Looking ahead: a case for human papillomavirus testing of self-sampled vaginal specimens as a cervical cancer screening strategy.
Even in the era of highly effective human papillomavirus (HPV) prophylactic vaccines, substantial reduction in worldwide cervical cancer mortality will only be realized if effective early detection and treatment of the millions of women already infected and the millions who may not receive vaccination in the next decade can be broadly implemented through sustainable cervical cancer screening programs. Effective programs must meet three targets: (i) at least 70% of the targeted population should be screened at least once in a lifetime, (ii) screening assays and diagnostic tests must be reproducible and sufficiently sensitive and specific for the detection of high-grade precursor lesions (i.e., CIN21), and (iii) effective treatment must be provided. We review the evidence that HPV DNA screening from swabs collected by the women in their home or village is sufficiently sound for consideration as a primary screening strategy in the developing world, with sensitivity and specificity for detection of CIN21 as good or better than Pap smear cytology and VIA. A key feature of a self-collected HPV testing strategy (SC-HPV) is the move of the primary screening activities from the clinic to the community. Efforts to increase the affordability and availability of HPV DNA tests, community education and awareness, development of strong partnerships between community advocacy groups, health care centers and regional or local laboratories, and resource appropriate strategies to identify and treat screen-positive women should now be prioritized to ensure successful public health translation of the technologic advancements in cervical cancer prevention.


Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the NLRP3 inflammasome.
The NLRP3 inflammasome has been recognized as one of the key components of the innate immunity by sensing a diversity of insults. Inflammasome activation results in the maturation of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Increased production of IL-1β is found in patients with gain-of-function polymorphisms in genes encoding the NLRP3 inflammasome. Since approximately 5% of the Swedish population are heterozygote carriers of these combined gene variants, their impact on inflammasome status and a relationship on disease development is therefore highly relevant to study. The present study investigates levels of inflammasome-produced cytokines as a measure of inflammasome activation in healthy individuals carrying Q705K polymorphism in the NLRP3 gene combined with C10X in the CARD8 gene. Genotyping of 1006 healthy blood donors was performed for the polymorphisms Q705K in the NLRP3 and C10X in the CARD8 genes. IL-1β, IL-18, IL-33, as well as a number of other pro-inflammatory cytokines, were analyzed by Luminex or ELISA in plasma from individuals carrying the polymorphisms and in age and gender matched non-carrier controls. The prevalence of the polymorphisms was in line with previous studies. Plasma levels of IL-1β and IL-33 were elevated among carriers of combined Q705K+C10X polymorphisms compared to controls, whereas no difference was found for IL-18 and the other cytokines measured. Moreover, carriers of C10X or Q705K per se had similar plasma levels of IL-1β as non-carriers. These data suggest that the combined polymorphisms create inflammasomes with increased basal activation state, which might provide a more favourable innate immune response. In spite of this, it could also represent the mechanisms by which the inflammatory loop is triggered into a long-term inflammatory phenotype.


The lived experiences of rural women diagnosed with the human immunodeficiency virus in the antenatal period.
In South Africa, pregnant women are diagnosed with human immunodeficiency virus (HIV) at antenatal clinics and simultaneously initiated on antiretroviral treatment (ART). An HIV diagnosis together with the initiation of ART has an emotional impact that may influence how pregnant women cope with pregnancy and their adherence to a treatment plan. The aim of the study was to explore the lived experiences of women diagnosed with HIV in the antenatal period in a rural area in the Eastern Cape province of South Africa. A qualitative approach with a descriptive phenomenological design was utilised. The study applied purposive sampling to select participants from a local community clinic in the Eastern Cape. Ten semistructured interviews were conducted, transcribed and analysed using Colaizzi's framework. Four themes formed the essential structure of the phenomenon being investigated: a reality that hits raw, a loneliness that hurts, hope for a fractured tomorrow and support of a few. Although the participants had to accept the harsh reality of being diagnosed with HIV and experienced loneliness and the support of only a few people, they had hope to live and see the future of their children. Women diagnosed with HIV during pregnancy are ultimately concerned with the well-being of their unborn children, and this concern motivates their adherence to ART. Women's lived experiences are situated in their unique sociocultural context, and although some known challenges remain, counselling and support strategies need to be informed by exploring context-specific issues and involving the local community.


Sickness absence and psychosocial work conditions: a multilevel study.
Psychosocial work conditions, particularly psychological job demands, are inconsistently associated with sickness absence rates. This might be the result of investigating the psychosocial work environment at the individual level, reflecting personal perceptions rather than actual demands. To investigate associations between sickness absence and psychosocial work conditions at both the individual and the workplace level. A cross-sectional study of insurance company employees (n = 395) in four departments. Psychological job demands, job control and job support were investigated at the individual level using the self-completed Questionnaire on Experience and Assessment of Work. An external occupational psychologist interviewed the supervisor and a group of employees of each department, assessing job demands, job control, job support and psychological distress at the workplace level. These data were related to the number of short (1-7 days), medium (8-21 days) and long (>21 days) episodes of sickness absence in the period January 2001 to December 2002. A total of 244 questionnaires (62%) were suitable for analysis. Quantitative job control scores at the individual level differed from qualitative data at the workplace level. Self-assessed job demands and control were unrelated to sickness absence. The rates of short and long episodes of absence were higher in the department with combined high demands and low control, assessed at the workplace level. The associations between psychosocial work conditions and sickness absence depended on the level at which the former were assessed. More multilevel research is needed to disentangle the relations between psychosocial work conditions and sickness absence.


Screening for mild cognitive impairment: comparing the SMMSE and the ABCS.
To compare the sensitivity and specificity of the AB Cognitive Screen (ABCS) with the Standardized Mini-Mental State Examination (SMMSE) to differentiate normal cognition from mild cognitive impairment (MCI), especially when educational level and age are taken into account. This cross-sectional study took place at geriatric outpatient memory clinics. Participants were community-dwelling adults, aged 55 years or over, referred from primary care settings (a minority of participants were referred from specialists) for assessment of memory loss and age-matched control subjects with no complaint of memory loss. Each participant had the ABCS and the SMMSE administered in random order on the same day. Participants included 124 patients diagnosed with MCI and 111 with normal cognitive function. The ABCS showed a statistically significant difference between normal cognition and MCI (ABCS score 111.7 and 104.6 points, respectively, P < 0.001) for the whole group. This difference was significant with the ABCS, regardless of participants' age or education. There was a significant difference between normal cognition and MCI for SMMSE scores (SMMSE score 27.8 and 27.2 points, respectively, P = 0.040), but the differences were not significant when age and education were taken into account. Age and education were shown to affect the scores of both instruments except for the ABCS scores of MCI subjects, which were not significantly affected by education (P = 0.059). The ABCS is more sensitive than the SMMSE in differentiating normal cognition from MCI. The ABCS appears to be less influenced by education. It has improved clinical utility with a wider range of scoring gradations, reduced ceiling effects, and shorter scoring and administration times.


The role of cognitive function in the relationship between age and health literacy: a cross-sectional analysis of older adults in Chicago, USA.
To investigate how 3 measures of health literacy correlate with age and the explanatory roles of fluid and crystallised cognitive abilities in these relationships among older adults. Cross-sectional baseline analysis of the 'LitCog' cohort study. 1 academic internal medicine clinic and 5 federally qualified health centres in Chicago, USA. English-speaking adults (n=828) aged 55-74 years, recruited from August 2008 through October 2011. Health literacy was measured by the Test of Functional Health Literacy in Adults (TOFHLA) and the Newest Vital Sign (NVS), both of which assess reading comprehension and numeracy in health contexts, and by the Rapid Estimate of Adult Literacy in Medicine (REALM), which assesses medical vocabulary. Fluid cognitive ability was assessed through the cognitive domains of processing speed, inductive reasoning, and working, prospective and long-term memories, and crystallised cognitive ability through the verbal ability domain. TOFHLA and NVS scores were lower at ages 70-74 years compared with all other age groups (p<0.05 for both tests). The inverse association between age and TOFHLA score was attenuated from β=-0.39 (95% CI -0.55 to -0.22) to β=-0.06 (95% CI -0.20 to 0.08) for ages 70-74 vs 55-59 years when fluid cognitive ability was added to the model (85% attenuation). Similar results were seen with NVS scores (68% attenuation). REALM scores did not differ by age group (p=0.971). Crystallised cognitive ability was stable across age groups, and did not influence the relationships between age and TOFHLA or NVS performance. Health literacy skills show differential patterns of age-related change, which may be explained by cognitive ageing. Researchers should select health literacy tests appropriate for their purposes when assessing the health literacy of older adults. Clinicians should be aware of this issue to ensure that health self-management tasks for older patients have appropriate cognitive and literacy demands.


The Ralstonia solanacearum csp22 peptide, but not flagellin-derived peptides, is perceived by plants from the Solanaceae family.
Ralstonia solanacearum, the causal agent of bacterial wilt disease, is considered one of the most destructive bacterial pathogens due to its lethality, unusually wide host range, persistence and broad geographical distribution. In spite of the extensive research on plant immunity over the last years, the perception of molecular patterns from R. solanacearum that activate immunity in plants is still poorly understood, which hinders the development of strategies to generate resistance against bacterial wilt disease. The perception of a conserved peptide of bacterial flagellin, flg22, is regarded as paradigm of plant perception of invading bacteria; however, no elicitor activity has been detected for R. solanacearum flg22. Recent reports have shown that other epitopes from flagellin are able to elicit immune responses in specific species from the Solanaceae family, yet our results show that these plants do not perceive any epitope from R. solanacearum flagellin. Searching for elicitor peptides from R. solanacearum, we found several protein sequences similar to the consensus of the elicitor peptide csp22, reported to elicit immunity in specific Solanaceae plants. A R. solanacearum csp22 peptide (csp22Rsol ) was indeed able to trigger immune responses in Nicotiana benthamiana and tomato, but not in Arabidopsis thaliana. Additionally, csp22Rsol treatment conferred increased resistance to R. solanacearum in tomato. Transgenic A. thaliana plants expressing the tomato csp22 receptor (SlCORE) gained the ability to respond to csp22Rsol and became more resistant to R. solanacearum infection. Our results shed light on the mechanisms for perception of R. solanacearum by plants, paving the way for improving current approaches to generate resistance against R. solanacearum.


