physical function measures based on demographic variables. Stepwise linear regressions then determined which demographic and/or outcome variable(s) accounted for the variance in FAAM ADL and PROMIS physical function scores. FAAM scores correlated strongly with PROMIS physical function (r = 0.70, p < 0.001), moderately with PROMIS pain interference (r = -0.65, p < 0.001), and weakly with PROMIS depression (r = -0.35, p < 0.001) scores. Regression analyses showed that PROMIS pain interference scores alone were associated with sizeable portions of the variance in FAAM ADL (R2 = 0.44, p < 0.001) and PROMIS physical function (R2 = 0.57, p < 0.001) measures. PROMIS function and pain measures correlated with FAAM ADL scores, highlighting the interrelationship of pain and function when assessing outcomes in patients with hallux valgus. PROMIS tools allow for more-efficient data collection across multiple domains and, moving forward, may be better poised to monitor changes in pain and function with time compared with traditional outcome measures like the FAAM. The relationships shown here between PROMIS and FAAM scores further support the use of PROMIS tools in outcomes-based research. In patients with hallux valgus, pain-related disability appears to be a central feature of the patient-experience. Future studies should assess the association of various outcome domains on other common foot and ankle diagnoses.


Androgens inhibit the stimulatory action of 17β-estradiol on normal human breast tissue in explant cultures.
The data concerning the effects and safety of androgen in human breast tissue are conflicting. Our aim was to analyze the effects of androgens on normal human breast tissue (HBT). We cultured explants of HBT (obtained from reduction mammoplasty operations of postmenopausal women) with or without testosterone (T) and 5α-dihydrotestosterone (DHT) or in combination with 17β-estradiol (E(2)) for 7 and 14 d to study the effects of androgens on proliferation, apoptosis, target gene expression, and steroid receptors. The androgen receptor (AR) and estrogen receptor (ER) dependences of the effects were studied with the antihormones bicalutamide and fulvestrant, respectively. The hormone responsiveness of cultured breast tissue was assessed by assaying apolipoprotein-D and prostate-specific antigen expression increased by androgens and amphiregulin and trefoil factor-1 expression induced by E(2) treatment. T and DHT reduced proliferation and increased apoptosis in breast epithelium, the effects of which were reversed by bicalutamide. In combination with E(2), they suppressed E(2)-stimulated proliferation and cell survival. DHT also inhibited basal (P < 0.05) and E(2)-induced expression of cyclin-D1 mRNA (P < 0.05). Immunohistochemistry showed that T (P < 0.05) and DHT (P < 0.05) increased the relative number of AR-positive cells, whereas ERα-positive (P < 0.001) cell numbers were strongly decreased. The percentage of ERβ-positive cells remained unchanged. E(2) treatment increased ERα-positive (P < 0.01) cells, whereas AR- (P < 0.05) and ERβ-expressing (P < 0.001) cells diminished. These effects were repressed in combination cultures of E(2) with T and DHT. T and DHT inhibited proliferation and increased apoptosis in the epithelium of cultured normal HBT and opposed E(2)-stimulated proliferation and cell survival in an AR-dependent manner. These effects were associated with changes in the proportions of ERα- and AR-positive epithelial cells.


Disruption of dynamic cell surface architecture of NIH3T3 fibroblasts by the N-terminal domains of moesin and ezrin: in vivo imaging with GFP fusion proteins.
Lamellipodia, filopodia, microspikes and retraction fibers are characteristic features of a dynamic and continuously changing cell surface architecture and moesin, ezrin and radixin are thought to function in these microextensions as reversible links between plasma membrane proteins and actin microfilaments. Full-length and truncated domains of the three proteins were fused to green fluorescent protein (GFP), expressed in NIH3T3 cells, and distribution and behaviour of cells were analysed by using digitally enhanced differential interference contrast (DIC) and fluorescence video microscopy. The amino-terminal (N-)domains of all three proteins localize to the plasma membrane and fluorescence recordings parallel the dynamic changes in cell surface morphology observed by DIC microscopy of cultured cells. Expression of this domain, however, significantly affects cell surface architecture by the formation of abnormally long and fragile filopodia that poorly attach and retract abnormally. Even more striking are abundant irregular, branched and motionless membraneous structures that accumulate during retraction of lamellipodia. These are devoid of actin, endogenous moesin, ezrin and radixin, but contain the GFP-labeled domain. While a large proportion of endogenous proteins can be extracted with non-ionic detergents as in untransfected control cells, >90% of N-moesin and >60% of N-ezrin and N-radixin remain insoluble. The minimal size of the domain of moesin required for membrane localization and change in behavior includes residues 1-320. Deletions of amino acid residues from either end result in diffuse intracellular distribution, but also in normal cell behavior. Expression of GFP-fusions of full-length moesin or its carboxy-terminal domain has no effect on cell behavior during the observation period of 6-8 hours. The data suggest that, in the absence of the carboxy-terminal domain, N-moesin, -ezrin and -radixin interact tightly with the plasma membrane and interfere with normal functions of endogeneous proteins mainly during retraction.


[Prevalence of Hepatitis B infection and risk factors in two groups of pregnant adolescents related to the number of sexual partners].
Hepatitis B has different routes of transmission and it is maintained in human populations mainly via transmission from person to person during intense physical contact, such as perinatal contact, contact during hetero and homosexual intercourse and non-sexual physical contact between children, their mothers and siblings.Migration from the provinces to the big cities of the country, added to changes in social behavior, specially among young people, have led to an increase in unprotected sexual encounters, with the resulting greater risk of contracting hepatitis B. We included 1048 adolescent women between the ages of 14 and 19, pregnant and apparently healthy, who came to the Perinatal Maternal Institute (IMP) between August 2003 and February 2004. The sample included 52 promiscuous pregnant young women with 3 or more sexual partners or contacts. After informed consent, they all filled a clinical epidemiological chart and a 5mL blood sample was taken to determine antiHBc IgG, HBsAg, HBeAg and anti-HBe using the third generation ELISA method. Sixty eight point seven percent (68.7%) were older than 16 years, 29.7% had not been born in Lima, 6.1% had been born in the jungle and 10.4% had lived in the jungle, 30.1% were from San Juan de Lurigancho. Fourteen point three percent (14.3%) referred having had two partners and 4.3% three or more, 5.4% had three or more sexual contacts and 61.5% said that their partner never used a condom. Over 98% referred that they had not had jaundice or Hepatitis A, B or C. Twelve point four percent (12.4%) of the partners were womanizers, 3.1% visited prostitutes, 8.4% had another partner, 23.3% said that they liked anal sex, 3% were alcoholics, 9% used drugs, 2% had been in jail and 5.7% had received blood transfusions. The prevalence of anti-HBc IgG was 3.53% and for HBsAg it was 0.67%. A statistically significant association (p<0.026) was found between the risk of infection and having been born elsewhere from Lima, with a history of jaundice (p<0.02) and with having lived in the jungle (p<0.001) and, surprisingly, with a history of hepatitis A (p<0.074). The application of the partner perception indicator established that when the partner had three or more infection risk factors compared to none, there was a 2.37 times greater risk of hepatitis B. The prevalence of HBV infection at the IMP has increased over the last 7 years by 18.45% and 76.31% the rate of HBsAg carriers. There was a positive correlation between HBV infection and the number of sexual partners, although it did not reach statistical significance. The risk indicator of the perception of the partners' sexual behavior is a marker of greater risk of HBV infection among those ranked as high risk.


The Public Access Defibrillation (PAD) trial: study design and rationale.
The PAD Trial is a prospective, multicenter, randomized clinical study testing whether volunteer, non-medical responders can improve survival from out-of-hospital cardiac arrest (OOH-CA) by using automated external defibrillators (AEDs). These lay volunteers, who have no traditional responsibility to respond to a medical emergency as part of their primary job description, will form part of a comprehensive, integrated community approach to the treatment of OOH-CA. The study is being conducted at 24 field centers in the United States and Canada. Approximately 1000 community units (e.g. apartment or office buildings, gated communities, sports facilities, senior centers, shopping malls, etc.) were randomized to treatment by trained laypersons who will provide either cardiopulmonary resuscitation (CPR) alone or CPR plus use of an AED, while awaiting arrival of the community's emergency medical services responders. The primary endpoint is the number of OOH-CA victims who survive to hospital discharge. Secondary endpoints include neurological status, health-related quality of life (HRQL), cost, and cost-effectiveness. Data collection will last approximately 15 months and is expected to be completed in September 2003.


