Sub-inner limiting membrane haemorrhage: causes and treatment with vitrectomy.
Preretinal haemorrhages usually occur at the interface between the posterior hyaloid and inner limiting membrane (ILM). Less frequently, they are located between the ILM and the retinal nerve fibre layer. Sub-ILM haemorrhages have been described in a variety of clinical settings and often lead to severe visual impairment because of their predilection for the macular region. A consecutive series of five cases in which sub-ILM haemorrhages were clinically suspected and confirmed during early vitrectomy with ILM peeling were reviewed. Sub-ILM haemorrhages were clinically suspected in five patients (median age 32 years) based on the fundoscopic appearance and clinical setting of Terson's syndrome (n = 1), Valsalva retinopathy (n = 2), blood dyscrasia (n = 1) and blunt facial trauma (n = 1). Vision was severely impaired in all patients (to hand movements in four of five) because of a premacular location of the haemorrhage. All patients were treated with early pars plana vitrectomy because of insufficient spontaneous visual recovery after a median of 6 weeks. The sub-ILM location of the haemorrhage could be confirmed intraoperatively in all patients by biostaining of the membrane overlying the haemorrhage. ILM peeling and aspiration of the haemorrhage resulted in excellent visual recovery in all patients. No procedure-related complications were observed. Sub-ILM haemorrhages often occur in a specific clinical context and can lead to severe visual impairment in young patients. Given the excellent results and low complication rates, timely surgical intervention is justified when spontaneous resorption is insufficient.


Loss of balancing selection in the betaS globin locus.
Probably the best example of the rise and maintenance of balancing selection as an evolutionary trend is the role of S-haemoglobin (HbS - rs334) in protecting from malaria. Yet, the dynamics of such a process remains poorly understood, particularly in relation to different malaria transmission rates and the genetic background of the affected populations. We investigated the association of haemoglobin HbS in protection from clinical episodes of malaria in two populations/villages where malaria is endemic, but mostly presenting in mild clinical forms. Five-hundred and forty-six individuals comprising 65 and 82 families from the Hausa and Massalit villages respectively were genotyped for HbS. Allele and genotype frequencies as well as departure from Hardy-Weinberg Equilibrium were estimated from four-hundred and seventy independent genotypes across different age groups. Age-group frequencies were used to calculate the coefficient-of-fitness and to simulate the expected frequencies in future generations. Genotype frequencies were within Hardy-Weinberg expectations in Hausa and Massalit in the total sample set but not within the different age groups. There was a trend for a decrease of the HbS allele frequency in Hausa and an increase of frequency in Massalit. Although the HbS allele was able to confer significant protection from the clinical episodes of malaria in the two populations, as suggested by the odds ratios, the overall relative fitness of the HbS allele seems to have declined in Hausa. Such loss of balancing selection could be due to a combined effect of preponderance of non-clinical malaria in Hausa, and the deleterious effect of the homozygous HbS under circumstances of endogamy.


Cost-benefit analysis of Level II fieldwork in occupational therapy.
This cost-benefit study of Level II (professional-level) fieldwork included 180 student-supervisor pairs from 12 occupational therapy educational programs. Costs and benefits were measured in time (valued at market rates) spent by students in patient treatment and by supervisors in fieldwork-related duties. Various factors were also evaluated to determine their relationship to overall cost or benefit. Results indicated a mean benefit of $4,700 for 12-week placements. Costs generated in the first few weeks of placement were generally recovered by the 6th week, with benefits gradually increasing, then declining slightly through the end of the fieldwork. Greater economic benefits resulted from physical dysfunction and psychiatric placements than from pediatric placements, and with second and third student experiences as compared with first experiences.


Comparison of baseline free testosterone and cortisol concentrations between elite and non-elite female athletes.
To compare the baseline free testosterone (T) and cortisol (C) concentrations of elite and non-elite female athletes. Eighteen females from different sports (track and field, netball, cycling, swimming, bob skeleton) were monitored over a 12-week period. Baseline measures of salivary free T and C concentrations were taken weekly prior to any training. The elites (n = 9) and non-elites (n = 9) were classified as international and national level competitors, respectively, with both groups matched by sport. The pooled free T concentrations of the elites (87 pg/ml) were significantly higher than the non-elites (41 pg/ml) and consistently so across all weekly time points (P < 0.001). Pooled free C concentrations were also greater in the elite group (2.90 ng/ml) than the non-elites (2.32 ng/ml) (P < 0.01). The pooled baseline T and C measures were higher in elite female athletes than non-elites. Higher free T and C concentrations could indicate a greater capacity for physical performance at higher work rates, which is commensurate with the demands of elite sport. Speculatively, the T differences observed could influence female behavior and thereby help to regulate sporting potential.


Thoracic endovascular aortic repair for the ascending aorta: experience and pitfalls.
Thoracic endovascular aortic repair (TEVAR) of the ascending aorta is a developing alternative treatment strategy, which currently is specifically aimed at patients who are too high risk for open surgery. TEVAR has been applied to patients with a variety of pathologies of the ascending aorta including type A dissection, intramural hematoma (IMH), penetrating ulcers, aneurysm and pseudoaneurysm. Here we discuss the current evidence regarding the use of TEVAR for the ascending aorta as well as the latest techniques and pitfalls of the procedure. The challenges of this modality are considerable, and the techniques that have been applied draw from the many facets of endovascular experience. There is limited literature regarding the use of stent grafts in the ascending aorta, and the pool of patients currently considered appropriate candidates for the procedure is small. This is an evolving intervention that warrants further study and the development of devices specifically engineered to meet the anatomical and physiologic challenges of the ascending aorta.


Induction of EMT-like phenotypes by an active metabolite of leflunomide and its contribution to pulmonary fibrosis.
Drug-induced interstitial lung disease (ILD), particularly pulmonary fibrosis, is a serious clinical concern and myofibroblasts have been suggested to have a major role, with it recently being revealed that some of these myofibroblasts are derived from lung epithelial cells through epithelial-mesenchymal transition (EMT). In this study, we examined the EMT-inducing abilities of drugs known to induce ILD clinically. EMT-like phenotypes were induced by A771726, an active metabolite of leflunomide having an inhibitory effect on dihydroorotate dehydrogenase (DHODH). Smad-interacting protein 1 (a transcription factor regulating EMT) and the Notch-signaling pathway but not transforming growth factor-β was shown to be involved in A771726-induced EMT-like phenotypes. When the cultures were supplemented with exogenous uridine, the A771726-induced EMT-like phenotypes and activation of the Notch-signaling pathway disappeared. Similarly, an A771726 analog without inhibitory activity on DHODH produced no induction, suggesting that this process is mediated through the inhibition of DHODH. In vivo, administration of leflunomide stimulated bleomycin-induced EMT-like phenomenon in pulmonary tissue, and exacerbated bleomycin-induced pulmonary fibrosis, both of which were suppressed by coadministration of uridine. Taken together, these findings suggest that leflunomide-dependent exacerbation of bleomycin-induced pulmonary fibrosis is mediated by stimulation of EMT of lung epithelial cells, providing the first evidence that drug-induced pulmonary fibrosis involves EMT of these cells.