Maternal depression in first 1000 days of life and early childhood caries prevalence at 48 months of age.
The aim of this study was to investigate the effect of maternal's depression trajectory in the first 1000 days of the child's life on the prevalence of early childhood dental caries (ECC), in a birth cohort. All infants born in Pelotas in 2015 were identified, and the mothers were invited to participate in the cohort. A total of 3645 children were included in the study. The outcome was ECC at 48 months of age assessed according to ICDAS. Maternal depression was collected using Edinburgh Postnatal Depression Scale (EPDS) antenatally, at 3, 12, and 24 months of age. Maternal depressive symptom trajectory variables were created using group-based trajectory models and adopting two cutoff points. Poisson regression model with robust variance was used to identify the total effect of maternal depressive symptom trajectories on ECC, adjusting by confounders. A total of 29.2% of the mothers presented a high trajectory for screening of depression, and 18.8% presented a high trajectory of depression diagnosis. The prevalence of ECC was 26.7%. After adjusted analysis, maternal depression trajectories (screening and diagnosis) from pregnancy to 24 months increased the risk for ECC at 48 months of age (RR = 1.14; 95% CI 1.02-1.28 and RR = 1.19; 95% CI 1.05-1.35). Children from mothers with high depression trajectory had higher risk of having dental caries at 48 months compared to children from mothers with low depression trajectory. Strategies of early detection and treatment of maternal mental disorders during the Golden Period should be considered of high priority in health services since it could impact positively in children's life.


Levels of chemerin and interleukin 8 in the synovial fluid of patients with inflammatory arthritides and osteoarthritis.
Chemerin and interleukin (IL)-8 are pro-inflammatory mediators whose role in joint inflammation and cartilage degradation has been demonstrated in in-vitro findings. Studies on their presence in synovial fluid (SF) samples may offer further information on their pathogenic role. The aim of this study was to investigate SF chemerin and IL-8 levels in patients with different joint diseases. 37 patients were enrolled: 18 with rheumatoid arthritis (RA), 8 with psoriatic arthritis (PsA) and 11 with osteoarthritis (OA). 41 SF samples were obtained by arthrocentesis in case of knee synovitis. Serum samples were obtained from 13 patients (4 with RA, 6 with PsA and 3 with OA) at the time of arthrocentesis. Chemerin, IL-8, TNF-α and IL-6 levels were measured using commercially available ELISA kits. Immunohistochemical analysis of synovial RA specimens was also performed. No difference in chemerin SF levels emerged between patients with immune-mediated inflammatory arthritides and those with OA (p=0.0656), while subjects with inflammatory arthritis displayed significantly higher levels of SF IL-8 compared to OA (p=0.0020). No significant difference emerged across the three conditions in the serum levels of both chemerin and IL-8. IL-8 strongly correlated with inflammatory markers as ESR, CRP, IL-6 and TNF-α. We observed similar chemerin SF and serum levels in the three conditions. Although flawed by some limitations, our findings support the emerging concept of OA as an inflammatory disorder. However the increased IL-8 levels we described in patients with inflammatory arthritis suggest a selective involvement of this pro-inflammatory and angiogenic cytokine in these conditions.


Effect of tyrosine kinase inhibition using imatinib on normal lymphohematopoietic cells.
Imatinib is a selective tyrosine kinase inhibitor used for the treatment of Philadelphia chromosome-positive leukemias and other malignancies. An important clinical observation is that imatinib can affect the function of normal nonmalignant cells resulting in myelosuppression in treated patients. This observation is supported by the recent findings suggesting that imatinib might affect mobilization, proliferation, and differentiation of hematopoietic progenitor cells while leaving hematopoietic stem cells unaffected. Furthermore, the induction of a specific T cell response seems to be impaired in chronic myeloid leukemia (CML) patients treated with imatinib in contrast to patients receiving interferon-alpha. Recent studies demonstrate that in vitro exposure of mobilized human CD34(+) progenitors to imatinib inhibits their differentiation into dendritic cells. This is of importance as some of the therapeutic effects in the treatment of patients with CML are mediated by the induction of leukemia-specific T cell responses. Studies investigating the effects of imatinib on normal hematopoiesis are of interest because they might help us better understand the side effects observed clinically and might lead to the identification of novel therapeutic applications of the drug (e.g., in Bcr-Abl(-) myeloproliferative disorders and potentially as an immunomodulatory agent).


Excitatory Amino acid transporter expression in the essential tremor dentate nucleus and cerebellar cortex: A postmortem study.
Genome-wide association studies have revealed a link between essential tremor (ET) and the gene SLC1A2, which encodes excitatory amino acid transporter type 2 (EAAT2). We explored EAAT biology in ET by quantifying EAAT2 and EAAT1 levels in the cerebellar dentate nucleus, and expanded our prior analysis of EAAT2 levels in the cerebellar cortex. To quantify EAAT2 and EAAT1 levels in the cerebellar dentate nucleus and cerebellar cortex of ET cases vs. We used immunohistochemistry to quantify EAAT2 and EAAT1 levels in the dentate nucleus of a discovery cohort of 16 ET cases and 16 controls. Furthermore, we quantified EAAT2 levels in the dentate nucleus in a replicate cohort (61 ET cases, 25 controls). Cortical EAAT2 levels in all 77 ET cases and 41 controls were quantified. In the discovery cohort, dentate EAAT2 levels were 1.5-fold higher in 16 ET cases vs. 16 controls (p = 0.007), but EAAT1 levels did not differ significantly (p = 0.279). Dentate EAAT2 levels were 1.3-fold higher in 61 ET cases vs. 25 controls in the replicate cohort (p = 0.022). Cerebellar cortical EAAT2 levels were 20% and 40% lower in ET cases vs. controls in the discovery and the replicate cohorts (respective p values = 0.045 and < 0.001). EAAT2 expression is enhanced in the ET dentate nucleus, in contrast to differentially reduced EAAT2 levels in the ET cerebellar cortex, which might reflect a compensatory mechanism to maintain excitation-inhibition balance in cerebellar nuclei.


[Autodermoplasty in the treatment of wound emaciation].
Different types of dermoplasty aimed at the closure of reactive wounds were applied in the treatment of 26 cases with protracted non-healing wounds (up to 30 years) following burns, frostbites, open fractures, outcomes of acute suppurative diseases with sepsis phenomena. The treatment failed only in one patient. The transplantation of free stamp-like skin grafts proved to be the most effective one. Biostimulating effect of the single grafts which fuse has been noted.


Decreased plasma isoleucine concentrations after upper gastrointestinal haemorrhage in humans.
A decrease in arterial isoleucine values after intragastric blood administration in pigs has been observed. This contrasted with increased values of most other amino acids, ammonia, and urea. After an isonitrogenous control meal in these pigs all amino acids including isoleucine increased, and urea increased to a lesser extent, suggesting a relation between the arterial isoleucine decrease and uraemia after gastrointestinal haemorrhage. To extend these findings to humans, plasma amino acids were determined after gastrointestinal haemorrhage in patients with peptic ulcers (n = 9) or oesophageal varices induced by liver cirrhosis (n = 4) and compared with preoperative patients (n = 106). After gastrointestinal haemorrhage, isoleucine decreased in all patients by more than 60% and normalised within 48 hours. Most other amino acids increased and also normalised within 48 hours. Uraemia occurred in both groups, hyperammonaemia was seen in patients with liver cirrhosis. These results confirm previous findings in animals and healthy volunteers that plasma isoleucine decreases after simulated upper gastrointestinal haemorrhage. This supports the hypothesis that the absence of isoleucine in blood protein causes decreased plasma isoleucine values after gastrointestinal haemorrhage, and may be a contributory factor to uraemia and hyperammonaemia in patients with normal and impaired liver function, respectively. Intravenous isoleucine administration after gastrointestinal haemorrhage could be beneficial and will be the subject of further research.


Scope and outcomes of surrogate decision making among hospitalized older adults.
Hospitalized older adults often lack decisional capacity, but outside of the intensive care unit and end-of-life care settings, little is known about the frequency of decision making by family members or other surrogates or its implications for hospital care. To describe the scope of surrogate decision making, the hospital course, and outcomes for older adults. Prospective, observational study conducted in medicine and medical intensive care unit services of 2 hospitals in 1 Midwestern city in 1083 hospitalized older adults identified by their physicians as requiring major medical decisions. Clinical characteristics, hospital outcomes, nature of major medical decisions, and surrogate involvement. According to physician reports, at 48 hours of hospitalization, 47.4% (95% CI, 44.4%-50.4%) of older adults required at least some surrogate involvement, including 23.0% (20.6%-25.6%) with all decisions made by a surrogate. Among patients who required a surrogate for at least 1 decision within 48 hours, 57.2% required decisions about life-sustaining care (mostly addressing code status), 48.6% about procedures and operations, and 46.9% about discharge planning. Patients who needed a surrogate experienced a more complex hospital course with greater use of ventilators (2.5% of patients who made decisions and 13.2% of patients who required any surrogate decisions; P < .001), artificial nutrition (1.7% of patients and 14.4% of surrogates; P < .001), and length of stay (median, 6 days for patients and 7 days for surrogates; P < .001). They were more likely to be discharged to an extended-care facility (21.2% with patient decisions and 40.9% with surrogate decisions; P < .001) and had higher hospital mortality (0.0% patients and 5.9% surrogates; P < .001). Most surrogates were daughters (58.9%), sons (25.0%), or spouses (20.6%). Overall, only 7.4% had a living will and 25.0% had a health care representative document in the medical record. Surrogate decision making occurs for nearly half of hospitalized older adults and includes both complete decision making by the surrogate and joint decision making by the patient and surrogate. Surrogates commonly face a broad range of decisions in the intensive care unit and the hospital ward setting. Hospital functions should be redesigned to account for the large and growing role of surrogates, supporting them as they make health care decisions.