Cytogenetic and molecular cytogenetic characterization of 6 new cases of idiopathic hypereosinophilic syndrome.
Idiopathic hypereosinophilic syndrome (HES) is defined as a peripheral blood eosiniphilia greater than 1, 500 cells/microL for longer than 6 months, absence of other apparent etiologies for eosinophilia and signs and symptoms of organ involvement. HES may be a reactive condition or a chronic myeloproliferative disorder but scanty information is available concerning its cytogenetic profile. Six patients with HES were studied by cytogenetic analysis. To increase the sensitivity of cytogenetic analysis, interphase FISH studies were performed to detect some cryptic chromosomal lesions involving the regions known to be frequently involved in myeloproliferative disorders (i.e. BCR/ABL, 5q31, 7q31.1, 11q23, 13q14, 17p13). Clinical parameters were recorded in all patients. A 3q deletion was detected in one patient; two unrelated clones with +14 and +11 were present in another patient who had a cryptic 5q31 deletion as disclosed by FISH; both patients had a mild clinical course. The 5q31 deletion was shown to involve the eosinophilic lineage and not the lymphoid cells. No chromosome abnormalities were found by karyotyping or interphase FISH in the remaining 4 cases. In two of these cases the clinical course was aggressive, with progressive leukocytosis and marked splenomegaly in one patient, central nervous system and cardiac involvement as well as bone marrow failure in the other. The 3q deletion, +11 and +14, and a cryptic 5q31 deletion involving the cells of the eosinophilic lineage are three novel chromosome abnormalities occurring in HES. We did not find a correlation between evolving or aggressive disease and the presence of chromosome anomalies. Our data confirm that HES is a clinically and biologically heterogeneous condition and suggest that more cases need to be studied to identify clinically significant chromosome changes in this rare condition. Some patients may benefit from treatment with interferon.


Colorectal cancer mouse models: integrating inflammation and the stroma.
Sequences of molecular events that initiate and advance the progression of human colorectal cancer (CRC) are becoming clearer. Accepting that these events, once they are in place, accumulate over time, rapid disease progression might be expected. Yet CRC usually develops slowly over decades. Emerging insights suggest that the tumor cell microenvironment encompassing fibroblasts and endothelial and immune cells dictate when, whether, and how malignancies progress. Signaling pathways that affect the microenvironment and the inflammatory response seem to play a central role in CRC. Indeed, some of these pathways directly regulate the stem/progenitor cell niche at the base of the crypt; it now appears that the survival and growth of neoplastic cells often relies upon their subverted engagement of these pathways. Spurned on by the use of gene manipulation technologies in the mouse, dissecting and recapitulating these complex molecular interactions between the tumor and its microenvironment in the gastrointestinal (GI) tract is a reality. In parallel, our ability to isolate and grow GI stem cells in vitro enables us, for the first time, to complement reductionist in vitro findings with complex in vivo observations. Surprisingly, data suggest that the large number of signaling pathways underpinning the reciprocal interaction between the neoplastic epithelium and its microenvironment converge on a small number of common transcription factors. Here, we review the separate and interactive roles of NFκB, Stat3, and Myb, transcription factors commonly overexpressed or excessively activated in CRC. They confer molecular links between inflammation, stroma, the stem cell niche, and neoplastic cell growth.


Biosynthesis of CMP-N,N'-diacetyllegionaminic acid from UDP-N,N'-diacetylbacillosamine in Legionella pneumophila.
Legionaminic acid is a nine-carbon alpha-keto acid that is similar in structure to other members of the sialic acid family that includes neuraminic acid and pseudaminic acid. It is found as a component of the lipopolysaccharide in several bacterial species and is perhaps best known for its presence in the O-antigen of the causative agent of Legionnaires' disease, Legionella pneumophila. In this work, the enzymes responsible for the biosynthesis and activation of N, N'-diacetyllegionaminic acid are identified for the first time. A cluster of three L. pneumophila genes bearing homology to known sialic acid biosynthetic genes ( neuA,B,C) were cloned and overexpressed in Escherichia coli. The NeuC homologue was found to be a hydrolyzing UDP- N, N'-diacetylbacillosamine 2-epimerase that converts UDP- N, N'-diacetylbacillosamine into 2,4-diacetamido-2,4,6-trideoxymannose and UDP. Stereochemical and isotopic labeling studies showed that the enzyme utilizes a mechanism involving an initial anti elimination of UDP to form a glycal intermediate and a subsequent syn addition of water to generate product. This is similar to the hydrolyzing UDP- N-acetylglucosamine 2-epimerase (NeuC) of sialic acid biosynthesis, but the L. pneumophila enzyme would not accept UDP-GlcNAc as an alternate substrate. The NeuB homologue was found to be a N, N'-diacetyllegionaminic acid synthase that condenses 2,4-diacetamido-2,4,6-trideoxymannose with phosphoenolpyruvate (PEP), although the in vitro activity of the recombinant enzyme (isolated as a MalE fusion protein) was very low. The synthase activity was dependent on the presence of a divalent metal ion, and the reaction proceeded via a C-O bond cleavage process, similar to the reactions catalyzed by the sialic acid and pseudaminic acid synthases. Finally, the NeuA homologue was shown to possess the CMP- N, N'-diacetyllegionaminic acid synthetase activity that generates the activated form of legionaminic acid used in lipopolysaccharide biosynthesis. Together, the three enzymes constitute a pathway that converts a UDP-linked bacillosamine derivative into a CMP-linked legionaminic acid derivative.


Comparative study of tongue protrusion in three iguanian lizards, Sceloporus undulatus, Pseudotrapelus sinaitus and Chamaeleo jacksonii.
The goal of this study was to investigate the function of the hyolingual muscles used during tongue protraction in iguanian lizards. High-speed videography and nerve-transection techniques were used to study prey capture in the iguanid Sceloporus undulatus, the agamid Pseudoptrapelus sinaitus and the chameleonid Chamaeleo jacksonii. Denervation of the mandibulohyoideus muscle slips had an effect only on P. sinaitus and C. jacksonii, in which tongue protrusion or projection distance was reduced. In C. jacksonii, denervation of the M. mandibulohyoideus completely prevented little hyoid protraction. Denervation of the M. verticalis had no effect on S. undulatus, but reduced tongue protrusion distance in P. sinaitus. Denervation of the accelerator muscle in C. jacksonii inhibited tongue projection completely. The function of the M. mandibulohyoideus and M. verticalis has become increasingly specialized in P. sinaitus and especially in C. jacksonii to allow greater tongue protrusion. The combined results of these treatments suggest that these three groups represent transitional forms, both morphologically and functionally, in the development of a projectile tongue.


Diagnostic and prognostic significance of cyclin A expression in low-grade astrocytomas: comparison with astrogliosis and high-grade tumours.
Definitive distinction between low-grade astrocytoma and astrogliosis is a long-standing difficulty due to their similar histopathological characteristics. To clarify differences in biological significance, this study focused on various components of the cell cycle machinery and proliferation as key parameters, comparing expression in astrogliosis, as well as low- and high-grade astrocytomas. The expression of p16, p21 and p27, and cyclin A, cyclin D1, cyclin E, Rb and Ki-67 was immunohistochemically examined in 40 cases of astrogliosis and 48 cases of low-grade astrocytomas (grade II), as well as 50 high-grade tumours (grades III and IV). The results were also compared with survival data for the astrocytomas. Cell proliferation determined by Ki-67 immunoreactivity did not differ between astrogliosis and low-grade tumours. Average labelling indices (LIs) for p16, p21, Rb, cyclin A and cyclin E showed a stepwise increase from astrogliosis, through low- to high-grade astrocytomas, indicating the possibility that over 9%, 6% and 4% of LIs for p16, p21 and cyclin A, respectively, may be useful predictors in the case of the latter, in contrast to significant decrease in p27 LIs. Significantly higher mean LI values for cyclin D1 were also evident in astrogliosis (12.42) as compared with astrocytomas (low grade, 2.26; high grade, 4.60). Positive correlations between LIs for Rb and Ki-67 were observed with astrogliosis and low- but not high-grade tumours. In addition, high cyclin A LI values were independently associated with poor outcome in low-grade tumours. These findings provide evidence that expression of cell-cycle-related molecules may be a reliable parameter for differential diagnosis of low-grade astrocytomas and astrogliosis. Moreover, detection of cyclin A appears to be useful for predicting behaviour of low-grade astrocytomas.


Induction of tolerance in rodent cardiac allotransplantation using an MHC class I-derived peptide and cyclosporin A.
The synthetic peptide corresponding to residues 75-84 of the human major histocompatibility complex class I molecule HLA-B7 (Allotrap 07) has been shown to inhibit differentiation of cytotoxic T lymphocyte precursors. Subsequent treatment of LEW-1A rats with this peptide was associated with a reduction in the level of cytotoxic activity directed to donor alloantigens. This study was undertaken to investigate the effect of Allotrap 07 on rodent heart allograft survival in LEW-1A recipients. Heart allografts from Lewis rats were heterotopically transplanted into the infrarenal abdominal aorta of ACI recipients. The treatment groups consisted of different regimens of short-term intravenous Allotrap 07 and oral cyclosporin A. All grafts were palpated daily, with rejection defined as the cessation of palpable contractions. Cardiac allografts transplanted from Lewis to ACI rats survived indefinitely after administration of intravenous Allotrap 07 and oral cyclosporin A. Tolerance induction was donor-specific because third-party Brown-Norway, but not Lewis, grafts were rapidly rejected after implantation into ACI recipients. Because donor-specific tolerance persisted long after cessation of peptide administration and did not occur when cyclosporin A was omitted from the immunosuppressive regimen, the mechanism may involve induction of clonal anergy.