Getting the basic rights - the role of water, sanitation and hygiene in maternal and reproductive health: a conceptual framework.
To explore linkages between water, sanitation and hygiene (WASH) and maternal and perinatal health via a conceptual approach and a scoping review. We developed a conceptual framework iteratively, amalgamating three literature-based lenses. We then searched literature and identified risk factors potentially linked to maternal and perinatal health. We conducted a systematic scoping review for all chemical and biological WASH risk factors identified using text and MeSH terms, limiting results to systematic reviews or meta-analyses. The remaining 10 complex behavioural associations were not reviewed systematically. The main ways poor WASH could lead to adverse outcomes are via two non-exclusive categories: 1. 'In-water' associations: (a) Inorganic contaminants, and (b) 'water-system' related infections, (c) 'water-based' infections, and (d) 'water borne' infections. 2. 'Behaviour' associations: (e) Behaviours leading to water-washed infections, (f) Water-related insect-vector infections, and (g-i) Behaviours leading to non-infectious diseases/conditions. We added a gender inequality and a life course lens to the above framework to identify whether WASH affected health of mothers in particular, and acted beyond the immediate effects. This framework led us to identifying 77 risk mechanisms (67 chemical or biological factors and 10 complex behavioural factors) linking WASH to maternal and perinatal health outcomes. WASH affects the risk of adverse maternal and perinatal health outcomes; these exposures are multiple and overlapping and may be distant from the immediate health outcome. Much of the evidence is weak, based on observational studies and anecdotal evidence, with relatively few systematic reviews. New systematic reviews are required to assess the quality of existing evidence more rigorously, and primary research is required to investigate the magnitude of effects of particular WASH exposures on specific maternal and perinatal outcomes. Whilst major gaps exist, the evidence strongly suggests that poor WASH influences maternal and reproductive health outcomes to the extent that it should be considered in global and national strategies.


The Long-Acting D3 Partial Agonist MC-25-41 Attenuates Motivation for Cocaine in Sprague-Dawley Rats.
The dopamine D3 receptor is a prime target for developing treatments for cocaine use disorders (CUDs). In this study, we conducted a pre-clinical investigation of the therapeutic potential of a long-acting, D3 receptor partial agonist, MC-25-41. Male rats were pre-treated with MC-25-41 (vehicle, 1.0, 3.0, 5.6, or 10 mg/kg, intraperitoneal (IP)) five minutes prior to tests of cocaine or sucrose intake on either a progressive ratio schedule of reinforcement or a variable interval 60 s multiple schedule consisting of 4, 15-min components with sucrose or cocaine available in alternating components. A separate cohort of rats was tested on a within-session, dose-reduction procedure to determine the effects of MC-25-41 on demand for cocaine using a behavioral economics analysis. Finally, rats were tested for effects of MC-25-41 on spontaneous and cocaine-induced locomotion. MC-25-41 failed to alter locomotion, but reduced reinforcement rates for both cocaine and sucrose on the low-effort, multiple schedule. However, on the higher-effort, progressive ratio schedule of cocaine reinforcement, MC-25-41 reduced infusions, and active lever presses at doses that did not alter sucrose intake. The behavioral economics analysis showed that MC-25-41 also increased cocaine demand elasticity compared to vehicle, indicating a reduction in consumption as price increases. Together, these results suggest that similar to other D3-selective antagonists and partial agonists, MC-25-41 reduces motivation for cocaine under conditions of high cost but has the added advantage of a long half-life (>10 h). These findings suggest that MC-25-41 may be a suitable pre-clinical lead compound for development of medications to treat CUDs.


Improvement in exercise capacity and delayed anaerobic metabolism induced by far-infrared-emitting garments in active healthy subjects: A pilot study.
Background Far-infrared-emitting garments have several biological properties including the capability to increase blood perfusion in irradiated tissues. Design The aim of the study was to evaluate whether far-infrared radiation increases exercise capacity and delays anaerobic metabolism in healthy subjects. Methods With a double-blind, crossover protocol, a maximal cardiopulmonary exercise test was performed in 20 volunteers, wearing far-infrared or common sport clothes, identical in texture and colour. Results Comparing far-infrared with placebo garments, higher oxygen uptake at peak of exercise and longer endurance time were observed (peak oxygen uptake 38.0 ± 8.9 vs. 36.2 ± 8.5 ml/kg/min, endurance time 592 ± 85 vs. 570 ± 71 seconds; P < 0.01); the anaerobic threshold was significantly delayed (anaerobic threshold time 461 ± 93 vs. 417 ± 103 seconds) and anaerobic threshold oxygen uptake and anaerobic threshold oxygen pulse were significantly higher (25.3 ± 6.4 vs. 20.9 ± 5.4 ml/kg/min and 13.3 ± 3.8 vs. 12.4 ± 3.3 ml/beat, respectively). In 10 subjects the blood lactate concentration was measured every 2 minutes during exercise and at peak; lower values were observed with far-infrared fabrics compared to placebo from the eighth minute of exercise, reaching a significant difference at 10 minutes (3.6 ± 0.83 vs. 4.4 ± 0.96 mmol/l; P = 0.02). Conclusions In healthy subjects, exercising with a far-infrared outfit is associated with an improvement in exercise performance and a delay in anaerobic metabolism. In consideration of the acknowledged non-thermic properties of functionalised clothes, these effects could be mediated by an increase in oxygen peripheral delivery secondary to muscular vasodilation. These data suggest the need for testing far-infrared-emitting garments in patients with exercise limitation or in chronic cardiovascular and respiratory patients engaged in rehabilitation programmes.


The nucleolar transcriptome regulates Piwi shuttling between the nucleolus and the nucleoplasm.
The nucleolus contains a lot of proteins unrelated to ribosome biogenesis. Some of these proteins shuttle between the nucleolus and the nucleoplasm regulating the cell cycle and stress response. The piRNA binding protein Piwi is involved in silencing of transposable elements (TEs) in the Drosophila gonads. Here we used cultured ovarian somatic cells (OSC) to characterize Piwi as a visitor to the nucleolus. Dynamic Piwi localization was shown to vary from its uniform distribution between the nucleoplasm and the nucleolus to pronounced nucleolar immobilization. We were intrigued by this localization behavior and revealed that nascent nucleolar transcripts recruit Piwi for nucleolar retention. Piwi eviction from the nucleolus was observed upon RNase treatment and after RNA polymerase (Pol) I inhibition, but not after Pol II inactivation. On the contrary, heat shock caused drastic Piwi redistribution from the nucleoplasm to the nucleolus, which occurred only in the presence of Pol I-mediated transcription. These results allow us to hypothesize that specific stress-induced transcripts made by Pol I promote the nucleolar sequestration of proteins in Drosophila, similar to previous observations in mammalian cells. We also found that in OSC, Piwi partially restricts expression of the rDNA copies containing R1 and R2 retrotransposon insertions especially upon heat shock-induced activation of these copies. Therefore, we suggest that Piwi intranuclear shuttling may have a functional role in ensuring a balance between silencing of rDNA-specific TEs under stress and the canonical Piwi function in non-nucleolar TE repression.


Using pay-for-success to increase investment in the nonmedical determinants of health.
The combination of fee-for-service payments and the US health care system's standing commitment to treating existing illness discourages spending on the behavioral, social, and environmental (that is, the nonmedical) conditions that contribute most to long-term health. Pay-for-success, alternatively known as social impact bonds, or SIBs, offers a possible solution. The pay-for-success model relies on an investor that is willing to fund a nonmedical intervention up front while bearing the risk that the intervention may fail to prevent disease in the future. Should the intervention succeed, however, the investor is repaid in full by a predetermined payer (such as a public health agency) and receives an additional return on its investment as a reward for taking on the risk. Pay-for-success pilots are being developed to reduce asthma-related emergencies among children, poor birth outcomes, and the progression of prediabetes to diabetes, among other applications. These efforts, supported by key policy reforms such as public agency data sharing and coordinated care, promise to increase the number of evidence-based nonmedical service providers and seed a new market that values health, not just health care.