Hormonal regulation of rat foetal lipogenesis in brown-adipocyte primary cultures.
Insulin stimulates lipogenesis by 100% for 5 h by a covalent modulation of acetyl-CoA carboxylase, and by 200% for 24 h by increasing malic enzyme and fatty acid synthase enzymic activities in brown-adipocyte primary cultures. At short times, noradrenaline and isoprenaline decrease lipogenesis. However, phenylephrine and glucagon have no effect. At long times, dexamethasone inhibits lipogenesis. This effect is precluded in the presence of insulin. Progesterone and tri-iodothyronine, alone or in the presence of insulin, produce a stimulation of the rates of lipogenesis.


Nicotinic receptor mechanisms and cognition in normal states and neuropsychiatric disorders.
Cigarette smoking rates in the American population are approximately 23%, whereas rates of smoking in clinical and population studies of individuals with neuropsychiatric disorders are typically two- to four-fold higher. Studies conducted in a variety of neuropsychiatric populations [e.g. attention-deficit hyperactivity disorder (ADHD), Alzheimer's disease, schizophrenia] have collectively suggested that nicotine may be efficacious in remediating selected cognitive deficits associated with these disorders, thus providing a framework for understanding the specific vulnerability of these patients to smoking initiation and maintenance. However, the specific gain in cognitive performance produced by nicotine administration in healthy subjects with normal cognitive function is less clear. This article reviews our current understanding of central nicotinic acetylcholine receptor (nAChRs) systems in normal and neuropsychiatric disease states and, specifically, their role with respect to cognitive dysfunction and clinical symptoms in several specific neuropsychiatric populations, including ADHD, Alzheimer's disease, Parkinson's disease, Tourette's Disorder, schizophrenia and affective disorders. The potential benefits of nicotinic agents for therapeutic use in neuropsychiatric disorders is discussed, as well as directions for further research in this area.


Study of the course of inferior epigastric artery with reference to laparoscopic portal.
Laparoscopy has been in vogue for more than 2 decades. Making portals in the anterior abdominal wall for introducing laparoscopic instruments is done with trocar and cannula which is a blind procedure. Stab incision and trocar insertion, though safe, at times can lead to injury of blood vessels of anterior abdominal wall more so the inferior epigastric artery (IEA). Trauma to abdominal wall vessels is 0.2%-2% of laparoscopic procedures and said to be 3 per 1000 cases. Injury to IEA is one of the commonest complications seen. Purpose of the present study was to observe the course of IEA in 50 formalin preserved cadavers, by dissection. In 50 formalin fixed cadavers, IEA was exposed by opening the rectus sheath. Rectus was divided and IEA was exposed. Five reference points A, B, C, D, and E were defined. A was at pubic symphysis, while E at umbilicus. B, C, and D were marked at the distance of 3.5, 7, and 10.5 cm, respectively from pubic symphysis. Distances of the IEA from these midline points were measured with the help of sliding vernier calipers. Significant observation was variations in the length of IEA. It was seen to end at a lower level than normal (three cases on right and four on left side) by piercing rectus. In 14, cadavers artery did not reach up to umbilicus on both sides. Nearest point of entry of IEA in to rectus sheath at the level of pubic symphysis was 1.2 cm on left and 3.2 cm on right side. Farthest point from point A was 6.8 cm on right and 6.9 cm on left side. Width of strip of abdominal wall which was likely to have IEA beneath was up to 4 cm till level C and beyond which it widened up to 5cm on left side and 6 cm on right at umbilicus. Present study did reveal notable variations in length and termination of IEA. No uniformity in entry of IEA in to the rectus sheath was observed. Findings did concur with earlier observations but the strip of skin of arterial zone was not equidistant from midline but had moved more medially on left side. Medial limit of this safety zone found to be lesser than 2 cm on left side. However, the lateral limit of the zone was within 7.5 cm. Additional variation was strip of abdominal wall likely to have IEA beneath was up to 4 cm till level C and had diverging limits beyond C. IEA was more notorious in its course. These variations prompt for a preoperative mapping of IEA and thus a useful step in preoperative protocol.


Expansion of a maternally derived monoclonal T cell population with CD3+/CD8+/T cell receptor-gamma/delta+ phenotype in a child with severe combined immunodeficiency.
The diagnosis of severe combined immunodeficiency complicated by chronic graft-vs-host disease affecting liver and skin in association with engraftment of maternal T cells was established in a 5-mo-old boy. Detailed immunologic and molecular genetic studies were performed because a unique T cell phenotype was identified on initial evaluation. A major proportion of the patient's peripheral T cells expressed a CD8+ and TCR-gamma/delta+ phenotype while CD4+ T cells were virtually absent. Southern blot analysis of cell subpopulations isolated by fluorescence activated cell sorting indicated that approximately 50% of CD8+/TCR-gamma/delta+ cells were clonally related. Immunophenotyping and -genotyping also identified a clonal TCR-gamma/delta+ cell population in the child's mother. Clonal identity of these T cell populations in mother and child was demonstrated by studies using a clonspecific TCR-delta probe generated by polymerase chain reaction as well DNA sequence analysis. HLA typing and DNA fingerprinting confirmed that the child had acquired this clone diaplacentally from the mother. According to immunohistology and DNA analysis the clone was found to be virtually absent in the liver tissue suggesting that this clonal T cell population plays a minor role, if any, in the pathogenesis of the liver abnormalities in the patient. In the mother the CD8+/TCR-gamma/delta+ clone spontaneously declined to a level around 1% of PBMC several months later and has remained at this level since. We conclude that 1) a clonal expansion of TCR-gamma/delta T cells, triggered by yet unknown stimuli, may occur in otherwise healthy individuals, 2) respective T cells are able to cross the placental barrier, and 3) in an microenvironment precluding rejection, i.e., in severely immunocompromised patients, these cells may persist and even represent a significant proportion of circulating T cells.


Analysis of human cytomegalovirus-encoded SUMO targets and temporal regulation of SUMOylation of the immediate-early proteins IE1 and IE2 during infection.
Post-translational modification of proteins by members of the small ubiquitin-like modifier (SUMO) is involved in diverse cellular functions. Many viral proteins are SUMO targets and also interact with the cellular SUMOylation system. During human cytomegalovirus (HCMV) infection, the immediate-early (IE) proteins IE1 and IE2 are covalently modified by SUMO. IE2 SUMOylation promotes its transactivation activity, whereas the role of IE1 SUMOylation is not clear. We performed in silico, genome-wide analysis to identify possible SUMOylation sites in HCMV-encoded proteins and evaluated their modification using the E. coli SUMOylation system and in vitro assays. We found that only IE1 and IE2 are substantially modified by SUMO in E. coli, although US34A was also identified as a possible SUMO target in vitro. We also found that SUMOylation of IE1 and IE2 is temporally regulated during viral infection. Levels of SUMO-modified form of IE1 were increased during the early phase of infection, but decreased in the late phase when IE2 and its SUMO-modified forms were expressed at high levels. IE2 expression inhibited IE1 SUMOylation in cotransfection assays. As in IE2 SUMOylation, PIAS1, a SUMO E3 ligase, interacted with IE1 and enhanced IE1 SUMOylation. In in vitro assays, an IE2 fragment that lacked covalent and non-covalent SUMO attachment sites, but was sufficient for PIAS1 binding, effectively inhibited PIAS1-mediated SUMOylation of IE1, indicating that IE2 expression negatively regulates IE1 SUMOylation. We also found that the IE2-mediated downregulation of IE1 SUMOylation correlates with the IE1 activity to repress the promoter containing the interferon stimulated response elements. Taken together, our data demonstrate that IE1 and IE2 are the main viral SUMO targets in HCMV infection and that temporal regulation of their SUMOylation may be important in the progression of this infection.


Complete vaginal occlusion in postmenopausal women.
The spontaneous development of total vaginal occlusion as the result of postmenopausal atrophy is unusual. This poorly described entity may give rise to diagnostic confusion, as the site of vaginal occlusion resembles an atrophic cervix flush with the top of a stenotic vaginal vault. Fluid collections above this site of occlusion may produce pelvic masses with a characteristic physical sign. The absence of any history of vaginal injury or disease distinguishes these cases from other types of acquired vaginal occlusion.


Tuberculosis as a Risk Factor for 1918 Influenza Pandemic Outcomes.
Tuberculosis (TB) mortality declined after the 1918 pandemic, suggesting that influenza killed those who would have died from TB. Few studies have analyzed TB as a direct risk factor for 1918 influenza morbidity and mortality by age and sex. We study the impacts of TB on influenza-like illness (% of population sick) and case fatality (% of cases dying) by age and sex through case-control comparisons of patients (N = 201) and employees (N = 97) from two Norwegian sanatoriums. Female patients, patients at Landeskogen sanatorium, and patients aged 10-39 years had significantly lower morbidity than the controls. None of the 62 sick employees died, while 15 of 84 sick patients did. The case-control difference in case fatality by sex was only significant for females at Lyster sanatorium and females at both sanatoriums combined. Non-significant case-control differences in case fatality for males were likely due to small samples. Patients 20-29 years for both sexes combined at Lyster sanatorium and at both sanatoriums combined, as well as females 20-29 years for both sanatoriums combined, had significantly higher case fatality. We conclude that TB was associated with higher case fatality, but morbidity was lower for patients than for employees. The results add to the study of interactions between bacterial and viral diseases and are relevant in preparing for pandemics in TB endemic areas.


Accelerometer-based detection of African swine fever infection in wild boar.
Infectious wildlife diseases that circulate at the interface with domestic animals pose significant threats worldwide and require early detection and warning. Although animal tracking technologies are used to discern behavioural changes, they are rarely used to monitor wildlife diseases. Common disease-induced behavioural changes include reduced activity and lethargy ('sickness behaviour'). Here, we investigated whether accelerometer sensors could detect the onset of African swine fever (ASF), a viral infection that induces high mortality in suids for which no vaccine is currently available. Taking advantage of an experiment designed to test an oral ASF vaccine, we equipped 12 wild boars with an accelerometer tag and quantified how ASF affects their activity pattern and behavioural fingerprint, using overall dynamic body acceleration. Wild boars showed a daily reduction in activity of 10-20% from the healthy to the viremia phase. Using change point statistics and comparing healthy individuals living in semi-free and free-ranging conditions, we show how the onset of disease-induced sickness can be detected and how such early detection could work in natural settings. Timely detection of infection in animals is crucial for disease surveillance and control, and accelerometer technology on sentinel animals provides a viable complementary tool to existing disease management approaches.