Melatonin treatment in peri- and postmenopausal women elevates serum high-density lipoprotein cholesterol levels without influencing total cholesterol levels.
The purpose of this study was to investigate the effects of melatonin on lipid metabolism in peri- and postmenopausal women. Forty-six women were enrolled in these studies. The relationship between night-time serum melatonin levels and serum total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol was investigated in 36 women. Night-time serum melatonin levels had a negative correlation with serum total cholesterol and LDL-cholesterol, and a loose positive correlation with HDL-cholesterol. To examine the effects of exogenous melatonin on lipid metabolism, serum levels of total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides were determined in 10 women before the onset of therapy and after 1 month of oral melatonin administration (1 mg melatonin daily). Melatonin administration significantly increased the serum levels of HDL-cholesterol. These results show that melatonin may influence cholesterol metabolism and suggest that the melatonin administration may become a new medical application for improvement of lipid metabolism and prevention of cardiovascular disease in peri- and postmenopausal women.


Molecular genetic and functional characterization implicate muscle-restricted coiled-coil gene (MURC) as a causal gene for familial dilated cardiomyopathy.
Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are classic forms of systolic and diastolic heart failure, respectively. Mutations in genes encoding sarcomere and cytoskeletal proteins are major causes of HCM and DCM. MURC, encoding muscle-restricted coiled-coil, a Z-line protein, regulates cardiac function in mice. We investigated potential causal role of MURC in human cardiomyopathies. We sequenced MURC in 1199 individuals, including 383 probands with DCM, 307 with HCM, and 509 healthy control subjects. We found 6 heterozygous DCM-specific missense variants (p.N128K, p.R140W, p.L153P, p.S307T, p.P324L, and p.S364L) in 8 unrelated probands. Variants p.N128K and p.S307T segregated with inheritance of DCM in small families (χ(2)=8.5, P=0.003). Variants p.N128K, p.R140W, p.L153P, and p.S364L were considered probably or possibly damaging. Variant p.P324L recurred in 3 independent probands, including 1 proband with a TPM1 mutation (p.M245T). A deletion variant (p.L232-R238del) was present in 3 unrelated HCM probands, but it did not segregate with HCM in a family who also had a MYH7 mutation (p.L907V). The phenotype in mutation carriers was notable for progressive heart failure leading to heart transplantation in 4 patients, conduction defects, and atrial arrhythmias. Expression of mutant MURC proteins in neonatal rat cardiac myocytes transduced with recombinant adenoviruses was associated with reduced RhoA activity, lower mRNA levels of hypertrophic markers and smaller myocyte size as compared with wild-type MURC. MURC mutations impart loss-of-function effects on MURC functions and probably are causal variants in human DCM. The causal role of a deletion mutation in HCM is uncertain.


Updated systematic review of exercise studies in breast cancer survivors: attention to the principles of exercise training.
To update our previous evaluation of the exercise interventions used in randomised controlled trials of breast cancer survivors in relation to (1) the application of the principles of exercise training in the exercise prescription; (2) the reporting of the components of the exercise prescription; and (3) the reporting of adherence of participants to the prescribed interventions. Systematic review. The OVID Medline, Embase, CINAHL and SPORTDiscus electronic databases were searched from January 2010 to January 2017. Randomised controlled trials of at least 4 weeks of aerobic and/or resistance exercise in women diagnosed with breast cancer, reporting on physical fitness or body composition outcomes. Specificity was appropriately applied by 84%, progression by 29%, overload by 38% and initial values by 67% of newly identified studies. Reversibility was reported by 3% anddiminishing returns by 22% of newly identified studies. No studies reported all components of the exercise prescription in the methods, or adherence to the prescribed intervention in the results. Reporting of reversibility has increased from 2010, but no other improvements in reporting were noted from the previous review. No studies of exercise in women with breast cancer attended to all principles of exercise training, or reported all components of the exercise prescription in the methods, or adherence to the prescription in the results. Full reporting of the exercise prescribed and completed is essential for study replication in research and translating research findings into the community, and should be prioritised in future trials.


Targeting the stromal microenvironment in chronic inflammation.
A characteristic feature of chronic inflammatory reactions is their persistence and predilection for certain sites. The molecular basis for such tissue tropism (as, for example, seen with metastatic spread) has until recently remained obscure, but recent studies have strongly implicated tissue-resident, stromal cells, such as macrophages, endothelial cells and fibroblasts. These cell types make attractive therapeutic targets as they help define the three-dimensional structure of tissues and are key orchestrators of the inflammatory infiltrate. Most current anti-inflammatory therapies target immune cells in an attempt to inhibit the production of pro-inflammatory mediators; however, an equally important target is the active induction of anti-inflammatory mediators involved in the resolution of inflammation. Recent work suggests that stromal cells are an important source of these mediators. Targeting of multiple signals may be required to inhibit tissue damage associated with inflammatory disease. Cells of the monocyte lineage are present as tissue-resident cells and interact closely with other stromal populations. These cells form an ideal target for modulation of the inflammatory environment as, in some cases, they appear to induce tissue repair. Therapeutic manipulation of the stromal microenvironment has been particularly effective in treating cancer and is likely to provide a novel method to achieve improved control of chronic inflammatory disease.


Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019.
Reducing the burden of death due to infection is an urgent global public health priority. Previous studies have estimated the number of deaths associated with drug-resistant infections and sepsis and found that infections remain a leading cause of death globally. Understanding the global burden of common bacterial pathogens (both susceptible and resistant to antimicrobials) is essential to identify the greatest threats to public health. To our knowledge, this is the first study to present global comprehensive estimates of deaths associated with 33 bacterial pathogens across 11 major infectious syndromes. We estimated deaths associated with 33 bacterial genera or species across 11 infectious syndromes in 2019 using methods from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, in addition to a subset of the input data described in the Global Burden of Antimicrobial Resistance 2019 study. This study included 343 million individual records or isolates covering 11 361 study-location-years. We used three modelling steps to estimate the number of deaths associated with each pathogen: deaths in which infection had a role, the fraction of deaths due to infection that are attributable to a given infectious syndrome, and the fraction of deaths due to an infectious syndrome that are attributable to a given pathogen. Estimates were produced for all ages and for males and females across 204 countries and territories in 2019. 95% uncertainty intervals (UIs) were calculated for final estimates of deaths and infections associated with the 33 bacterial pathogens following standard GBD methods by taking the 2·5th and 97·5th percentiles across 1000 posterior draws for each quantity of interest. From an estimated 13·7 million (95% UI 10·9-17·1) infection-related deaths in 2019, there were 7·7 million deaths (5·7-10·2) associated with the 33 bacterial pathogens (both resistant and susceptible to antimicrobials) across the 11 infectious syndromes estimated in this study. We estimated deaths associated with the 33 bacterial pathogens to comprise 13·6% (10·2-18·1) of all global deaths and 56·2% (52·1-60·1) of all sepsis-related deaths in 2019. Five leading pathogens-Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae, and Pseudomonas aeruginosa-were responsible for 54·9% (52·9-56·9) of deaths among the investigated bacteria. The deadliest infectious syndromes and pathogens varied by location and age. The age-standardised mortality rate associated with these bacterial pathogens was highest in the sub-Saharan Africa super-region, with 230 deaths (185-285) per 100 000 population, and lowest in the high-income super-region, with 52·2 deaths (37·4-71·5) per 100 000 population. S aureus was the leading bacterial cause of death in 135 countries and was also associated with the most deaths in individuals older than 15 years, globally. Among children younger than 5 years, S pneumoniae was the pathogen associated with the most deaths. In 2019, more than 6 million deaths occurred as a result of three bacterial infectious syndromes, with lower respiratory infections and bloodstream infections each causing more than 2 million deaths and peritoneal and intra-abdominal infections causing more than 1 million deaths. The 33 bacterial pathogens that we investigated in this study are a substantial source of health loss globally, with considerable variation in their distribution across infectious syndromes and locations. Compared with GBD Level 3 underlying causes of death, deaths associated with these bacteria would rank as the second leading cause of death globally in 2019; hence, they should be considered an urgent priority for intervention within the global health community. Strategies to address the burden of bacterial infections include infection prevention, optimised use of antibiotics, improved capacity for microbiological analysis, vaccine development, and improved and more pervasive use of available vaccines. These estimates can be used to help set priorities for vaccine need, demand, and development. Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Health and Social Care, using UK aid funding managed by the Fleming Fund.