Brain atrophy in cognitively impaired elderly: the importance of long-chain ω-3 fatty acids and B vitamin status in a randomized controlled trial.
Increased brain atrophy rates are common in older people with cognitive impairment, particularly in those who eventually convert to Alzheimer disease. Plasma concentrations of omega-3 (ω-3) fatty acids and homocysteine are associated with the development of brain atrophy and dementia. We investigated whether plasma ω-3 fatty acid concentrations (eicosapentaenoic acid and docosahexaenoic acid) modify the treatment effect of homocysteine-lowering B vitamins on brain atrophy rates in a placebo-controlled trial (VITACOG). This retrospective analysis included 168 elderly people (≥70 y) with mild cognitive impairment, randomly assigned either to placebo (n = 83) or to daily high-dose B vitamin supplementation (folic acid, 0.8 mg; vitamin B-6, 20 mg; vitamin B-12, 0.5 mg) (n = 85). The subjects underwent cranial magnetic resonance imaging scans at baseline and 2 y later. The effect of the intervention was analyzed according to tertiles of baseline ω-3 fatty acid concentrations. There was a significant interaction (P = 0.024) between B vitamin treatment and plasma combined ω-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) on brain atrophy rates. In subjects with high baseline ω-3 fatty acids (>590 μmol/L), B vitamin treatment slowed the mean atrophy rate by 40.0% compared with placebo (P = 0.023). B vitamin treatment had no significant effect on the rate of atrophy among subjects with low baseline ω-3 fatty acids (<390 μmol/L). High baseline ω-3 fatty acids were associated with a slower rate of brain atrophy in the B vitamin group but not in the placebo group. The beneficial effect of B vitamin treatment on brain atrophy was observed only in subjects with high plasma ω-3 fatty acids. It is also suggested that the beneficial effect of ω-3 fatty acids on brain atrophy may be confined to subjects with good B vitamin status. The results highlight the importance of identifying subgroups likely to benefit in clinical trials. This trial was registered at www.controlled-trials.com as ISRCTN94410159.


Inhibition of Fosfomycin Resistance Protein FosA by Phosphonoformate (Foscarnet) in Multidrug-Resistant Gram-Negative Pathogens.
FosA proteins confer fosfomycin resistance to Gram-negative pathogens via glutathione-mediated modification of the antibiotic. In this study, we assessed whether inhibition of FosA by sodium phosphonoformate (PPF) (foscarnet), a clinically approved antiviral agent, would reverse fosfomycin resistance in representative Gram-negative pathogens. The inhibitory activity of PPF against purified recombinant FosA from Escherichia coli (FosA3), Klebsiella pneumoniae (FosAKP), Enterobacter cloacae (FosAEC), and Pseudomonas aeruginosa (FosAPA) was determined by steady-state kinetic measurements. The antibacterial activity of PPF against FosA in clinical strains of these species was evaluated by susceptibility testing and time-kill assays. PPF increased the Michaelis constant (Km ) for fosfomycin in a dose-dependent manner, without affecting the maximum rate (Vmax) of the reaction, for all four FosA enzymes tested, indicating a competitive mechanism of inhibition. Inhibitory constant (Ki ) values were 22.6, 35.8, 24.4, and 56.3 μM for FosAKP, FosAEC, FosAPA, and FosA3, respectively. Addition of clinically achievable concentrations of PPF (∼667 μM) reduced the fosfomycin MICs by ≥4-fold among 52% of the K. pneumoniae, E. cloacae, and P. aeruginosa clinical strains tested and led to a bacteriostatic or bactericidal effect in time-kill assays among representative strains. PPF inhibits FosA activity across Gram-negative species and can potentiate fosfomycin activity against the majority of strains with chromosomally encoded fosA These data suggest that PPF may be repurposed as an adjuvant for fosfomycin to treat infections caused by some FosA-producing, multidrug-resistant, Gram-negative pathogens.


Heterogeneity of lymphokine-activated killer cells induced by IL-2. Separate lymphoid subpopulations lyse tumor, allogeneic blasts, and modified syngeneic blasts.
Murine splenocytes incubated for 3 to 4 days with the lymphokine, IL-2, acquire the ability to mediate the lysis of a wide variety of fresh tumor targets in short term chromium release assays. We undertook these studies to examine the lysis of splenocyte blasts by these lymphokine-activated killer (LAK) cells, to help gain an understanding of the mechanisms of target cell recognition. Allogeneic blast targets but not syngeneic blasts are highly lysable by LAK effector cells. By using congenic mice, we have shown that only the H-2 haplotype, and not other differences, determines the recognition and lysis of a blast target cell. Both Con A- and LPS-induced allogeneic splenocyte blasts are lysed and thus lectin-induced binding of effectors and targets is unlikely to be responsible for this effect. By using in vivo antibody depletion experiments, we showed that different populations of effector cells mediate the lysis of tumor cells and allogeneic blasts. Furthermore, we observed that the lysis of a susceptible blast can be inhibited only by like cold blasts of the same haplotype. These results suggest that there is a separate population of LAK cells responsible for the lysis of each type of blast target cell. Though syngeneic blasts were not lysed by LAK cells, TNP modification of syngeneic blasts converted them into cells that were recognized and lysed by LAK cells. In cold target inhibition studies, the lysis of fresh syngeneic tumor was not inhibited by TNP-modified syngeneic blasts. Similarly, the lysis of TNP-modified syngeneic blasts was not inhibited by fresh tumor. By using in vitro antibody depletion, we determined that TNP-modified blasts are lysed by LAK cells with Thy-1+ precursors, in distinction to the Thy-1- precursors involved in tumor cell lysis. Elimination of the Thy-1+ cells at the precursor stage completely abrogated the lysis of blasts but did not diminish the lysis of tumor cells. We conclude that IL-2 promotes the growth of numerous populations of effector cells with Thy-1+ precursors that have a narrow range of specificity, in contrast to the broad lytic ability for fresh tumor mediated by LAK cells with Thy-1- precursors.


Pharmacokinetics of nifedipine slow-release during sustained tocolysis.
The pharmacokinetics of nifedipine as a tocolytic agent has not been studied in great detail in pregnant women and has instead focused on immediate release tablets and gastrointestinal therapeutic system (GITS) tablets. The aim of this study was to determine nifedipine slow-release half-life and distribution volume in pregnant women and to compare these with pharmacokinetic parameters of nifedipine in non-pregnant subjects described in the literature. This is a study parallel to a trial studying women with threatened preterm labor between 26 + 0 and 32 + 2 weeks after initial tocolysis and a completed course of corticosteroids, who were randomly allocated to maintenance nifedipine (slow-release tablets 20 mg 4 times daily) or placebo. Exclusion criteria for the pharmacokinetic study were contra-indications for nifedipine, impaired liver function, and concomitant intake of inhibitors or inducers of the cytochrome P450 3A4 isoenzyme. Blood samples for measuring nifedipine plasma concentrations were drawn at t = 0, t = 12 hours, t = 24 hours, t = 48 hours, t = 72 hours, t = 7 days, and t = 9 days. Pharmacokinetic parameters were estimated using iterative two-stage Bayesian population pharmacokinetic analysis by MWPharm© software. The study was designed to establish a correlation between body weight and nifedipine plasma level. The pharmacokinetic parameters of nifedipine slow-release tablets were determined from the data of 8 pregnant women. Nifedipine slow-release had a half-life of 2 - 5 hours, a mean distribution volume of 6.2 ± 1.9 L/kg (calculated while using a fixed biological availability of 0.45 taken from the literature due to lack of intravenous data in this population) compared to a half-life of 6 - 11 hours, and a distribution volume of 1.2 - 1.3 L/kg described in non-pregnant subjects in the literature. None of the women delivered during study medication. Study medication was continued for the duration of the pharmacokinetic study (9 days) in all women. A correlation between nifedipine plasma levels and maternal body weight was not demonstrated. This may have been caused by lack of power. Pregnant subjects in this study, using nifedipine slow-release tablets, showed a larger volume of distribution and a shorter elimination half-life than for non-pregnant subjects as published in the literature.