Differences in the Spirometry Parameters Between Indigenous and Non-Indigenous Patients with COPD: A Matched Control Study.
Comparison of spirometry parameters between Indigenous and non-Indigenous patients with underlying chronic obstructive pulmonary disease (COPD) has been sparsely reported in the past. In this study, differences in the lung function parameters (LFPs), in particular spirometry values for forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and FEV1/FVC ratio between Indigenous and non-Indigenous patients with COPD were assessed. In this retrospective study, Indigenous and non-Indigenous patients with a diagnosis of COPD between 2012-2020 according to spirometry criteria (ie; post-bronchodilator (BD) FEV1/FVC < 0.7) were included. A further analysis was undertaken to compare the differences in the spirometry parameters, including lower limit of normal (LLN) values matching for age, sex, height and smoking status between these two diverse ethnic populations. A total of 240/742 (32%) Indigenous and 873/4579 (19%) non-Indigenous patients were identified to fit the criteria for COPD. Indigenous patients were significantly younger (mean difference 9.9 years), with a greater proportion of females (50% vs 33%), underweight (20% vs 8%) and current smokers (47% vs 32%). Prior to matching, Indigenous patients' post-BD percent predicted values for FVC, FEV1, and FEV1/FVC ratio were 17, 17%, and -2 points lower (Hedges G measure of effect size large (0.91), large (0.87), and small (0.25), respectively). Among the matched cohort (111 Indigenous and non-Indigenous), Indigenous patients LFPs remained significantly lower, with a mean difference of 16%, 16%, and -4, respectively (Hedges G large (0.94), large (0.92) and small (0.41), respectively). The differences persisted despite no significant differences in LLN values for these parameters. Indigenous Australian patients with COPD display a significantly different demographic and clinical profile than non-Indigenous patients. LFPs were significantly lower, which may or may not equate to greater severity of disease in the absence of normative predictive lung function reference values specific to this population.


New therapeutic vaccination strategies for the treatment of chronic hepatitis B.
Chronic hepatitis B virus (CHB) is currently treated with either interferon-based or nucleot(s)ide-based antiviral therapies. However, treatment with pegylated interferon alpha results in a durable antiviral response in only about 30% patients and is associated with side effects. Most patients receiving nucleot(s)ide analogue treatment do not establish long-term, durable control of infection and have rebounding viremia after cessation of therapy. Thus, novel therapy strategies are necessary to achieve the induction of potent and durable antiviral immune responses of the patients which can maintain long-term control of viral replication. Therapeutic vaccination of HBV carriers is a promising strategy for the control of hepatitis B. Here the authors review new therapeutic vaccination strategies to treat chronic hepatitis B which may be introduced for patient treatment in the future.


Infectivity of human coronavirus strain 229E.
The replication of human coronavirus strain 229E was observed by using indirect immunofluorescence in infected monolayers of MRC continuous cells. By 8 h after infection, bright cytoplasmic fluorescence was detected in cells infected with human coronavirus 229E. Discrete foci of infection were observed from 8 to 16 h after infection in cells infected with high dilutions of human coronavirus 229E; each fluorescent focus corresponded to a single virus infection. A fluorescent focus assay is described, using indirect immunofluorescence, which is more sensitive than the established techniques of tube titration and plaque assay. Particle/infectivity ratios for unpurified and purified virus preparations revealed a considerable drop in infectivity on purification.


An efficacy trial of brief lifestyle intervention delivered by generalist community nurses (CN SNAP trial).
Lifestyle risk factors, in particular smoking, nutrition, alcohol consumption and physical inactivity (SNAP) are the main behavioural risk factors for chronic disease. Primary health care (PHC) has been shown to be an effective setting to address lifestyle risk factors at the individual level. However much of the focus of research to date has been in general practice. Relatively little attention has been paid to the role of nurses working in the PHC setting. Community health nurses are well placed to provide lifestyle intervention as they often see clients in their own homes over an extended period of time, providing the opportunity to offer intervention and enhance motivation through repeated contacts. The overall aim of this study is to evaluate the impact of a brief lifestyle intervention delivered by community nurses in routine practice on changes in clients' SNAP risk factors. The trial uses a quasi-experimental design involving four generalist community nursing services in NSW Australia. Services have been randomly allocated to an 'early intervention' group or 'late intervention' (comparison) group. 'Early intervention' sites are provided with training and support for nurses in identifying and offering brief lifestyle intervention for clients during routine consultations. 'Late intervention site' provide usual care and will be offered the study intervention following the final data collection point. A total of 720 generalist community nursing clients will be recruited at the time of referral from participating sites. Data collection consists of 1) telephone surveys with clients at baseline, three months and six months to examine change in SNAP risk factors and readiness to change 2) nurse survey at baseline, six and 12 months to examine changes in nurse confidence, attitudes and practices in the assessment and management of SNAP risk factors 3) semi-structured interviews/focus with nurses, managers and clients in 'early intervention' sites to explore the feasibility, acceptability and sustainability of the intervention. The study will provide evidence about the effectiveness and feasibility of brief lifestyle interventions delivered by generalist community nurses as part of routine practice. This will inform future community nursing practice and PHC policy. ACTRN12609001081202.


Current concepts in the management of varicose veins.
Varicose veins are a very common problem, affecting women more than men. The major concern is usually the unsightly appearance of the veins. Various options to deal with this problem are discussed-- compression stockings, compression sclerotherapy and surgery. For good results and patient satisfaction, the cause and natural history of varicose veins must be understood. Depending on the type of varicose vein, different modalities of treatment are required and may need to be combined. "Cosmetic" varicosities can usually be managed conservatively with compression stockings. Sclerotherapy is best used for dilated superficial or residual varicose veins, recurrent varicosities or leg perforators. Operation should be reserved for very large varicose veins or an incompetent long or short saphenous vein. A sound understanding of the problems and discussion of anticipated results with the patient will prevent unrealistic expectations.


Eye gaze during comprehension of American Sign Language by native and beginning signers.
An eye-tracking experiment investigated where deaf native signers (N = 9) and hearing beginning signers (N = 10) look while comprehending a short narrative and a spatial description in American Sign Language produced live by a fluent signer. Both groups fixated primarily on the signer's face (more than 80% of the time) but differed with respect to fixation location. Beginning signers fixated on or near the signer's mouth, perhaps to better perceive English mouthing, whereas native signers tended to fixate on or near the eyes. Beginning signers shifted gaze away from the signer's face more frequently than native signers, but the pattern of gaze shifts was similar for both groups. When a shift in gaze occurred, the sign narrator was almost always looking at his or her hands and was most often producing a classifier construction. We conclude that joint visual attention and attention to mouthing (for beginning signers), rather than linguistic complexity or processing load, affect gaze fixation patterns during sign language comprehension.


Methimazole therapy in Graves' disease influences the abnormal expression of CD69 (early activation antigen) on T cells.
At present, the in vivo response of T, B and natural killer (NK) cells to antithyroid drug therapy remains largely unknown. In the present study, we have prospectively analyzed the in vivo effects of methimazole treatment on a large number of circulating T and NK cell subsets, some of them expressing cell surface activation antigens involved in the very early phase of the immune response, in a group of 17 hyperthyroid, untreated patients with Graves' disease (GD). As one of the first events during T cell activation is the expression of interleukin (IL) receptors, we also studied the binding of IL-2 and IL-6 to T cells. Patients with Graves' disease were sequentially studied at diagnosis/before treatment (day 0) and 7, 14, 30, 90 and 180 days after methimazole therapy. The results were compared with both a group of 19 age- and sex-matched control volunteers and a group of 20 untreated/euthyroid patients with Graves' disease in long-term remission. The combination of flow cytometry and three-color immunofluorescence revealed a clear (P < 0.01) decrease in the percentage of NK cells before and during the whole course of therapy with respect to both controls and patients with Graves' disease who were in long-term remission. Before therapy, a marked increase (P < 0.001) in the ratio of B to NK cells was also observed; thereafter, a slight decrease in this ratio was observed, although normal values were detected only in patients in long-term remission. Expression of the CD69 early activation antigen in the hyperthyroid untreated patients with Graves' disease was clearly increased (P < 0.01) with respect to both controls and patients with Graves' disease who were in long-term remission. This abnormal CD69 expression was found to be significantly reduced (P < 0.001) by methimazole therapy, and this represents a new effect of the drug. Expression of the low-affinity receptor for IL-2 (CD25)--another early T cell activation marker--was not altered in Graves' disease, but the binding of IL-2 and IL-6 to T cells exhibited a progressive and parallel increase during the first 30 days of therapy, decreasing thereafter. Our results show that methimazole therapy downregulates the abnormally high expression of the CD69 early activation antigen on T cells, being less effective on inducing changes in other T cell activation markers and in NK cells.


Conjugated linoleic acid reduces body fat accretion and lipogenic gene expression in neonatal pigs fed low- or high-fat formulas.
Childhood obesity is an increasing problem and may predispose children to adult obesity. Weight gain during infancy has been linked to excessive weight later in life. Conjugated linoleic acids (CLA) have been shown to reduce fat gain and body fat mass in animal models and in humans. The effects of CLA in a piglet model of human infancy have not been determined. The objective of this experiment was to examine the regulation of body composition and lipid metabolism in pigs fed low- and high-fat milk formulas supplemented with CLA. Twenty-four piglets were fed low- (3%) or high-fat (25%) diets with or without 1% CLA in a 2 x 2 factorial design. Formulas were fed for 16-17 d. Piglet body weight gains did not differ, although pigs fed the low-fat diets consumed greater amounts of diet. Piglets fed the high-fat formula accreted 50% more body fat during the feeding period than low-fat fed piglets and CLA reduced body fat accretion regardless of dietary fat content. Liver and muscle in vitro oxidation of palmitate was not influenced by dietary treatments. Adipose tissue expression of acetyl-CoA carboxylase-alpha and lipoprotein lipase were significantly reduced by CLA treatment. Overall, CLA reduced body fat accretion without influencing daily gain in a piglet model of human infancy. Results indicate that inhibition of fatty acid uptake and synthesis by adipose tissue, and not increased fatty acid oxidation in liver or muscle, were involved in reducing body fat gain.