Understanding the influence of parent-clinician communication on antibiotic prescribing for children with respiratory tract infections in primary care: a qualitative observational study using a conversation analysis approach.
Acute respiratory tract infections (RTI) in children are a common reason for antibiotic prescribing. Clinicians' prescribing decisions are influenced by perceived parental expectations for antibiotics, however there is evidence that parents actually prefer to avoid antibiotics. This study aimed to investigate the influence of parent-clinician communication on antibiotic prescribing for RTI in children in England. A mixed methods analysis of videoed primary care consultations for children (under 12 years) with acute cough and RTI. Consultations were video-recorded in six general practices in southern England, selected for socio-economic diversity. 56 recordings were transcribed in detail and a subset of recordings and transcripts used to develop a comprehensive interaction-based coding scheme. The scheme was used to examine communication practices between parents and clinicians and how these related to antibiotic or non-antibiotic treatment strategies. Parents' communication rarely implied an expectation for antibiotics, some explicitly offering a possible viral diagnosis. Clinicians mostly gave, or implied, a viral diagnosis and mainly recommended non-antibiotic treatment strategies. In the minority of cases where parents' communication behaviours implied they may be seeking antibiotic treatment, antibiotics were not usually prescribed. Where clinicians did prescribe antibiotics, they voiced concern about symptoms or signs, including chest pain, discoloured phlegm, prolonged fever, abnormal chest sounds, or pink /bulging ear drums. We found little evidence of a relationship between parents' communication behaviours and antibiotic prescribing. Rather, where antibiotics were prescribed, this was associated with clinicians' expressed concerns regarding symptoms and signs.


Measurements of periodically perturbed dewetting force fields and their consequences on the symmetry of the resulting patterns.
We studied the origin of breaking the symmetry for moving circular contact lines of dewetting polymer films suspended on a periodic array of pillars. There, dewetting force fields driving polymer flow were perturbed by elastic micro-pillars arranged in a regular square pattern. Elastic restoring forces of deformed pillars locally balance driving capillary forces and broke the circular symmetry of expanding dewetting holes. The observed envelope of the dewetting holes reflected the symmetry of the underlying pattern, even at sizes much larger than the characteristic period of the pillar array, demonstrating that periodic perturbations in a driving force field can establish a well-defined pattern of lower symmetry. For the presented system, we succeeded in squaring the circle.


Variations in ambulance use in the United States: the role of health insurance.
The purpose of this study was to describe the associations between individual health insurance and ambulance utilization using a national sample of patients who receive emergency department (ED) care. The data source was the National Hospital Ambulatory Medical Care Survey, years 2004 through 2006. Noninstitutionalized patients between ages 18 and 65 years were included. The primary dependent variable was ambulance use. Multivariable logistic regression methods were used to assess the associations between health insurance status and ambulance use and to adjust for confounders. A total of 61,013 ED visits were included, representing a national sample of approximately 70 million annual ED visits over 3 years. Ambulance transport was used in 11% of private insurance visits, 16% of Medicaid visits, and 13% of uninsured visits. In the adjusted model, visits by patients with Medicaid (adjusted odds ratio [aOR] = 1.60, 99% confidence interval (CI) = 1.37 to 1.86) and the uninsured (aOR = 1.43, 99% CI = 1.23 to 1.66) were more likely to arrive by ambulance than visits by patients with private insurance. Ambulance use among the uninsured was most pronounced in metropolitan areas. Ambulance use varies by health insurance status. Medicaid coverage and lack of insurance are each independently associated with increased odds of ambulance use, suggesting a disproportionate role for emergency medical services (EMS) in the care of patients with limited financial resources.


The effects of excluding patients from the analysis in randomised controlled trials: meta-epidemiological study.
To examine whether excluding patients from the analysis of randomised trials are associated with biased estimates of treatment effects and higher heterogeneity between trials. Meta-epidemiological study based on a collection of meta-analyses of randomised trials. 14 meta-analyses including 167 trials that compared therapeutic interventions with placebo or non-intervention control in patients with osteoarthritis of the hip or knee and used patient reported pain as an outcome. Effect sizes were calculated from differences in means of pain intensity between groups at the end of follow-up, divided by the pooled standard deviation. Trials were combined by using random effects meta-analysis. Estimates of treatment effects were compared between trials with and trials without exclusions from the analysis, and the impact of restricting meta-analyses to trials without exclusions was assessed. 39 trials (23%) had included all patients in the analysis. In 128 trials (77%) some patients were excluded from the analysis. Effect sizes from trials with exclusions tended to be more beneficial than those from trials without exclusions (difference -0.13, 95% confidence interval -0.29 to 0.04). However, estimates of bias between individual meta-analyses varied considerably (tau(2)=0.07). Tests of interaction between exclusions from the analysis and estimates of treatment effects were positive in five meta-analyses. Stratified analyses indicated that differences in effect sizes between trials with and trials without exclusions were more pronounced in meta-analyses with high between trial heterogeneity, in meta-analyses with large estimated treatment benefits, and in meta-analyses of complementary medicine. Restriction of meta-analyses to trials without exclusions resulted in smaller estimated treatment benefits, larger P values, and considerable decreases in between trial heterogeneity. Excluding patients from the analysis in randomised trials often results in biased estimates of treatment effects, but the extent and direction of bias is unpredictable. Results from intention to treat analyses should always be described in reports of randomised trials. In systematic reviews, the influence of exclusions from the analysis on estimated treatment effects should routinely be assessed.


Transport function of the renal type IIa Na+/P(i) cotransporter is codetermined by residues in two opposing linker regions.
Two highly similar regions in the predicted first intracellular (ICL-1) and third extracellular loop (ECL-3) of the type IIa Na+/P(i) cotransporter (NaPi-IIa) have been shown previously to contain functionally important sites by applying the substituted cysteine accessibility method (SCAM). Incubation in methanethiosulfonate (MTS) reagents of mutants that contain novel cysteines in both loops led to full inhibition of cotransport activity. To elucidate further the role these regions play in defining the transport mechanism, a double mutant (A203C-S460C) was constructed with novel cysteines in each region. The effect of cysteine modification by different MTS reagents on two electrogenic transport modes (leak and cotransport) was investigated. MTSEA (2-aminoethyl MTS hydrobromide) and MTSES (MTS ethylsulfonate) led to full inhibition of cotransport and increased the leak, whereas incubation in MTSET (2-[trimethylammonium]ethyl MTS bromide) inhibited only cotransport. The behavior of other double mutants with a cysteine retained at one site and hydrophobic or hydrophilic residues substituted at the other site, indicated that most likely only Cys-460 was modifiable, but the residue at Ala-203 was critical for conferring the leak and cotransport mode behavior. Substrate interaction with the double mutant was unaffected by MTS exposure as the apparent P(i) and Na+ affinities for P(i)-induced currents and respective activation functions were unchanged after cysteine modification. This suggested that the modified site did not interfere with substrate recognition/binding, but prevents translocation of the fully loaded carrier. The time-dependency of cotransport loss and leak growth during modification of the double cysteine mutant was reciprocal, which suggested that the modified site is a kinetic codeterminant of both transport modes. The behavior is consistent with a kinetic model for NaPi-IIa that predicts mutual exclusiveness of both transport modes. Together, these findings suggest that parts of the opposing linker regions are associated with the NaPi-IIa transport pathway.


Spatiotemporal distribution of marine magnetotactic bacteria in a seasonally stratified coastal salt pond.
The occurrence and distribution of magnetotactic bacteria (MB) were studied as a function of the physical and chemical conditions in meromictic Salt Pond, Falmouth, Mass., throughout summer 2002. Three dominant MB morphotypes were observed to occur within the chemocline. Small microaerophilic magnetite-producing cocci were present at the top of the chemocline, while a greigite-producing packet-forming bacterium occurred at the base of the chemocline. The distributions of these groups displayed sharp changes in abundance over small length scales within the water column as well as strong seasonal fluctuations in population abundance. We identified a novel, greigite-producing rod in the sulfidic hypolimnion that was present in relatively constant abundance over the course of the season. This rod is the first MB that appears to belong to the gamma-Proteobacteria, which may suggest an iron- rather than sulfur-based respiratory metabolism. Its distribution and phylogenetic identity suggest that an alternative model for the ecological and physiological role of magnetotaxis is needed for greigite-producing MB.


Ca(2+)/calmodulin-dependent protein kinase II is stimulated by Wnt and Frizzled homologs and promotes ventral cell fates in Xenopus.
Wnt ligands working through Frizzled receptors have a differential ability to stimulate release of intracellular calcium (Ca(2+)) and activation of protein kinase C (PKC). Since targets of this Ca(2+) release could play a role in Wnt signaling, we first tested the hypothesis that Ca(2+)/calmodulin-dependent protein kinase II (CamKII) is activated by some Wnt and Frizzled homologs. We report that Wnt and Frizzled homologs that activate Ca(2+) release and PKC also activate CamKII activity in Xenopus embryos, while Wnt and Frizzled homologs that activate beta-catenin function do not. This activation occurs within 10 min after receptor activation in a pertussis toxin-sensitive manner, concomitant with autophosphorylation of endogenous CamKII. Based on data that Wnt-5A and Wnt-11 are present maternally in Xenopus eggs, and activate CamKII, we then tested the hypothesis that CamKII participates in axis formation in the early embryo. Measurements of endogenous CamKII activity from dorsal and ventral regions of embryos revealed elevated activity on the prospective ventral side, which was suppressed by a dominant negative Xwnt-11. If this spatial bias in CamKII activity were involved in promoting ventral cell fate one might predict that elevating CamKII activity on the dorsal side would inhibit dorsal cell fates, while reducing CamKII activity on the ventral side would promote dorsal cell fates. Results obtained by expression of CamKII mutants were consistent with this prediction, revealing that CamKII contributes to a ventral cell fate.