Putting students in charge: a symposium on student-centered learning.
Many symposia and workshops are held to discuss issues of student-centered learning, but few put students in charge. An international meeting was held at McMaster University, Hamilton, Ontario, Canada, to discuss Student-Centered Learning in the Life and Health Sciences where there were no plenary, oral, or poster presentations. Sessions were run in a problem-based, small-group format. Educational problems written specifically for the symposium served as springboards for learning. Undergraduate and graduate science students took center stage by taking an active role in the planning and organization of the event and serving as chairs and facilitators for the sessions. In addition, they summarized the sessions in written reports, which thus enabled their opinions to be documented. Eminent educators from several countries (Australia, Denmark, Spain, Portugal, Finland, the UK, and the United States) participated in these sessions as both learners and content experts. A questionnaire as well as comments suggested that the participants enjoyed the learning experience, which gave faculty, staff, and students opportunity to discuss in-depth educational issues related to process, content, and delivery of curricula.


Toolbox to Reduce Lumpectomy Reoperations and Improve Cosmetic Outcome in Breast Cancer Patients: The American Society of Breast Surgeons Consensus Conference.
Multiple recent reports have documented significant variability of reoperation rates after initial lumpectomy for breast cancer. To address this issue, a multidisciplinary consensus conference was convened during the American Society of Breast Surgeons 2015 annual meeting. The conference mission statement was to "reduce the national reoperation rate in patients undergoing breast conserving surgery for cancer, without increasing mastectomy rates or adversely affecting cosmetic outcome, thereby improving value of care." The goal was to develop a toolbox of recommendations to reduce the variability of reoperation rates and improve cosmetic outcomes. Conference participants included providers from multiple disciplines involved with breast cancer care, as well as a patient representative. Updated systematic reviews of the literature and invited presentations were sent to participants in advance. After topic presentations, voting occurred for choice of tools, level of evidence, and strength of recommendation. The following tools were recommended with varied levels of evidence and strength of recommendation: compliance with the SSO-ASTRO Margin Guideline; needle biopsy for diagnosis before surgical excision of breast cancer; full-field digital diagnostic mammography with ultrasound as needed; use of oncoplastic techniques; image-guided lesion localization; specimen imaging for nonpalpable cancers; use of specialized techniques for intraoperative management, including excisional cavity shave biopsies and intraoperative pathology assessment; formal pre- and postoperative planning strategies; and patient-reported outcome measurement. A practical approach to performance improvement was used by the American Society of Breast Surgeons to create a toolbox of options to reduce lumpectomy reoperations and improve cosmetic outcomes.


Myocyte enhancer factor (MEF) 2C: a tissue-restricted member of the MEF-2 family of transcription factors.
MEF-2 is a muscle-specific DNA binding activity that recognizes an A+T-rich sequence found in the control regions of numerous muscle-specific genes. The recent cloning of MEF-2 showed that it belongs to the MADS (MCM1, Agamous, Deficiens, and serum-response factor) box family of transcription factors and that MEF-2 mRNA is expressed ubiquitously. Here we describe the cloning of a member of the MEF-2 gene family, referred to as MEF-2C, that is nearly identical to other MEF-2 gene products in the MADS box but diverges from other members of the family outside of this domain. MEF-2C binds the MEF-2 site with high affinity and can activate transcription of a reporter gene linked to tandem copies of that site. In contrast to previously described members of the MEF-2 family, MEF-2C transcripts are highly enriched in skeletal muscle, spleen, and brain of adult mice and are upregulated during myoblast differentiation. These results suggest that the MEF-2 site is a target for a diverse family of proteins that regulates transcription in a variety of cell types.


the risk of cancer among Taiwanese female registered nurses: a nationwide retrospective study.
To evaluate the risk of cancer among Taiwanese female registered nurses (RNs) using a nationwide population-based dataset. We recruited female RNs without antecedent cancer from the Taiwan National Health Insurance Research database during 2000-2010. Standardized incidence ratios (SIRs) of cancer were calculated. We also compared rates of Papanicolaou (Pap) smear use between the RNs and the general population matched by age and sex. A total of 2,077 cancers developed among 184,809 female RNs, with a follow-up of 1,371,910 person-years (median follow-up of 7.86 years), leading to an increased SIR of 1.10 [95% confidence interval (CI) 1.05-1.15]. RNs aged between 40-59 years also had a significantly increased SIR (1.14, 95% CI 1.08-1.21). For specific cancer types, RNs had an increased SIR for breast (1.28, 95% CI 1.19-1.37), thyroid (1.26, 95% CI 1.10-1.43), lung and mediastinum (1.36, 95% CI 1.13-1.62), and uterine cancers (1.23, 95% CI 1.01-1.49). A decreased SIR was found for cervix (0.48, 95% CI 0.37-0.61) and liver and biliary tract cancers (0.68, 95% CI 0.50-0.90). Pap smear use averaged 5.80 times per person among female RNs aged 35 years or older and 5.50 times per person in the age-matched control group (p = 0.009). This study found that overall cancer risk was higher among female RNs than general population. For individual cancers, the risks of breast, lung, thyroid and uterine cancer were higher and the risks of cervix and liver cancer were lower than general population. The lower risk of cervical cancer might be partially explained by the increased use of Pap smears in the RNs group. Further large, unbiased population-based prospective studies are needed to investigate the association between nurses and cancer risk and identify the risk factors of cancer in nurses.


Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47.
Under normal physiological conditions, cellular homeostasis is partly regulated by a balance of pro- and anti-phagocytic signals. CD47, which prevents cancer cell phagocytosis by the innate immune system, is highly expressed on several human cancers including acute myeloid leukemia, non-Hodgkin's lymphoma, and bladder cancer. Blocking CD47 with a monoclonal antibody results in phagocytosis of cancer cells and leads to in vivo tumor elimination, yet normal cells remain mostly unaffected. Thus, we postulated that cancer cells must also display a potent pro-phagocytic signal. Here, we identified calreticulin as a pro-phagocytic signal that was highly expressed on the surface of several human cancers, but was minimally expressed on most normal cells. Increased CD47 expression correlated with high amounts of calreticulin on cancer cells and was necessary for protection from calreticulin-mediated phagocytosis. Blocking the interaction of target cell calreticulin with its receptor, low-density lipoprotein receptor-related protein, on phagocytic cells prevented anti-CD47 antibody-mediated phagocytosis. Furthermore, increased calreticulin expression was an adverse prognostic factor in diverse tumors including neuroblastoma, bladder cancer, and non-Hodgkin's lymphoma. These findings identify calreticulin as the dominant pro-phagocytic signal on several human cancers, provide an explanation for the selective targeting of tumor cells by anti-CD47 antibody, and highlight the balance between pro- and anti-phagocytic signals in the immune evasion of cancer.