[Effect of polyamines on actomyosine-ATP-ase activity in smooth muscles of the uterus].
The ability of the aliphatic polyamines to inhibit [figure: see text] the ATPase activity of smooth muscle actomyosine satisfies the succession: spermine > spermidine > putrescine that is correlated with magnitude of positive charge at physiological value of pH. The most effective inhibitor of the ATP hydrolysis process is the spermine, which highest inhibitory action is manifested at 10(-3) M concentration, in lesser concentration (10(-5) M) activates the actomyosine ATPase. While defining the kinetic parameters of the ATP hydrolysis reaction catalyzed by uterus myometrium the correlation between inhibiting the ATPase activity of myometrium contractile complex under introduction into the incubation medium of 10(-3) M spermine and decreasing the affinity of actomyosine for ATP was made; the activating effect of spermine on ATPase activity of actomyosine complex in the presence of 10(-5) M spermine correlated with the increase of actomyosine affinity for Mg2+.


Boosting cytotoxicity of adoptive allogeneic NK cell therapy with an oncolytic adenovirus encoding a human vIL-2 cytokine for the treatment of human ovarian cancer.
Despite good results in the treatment of hematological malignancies, Natural killer (NK) cells have shown limited effectiveness in solid tumors, such as ovarian cancer (OvCa). Here, we assessed the potential of an oncolytic adenovirus expressing a variant interleukin-2 (vIL-2) cytokine, Ad5/3-E2F-d24-vIL2 (vIL-2 virus), also known as TILT-452, to enhance NK cell therapy efficacy in human OvCa ex vivo. Human OvCa surgical specimens were processed into single-cell suspensions and NK cells were expanded from healthy blood donors. OvCa sample digests were co-cultured ex vivo with NK cells and vIL-2 virus and cancer cell killing potential assessed in real time through cell impedance measurement. Proposed therapeutic combination was evaluated in vivo with an OvCa patient-derived xenograft (PDX) in mice. Addition of vIL-2 virus significantly enhanced NK cell therapy killing potential in treated OvCa co-cultures. Similarly, vIL-2 virus in combination with NK cell therapy promoted the best in vivo OvCa tumor control. Mechanistically, vIL-2 virus induced higher percentages of granzyme B in NK cells, and CD8+ T cells, while T regulatory cell proportions remained comparable to NK cell monotherapy in vivo. Ad5/3-E2F-d24-vIL2 virus treatment represents a promising strategy to boost adoptive NK cell therapeutic effect in human OvCa.


Oligomerization, transport, and Golgi retention of Punta Toro virus glycoproteins.
We have investigated the oligomerization and intracellular transport of the membrane glycoproteins of Punta Toro virus, a member of the Phlebovirus genus of the family Bunyaviridae, which is assembled by budding in the Golgi complex. By using one- or two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis, chemical cross-linking, and sucrose gradient centrifugation, we found that the majority of the G1 and G2 glycoproteins are assembled into noncovalently linked G1-G2 heterodimers. At the same time, a fraction of the G2 protein, possibly produced independently of the G1 protein, is assembled into G2 homodimers. Kinetic analysis indicates that heterodimerization occurs between newly synthesized G1 and G2 within 3 min after protein synthesis, and that the G1 and G2 glycoproteins are associated as dimeric forms both during transport and after accumulation in the Golgi complex. Analysis of a G1-truncated G2 mutant, which is also targeted to the Golgi complex, showed that these molecules also assemble into dimeric forms, which are linked by disulfide bonds. Both the G1-G2 heterodimer and the G2 homodimer were found to be able to exit from the endoplasmic reticulum. Differences in transport kinetics observed for the G1 and G2 proteins may be due to the differences in the transport efficiency between the G1-G2 heterodimer and the G2 homodimer from the endoplasmic reticulum to the Golgi complex. These and previous results (S.-Y. Chen, Y. Matsuoka, and R.W. Compans, Virology 183:351-365, 1991) suggest that Golgi retention of the G2 homodimer occurs by association with the G1-G2 heterodimer, whereas the Golgi targeting of the G1-G2 heterodimer occurs by a specific retention mechanism.


[Drainage of the pancreatic duct].
An original drainage was used for preventing acute postoperative pancreatitis which had a construction providing preventive decompression of the pancreatic duct system acting on the pathogenetic mechanisms of its development, i.e. intraduct hypertension. The principal distinction of the proposed drainage construction is the duct system decompression with the saved physiological way of outflow of the pancreas secretion that eliminates the shortcomings of the external drainage. The drainage described was used in 6 patients after operations on the major duodenal papilla, cicatricial stricture of the papilla, choledocholithiasis. High clinical effectiveness of the method of the pancreatic duct system decompression is shown.


Multiple sclerosis in North African migrants to France.
Among some 7500 respondents with known place of birth who had completed a nationwide questionnaire survey for multiple sclerosis (MS) in France in 1986, there were 260 born in former French North Africa (Algeria, Morocco, Tunisia). They had migrated to France between 1923 and 1986, but 66% came between 1956 and 1964. Two-thirds were from Algeria, where virtually the entire European population had emigrated in 1962 at the end of the Algerian war for independence. The migrants were younger at prevalence day (mean 43.4 years) and at onset (29.4 years) than the French-born MS (46.6; 31.3 years). Eight migrants lacked age information. The 225 migrants with onset more than 1 year after immigration presumably acquired their MS in France. They provided an age adjusted (US 1960) MS prevalence rate 1.54 times that for all France. If the latter is taken at 50 per 100,000 population their estimated adjusted rate is 76.8 with 95% confidence interval of 67.1 to 87.5. The other 27 with presumed acquisition in North Africa gave an estimated adjusted prevalence of 16.6 per 100,000 (95% CI 10.9-24.1). For those migrants with acquisition in France there was a mean interval of 13 years between immigration or age 11 and clinical onset, with a minimum of 3 years. This series provides further support for the theses: 1) that MS is primarily an environmental disease acquired after childhood; 2) that acquisition requires prolonged or repeated exposure (here 3 years for these medium-to-high MS risk migrants) followed by a prolonged latent or incubation period between acquisition and symptom onset (here 10 years); and 3) that this disease is most likely a widespread but unknown persistent infection which results in clinical MS in only a small proportion of those affected.


An insulin-like growth factor-mediated, phosphatidylinositol 3' kinase-independent survival signaling pathway in beta tumor cells.
Hyperproliferation of tumor cells usually coincides with increased tumor cell apoptosis. To overcome apoptosis, tumor cells frequently induce the expression of growth factors that mediate cell survival. In nontransformed cells, including fibroblasts and neurons, survival factor-mediated signal transduction involves the activation of phosphatidylinositol 3' kinase (PI-3K) and protein kinase B/c-Akt (PKB). Here we demonstrate that tumor cell lines derived from a transgenic mouse model of pancreatic beta cell carcinogenesis use insulin-like growth factors to repress apoptosis independently of PI-3K and PKB. The results indicate that tumor cells can use additional survival signal transduction pathways.


Systematic conservation planning in the face of climate change: bet-hedging on the Columbia Plateau.
Systematic conservation planning efforts typically focus on protecting current patterns of biodiversity. Climate change is poised to shift species distributions, reshuffle communities, and alter ecosystem functioning. In such a dynamic environment, lands selected to protect today's biodiversity may fail to do so in the future. One proposed approach to designing reserve networks that are robust to climate change involves protecting the diversity of abiotic conditions that in part determine species distributions and ecological processes. A set of abiotically diverse areas will likely support a diversity of ecological systems both today and into the future, although those two sets of systems might be dramatically different. Here, we demonstrate a conservation planning approach based on representing unique combinations of abiotic factors. We prioritize sites that represent the diversity of soils, topographies, and current climates of the Columbia Plateau. We then compare these sites to sites prioritized to protect current biodiversity. This comparison highlights places that are important for protecting both today's biodiversity and the diversity of abiotic factors that will likely determine biodiversity patterns in the future. It also highlights places where a reserve network designed solely to protect today's biodiversity would fail to capture the diversity of abiotic conditions and where such a network could be augmented to be more robust to climate-change impacts.


Health Care Experiences of Latino Children in Emerging and Traditional Destinations.
Latino populations have disproportionately moved to areas in the Southeast and Midwest (emerging destinations), outside traditional Latino enclaves, in recent years. To examine whether health care experiences differ between traditional and emerging destinations for Latino children. We defined traditional and emerging destination counties based on levels and changes in the Latino population between 2000 and 2010. Measures were linked to the restricted National Survey of Children's Health along with county-level data from the Area Resource File and Census of State and Local Governments. To compare outcomes among Latino children across destinations, linear probability models adjusted for individual-level characteristics, area-level characteristics, and state fixed effects. Outcomes were access to a usual source of care, unmet health care needs, preventive health visit in prior year, and family-centered care. Compared with traditional destination counterparts, Latino children in emerging destinations tended to be younger, healthier, and more likely to be in families speaking English at home. Latino children in emerging destinations were significantly less likely to have a usual source of care adjusting for individual-level and county-level variables, but other dimensions of access were similar between destinations. Differences in usual source of care may reflect lower supply of culturally competent providers or limited information about where and how to seek care. For realized access to care, protective factors in emerging destinations, such as higher average incomes in the area and lower community uninsurance rates, might counteract any negative effects of emerging destinations.


The Global Status of Occupational Therapy Workforce Research Worldwide: A Scoping Review.
To fulfill their societal role, occupational therapists need to exist in sufficient supply, be equitably distributed, and meet competency standards. Occupational therapy workforce research is instrumental in reaching these aims, but its global status is unknown. To map the volume and nature (topics, methods, geography, funding) of occupational therapy workforce research worldwide. Six scientific databases (MEDLINE/PubMed, Scopus, CINAHL, Web of Science Core Collection, PDQ-Evidence for Informed Health Policymaking, OTseeker), institutional websites, snowballing, and key informants. Research articles of any kind were included if they involved data regarding occupational therapists and addressed 1 of 10 predefined workforce research categories. Two reviewers were used throughout study selection. No language or time restrictions applied, but the synthesis excluded publications before 1996. A linear regression examined the publications' yearly growth. Seventy-eight studies met the inclusion criteria, 57 of which had been published since 1996. Although significant (p < .01), annual publication growth was weak (0.07 publications/yr). "Attractiveness and retention" was a common topic (27%), and cross-sectional surveys were frequent study designs (53%). Few studies used inferential statistics (39%), focused on resource-poor countries (11%), used standardized instruments (10%), or tested a hypothesis (2%). Only 30% reported funding; these studies had stronger methodology: 65% used inferential statistics, and just 6% used exploratory cross-sectional surveys. Worldwide occupational therapy workforce research is scant and inequitably distributed, uses suboptimal methods, and is underfunded. Funded studies used stronger methods. Concerted efforts are needed to strengthen occupational therapy workforce research. What This Article Adds: This review highlights the opportunity to develop a stronger, evidence-based strategy for workforce development and professional advocacy.