Referring patients to specialists: a structured vignette survey of Australian and British GPs.
In Australia and in the United Kingdom (UK) access to specialists is sanctioned by General Practitioners (GPs). It is important to understand how practitioners determine which patients warrant referral. A self-administered structured vignette postal survey of General Practitioners in Western Australia and the United Kingdom. Sixty-four vignettes describing patients with colorectal symptoms were constructed encompassing six clinical details. Nine vignettes, chosen at random, were presented to each individual. Respondents were asked if they would refer the patient to a specialist and how urgently. Logistic regression and parametric tests were used to analyse the data We received 260 completed questionnaires. 58% of 'cancer vignettes' were selected for 'urgent' referral. 1632/2367 or 69% of all vignettes were selected for referral. After adjusting for clustering the model suggests that 38.4% of the variability is explained by all the clinical variables as well as the age and experience of the respondents. 1012 or 42.8 % of vignettes were referred 'urgently'. After adjusting for clustering the data suggests that 31.3 % of the variability is explained by the model. The age of the respondents, the location of the practice and all the clinical variables were significant in the decision to refer urgently. GPs' referral decisions for patients with lower bowel symptoms are similar in the two countries. We question the wisdom of streaming referrals from primary care without a strong evidence base and an effective intervention for implementing guidelines. We conclude that implementation must take into account the profile of patients but also the characteristics of GPs and referral policies.


IgG Responses to Porins and Lipopolysaccharide within an Outer Membrane-Based Vaccine against Nontyphoidal Salmonella Develop at Discordant Rates.
Antibodies acquired after vaccination or natural infection with Gram-negative bacteria, such as invasive Salmonella enterica serovar Typhimurium, can protect against disease. Immunization with naturally shed outer membrane vesicles from Gram-negative bacteria is being studied for its potential to protect against many infections, since antigens within vesicles maintain their natural conformation and orientation. Shedding can be enhanced through genetic modification, and the resulting particles, generalized modules for membrane antigens (GMMA), not only offer potential as vaccines but also can facilitate the study of B-cell responses to bacterial antigens. Here we show that the response to immunization with GMMA from S Typhimurium (STmGMMA) provides B-cell-dependent protection and induces antibodies to two immunodominant antigens, lipopolysaccharide (LPS) and porins. Antibodies to LPS O antigen (O-Ag) markedly enhance protection in the spleen, but this effect is less marked in the liver. Strikingly, IgG responses to LPS and porins develop with distinct kinetics. In the first week after immunization, there is a dramatic T-cell-independent B1b-cell-associated induction of all IgG isotypes, except IgG1, to porins but not to LPS. In contrast, production of IgG1 to either antigen was delayed and T cell dependent. Nevertheless, after 1 month, cells in the bone marrow secreting IgG against porins or LPS were present at a similar frequency. Unexpectedly, immunization with O-Ag-deficient STmGMMA did not substantially enhance the anti-porin response. Therefore, IgG switching to all antigens does not develop synchronously within the same complex and so the rate of IgG switching to a single component does not necessarily reflect its frequency within the antigenic complex.IMPORTANCE Vaccines save millions of lives, yet for some infections there are none. This includes some types of Salmonella infections, killing hundreds of thousands of people annually. We show how a new type of vaccine, called GMMA, that is made from blebs shed from the Salmonella cell wall, works to protect against infection in mice by inducing host proteins (antibodies) specifically recognizing bacterial components (antigens). The rate of development of IgG antibody to antigens within GMMA occurred with different kinetics. However, the antibody response to GMMA persists and is likely to provide prolonged protection for those who need it. These results help show how antibody responses to bacterial antigens develop and how vaccines like GMMA can work and help prevent infection.


Positron emission tomography imaging of regional lung function.
Regional pulmonary perfusion and ventilation can be assessed by imaging, with positron emission tomography (PET), the pulmonary kinetics of [13N]nitrogen (13N2). Because of its low solubility in blood and tissues, 13N2 infused intravenously in saline solution evolves into the alveolar airspace at first pass, where it accumulates in proportion to regional perfusion during a short apnea. In contrast, infused 13N2 is not retained in non-aerated regions, which do not exchange gas. Robust estimates of regional perfusion and shunt are obtained by modeling the pulmonary kinetics of 13N2 infused as a bolus during a short apnea. Regional ventilation is measured by modeling the washout of 13N2 after breathing is resumed. Regional gas content and dead space ventilation can be measured with inhalation of 13N2. Application of this novel functional imaging technique can further the understanding of the pathophysiology of a variety of pulmonary processes. This review briefly describes the methodological aspects of PET imaging of regional perfusion and ventilation and then focuses on insights in the pathophysiology of acute lung injury and asthma that have been gained by imaging the pulmonary kinetics of 13N2 with PET.


Atypical gap junctions in the ciliary epithelium of the albino rabbit eye.
Gap junctions are present between nonpigmented and pigmented epithelial cells layers, as well as between the adjacent pigmented cells, but not between the nonpigmented epithelial cells which face the posterior chamber. The unusual feature of these gap junctions is a dark banding which regularly appears every three rows of subunits. This dark band is the equivalent width of two rows of facets.


Applying proteomic technology to clinical virology.
Developing antiviral drugs, vaccines and diagnostic markers is still the most ambitious challenge in clinical virology. In the past few decades, data from high-throughput technologies have allowed for the rapid development of new antiviral therapeutic strategies, thus making a profound impact on translational research. Most of the current preclinical studies in virology are aimed at evaluating the dynamic composition and localization of the protein platforms involved in various host-virus interactions. Among the different possible approaches, mass spectrometry-based proteomics is increasingly being used to define the protein composition in subcellular compartments, quantify differential protein expression among samples, characterize protein complexes, and analyse protein post-translational modifications. Here, we review the current knowledge of the most useful proteomic approaches in the study of viral persistence and pathogenicity, with a particular focus on recent advances in hepatitis C research.


Circuit simulation of genetic networks.
Genetic networks with tens to hundreds of genes are difficult to analyze with currently available techniques. Because of the many parallels in the function of these biochemically based genetic circuits and electrical circuits, a hybrid modeling approach is proposed that integrates conventional biochemical kinetic modeling within the framework of a circuit simulation. The circuit diagram of the bacteriophage lambda lysislysogeny decision circuit represents connectivity in signal paths of the biochemical components. A key feature of the lambda genetic circuit is that operons function as active integrated logic components and introduce signal time delays essential for the in vivo behavior of phage lambda.


Comorbid depression and anxiety in later life: patterns of association, subjective well-being, and impairment.
Very little epidemiological work has examined comorbidity between depression and anxiety disorders in community-dwelling older adults, despite the fact these disorders are known to co-occur in younger adults and that this co-occurrence is associated with greater clinical severity. In this study, the authors examine psychiatric comorbidity and associated impairment of four disorders (major depression, panic disorder, social phobia, and agoraphobia) in a community-based sample of adults aged 55 and older. Population-based sample of older adults (N=12,792) from the Canadian Community Health Survey-Mental Health and Well-Being (CCHS 1.2). The World Mental Health Composite International Diagnostic Interview was used to identify cases of 12-month disorder. Descriptive analysis and regression analysis is used to examine patterns of association between disorders and related impairment. Among adults aged 55 years and older, 4.4% met the criteria for at least one disorder and 0.8% had two or more. Social phobia was the most common comorbid disorder among respondents with depression, and depression was the most common comorbid disorder among respondents with any of the anxiety disorders. Respondents who report comorbid disorders reported significantly lower well-being and greater impairment. Although comorbidity between physical health conditions and depression, and between dementias and depression, are well documented among older adults, these results suggest that comorbid depression and anxiety are also prevalent in later life. The significant impact of comorbidity on function and well-being underlines the need to screen for comorbid disorders in this population.