Effectiveness of the Malnutrition eLearning Course for Global Capacity Building in the Management of Malnutrition: Cross-Country Interrupted Time-Series Study.
Scaling up improved management of severe acute malnutrition has been identified as the nutrition intervention with the largest potential to reduce child mortality, but lack of operational capacity at all levels of the health system constrains scale-up. We therefore developed an interactive malnutrition eLearning course that is accessible at scale to build capacity of the health sector workforce to manage severely malnourished children according to the guidelines of the World Health Organization. The aim of this study was to test whether the malnutrition eLearning course improves knowledge and skills of in-service and preservice health professionals in managing children with severe acute malnutrition and enables them to apply the gained knowledge and skills in patient care. This 2-year prospective, longitudinal, cross-country, interrupted time-series study took place in Ghana, Guatemala, El Salvador, and Colombia between January 2015 and February 2017. A subset of 354 in-service health personnel from 12 hospitals and 2 Ministries of Health, 703 preservice trainees from 9 academic institutions, and 204 online users participated. Knowledge gained after training and retention over time was measured through pre- and postassessments comprising questions pertaining to screening, diagnosis, pathophysiology and treatment, and prevention of malnutrition. Comprehension, application, and integration of knowledge were tested. Changes in perception, confidence, and clinical practice were assessed through questionnaires and interviews. Before the course, awareness of the World Health Organization guidelines was 36.73% (389/1059) overall, and 26.3% (94/358) among in-service professionals. The mean score gain in knowledge after access to the course in 606 participants who had pre- and postassessment data was 11.8 (95% CI 10.8-12.9; P<.001)-a relative increase of 41.5%. The proportion of participants who achieved a score above the pass mark posttraining was 58.7% (356/606), compared with 18.2% (110/606) in pretraining. Of the in-service professionals, 85.9% (128/149) reported applying their knowledge by changing their clinical practice in screening, assessment, diagnosis, and management. This group demonstrated significantly increased retained knowledge 6 months after training (mean difference [SD] from preassessment of 12.1 [11.8]), retaining 65.8% (12.1/18.4) of gained knowledge from the training. Changes in the management of malnutrition were reported by trained participants, and institutional, operational, and policy changes were also found. The malnutrition eLearning course improved knowledge, understanding, and skills of health professionals in the diagnosis and management of children with severe acute malnutrition, and changes in clinical practice and confidence were reported following the completion of the course.


Proteolysis-Dependent Remodeling of the Tubulin Homolog FtsZ at the Division Septum in Escherichia coli.
During bacterial cell division a dynamic protein structure called the Z-ring assembles at the septum. The major protein in the Z-ring in Escherichia coli is FtsZ, a tubulin homolog that polymerizes with GTP. FtsZ is degraded by the two-component ATP-dependent protease ClpXP. Two regions of FtsZ, located outside of the polymerization domain in the unstructured linker and at the C-terminus, are important for specific recognition and degradation by ClpXP. We engineered a synthetic substrate containing green fluorescent protein (Gfp) fused to an extended FtsZ C-terminal tail (residues 317-383), including the unstructured linker and the C-terminal conserved region, but not the polymerization domain, and showed that it is sufficient to target a non-native substrate for degradation in vitro. To determine if FtsZ degradation regulates Z-ring assembly during division, we expressed a full length Gfp-FtsZ fusion protein in wild type and clp deficient strains and monitored fluorescent Z-rings. In cells deleted for clpX or clpP, or cells expressing protease-defective mutant protein ClpP(S97A), Z-rings appear normal; however, after photobleaching a region of the Z-ring, fluorescence recovers ~70% more slowly in cells without functional ClpXP than in wild type cells. Gfp-FtsZ(R379E), which is defective for degradation by ClpXP, also assembles into Z-rings that recover fluorescence ~2-fold more slowly than Z-rings containing Gfp-FtsZ. In vitro, ClpXP cooperatively degrades and disassembles FtsZ polymers. These results demonstrate that ClpXP is a regulator of Z-ring dynamics and that the regulation is proteolysis-dependent. Our results further show that FtsZ-interacting proteins in E. coli fine-tune Z-ring dynamics.


Organized dentistry as an agent for helping others: the leadership of Donna J. Rumberger.
Dr Donna Rumberger graduated from New York University College of Dentistry in 1980 and has practiced dentistry in Manhattan ever since. Even before her graduation, she was active in organized dentistry, always viewing it as a conduit for helping other people. Working with the American Association of Women Dentists, she was cofounder of the Smiles for Success Foundation, a program started in New York City that helps women advance from welfare into the workforce with restored, healthy smiles. That program now has expanded to 14 other cities. Working with organized dentistry in New York City, she has been instrumental in initiating and running the Skate Safe program, which provides mouthguards and oral home care education for inner city children in Harlem. In addition, she has worked with the dentistry merit badge program for the Boy Scouts of America Jamborees, helped coalesce women's dental organizations in New York City, and led her dental society to collaborate with Columbia University in a program to improve access to dental care. As further evidence of her ability to get things done, she also has served as president of the American Association of Women Dentists, the Midtown Dental Society, and the New York County Dental Society--one of the largest dental societies in the country.


Outcomes Associated With a Five-Point Surgical Site Infection Prevention Bundle in Women Undergoing Surgery for Ovarian Cancer.
To identify risk factors for surgical site infection and to define rates associated with cytoreductive surgery before and after implementation of an infection prevention bundle. We conducted a prospective quality improvement study. Patients who underwent ovarian, fallopian tube, or peritoneal cancer cytoreductive surgery at an academic tertiary care center from April 2014 to April 2016 were prospectively enrolled. Patient demographics, surgical variables, and surgical site infection rates were compared with a historical cohort after introduction of a 5-point infection prevention bundle, including: 1) preoperative and intraoperative skin preparation with 4% chlorhexidine and intraoperative vaginal preparation with 4% chlorhexidine; 2) preoperative use of oral antibiotics and mechanical bowel preparation; 3) appropriate timing of intraoperative antibiotics; 4) adoption of enhanced sterile surgical techniques for colon procedures and incisional closure; and 5) perioperative incision management. During the study period, 219 women underwent surgery: 91 prebundle and 128 treated in the postbundle period. Stage, body mass index, proportion of patients undergoing colon or upper abdominal surgery, and estimated blood loss were not different between the cohorts. Overall, the surgical site infection rate prebundle was 18 (20%); this was reduced to four (3%) postbundle (odds ratio [OR] 0.13, 95% CI 0.037-0.53; P<.001). Patients who underwent a colon resection prebundle had an infection rate of 14 (33%) compared with three (7%) in the postbundle group (OR 0.14, 95% CI 0.037-0.53; P<.001). Additionally, rates of surgical site infection-related hospital readmission were also lower in the postbundle (4/128 [3%]) compared with the prebundle group (12/91 [13%]; P=.005). Infection is common after ovarian cancer cytoreductive surgery. Implementation of a 5-point surgical site infection prevention bundle in women undergoing ovarian cancer operations was associated with dramatically decreased infection rates and lower hospital readmission rates.


Leishmania tarentolae: Taxonomic classification and its application as a promising biotechnological expression host.
In this review, we summarize the current knowledge concerning the eukaryotic protozoan parasite Leishmania tarentolae, with a main focus on its potential for biotechnological applications. We will also discuss the genus, subgenus, and species-level classification of this parasite, its life cycle and geographical distribution, and similarities and differences to human-pathogenic species, as these aspects are relevant for the evaluation of biosafety aspects of L. tarentolae as host for recombinant DNA/protein applications. Studies indicate that strain LEM-125 but not strain TARII/UC of L. tarentolae might also be capable of infecting mammals, at least transiently. This could raise the question of whether the current biosafety level of this strain should be reevaluated. In addition, we will summarize the current state of biotechnological research involving L. tarentolae and explain why this eukaryotic parasite is an advantageous and promising human recombinant protein expression host. This summary includes overall biotechnological applications, insights into its protein expression machinery (especially on glycoprotein and antibody fragment expression), available expression vectors, cell culture conditions, and its potential as an immunotherapy agent for human leishmaniasis treatment. Furthermore, we will highlight useful online tools and, finally, discuss possible future applications such as the humanization of the glycosylation profile of L. tarentolae or the expression of mammalian recombinant proteins in amastigote-like cells of this species or in amastigotes of avirulent human-pathogenic Leishmania species.