Activation of the Janus kinase/STAT (signal transducer and activator of transcription) signal transduction pathway by interleukin-6-type cytokines promotes osteoblast differentiation.
We have previously established that stromal/osteoblastic cells collectively express receptors for all members of the cytokine subfamily that share the gp130 signal transducer and that different receptor repertoires may be expressed at different stages of differentiation of this lineage. We have now used human (MG-63) and murine (MC3T3-E1) osteoblastic cell lines as well as primary murine calvaria cells to test the hypothesis that these receptors mediate effects of the cytokines on the biology of osteoblasts. We report that as in other cell types, all of the osteoblastic cell models responded to interleukin-6 (IL-6)-type cytokines with activation of both the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and the mitogen-activated protein kinase (MAPK) pathways. In addition, IL-6-type cytokines stimulated alkaline phosphatase activity and osteocalcin expression and inhibited (MG-63), stimulated (MC3T3-E1), or had no effect (calvaria cells) on the rate of cell proliferation. The ability of a given cell type to respond to a particular member of this family of cytokines was strictly dependent on the presence of the corresponding ligand-binding subunit (alpha) of the cytokine receptor, and the magnitude of all the effects was closely correlated with the concentration of this subunit. The relative contribution of the JAK/STAT and MAPK pathways to the biological effects of the cytokines was evaluated using kinase inhibitors. Cytokine-mediated modulation of cell proliferation as well as stimulation of alkaline phosphatase activity were abrogated by tyrosine kinase inhibitors as well as a threonine/serine kinase inhibitor, but were only minimally affected by a specific inhibitor of MAPK phosphorylation. These results demonstrate that IL-6-type cytokines, besides their osteoclastogenic properties, promote differentiation of committed osteoblastic cells toward a more mature phenotype and that this action is mediated primarily via the activation of the JAK/STAT pathway.


Differential extraction and protein sequencing reveals major differences in patterns of primary cell wall proteins from plants.
The proteins of the primary cell walls of suspension cultured cells of five plant species, Arabidopsis, carrot, French bean, tomato, and tobacco, have been compared. The approach that has been adopted is differential extraction followed by SDS-polyacrylamide gel electrophoresis (PAGE), rather than two-dimensional gel analysis, to facilitate protein sequencing. Whole cells were washed sequentially with the following aqueous solutions, CaCl2, CDTA (cyclohexane diaminotetraacetic acid, DTT (dithiothreitol), NaCl, and borate. SDS-PAGE analysis showed consistent differences between species. From the 233 proteins that were selected for sequencing, 63% gave N-terminal data. This analysis shows that (i) patterns of proteins revealed by SDS-PAGE are strikingly different for all five species, (ii) a large number of these proteins cannot be identified by data base searches indicating that a significant proportion of wall proteins have not been previously described, (iii) the major proteins that can be identified belong to very different classes of proteins, (iv) the majority of proteins found in the extracellular growth media are absent from their respective cell wall extracts, and (v) the results of the extraction process are indicative of higher order structure. It appears that aspects of speciation reside in the complement of extracellular wall proteins. The data represent a protein resource for cell wall studies complementary to EST (expressed sequence tag) and DNA sequencing strategies.


Directing clinical care using lower extremity biomechanics in patients with ankle osteoarthritis and ankle arthroplasty.
Ankle osteoarthritis is a debilitating disease with approximately 50,000 new cases per year leading to skeletal deformity, severe and recurrent pain, cartilage breakdown, and gait dysfunction limiting patient mobility and well-being. Although many treatments (total ankle arthroplasty [TAA], ankle fusion [arthrodesis], and ankle distraction arthroplasty) relieve pain, it is not clear that these procedures significantly improve patient mobility. The goal of the research presented here is to summarize what is presently known about lower extremity gait mechanics and outcomes and to quantify the impact of ankle osteoarthritis and TAA have on these measures using an explicitly holistic and mechanistic approach. Our recent studies have explored physical performance and energy recovery and revealed unexpected patterns and sequelae to treatment including incomplete restoration of gait function. These studies demonstrated for the first time the extreme levels and range of gait and balance dysfunction present in ankle osteoarthritis patients as well as quantifying the ways in which the affected joint alters movement and loading patterns not just in the painful joint, but throughout both the ipsilateral and contralateral lower extremity. Through this work, we determined that relieving pain alone through TAA is not enough to restore normal walking mechanics and balance due to underlying causes including limited ankle range of motion and balance deficits leading to long-term disability despite treatment. The results indicate the need to consider additional therapeutic interventions aimed at restoring balance, ankle range of motion, and movement symmetry in order to improve long-term health and function. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2345-2355, 2017.


Superficial x-ray in the treatment of basal and squamous cell carcinomas: a viable option in select patients.
Effective nonsurgical modalities are limited in the treatment of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). We sought to evaluate the efficacy and viability of superficial x-ray therapy in the treatment of BCC and SCC in an outpatient setting. A retrospective analysis was performed on 1715 histologically confirmed primary cutaneous BCC and SCC treated with superficial x-ray therapy at Dermatology Associates of Tallahassee in Florida between 2000 and 2010. Of the 1715 tumors reviewed during this period, 712 were histologically proven BCC (631 nodular and 81 superficial), 994 were SCC (861 SCC in situ and 133 invasive SCC), and 9 displayed distinct features of both BCC and SCC in the same biopsy specimen. Kaplan-Meier estimates (with 95% confidence intervals) of cumulative recurrence rates of all tumors at 2 and 5 years were 1.9% (1%-2.7%) and 5.0% (3.2%-6.7%), respectively; of BCC at 2 and 5 years were 2% (0.8%-3.3%) and 4.2% (1.9%-6.4%), respectively; and of all SCC at 2 and 5 years were 1.8% (0.8%-2.8%) and 5.8% (2.9%-8.7%), respectively. Tumors on male patients and those with a diameter greater than 2 cm were associated with a statistically significant increase in recurrence likelihood. This study represents only patients treated in 1 dermatology office in North Florida and may not be representative of the general patient population. Superficial x-ray therapy remains a viable nonsurgical option for the treatment of primary BCC and SCC in patients where surgical intervention is declined, unadvisable, or potentially associated with significant cosmetic or functional limitations.


Systemic hypoxia dehydrates the space surrounding photoreceptors in the cat retina.
To assess the effects of systemic hypoxia and hyperoxia on the volume of the subretinal space (SRS). The authors measured the concentration of the extracellular space marker tetramethylammonium (TMA+) in the intact cat eye using double-barreled ion-selective microelectrodes. The retina was loaded with TMA+ by a single intravitreal injection. Systemic hypoxia was induced by adding nitrogen to the breathing mixture, and hyperoxia was induced by adding oxygen. Hypoxia produced a slow increase in dark- adapted [TMA+]0, which was prominent in amplitude in the distal portion of the retina, suggesting a shrinkage of the SRS. This effect was essentially proportional to the decrease in arterial oxygen tension (PaO2) below the normoxic level. Dark-adapted (TMA+)0 began to increase at a PaO2 of 60 to 80 mm Hg and was enhanced by 13% to 15% at a PaO2 of 40 mm Hg. Because of its slow onset, the size of the increase also was related to the duration of hypoxia. The light-evoked decrease in (TMA+)0 in the SRS was larger in amplitude during hypoxia than in normoxia. This difference increased with severity of hypoxia, beginning at approximately the same PaO2 as the increase in dark-adapted (TMA+)0. Interestingly, the hypoxic increase in amplitude depended on light intensity, i.e., it was proportionally greater at lower intensities versus higher ones. Background illumination suppressed the hypoxia-induced increase in (TMA+)0 in SRS, inhibiting it by approximately 50% at levels of hypoxia down to a PaO2 of 40 mm Hg. Systemic hyperoxia produced the reverse effect of hypoxia. Between two extreme states, e.g., illumination during hyperoxia (PaO2 > 200 mm Hg) versus severe hypoxia in darkness (PaO2 approximately 40 mm Hg), extracellular volume may change more than 4-fold. The observations of this study indicate that the space surrounding photoreceptors shrinks in response to hypoxia. This shrinkage should affect concentrations of all ions and metabolites located in the subretinal space.


Unusual field dependence of remanent magnetization in granular CrO2: the possible relevance of piezomagnetism.
We present low field thermoremanent magnetization (TRM) measurements in granular CrO(2) and composites of ferromagnetic (FM) CrO(2) and antiferromagnetic (AFM) Cr(2)O(3). TRM in these samples is seen to display two distinct timescales. A quasi-static part of remanence, appearing only in the low field regime, exhibits a peculiar field dependence. TRM is seen to first rise and then fall with increasing cooling fields, eventually vanishing above a critical field. Similar features in TRM have previously been observed in some antiferromagnets that exhibit the phenomenon of piezomagnetism. Scaling analysis of the TRM data suggest that presumably piezomoments generated in the AFM component drive the FM magnetization dynamics in these granular systems in the low field regime.