Awareness of the German population of common available guidelines of how to cope with lower back pain.
Several countries developed guidelines in order to provide a systematic approach for treatment of (chronic) lower back pain. The risk of suffering from (chronic) lower back pain differs significantly within the general population. A serious lack of research exists concerning the risk factor "dysfunctional behavior of the subjects in terms of acute lower back pain." The purpose of this study was to assess the knowledge of the German population regarding the availability of guidelines about managing lower back pain. Prospective observational cohort study. We interviewed 983 subjects by phone. The study population included 50 - 70-year-old men and women with German residency and sufficient language ability. Of all the subjects, 70.2% claimed that they suffered at least once in their lifetime with lower back pain. Lower back pain with radiating symptoms occurred in 28.7%. Women were affected significantly more frequently compared to the epidemiological data. Of all the subjects with lower education, 82.9% suffered from lower back pain at least once in their lifetime compared to only 62.4% of people with university degrees. Education was also a protective factor for lower back pain with radiating pain. People who completed secondary modern school were 42% less likely to suffer from lower back pain than those who did not graduate. Knowing active rules of conduct occurred significantly more often at higher educational levels (i.e. all kinds of sports and exercises requiring physical strength, flexibility, power, agility, coordination, grace, balance and control, in particular stretching exercises) odds ratio = 7.78, physical activities odds ratio = 3.92, relaxation exercises odds ratio = 3.51). Data acquisition was performed by an external company and therefore provided only limited options for external validity. Furthermore data acquisition was restricted to 50 - 70-year-old patients, since this age group is at higher risk of suffering from lower back pain. A conclusion upon the knowledge of the whole population has to be drawn with caution, especially when considering the size of the study population. The life-time prevalence of lower back pain was assessed by interviewing patients about prior episodes of lower back pain. Slightly biased results may have occurred since the memory of prior episodes might result in too many or too few episodes. The study revealed a lack of awareness of common available guidelines and an uneven distribution of existing knowledge throughout the population. Passive coping strategies like taking pain medication or ointment therapy were favored over active coping strategies like gymnastics, physical activities, and relaxation exercises. Respondents with a higher level of education suffered significantly less often from lower back pain and tended toward active treatment strategies. Respondents with lower levels of education more often demanded passive treatment strategies. The general population, especially those with lower education, is not sufficiently aware of behavioral strategies for managing lower back pain as proposed in available guidelines.


Exploring Environmental Factors in Nursing Workplaces That Promote Psychological Resilience: Constructing a Unified Theoretical Model.
Building nurses' resilience to complex and stressful practice environments is necessary to keep skilled nurses in the workplace and ensuring safe patient care. A unified theoretical framework titled Health Services Workplace Environmental Resilience Model (HSWERM), is presented to explain the environmental factors in the workplace that promote nurses' resilience. The framework builds on a previously-published theoretical model of individual resilience, which identified the key constructs of psychological resilience as self-efficacy, coping and mindfulness, but did not examine environmental factors in the workplace that promote nurses' resilience. This unified theoretical framework was developed using a literary synthesis drawing on data from international studies and literature reviews on the nursing workforce in hospitals. The most frequent workplace environmental factors were identified, extracted and clustered in alignment with key constructs for psychological resilience. Six major organizational concepts emerged that related to a positive resilience-building workplace and formed the foundation of the theoretical model. Three concepts related to nursing staff support (professional, practice, personal) and three related to nursing staff development (professional, practice, personal) within the workplace environment. The unified theoretical model incorporates these concepts within the workplace context, linking to the nurse, and then impacting on personal resilience and workplace outcomes, and its use has the potential to increase staff retention and quality of patient care.


Sequences regulating tropism of human immunodeficiency virus type 1 for brain capillary endothelial cells map to a unique region on the viral genome.
Two infectious molecular clones of human immunodeficiency virus type 1, NL4-3 and JR-CSF, differ in their abilities to productively infect human brain capillary endothelial (HBCE) cells. The phenotypes of recombinants between these two molecular strains were examined to identify viral sequences responsible for the difference in HBCE cell tropism between the two parental strains. Our results indicate that HBCE cell tropism maps to a region that encompasses the C1 region of env and includes overlapping reading frames for the accessory genes vpr, vpu, tat, and rev. This region was unique for HBCE cell tropism and did not cosegregate with either macrophage or T-cell line tropism. However, several recombinant clones displayed dual tropism for both HBCE cells and macrophages. These endothelial cell- and macrophage-tropic strains may have a unique pathogenic advantage by entering the brain via HBCE cells and subsequently infecting microglial cells with high efficiency, leading to the induction of human immunodeficiency virus dementia.


The potential impact of new generation molecular point-of-care tests on gonorrhoea and chlamydia in a setting of high endemic prevalence.
Background Despite the availability of testing and treatment, bacterial sexually transmissible infections (STIs) continue to occur at endemic levels in many remote Indigenous communities in Australia. New generation molecular point-of-care (POC) tests have high sensitivity, comparable with conventional diagnostic tests, and have the potential to increase the impact of STI screening. We developed mathematical models of gonorrhoea (Neisseria gonorrhoeae) and chlamydia (Chlamydia trachomatis) transmission in remote Indigenous communities in Australia to evaluate screening and treatment strategies that utilise POC tests. The introduction of POC testing with 95% sensitivity could reduce the prevalence of gonorrhoea and chlamydia from 7.1% and 11.9% to 5.7% and 8.9%, respectively, under baseline screening coverage of 44% per year. If screening coverage is increased to 60% per year, prevalence is predicted to be reduced to 3.6% and 6.7%, respectively, under conventional testing, and further reduced to 1.8% and 3.1% with the introduction of POC testing. Increasing screening coverage to 80% per year will result in a reduction in the prevalence of gonorrhoea and chlamydia to 0.6% and 1.5%, respectively, and the virtual elimination of both STIs if POC testing is introduced. Modelling suggests that molecular POC tests of high sensitivity have great promise as a public health strategy for controlling chlamydia and gonorrhoea. However, evaluation of the cost-effectiveness of POC testing needs to be made before widespread implementation of this technology can be considered.


Syphilis, gonorrhoea, and drug abuse among pregnant women in Jefferson County, Alabama, US, 1980-94: monitoring trends through systematically collected health services data.
To assess the association between self reported drug abuse and syphilis and gonorrhoea among pregnant women, Jefferson County, Alabama, United States, 1980-94. We analysed a prenatal care database and assessed the association of self reported drug use with seropositive syphilis and gonorrhoea using prevalence rates, multiple logistic regression models, and the Pearson correlation coefficient (r) for trends. Overall, 5.5% of the women acknowledged drug abuse, 1.4% had seropositive syphilis, and 4.8% had gonorrhoea. In a multivariate analysis, drug abuse was associated with syphilis (odds ratio 2.9, 95% confidence interval 1.6, 5.3) but not with gonorrhoea. Trends in the annual prevalence of drug abuse closely paralleled trends in the annual prevalence of syphilis, including simultaneous peaks in 1992 (drug abuse, 9.1%; syphilis, 3.2%). There was no such parallel trend between drug abuse and gonorrhoea. Annual prevalence of drug abuse correlated with the prevalence of syphilis (r = 0.89, p = 0.001) more than with the prevalence of gonorrhoea (r = 0.45, p = 0.201). Among pregnant women, an increase in drug abuse was closely associated with an epidemic of syphilis, but not of gonorrhoea. Systematically collected prenatal care data can usefully supplement surveillance of diseases and behavioural risk factors associated with them.


Supplementation with fish oil increases first-line chemotherapy efficacy in patients with advanced nonsmall cell lung cancer.
Palliative chemotherapy is aimed at increasing survival and palliating symptoms. However, the response rate to first-line chemotherapy in patients with nonsmall cell lung cancer (NSCLC) is less than 30%. Experimental studies have shown that supplementation with fish oil (FO) can increase chemotherapy efficacy without negatively affecting nontarget tissue. This study evaluated whether the combination of FO and chemotherapy (carboplatin with vinorelbine or gemcitabine) provided a benefit over standard of care (SOC) on response rate and clinical benefit from chemotherapy in patients with advanced NSCLC. Forty-six patients completed the study, n = 31 in the SOC group and n = 15 in the FO group (2.5 g EPA + DHA/day). Response to chemotherapy was determined by clinical examination and imaging. Response rate was defined as the sum of complete response plus partial response, and clinical benefit was defined as the sum of complete response, partial response, and stable disease divided by the number of patients. Toxicities were graded by a nurse before each chemotherapy cycle. Survival was calculated 1 year after study enrollment. Patients in the FO group had an increased response rate and greater clinical benefit compared with the SOC group (60.0% vs 25.8%, P = .008; 80.0% vs 41.9%, P = .02, respectively). The incidence of dose-limiting toxicity did not differ between groups (P = .46). One-year survival tended to be greater in the FO group (60.0% vs 38.7%; P = .15). Compared with SOC, supplementation with FO results in increased chemotherapy efficacy without affecting the toxicity profile and may contribute to increased survival.


Elucidating sequence and solvent specific design targets to protect and stabilize enzymes for biocatalysis in ionic liquids.
For many different frameworks, the structure, function, and dynamics of an enzyme is largely determined by the nature of its interactions with the surrounding host environment, thus a molecular level understanding of enzyme/host interactions is essential to the design of new processes and applications. Ionic liquid (IL) solvents are a popular class of solvents in which to study enzyme behavior, yet it is still not possible to predict how a given enzyme will behave in a given IL solvent. Furthermore, a dearth of experimental data with which to evaluate simulation force fields has prevented the full integration of experimental and computational techniques to gain a complete picture of enzyme/IL interactions. Utilizing recently published crystallographic data of an enzyme in complex with an IL, this study aims to validate the use of current molecular force fields for studying enzyme/IL interactions, and to provide new mechanistic insight into enzyme stabilization in IL solvents. Classical molecular dynamics (MD) simulations have been performed on both the folded and unfolded state of Bacillus subtilis lipase A and a quadruple-mutant version of lipase A, in solutions of aqueous 1-butyl-3-methylimidazolium chloride. Results show classical MD simulations can predict the preferred surface binding locations of IL cations as well as reductions in IL anion binding to mutated surface residues with high accuracy. The results also point to a mechanistic difference between IL binding to the folded and unfolded state of an enzyme, which we call the "counter-ion effect". These findings could have important implications for future rational design efforts to stabilize enzymes in non-conventional media.