Epidemiology of Emergency Department Sepsis: A National Cohort Study Between 2001 and 2012.
The aim of this study is to examine the incidence trend of sepsis over 11 years and compared mortality outcomes among Taiwanese patients with sepsis admitted from emergency department (ED) and non-ED routes. We used a nationwide health insurance database from Taiwan, which comprise of 23 million beneficiaries. Patients with sepsis were identified by ICD-9 CM codes for infection and organ dysfunction from 2001 to 2012. We performed propensity score matching and compared mortality rates between ED-admitted and non ED-admitted patients.During the 11-year study period, we identified 1,256,684 patients with sepsis. 493,397 (29.3%) were admitted through the ED, and 763,287 (70.7%) were admitted directly to the floor. For patients with sepsis, mortality in ED-admitted patients decreased from 27.2% in 2002 to 21.1% in 2012 while that in non-ED admitted patients decreased from 35.3% in 2002 to 30.7% in 2012. Although patients with sepsis admitted through the ED had a higher incidence of organ dysfunction than patients who were directly admitted, they had more favorable outcomes in mortality, length of intensive care unit stay, and hospital stay. After propensity score matching, ED-admitted patients had a 7% lower risk of 90-day mortality (HR, 0.93, 95% CI, 0.89-0.97) compared with directly admitted patients. During the study period, mortality declined faster among ED admitted sepsis patients than directly admitted sepsis patients. Results of this study should be interpreted in light of limitations. Like other administrative database studies, treatment details are not available. Further clinical studies evaluating the treatment and outcome difference between ED and non-ED admitted sepsis patients are warranted.


Prognostic value of epidermal growth factor receptor expression in cervical carcinoma.
To investigate the pattern of epidermal growth factor receptor expression and its prognostic value in the three main types of cervical carcinoma. 62 cases of stage IB/IIA cervical carcinoma, all with a minimum of five years of follow up, were studied. Representative sections were stained for mucin to permit accurate tumour typing and a standard avidin-biotin immunoperoxidase technique using the polyclonal antibody 12E was used to demonstrate the presence of epidermal growth factor receptor. A proportion of all three tumour types expressed epidermal growth factor receptor, it being most common in squamous cell carcinomas (50%). Overall, there was a correlation between epidermal growth factor expression and mortality. This was particularly obvious in the absence of lymph node metastases. When the individual tumour types were considered this association with prognosis was not demonstrable for squamous cell carcinomas or adenocarcinomas but was a very prominent feature of adenosquamous carcinomas. Immunohistochemical demonstration of epidermal growth factor receptor expression may be useful in identifying those patients with a poor prognosis, particularly those with adenosquamous carcinomas which have not metastasised to the regional lymph nodes.


Detecting long-term metabolic shifts using isotopomers: CO2-driven suppression of photorespiration in C3 plants over the 20th century.
Terrestrial vegetation currently absorbs approximately a third of anthropogenic CO2 emissions, mitigating the rise of atmospheric CO2. However, terrestrial net primary production is highly sensitive to atmospheric CO2 levels and associated climatic changes. In C3 plants, which dominate terrestrial vegetation, net photosynthesis depends on the ratio between photorespiration and gross photosynthesis. This metabolic flux ratio depends strongly on CO2 levels, but changes in this ratio over the past CO2 rise have not been analyzed experimentally. Combining CO2 manipulation experiments and deuterium NMR, we first establish that the intramolecular deuterium distribution (deuterium isotopomers) of photosynthetic C3 glucose contains a signal of the photorespiration/photosynthesis ratio. By tracing this isotopomer signal in herbarium samples of natural C3 vascular plant species, crops, and a Sphagnum moss species, we detect a consistent reduction in the photorespiration/photosynthesis ratio in response to the ∼100-ppm CO2 increase between ∼1900 and 2013. No difference was detected in the isotopomer trends between beet sugar samples covering the 20th century and CO2 manipulation experiments, suggesting that photosynthetic metabolism in sugar beet has not acclimated to increasing CO2 over >100 y. This provides observational evidence that the reduction of the photorespiration/photosynthesis ratio was ca. 25%. The Sphagnum results are consistent with the observed positive correlations between peat accumulation rates and photosynthetic rates over the Northern Hemisphere. Our results establish that isotopomers of plant archives contain metabolic information covering centuries. Our data provide direct quantitative information on the "CO2 fertilization" effect over decades, thus addressing a major uncertainty in Earth system models.


Quality of life of patients operated on for lumbar stenosis: a long-term follow-up.
We evaluated a sample of 28 patients surgically treated for lumbar stenosis (LS) four years after the first evaluation (length of the first follow-up mean 44.6 months, range 15-88) in order to evaluate the long-term follow-up of Quality of Life (QoL) after surgical treatment as LS may greatly impair the patients' QoL. We previously assessed QoL in 30 patients operated on for LS four years before, by performing a retrospective follow-up through the Short-Form 36 Health Survey (SF-36). In this current study we performed a phone call evaluation administering the SF-36 and the official Italian version of the North American Spine Society (NASS) lumbar spine outcome assessment instrument. With regard to the SF-36 results at long term follow-up we observed a significant improvement of Physical Function, Bodily Pain, Mental Health and the Physical Composite Score with respect to the first follow-up. Conversely, Vitality worsened. Regarding the results of NASS an improvement of neurological symptoms was observed. Comparison of SF-36 mean scores in the current LS sample vs. the Italian normal population at the same age, showed similar QoL pattern. The long-term follow-up showed that patients operated on for LS continue to improve their QoL pattern even between the 4th and the 8th year after surgery.


Life cycle studies of the hexose transporter of Plasmodium species and genetic validation of their essentiality.
A Plasmodium falciparum hexose transporter (PfHT) has previously been shown to be a facilitative glucose and fructose transporter. Its expression in Xenopus laevis oocytes and the use of a glucose analogue inhibitor permitted chemical validation of PfHT as a novel drug target. Following recent re-annotations of the P. falciparum genome, other putative sugar transporters have been identified. To investigate further if PfHT is the key supplier of hexose to P. falciparum and to extend studies to different stages of Plasmodium spp., we functionally analysed the hexose transporters of both the human parasite P. falciparum and the rodent parasite Plasmodium berghei using gene targeting strategies. We show here the essential function of pfht for the erythrocytic parasite growth as it was not possible to knockout pfht unless the gene was complemented by an episomal construct. Also, we show that parasites are rescued from the toxic effect of a glucose analogue inhibitor when pfht is overexpressed in these transfectants. We found that the rodent malaria parasite orthologue, P. berghei hexose transporter (PbHT) gene, was similarly refractory to knockout attempts. However, using a single cross-over transfection strategy, we generated transgenic P. berghei parasites expressing a PbHT-GFP fusion protein suggesting that locus is amenable for gene targeting. Analysis of pbht-gfp transgenic parasites showed that PbHT is constitutively expressed through all the stages in the mosquito host in addition to asexual stages. These results provide genetic support for prioritizing PfHT as a target for novel antimalarials that can inhibit glucose uptake and kill parasites, as well as unveiling the expression of this hexose transporter in mosquito stages of the parasite, where it is also likely to be critical for survival.