Re-designing the Mozambique vaccine supply chain to improve access to vaccines.
Populations and routine childhood vaccine regimens have changed substantially since supply chains were designed in the 1980s, and introducing new vaccines during the "Decade of Vaccine" may exacerbate existing bottlenecks, further inhibiting the flow of all vaccines. Working with the Mozambique Ministry of Health, our team implemented a new process that integrated HERMES computational simulation modeling and on-the-ground implementers to evaluate and improve the Mozambique vaccine supply chain using a system-re-design that integrated new supply chain structures, information technology, equipment, personnel, and policies. The alternative system design raised vaccine availability (from 66% to 93% in Gaza; from 76% to 84% in Cabo Delgado) and reduced the logistics cost per dose administered (from $0.53 to $0.32 in Gaza; from $0.38 to $0.24 in Cabo Delgado) as compared to the multi-tiered system under the current EPI. The alternative system also produced higher availability at lower costs after new vaccine introductions. Since reviewing scenarios modeling deliveries every two months in the north of Gaza, the provincial directorate has decided to pilot this approach diverging from decades of policies dictating monthly deliveries. Re-design improved not only supply chain efficacy but also efficiency, important since resources to deliver vaccines are limited. The Mozambique experience and process can serve as a model for other countries during the Decade of Vaccines. For the Decade of Vaccines, getting vaccines at affordable prices to the market is not enough. Vaccines must reach the population to be successful.


Demographics and outcome of dogs and cats enrolled in the PetSafe program at the Purdue University College of Veterinary Medicine: 2004-2019.
To determine the number and species of animals cared for by the PetSafe program at the Purdue University College of Veterinary Medicine (a community service offered to meet the short-term housing needs of pets, especially pets owned by victims of intimate partner violence) from 2004 through 2019 and collect information on duration of stay, outcome, health problems, and expenses. 229 animals cared for by the PetSafe program. Medical records were reviewed for information on species, breed, age, duration of stay, outcome of stay, client referral source, whether the animal had been cared for previously, health problems, medical interventions, and expenses incurred. There were 124 dogs, 95 cats, 6 ferrets, and 4 sugar gliders; 187 of the animals were returned to their owners, 37 were rehomed, and 5 were euthanized because of medical conditions. The most common health problems were dental disease and dermatological complaints (eg, flea infestation and resulting fleabite dermatitis). None of the animals had physical evidence of abuse. Mean duration of stay was 22 days (range, 1 to 93 days), and mean ± SD cost per animal was $368 ± $341. Over the 16-year period of the study, the number and species of animals cared for by the PetSafe program at Purdue and the health problems encountered in those animals were relatively stable, and the program was able to meet the relatively predictable financial costs incurred through existing sources of funding.


Octavolateral projections and organization in the medulla of a teleost fish, the sleeper goby (Dormitator latifrons).
This study is the first to employ simultaneous labeling with different colored fluorescent dyes and confocal microscopy to investigate the central projections of the octavolateral nerves in any fish. Three-dimensional reconstructions of the hindbrain octavolateral nuclei were made and overlap of octavolateral projections was assessed in a teleost, the sleeper goby (Dormitator latifrons). The octavolateral nerves, which innervate the otolithic organs, semicircular canals, and lateral lines, project to seven hindbrain nuclei in diverse, complex patterns. The medulla is generally organized with auditory regions dorsal to vestibular regions. The intermediate subdivision of the descending octaval nucleus (DON) receives interdigitating projections from the otolithic organs, and the dorsomedial DON likely integrates multiple auditory inputs. Afferents from the three otolithic organs (the utricle, saccule, and lagena) project to the intermediate DON in approximately equal proportion, supporting physiological evidence that suggests auditory roles for all three otolithic organs in the sleeper goby. The anterior octaval nucleus receives partially segregated inputs from the octavolateral organs. The dorsal division of the magnocellular octaval nucleus (MgON) receives highly overlapping otolithic organ and semicircular canal input, and we propose that this region is a major octaval integration center. Regions in the ventral medulla (the tangential octaval nucleus, ventral DON, and ventral MgON) receive mainly utricular and semicircular canal inputs, suggesting vestibular roles. Each semicircular canal nerve projects to distinct regions of the hindbrain, with little overlap in most octaval nuclei. Efferent neurons receive bilateral input and project unilaterally to the octavolateral organs.


Quantification of Nitric Oxide in Single Cells Using the Single-Probe Mass Spectrometry Technique.
Nitric oxide (NO) is a small molecule that plays important roles in biological systems and human diseases. The abundance of intracellular NO is tightly related to numerous biological processes. Due to cell heterogeneity, the intracellular NO amounts significantly vary from cell to cell, and therefore, any meaningful studies need to be conducted at the single-cell level. However, measuring NO in single cells is very challenging, primarily due to the extremely small size of single cells and reactive nature of NO. In the current studies, the quantitative reaction between NO and amlodipine, a compound containing the Hantzsch ester group, was performed in live cells. The product dehydro amlodipine was then detected by the Single-probe single-cell mass spectrometry technique to quantify NO in single cells. The experimental results indicated heterogeneous distributions of intracellular NO amounts in single cells with the existence of subpopulations.


Surgical management of chronic occlusive disease of the aortic arch vessels and vertebral arteries.
Occlusive disease of the aortic arch vessels is relatively rare and often missed initially. Of 41 patients treated surgically for this condition over a 10-year period 38 had arteriosclerotic lesions, 2 had symptoms secondary to vasculitis (Takayasu's arteritis) and 1 had a radiation injury to a subclavian artery. In 22 cases the left subclavian artery was involved; the right subclavian and innominate arteries were the next most commonly affected. Only four vertebral stenoses were treated. Most patients presented with a combination of arm and hindbrain ischemia that was shown radiologically to be associated with a subclavian steal syndrome, but in some only isolated arm symptoms or severe vertigo alone was experienced. There was a difference in blood pressure between the arms of at least 20 mm Hg in 88% of the patients. The treatment for 28 patients was creation of a carotid-subclavian bypass, for 6 the placement of a bypass graft from the ascending aorta to the subclavian or carotid artery or both, for a 3 a subclavian endarterectomy and for 4 vertebral angioplasty. There were no operative deaths, and 90% of the grafts were patent 1 to 72 months later. however, only 30 (73%) of the patients were asymptomatic and 9 (22%) had improved.


Allogeneic marrow grafting for treatment of aplastic anemia: a follow-up on long-term survivors.
Eleven of twenty-four patients with severe aplastic anemia given marrow grafts from HLA-identical siblings between October 1970 and March 1973 are alive with normal marrow function and continued evidence of engraftment 3-5 yr later. Ten have been leading normal lives with no immunosuppressive or other drug therapy since day 100 postgrafting. One has had chronic graft-versus-host disease of the skin which is now slowly improving with no therapy. He returned to full-time employment in the summer of 1975. The long-term well-being of almost half of our initial patients emphasizes the importance of marrow transplantation for the treatment of severe aplastic anemia.


Virological surveillance in Africa can contribute to early detection of new genetic and antigenic lineages of influenza viruses.
In Africa, the burden of influenza is largely unknown since surveillance schemes exist in very few countries. The National Institute of Hygiene in Morocco implemented a sentinel network for influenza surveillance in 1996. Epidemiological and virological surveillances were established and influenza viruses circulating in Morocco were characterised. Four practice-specific indicators were collected during the 1996-1997 season and nasopharyngeal swabs were collected from patients with an influenza-like illness during a three-year period (between 1996 and1998). Laboratory diagnosis was done by viral isolation. The isolates were characterized by hemagglutination- and neuraminidase-inhibition assays and by sequencing the hemagglutinin gene and phylogenetic analysis. Among a total of 673 specimens, 107 (16%) were positive for influenza virus. Seasonal influenza strains were isolated from November to February. Antigenically, A(H1N1), A(H3N2) and B isolates were related to the vaccine strains. Genetically, one 1996/97 isolate A/Rabat/33/96 and the 1997/98 A(H3N2) isolates clustered with the new drift variant A/Sydney/5/97, a vaccine component of the 1998/99 season. These results indicate a seasonal circulation of influenza in Morocco concentrated between November and February. Further, the results demonstrate the importance of including the maximum number of countries in influenza surveillance to contribute to the definition of the influenza vaccine composition.


Indentation and self-healing mechanisms of a self-assembled monolayer--a combined experimental and modeling study.
A combination of in situ vibrational sum-frequency generation (SFG) spectroscopy and molecular-dynamics (MD) simulations has allowed us to study the effects of indentation of self-assembled octadecylphosphonic acid (ODPA) monolayers on α-Al2O3(0001). Stress-induced changes in the vibrational signatures of C-H stretching vibrations in SFG spectra and the results of MD simulations provide clear evidence for an increase in gauche-defect density in the monolayer as a response to indentation. A stress-dependent analysis indicates that the defect density reaches saturation at approximately 155 MPa. After stress is released, the MD simulations show an almost instantaneous healing of pressure-induced defects in good agreement with experimental results. The lateral extent of the contact areas was studied with colocalized SFG spectroscopy and compared to theoretical predictions for pressure gradients from Hertzian contact theory. SFG experiments reveal a gradual increase in gauche-defect density with pressure before saturation close to the contact center. Furthermore, our MD simulations show a spatial anisotropy of pressure-induced effects within ODPA domains: molecules tilted in the direction of the pressure gradient increase in tilt angle while those on the opposite side form gauche-defects.


Extrinsic compression of popliteal artery in asymptomatic athlete and non-athlete individuals. A comparative study using duplex scan (color duplex sonography).
Extrinsic compression of the popliteal artery and absence of surrounding anatomical abnormalities characterize the functional popliteal artery entrapment syndrome (PAES). The diagnosis is confirmed to individuals who have typical symptoms of popliteal entrapment and occlusion or important stenosis of the popliteal artery with color duplex sonography (CDS), magnetic resonance imaging (MRI) or arteriography during active plantar flexion-extension maneuvers. However, variable result findings in normal asymptomatic subjects have raised doubts as to the validity of these tests. The purpose of this study was to compare the frequency of popliteal artery compression in 2 groups of asymptomatic subjects, athletes and non-athletes. Forty-two individuals were studied. Twenty-one subjects were indoor soccer players, and 21 were sedentary individuals. Physical activity was evaluated through questionnaires, anthropometric measurements, and cardiopulmonary exercise test. Evaluation of popliteal artery compression was performed in lower limbs with CDS, ankle-brachial index (ABI) measurements and continuous wave Doppler of the posterior tibial artery. The athletes studied fulfilled the criteria of high level of physical activity whereas sedentary subjects met the criteria of low level of activity. Popliteal artery compression was observed with CDS in 6 (14.2%) studied subjects; 2 of whom (4.7%) were athletes and 4 (9.5%) were non-athletes. This difference was not statistically significant (p=0.21). Doppler of the tibial arteries and ABI measurements gave good specificity and sensibility in the identification of popliteal artery compression. The frequency of popliteal artery compression during maneuvers in normal subjects was 14.2% irrespective of whether or not they performed regular physical activities. Both Doppler and ABI showed good agreement with CDS and should be considered in screening popliteal arteries in individuals suspected of PAES.