Vocabulary Instruction Embedded in Narrative Intervention: A Repeated Acquisition Design Study With First Graders at Risk of Language-Based Reading Difficulty.
The purpose of the current study was to investigate the effect of vocabulary instruction embedded in the narrative intervention on the immediate and retained definitional knowledge of taught words for first graders at risk for language-related reading difficulties. We employed a repeated acquisition design with innovative quality features and supplemental statistics with 11 treatment students and three control students. In the context of the school's multitiered system of supports, treatment students received 30-min small group interventions, 4 days a week for 12 weeks. Intervention involved story retelling and personal story generation lessons, both of which emphasized the learning and practicing of target vocabulary words in each story. Pre- and postprobes of the taught definitions were conducted every week. According to visual analysis conventions of single-case research, there was a consistent pattern of improvement from pre- to postprobes for all treatment participants, but for none of the control participants. Retention was also consistently observed, when measured at Week 13. Supplemental statistics confirmed that large effects were associated with the intervention. Vocabulary instruction embedded in narrative intervention led to meaningful acquisition and retention of taught vocabulary for students at risk of language-based reading difficulty.


Potential of high-dose cefepime/tazobactam against multiresistant Gram-negative pathogens.
Early β-lactamase inhibitors were combined with established penicillins, but different combinations may be more appropriate to counter current β-lactamase threats, with development facilitated by the US Generating Antibiotic Incentives Now (GAIN) Act. Cefepime/tazobactam is especially attractive, combining an AmpC-stable cephalosporin with a clinically established inhibitor, active against ESBLs and suitable for high-dose administration. Organisms (n = 563) were clinical isolates submitted to the UK national reference laboratory. MICs were determined by CLSI agar dilution with tazobactam at 4 mg/L and, for a subset, at 8 mg/L. Cefepime/tazobactam 8 + 4 mg/L achieved coverage of 96%-100% of Enterobacteriaceae with penicillinases, AmpC, ESBL, K1 or OXA-48 β-lactamases. Even at 1 + 4 mg/L, the combination inhibited >94% of isolates with penicillinases, AmpC enzymes or ESBLs. Most Enterobacteriaceae with KPC and NDM carbapenemase were resistant at current cefepime breakpoints but 80% of those with VIM types were susceptible at 8 + 4 mg/L. Tazobactam did little to potentiate cefepime against non-fermenter groups, though gains were seen against AmpC-producing Acinetobacter spp. and Stenotrophomonas maltophilia. Increasing the tazobactam concentration to 8 mg/L gave further small increases in activity against Enterobacteriaceae groups. High-dose cefepime/tazobactam, justifying an 8 + 4 or 8 + 8 mg/L breakpoint, can achieve a carbapenem-like spectrum, with some additional coverage of OXA-48 (and maybe VIM) Enterobacteriaceae. Clinical evaluation is warranted.


Pacemaker Implantation and Dependency After Transcatheter Aortic Valve Replacement in the REPRISE III Trial.
Background As transcatheter aortic valve replacement expands to younger and/or lower risk patients, the long-term consequences of permanent pacemaker implantation are a concern. Pacemaker dependency and impact have not been methodically assessed in transcatheter aortic valve replacement trials. We report the incidence and predictors of pacemaker implantation and pacemaker dependency after transcatheter aortic valve replacement with the Lotus valve. Methods and Results A total of 912 patients with high/extreme surgical risk and symptomatic aortic stenosis were randomized 2:1 (Lotus:CoreValve) in REPRISE III (The Repositionable Percutaneous Replacement of Stenotic Aortic Valve through Implantation of Lotus Valve System-Randomized Clinical Evaluation) trial. Systematic assessment of pacemaker dependency was pre-specified in the trial design. Pacemaker implantation within 30 days was more frequent with Lotus than CoreValve. By multivariable analysis, predictors of pacemaker implantation included baseline right bundle branch block and depth of implantation; diabetes mellitus was also a predictor with Lotus. No association between new pacemaker implantation and clinical outcomes was found. Pacemaker dependency was dynamic (30 days: 43%; 1 year: 50%) and not consistent for individual patients over time. Predictors of pacemaker dependency at 30 days included baseline right bundle branch block, female sex, and depth of implantation. No differences in mortality or stroke were found between patients who were pacemaker dependent or not at 30 days. Rehospitalization was higher in patients who were not pacemaker dependent versus patients without a pacemaker or those who were dependent. Conclusions Pacemaker implantation was not associated with adverse clinical outcomes. Most patients with a new pacemaker at 30 days were not dependent at 1 year. Mortality and stroke were similar between patients with or without pacemaker dependency and patients without a pacemaker. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier NCT02202434.


AI-Based Early Change Detection in Smart Living Environments.
In the smart environments we live today, a great variety of heterogeneous sensors are being increasingly deployed with the aim of providing more and more value-added services. This huge availability of sensor data, together with emerging Artificial Intelligence (AI) methods for Big Data analytics, can yield a wide array of actionable insights to help older adults continue to live independently with minimal support of caregivers. In this regard, there is a growing demand for technological solutions able to monitor human activities and vital signs in order to early detect abnormal conditions, avoiding the caregivers' daily check of the care recipient. The aim of this study is to compare state-of-the-art machine and deep learning techniques suitable for detecting early changes in human behavior. At this purpose, specific synthetic data are generated, including activities of daily living, home locations in which such activities take place, and vital signs. The achieved results demonstrate the superiority of unsupervised deep-learning techniques over traditional supervised/semi-supervised ones in terms of detection accuracy and lead-time of prediction.


Cavernous malformations of the brain stem. A review of 139 cases.
A retrospective analysis of 139 patients with brain stem cavernous malformations is presented. The material consists of 41 cases from Bern and Phoenix and 98 further well-documented cases from the literature. Sixty-eight patients were male, 70 were female. The average age was 31.8 + 11.8 years. Sixty-two percent of the cavernous malformations were in the pons, 14% were in the mesencephalon, 12% were in the pontomesencephalic and in the pontomedullary junction, and 5% were in the medulla. Eighty-eight percent of the patients showed evidence of recent or previous hemorrhage, 55% had one hemorrhage. 17% had two hemorrhages, and 17% had three or more hemorrhages. Twelve patients died from a hemorrhage, 5 with the first bleeding and 7 with a rebleeding. The minimum bleeding rate was 2.7% per year and the average rebleeding rate 21% per year and per lesion. Most lesions had a diameter between 10 and 30 mm. Increase in size was observed in 12 of the patients; this corresponds to about 21% when only patients with a follow-up of at least one year are considered. In 93 patients the cavernous malformation was removed operatively while in 30 patients the lesion was not removed. In the group with conservative management at the end of the observation period (up to 25 and 32 years), 66.6% had no or only a slight neurological deficit, 6.7% were moderately disabled, 6.7% were completely dependent, and 20% had died. In the group treated surgically 83.9% had no or only a slight neurological deficit, and 15% were moderately disabled. One patient remained severely disabled, no patient died. The limitations of the retrospective nature of this study are stressed.


Familial aggregation of stroke. The Framingham Study.
Family history is perceived to be an important risk factor for stroke despite conflicting published data. We examined patterns of familial aggregation of stroke among three generations using data from the Framingham Study. Cox proportional hazards analyses, adjusting for known stroke risk factors, were used to examine familial concordance in three groups: (1) members of the original Framingham cohort using reported parental stroke death; (2) members of the Framingham Offspring Study and their parents (members of the original Framingham Study); and (3) sibships within the original Framingham cohort. We found no association between stroke or transient ischemic attack among original cohort members and their reported parental stroke death (n = 4933; relative risk [RR] = 1.07). Using verified cases of parental stroke or transient ischemic attack, the Offspring analyses revealed that both paternal (n = 1762; RR = 2.4; 95% confidence interval [CI], 0.96 to 6.03) and maternal (n = 2074; RR = 1.4; 95% CI, 0.60 to 3.25) histories were associated with an increased risk. Parental history of coronary heart disease was strongly associated with stroke or transient ischemic attack among Offspring Study members (RR = 3.33; 95% CI, 1.27 to 8.72). Sibling history of stroke or transient ischemic attack was not associated with stroke or transient ischemic attack among original cohort members, although a non-statistically significant increased risk associated with sibling history of atherothrombotic brain infarction was observed (RR = 1.8; 95% CI, 0.68 to 4.94). These analyses suggest that parental history of stroke may be a risk factor for stroke. As more stroke or transient ischemic attack events develop among the Offspring Study members, it will be valuable to reexamine these associations.