Sex differences in in-hospital mortality in acute decompensated heart failure with reduced and preserved ejection fraction.
There are no sex-specific survival comparisons between patients with heart failure (HF) with reduced and those with preserved ejection fraction. Large registries noting women have better survival than men combined HF patients with reduced and preserved EF. Other registries that compared patients with reduced and preserved EF did not analyze their data by sex. We sought to evaluate sex/EF differences in mortality and risk factors for survival in hospitalized patients with HF. We included hospitals fully participating in Get With The Guidelines-Heart Failure that admitted HF patients with reduced (EF <40%) or preserved (EF ≥50%) EF. The primary end point was in-hospital mortality. Multivariate generalized estimating equation logistic models were used to compute odds ratios accounting for hospital clustering. The study cohort consisted of 51,428 patients with EF <40% (36% women, 64% men) and 37,699 patients with EF ≥50% (65% women, 35% men). Women compared with men with reduced and preserved EF were older and more likely to have hypertension, depression, or valvular heart disease and less likely to have coronary artery disease or peripheral vascular disease. There were no sex differences in in-hospital mortality (EF <40%, 2.69% women vs 2.89% men, P = .20; EF ≥50%, 2.61% women vs 2.62% men, P = .96), and risk factors such as age, systolic blood pressure, heart rate, and history of renal failure/dialysis were highly predictive of death for each sex/EF subgroup. In a large, multicenter registry, we found that despite differences in baseline characteristics, women and men with reduced and preserved EF have similar in-hospital mortality and risk factors predicting death.


Bacteria detection with thin wetting film lensless imaging.
Lensless on-chip imaging is a promising technique to count and monitor cells and micro-objects in liquid sample. In this paper we apply this technique to the observation of µL sample containing bacteria evaporated onto a microscope slide. Compared with previously reported techniques, a large improvement in signal to noise ratio is obtained due to the presence of a few μm thick wetting film creating a micro-lens on top of each bacteria. In these conditions, standard CMOS sensor are able to detect micro-objects as small as few μm, e.g. E.coli and Bacillus subtilis bacteria and 1 μm polymer beads with a large signal to noise ratio of 45 ± 10. An overall detection efficiency of 85 ± 7% and a co-localization error of σ(1D) = 1.1μm compared with reference fluorescence microscopy images are achieved. This novel technique will be used as a pre-positioning tool prior to other optical identification methods, e.g. Raman spectroscopy.


Assessing allele-specific expression across multiple tissues from RNA-seq read data.
RNA sequencing enables allele-specific expression (ASE) studies that complement standard genotype expression studies for common variants and, importantly, also allow measuring the regulatory impact of rare variants. The Genotype-Tissue Expression (GTEx) project is collecting RNA-seq data on multiple tissues of a same set of individuals and novel methods are required for the analysis of these data. We present a statistical method to compare different patterns of ASE across tissues and to classify genetic variants according to their impact on the tissue-wide expression profile. We focus on strong ASE effects that we are expecting to see for protein-truncating variants, but our method can also be adjusted for other types of ASE effects. We illustrate the method with a real data example on a tissue-wide expression profile of a variant causal for lipoid proteinosis, and with a simulation study to assess our method more generally.


Compassion fatigue is similar in emergency medicine residents compared to other medical and surgical specialties.
Compassion fatigue (CF) is the emotional and physical burden felt by those helping others in distress, leading to a reduced capacity and interest in being empathetic towards future suffering. Emergency care providers are at an increased risk of CF secondary to their first responder roles and exposure to traumatic events. We aimed to investigate the current state of compassion fatigue among emergency medicine (EM) resident physicians, including an assessment of contributing factors. We distributed a validated electronic questionnaire consisting of the Professional Quality of Life Scale with subscales for the three components of CF (compassion satisfaction, burnout and secondary traumatic stress), with each category scored independently. We collected data pertaining to day- versus night-shift distribution, hourly workload and child dependents. We included residents in EM, neurology, orthopedics, family medicine, pediatrics, obstetrics, and general surgery. We surveyed 255 residents, with a response rate of 75%. Of the 188 resident respondents, 18% worked a majority of their clinical shifts overnight, and 32% had child dependents. Burnout scores for residents who worked greater than 80 hours per week, or primarily worked overnight shifts, were higher than residents who worked less than 80 hours (mean score 25.0 vs 21.5; p=0.013), or did not work overnight (mean score 23.5 vs 21.3; p=0.022). EM residents had similar scores in all three components of CF when compared to other specialties. Secondary traumatic stress scores for residents who worked greater than 80 hours were higher than residents who worked less than 80 hours (mean score 22.2 vs 19.5; p=0.048), and those with child dependents had higher secondary traumatic stress than those without children (mean score 21.0 vs 19.1; p=0.012). CF scores in EM residents are similar to residents in other surgical and medical specialties. Residents working primarily night shifts and those working more than 80 hours per week appear to be at high risk of developing compassion fatigue. Residents with children are more likely to experience secondary traumatic stress.


Clinical and immune responses to inactivated influenza A(H1N1)pdm09 vaccine in children.
As the influenza A H1N1 pandemic emerged in 2009, children were found to experience high morbidity and mortality and were prioritized for vaccination. This multicenter, randomized, double-blind, age-stratified trial assessed the safety and immunogenicity of inactivated influenza A(H1N1)pdm09 vaccine in healthy children aged 6 months to 17 years. Children received 2 doses of approximately 15 or 30 µg hemagglutin antigen 21 days apart. Reactogenicity was assessed for 8 days after each dose, adverse events through day 42, and serious adverse events or new-onset chronic illnesses through day 201. Serum hemagglutination inhibition titers were measured on days 0 (prevaccination), 8, 21, 29 and 42. A total of 583 children received the first dose and 571 received the second dose of vaccine. Vaccinations were generally well-tolerated and no related serious adverse events were observed. The 15 µg dosage elicited a seroprotective hemagglutination inhibition (≥ 1:40) in 20%, 47% and 93% of children in the 6-35 month, 3-9 year and 10-17 year age strata 21 days after dose 1 and in 78%, 82% and 98% of children 21 days after dose 2, respectively. The 30 µg vaccine dosage induced similar responses. The inactivated influenza A(H1N1)pdm09 vaccine exhibited a favorable safety profile at both dosage levels. While a single 15 or 30 µg dose induced seroprotective antibody responses in most children 10-17 years of age, younger children required 2 doses, even when receiving dosages 4- to 6-fold higher than recommended. Well-tolerated vaccines are needed that induce immunity after a single dose for use in young children during influenza pandemics.


Challenging Breast Augmentations: The Influence of Preoperative Anatomical Features on the Final Result.
Achieving satisfactory results may be difficult in augmentation mammaplasty patients in the presence of breast, chest wall, or vertebral deformities. These deformities have not been classified previously, and the impact of each deformity or combination of deformities has not been defined. The aims of this study are to determine the complicating factors in augmentation mammaplasty, to classify these factors according to their influence on surgical outcome, and to develop an identification system for simplifying the recognition of challenging cases. We retrospectively analyzed photographs and records of 100 consecutive patients who underwent augmentation mammaplasty. We observed suboptimal results in 18 cases. Preoperative deformities of the breast, chest wall, and vertebra were recorded in order to determine which factor or factors had complicated the surgeries. Eventually, the relationship between suboptimal surgical results and complicating factors was evaluated. We observed that some deformities alone caused suboptimal results, whereas others did not. Deformities that caused suboptimal results alone were called major complicating factors, and any others were called minor complicating factors. We observed that suboptimal results were also obtained in patients who had four minor complicating factors. Patients who had suboptimal results because of major or minor complicating factors were considered challenging cases. In this study, complicating factors for augmentation mammaplasty were defined and classified as major or minor depending on their effect on the surgical outcome. We suggest an identification system that simplifies the recognition of challenging cases in breast augmentation.