Cause-specific mortality of dialysis patients after coronary revascularization: why don't dialysis patients have better survival after coronary intervention?
The risk of death after coronary revascularization is markedly higher for dialysis patients than for the general population and the cause is inadequately explained. We analyzed cause-specific mortality of dialysis patients after coronary revascularization. This was a retrospective analysis of dialysis patients hospitalized for first surgical coronary revascularization after renal replacement therapy initiation from 1 January 1999 to 31 December 2002. Patients were identified from the US Renal Data System database (n = 1,516,251) by the International Classification of Diseases, Ninth Edition, Clinical Modification code for coronary artery bypass (CAB) surgery (36.1x). Endpoints were deaths due to all causes, all cardiac causes, cardiac arrest or arrhythmia, myocardial infarction, infection and other causes. Cause-specific mortality information was obtained from Centers for Medicare & Medicaid Services End-Stage Renal Disease Death Notification form (CMS 2746-U3). For CAB patients (n = 5830), the all-cause mortality rate was 290 per 1000 patient-years and the rate for arrhythmically mediated deaths was 76 per 1000 patient-years. The largest cause of attributable mortality is cardiac arrest or arrhythmia, accounting for approximately one-fourth of all-cause mortality. The risk of arrhythmically mediated death may contribute to poor long-term outcomes after coronary revascularization in dialysis patients. A treatment strategy employing coronary revascularization and other interventions to reduce the sudden cardiac death risk might improve long-term survival.


Nucleoporin 93, a new substrate of the E3 ubiquitin protein ligase HECTD1, promotes esophageal squamous cell carcinoma progression.
Nucleoporin 93 (NUP93) is an important component of the nuclear pore complex, exhibiting pro-tumorigenic properties in some cancers. However, its function in esophageal squamous cell carcinoma (ESCC) has not been elucidated. This study aimed to investigate the effects of NUP93 in ESCC and the underlying mechanisms involved. Through analysis of public human cancer datasets, we observed higher expression of NUP93 in esophageal cancer tissues than in normal tissues. Stable ESCC cell lines with NUP93 overexpression or knockdown were established by lentiviral vector transduction and puromycin selection. NUP93 knockdown suppressed the proliferation, colony formation, cell cycle transition, migration, and invasion of ESCC cells, while the overexpression of NUP93 displayed opposite effects. NUP93 positively regulated epithelial-mesenchymal transition and AKT signaling transduction in ESCC cells. In addition, NUP93 increased the expression of programmed death ligand 1 (PD-L1) in ESCC cells and attenuated NK cell-mediated lysis of ESCC cells. In vivo experiments demonstrated that NUP93 promotes the growth of ESCC in nude mice, enhances Ki67 and PD-L1 expression, and promotes AKT signaling transduction in xenografts. Mechanistically, we demonstrated that the HECT domain E3 ubiquitin protein ligase 1 (HECTD1) contributes to the ubiquitination and degradation of NUP93 and acts as a tumor suppressor in ESCC. To conclude, this study has shown that NUP93 has pro-tumor properties in ESCC and that HECTD1 functions as an upstream regulator of NUP93 in ESCC. These findings may contribute to the investigation of potential therapeutic targets in ESCC.


Physician Variation and the Impact of Payment Model in Cardiac Imaging.
The influence of fee-for-service reimbursement on cardiac imaging has not been compared with other payment models. Furthermore, variation in ordering practices is not well understood. This retrospective, population-based cohort study using linked administrative data from Alberta, Canada included adults with chronic heart disease (atrial fibrillation, coronary artery disease, and heart failure) seen by cardiac specialists for a new outpatient consultation April 2012 to December 2018. Generalized linear mixed-effects models estimated the association of payment model (including the ability to bill to interpret imaging tests) and the use of cardiac imaging and quantified variation in cardiac imaging. Among 31 685 adults seen by 308 physicians at 136 sites, patients received an observed mean of 0.67 (95% CI, 0.67-0.68) imaging tests per consultation. After adjustment, patients seeing fee-for-service physicians had 2.07 (95% CI, 1.68-2.54) and fee-for-service physicians with ability to interpret had 2.87 (95% CI, 2.16-3.81) times the rate of receiving a test than those seeing salaried physicians. Measured patient, physician, and site effects accounted for 31% of imaging variation and, following adjustment, reduced unexplained site-level variation 40% and physician-level variation 29%. We identified substantial variation in the use of outpatient cardiac imaging related to physician and site factors. Physician payment models have a significant association with imaging use. Our results raise concern that payment models may influence cardiac imaging practice. Similar methods could be applied to identify the source and magnitude of variation in other health care processes and outcomes.


Omega-conotoxins as experimental tools and therapeutics in pain management.
Neuropathic pain afflicts a large percentage of the global population. This form of chronic, intractable pain arises when the peripheral or central nervous systems are damaged, either directly by lesion or indirectly through disease. The comorbidity of neuropathic pain with other diseases, including diabetes, cancer, and AIDS, contributes to a complex pathogenesis and symptom profile. Because most patients present with neuropathic pain refractory to current first-line therapeutics, pharmaceuticals with greater efficacy in pain management are highly desired. In this review we discuss the growing application of ω-conotoxins, small peptides isolated from Conus species, in the management of neuropathic pain. These toxins are synthesized by predatory cone snails as a component of paralytic venoms. The potency and selectivity with which ω-conotoxins inhibit their molecular targets, voltage-gated Ca2+ channels, is advantageous in the treatment of neuropathic pain states, in which Ca2+ channel activity is characteristically aberrant. Although ω-conotoxins demonstrate analgesic efficacy in animal models of neuropathic pain and in human clinical trials, there remains a critical need to improve the convenience of peptide drug delivery methods, and reduce the number and severity of adverse effects associated with ω-conotoxin-based therapies.


[Sepsis: new insights into its pathogenesis and treatment].
The incidence of sepsis is increasing worldwide, yet the mortality rate has barely decreased during the past decades and remains unacceptably high at between 20% - 40%. New knowledge on host-pathogen interactions has greatly increased our insights in the pathogenesis of sepsis. It is now clear that sepsis is not only characterized by proinflammation but also by immunosuppression. Here we give an overview of the functional interactions between bacteria and our immune system. Microbial virulence factors, pathogen recognition receptors, activation of coagulation, apoptosis and a wide range of new mediators of sepsis play a role in these interactions. Implementation of evidence-based guidelines for the rapid diagnosis and adequate treatment of sepsis has been shown to be instrumental in improving survival in sepsis. The increasing insights into the pathogenesis of sepsis have identified a whole new range of potential drugs which are currently being tested in clinical trials.


Crystal structures of Phd-Doc, HigA, and YeeU establish multiple evolutionary links between microbial growth-regulating toxin-antitoxin systems.
Bacterial toxin-antitoxin (TA) systems serve a variety of physiological functions including regulation of cell growth and maintenance of foreign genetic elements. Sequence analyses suggest that TA families are linked by complex evolutionary relationships reflecting likely swapping of functional domains between different TA families. Our crystal structures of Phd-Doc from bacteriophage P1, the HigA antitoxin from Escherichia coli CFT073, and YeeU of the YeeUWV systems from E. coli K12 and Shigella flexneri confirm this inference and reveal additional, unanticipated structural relationships. The growth-regulating Doc toxin exhibits structural similarity to secreted virulence factors that are toxic for eukaryotic target cells. The Phd antitoxin possesses the same fold as both the YefM and NE2111 antitoxins that inhibit structurally unrelated toxins. YeeU, which has an antitoxin-like activity that represses toxin expression, is structurally similar to the ribosome-interacting toxins YoeB and RelE. These observations suggest extensive functional exchanges have occurred between TA systems during bacterial evolution.


Effects of alcohol and other psychotropic drugs on eye movements: relevance to traffic safety.
The effects of alcohol and other psychotropic drugs on eye movements are reviewed with particular attention to the possible relevance of these effects for traffic safety. Alcohol has been shown to have diverse effects, including reduction of the velocity of both saccadic and smooth pursuit eye movements, increased saccadic latency, impairment of convergence and induction of nystagmus. These effects probably contribute to impaired visual information processing, which reduces driving ability. Barbiturates have been reported to produce effects similar to alcohol, and the effects of benzodiazepines and opioids seem to be more limited but still substantial. Marihuana has relatively little effect on eye movements.


Molecular detection of Streptococcus agalactiae in bovine raw milk samples obtained directly from bulk tanks.
Mastitis is the most common infectious disease affecting dairy cattle; in addition, it remains the most economically important disease of dairy industries around the world. Streptococcus agalactiae, a contagious pathogen associated with subclinical mastitis, is highly infectious. This bacterium can cause an increase in bulk tank bacterial counts (BTBC) and bulk tank somatic cell counts (BTSCC). The microbiological identification of S. agalactiae in samples from bulk tanks is an auxiliary method to control contagious mastitis. Thus, there are some limitations for time-consuming cultures or identification methods and additional concerns about the conservation and transport of samples. Bulk tank samples from 247 dairy farms were cultured and compared through polymerase chain reaction (PCR), directed to 16S rRNA genes of S. agalactiae, followed by BTBC and S. agalactiae isolation. The mean value of BTBC was 1.08×10(6) CFU mL(-1) and the bacterium was identified through the microbiological method in 98 (39.7%; CI(95%)=33.8-45.9%) and through PCR in 110 (44.5%; CI(95%)=38.5-50.8%) samples. Results indicated sensitivity of 0.8571±0.0353 (CI(95%)=0.7719-0.9196) and specificity of 0.8255±0.0311 (CI(95%)=0.7549-0.8827). The lack of significant difference between microbiological and molecular results (κ=0.6686±0.0477 and CI(95%)=0.5752-0.7620) indicated substantial agreement between the methods. This suggests that PCR can be used for bulk tank samples to detect contagious mastitis caused by S. agalactiae.