Heart failure in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.
The incidence and prevalence of heart failure (HF) and chronic kidney disease (CKD) are increasing, and as such a better understanding of the interface between both conditions is imperative for developing optimal strategies for their detection, prevention, diagnosis, and management. To this end, Kidney Disease: Improving Global Outcomes (KDIGO) convened an international, multidisciplinary Controversies Conference titled Heart Failure in CKD. Breakout group discussions included (i) HF with preserved ejection fraction (HFpEF) and nondialysis CKD, (ii) HF with reduced ejection fraction (HFrEF) and nondialysis CKD, (iii) HFpEF and dialysis-dependent CKD, (iv) HFrEF and dialysis-dependent CKD, and (v) HF in kidney transplant patients. The questions that formed the basis of discussions are available on the KDIGO website http://kdigo.org/conferences/heart-failure-in-ckd/, and the deliberations from the conference are summarized here.


The Braincase and Endosseous Labyrinth of Plioplatecarpus peckensis (Mosasauridae, Plioplatecarpinae), With Functional Implications for Locomotor Behavior.
Adaptations of mosasaurs to the aquatic realm have been extensively studied from the perspective of modifications to the post-cranial skeleton. In recent years, imaging techniques such as computed tomography have permitted the acquisition of anatomical data from previously inaccessible sources. An exquisitely preserved specimen of the plioplatecarpine mosasaur Plioplatecarpus peckensis presents an opportunity to examine the detailed structure of the braincase, as well as the form of the otic capsule endocast. These data elaborate upon previous descriptions of the braincase of Plioplatecarpus, and provide a detailed, three dimensional reconstruction of the osseous labyrinth for the first time. The otic capsule endocasts reveal that the size of the labyrinth relative to head size is comparable to that of other squamates, suggesting that labyrinth size was not a factor in increasing sensitivity. However, all three semicircular canals are tall and strongly arced to a degree comparable to, and even exceeding, that observed in arboreal and aquatic lizards. Comparison of the sensitivity of the canals in each of the three major axes of rotation suggests Plioplatecarpus peckensis may have been most sensitive to movements in the pitch axis. Although early mosasaurs were probably anguilliform swimmers, most are thought to have been subcarangiform to thunniform locomotors with a near-rigid body form and likely decreased maneuverability. The data from the labyrinth presented here add a potential new dimension to this model of locomotion for further consideration, wherein changes in orientation, such as pitch, may have been more common locomotor behaviors than previously thought.


Effectiveness of psychosomatic therapy for patients with persistent somatic symptoms: Results from the CORPUS randomised controlled trial in primary care.
To evaluate the effectiveness of psychosomatic therapy versus care as usual in primary care for patients with persistent somatic symptoms (PSS). We conducted a pragmatic, two-armed, randomised controlled trial among primary care patients with PSS in the Netherlands that included 39 general practices and 34 psychosomatic therapists. The intervention, psychosomatic therapy, consisted of 6-12 sessions delivered by specialised exercise- and physiotherapists. patient's level of functioning. severity of physical and psychosocial symptoms, health-related quality of life, health-related anxiety, illness behaviour and number of GP contacts. Compared to usual care (n = 85), the intervention group (n = 84) showed no improvement in patient's level of functioning (mean difference - 0.50 [95% CI -1.10 to 0.10]; p = .10), and improvement in health-related anxiety (mean difference - 1.93 [95% CI -3.81 to -0.04]; p = .045), over 12 months. At 5-month follow-up, we found improvement in physical functioning, somatisation, and health-related anxiety. The 12-month follow-up revealed no therapy effects. Subgroup analyses showed an overall effect in patient's level of functioning for the group with moderate PSS (mean difference - 0.91 [95% CI -1.78 to -0.03]; p = .042). In the year after the end of therapy, the number of GP contacts did not differ significantly between the two groups. We only found effects on some secondary outcome measures, and on our primary outcome measure especially in patients with moderate PSS, the psychosomatic therapy appears promising for further study. the trial is registered in the Netherlands Trial Registry, https://trialsearch.who.int/Trial2.aspx?TrialID=NTR7356 under ID NTR7356.


Usefulness of live/real time three-dimensional transthoracic echocardiography in evaluation of prosthetic valve function.
We studied 31 patients with prosthetic valves (PVs) using two-dimensional and three-dimensional transthorathic echocardiography (2DTTE and 3DTTE, respectively) in order to determine whether 3DTTE provides an incremental value on top of 2DTTE in the evaluation of these patients. With 3DTTE both leaflets of the St. Jude mechanical PV can be visualized simultaneously, thereby increasing the diagnostic confidence in excluding valvular abnormalities and overcoming the well-known limitations of 2DTTE in the examination of PVs, which heavily relies on Doppler. Three-dimensional transthorathic echocardiography provides a more comprehensive evaluation of PV regurgitation than 2DTTE with its ability to more precisely quantify PV regurgitation, in determining the mechanism causing regurgitation, and in localizing the regurgitant defect. Furthermore, 3DTTE is superior in identifying, quantifying, and localizing PV thrombi and vegetations, in addition to the unique feature of providing a look inside mass lesions by serial sectioning. These preliminary results suggest the superiority of 3DTTE over 2DTTE in the evaluation of PVs and that it provides incremental knowledge to the echocardiographer.


Molecular characteristics and epidemiology of meningococcal carriage, Burkina Faso, 2003.
To describe Neisseria meningitidis strains in the African meningitis belt in 2003, we obtained 2,389 oropharyngeal swabs at 5 monthly visits a representative population sample (age range 4-29 years) in Bobo-Dioulasso, Burkina Faso. A total of 152 carriage isolates were grouped, serotyped, and genotyped. Most isolates were NG:NT:NST sequence type (ST) 192 (63% of all N. meningitidis), followed by W135:2a:P1.5,2 of ST-11 (16%) and NG:15:P1.6 of ST-198 (12%). We also found ST-2881 (W135:NT:P1.5,2), ST-751 (X:NT:P1.5), and ST-4375 (Y:14:P1.5,2) but not serogroups A or C. Estimated average duration of carriage was 30 days (95% confidence interval 24-36 days). In the context of endemic group W135 and meningococcal A disease, we found substantial diversity in strains carried, including all strains currently involved in meningitis in this population, except for serogroup A. These findings show the need for large samples and a longitudinal design for N. meningitidis serogroup A carriage studies.


Active learning strategies to teach renal-cardiovascular integration with high student-to-teacher ratios.
To address the challenge of increasing opportunities for active learning into a medical physiology course with approximately 190 students enrolled, we chose an integrated approach. This was facilitated by the availability of a patient simulator facility at the School of Nursing at the Medical College of Georgia, and an approximately 20-min simulation of acute hemorrhage on the simulators comprised the first of three components in our approach. The second component was a small-group problem-solving session that each group conducted immediately after their patient simulator session. It brought in the more complex physiological responses to acute hemorrhage using an exercise we designed using free downloadable simulation software from the Department of Physiology and Biophysics at the University of Mississippi Medical Center. The third component was a student worksheet exercise that was built around data collected from 12 students who volunteered to collect a 24-h urine sample and have blood pressure measured after 3 days on either high or low salt intake. The worksheet was completed independently, and the answers and student data formed the basis for a classroom lecture. The approach has met with increasingly positive reviews due to testing the first two components on second-year medical student volunteers before its implementation, keeping the first component as simple as possible, keeping the second component to <30 min, and continued revision of the third component to increase clinical context of the study questions. An integrated active learning approach can enhance student interest in integrating cardiovascular-renal physiology, particularly if faculty members are willing to revise the approach in response to student feedback.


Dipolar antiferromagnetism and quantum criticality in LiErF₄.
Magnetism has been predicted to occur in systems in which dipolar interactions dominate exchange. We present neutron scattering, specific heat, and magnetic susceptibility data for LiErF(4), establishing it as a model dipolar-coupled antiferromagnet with planar spin-anisotropy and a quantum phase transition in applied field H(c|| = 4.0 ± 0.1 kilo-oersteds. We discovered non-mean-field critical scaling for the classical phase transition at the antiferromagnetic transition temperature that is consistent with the two-dimensional XY/h(4) universality class; in accord with this, the quantum phase transition at H(c) exhibits three-dimensional classical behavior. The effective dimensional reduction may be a consequence of the intrinsic frustrated nature of the dipolar interaction, which strengthens the role of fluctuations.


Cutaneous innervation in hereditary sensory and autonomic neuropathy type IV.
The authors investigated immunocytochemically the innervation of a skin biopsy in a rare case of hereditary sensory and autonomic neuropathy type IV. A few protein gene product 9.5-, growth-associated protein 43-, calcitonin gene-related peptide-, and substance P-immunoreactive nerve fibers were observed in the deeper regions of the dermis. Neuropeptide Y-, nitric oxide-, and vasoactive intestinal polypeptide-immunoreactive fibers were completely absent. Their observations support the hypothesis that the sensory and autonomic defects reported in hereditary sensory and autonomic neuropathy are based on profound developmental alterations of the peripheral nervous system.