Economic evaluation of an integrated diagnostic approach for psychogeriatric patients: results of a randomized controlled trial.
Because of the increasing number of elderly people with dementia, the costs of dementia and dementia care are expected to grow rapidly in the coming decades. Cost-effectiveness results are relevant for decision making about new strategies in dementia care. To evaluate the cost-effectiveness of an integrated multidisciplinary diagnostic facility for diagnosing dementia in ambulatory psychogeriatric patients. Randomized controlled trial with an economic evaluation component. The Maastricht Evaluation of a Diagnostic Intervention for Cognitively Impaired Elderly, Maastricht University Hospital, Maastricht, the Netherlands. A total of 137 patients who received care in the multidisciplinary diagnostic facility and 93 who received usual care. Quality-adjusted life-years (QALYs) as the main outcome measure and cognition and behavioral problems as secondary outcome measures. Compared with patients receiving usual care, patients who visited the diagnostic facility gained a mean 0.05 QALY at the extra cost of euro65. The incremental cost per QALY amounted to euro1267. This point estimate lies beneath commonly accepted thresholds and is within an acceptable range of uncertainty. With regard to the secondary analyses, cost-effectiveness results showed a substantial amount of uncertainty and were therefore indecisive. On the basis of the main cost-per-QALY analysis, the use of the integrated multidisciplinary diagnostic facility is cost-effective for the diagnosis and management of dementia in ambulatory patients.


Protective effects of lycium barbarum polysaccharides on blood-retinal barrier via ROCK1 pathway in diabetic rats.
Lycium barbarum polysaccharides (LBP) is commonly known as a traditional Chinese medicine, which has protective effects against diabetic complications in clinic, such as diabetic retinopathy (DR). Previous studies have revealed that Rho/ROCK pathway play an important role in DR development. However, the mechanism between LBP and DR remains unknown. This study aims to explore the clear mechanism of the protective effect of LBP in diabetic retinopathy. In this study, streptozocin (STZ, 45 mg/kg) was administered for diabetic rats modeling. Weight, blood glucose levels and blood lipid were measured to assess the metabolic changes by LBP on diabetic rats. Evans blue (EB) extravasation was determined to assess blood-retinal barrier (BRB) disruption. Hematoxylin and Eosin (HE) staining and immunohistochemistry assay were applied for retina morphology exploration. The membranous disks of retina were examined by transmission electron microscope. Further, high glucose condition was induced in choroidal-retinal endothelial cells (RF/6A). Western blotting was performed for P-Occludin, ROCK1 and P-MLC protein expression. The results indicated that the blood glucose levels, blood lipid and EB infiltration capacity were decreased while the weight was increased in LBP-treated diabetic rats compared with model rats. Moreover, LBP could thicken the overall retina, prevent the disturbance of photoreceptor cell membranous disks and inhibit pathological angiogenesis in diabetes. In addition, the decreased expression of P-Occludin and increased expression of RhoA-associated protein kinase (ROCK) or phosphorylated myosin light chain (P-MLC) were observed in retinal tissue of diabetic rats and high glucose induced by RF/6A cells, which could be rescued by LBP and/or Fasudil. LBP has the protective effects on blood-retinal barrier by regulating the Rho/ROCK signaling pathway in diabetic rats. LBP may be served as a Rho/ROCK inhibitor for the treatment of DR.


Generation of signals activating neutrophil functions by leukocyte integrins: LFA-1 and gp150/95, but not CR3, are able to stimulate the respiratory burst of human neutrophils.
To address the question whether leukocyte integrins are able to generate signals activating neutrophil functions, we investigated the capability of mAbs against the common beta chain (CD18), or the distinct alpha chains of CR3, LFA-1, or gp150/95, to activate neutrophil respiratory burst. These investigations were performed with mAbs bound to protein A immobilized to tissue culture polystyrene. Neutrophils plated in wells coated with the anti-CD18 mAbs IB4 and 60.3 released H2O2; H2O2 release did not occur when neutrophils were plated in wells coated with an irrelevant, isotype-matched mAb (OKDR), or with mAbs against other molecules (CD16, beta 2-microglobulin) expressed on the neutrophil surface at the same density of CD18. Four different mAbs, OKM1, OKM9, OKM10, 60.1, which recognize distinct epitopes of CR3 were unable to trigger H2O2 or O2- release from neutrophils. However, mAbs against LFA-1 or gp150/95 triggered both H2O2 and O2- release from neutrophils. Stimulation of neutrophils respiratory burst by both anti-CD18, and anti-LFA-1 or gp150/95 mAbs was totally inhibited by the microfilaments disrupting agent, cytochalasin B, and by a permeable cAMP analogue. While the capability to activate neutrophil respiratory burst was restricted to anti-LFA-1 and gp150/95 mAbs, we observed that mAbs against all members of leukocyte integrins, including CR3, were able to trigger neutrophil spreading. These findings indicate that, in neutrophils, all three leukocyte integrins can generate signals activating spreading, but only LFA-1 and gp150/95 can generate signals involved in activation of the respiratory burst. This observation can be relevant to understand the mechanisms responsible for the activation of neutrophil respiratory burst by tumor necrosis factor-alpha, which has been shown to be strictly dependent on expression of leukocyte integrins (Nathan, C., S. Srimal, C. Farber, E. Sanchez, L. Kabbash, A. Asch, J. Gailit, and S. Wright. 1989. J. Cell Biol. 109:13411349.


Impact of behavioral inhibition and parenting style on internalizing and externalizing problems from early childhood through adolescence.
Behavioral inhibition (BI) is characterized by a pattern of extreme social reticence, risk for internalizing behavior problems, and possible protection against externalizing behavior problems. Parenting style may also contribute to these associations between BI and behavior problems (BP). A sample of 113 children was assessed for BI in the laboratory at 14 and 24 months of age, self-report of maternal parenting style at 7 years of age, and maternal report of child internalizing and externalizing BP at 4, 7, and 15 years. Internalizing problems at age 4 were greatest among behaviorally inhibited children who also were exposed to permissive parenting. Furthermore, greater authoritative parenting was associated with less of an increase in internalizing behavior problems over time and greater authoritarian parenting was associated with a steeper decline in externalizing problems. Results highlight the importance of considering child and environmental factors in longitudinal patterns of BP across childhood and adolescence.


Altered cortical and subcortical local coherence in obstructive sleep apnea: a functional magnetic resonance imaging study.
Obstructive sleep apnea (OSA) syndrome is the most common sleep-related breathing disorder, characterized by excessive snoring and repetitive apneas and arousals, which leads to fragmented sleep and, most importantly, to intermittent nocturnal hypoxaemia during apneas. Considering previous studies about morphovolumetric alterations in sleep apnea, in this study we aimed to investigate for the first time the functional connectivity profile of OSA patients and age-gender-matched healthy controls, using resting-state functional magnetic resonance imaging (fMRI). Twenty severe OSA patients (mean age 43.2 ± 8 years; mean apnea-hypopnea index, 36.3 h(-1) ) and 20 non-apneic age-gender-body mass index (BMI)-matched controls underwent fMRI and polysomnographic (PSG) registration, as well as mood and sleepiness evaluation. Cerebro-cerebellar regional homogeneity (ReHo) values were calculated from fMRI acquisition, in order to identify pathology-related alterations in the local coherence of low-frequency signal (<0.1 Hz). Multivariate pattern classification was also performed using ReHo values as features. We found a significant pattern of cortical and subcortical abnormal local connectivity in OSA patients, suggesting an overall rearrangement of hemispheric connectivity balance, with a decrease of local coherence observed in right temporal, parietal and frontal lobe regions. Moreover, an increase in bilateral thalamic and somatosensory/motor cortices coherence have been found, a finding due possibly to an aberrant adaptation to incomplete sleep-wake transitions during nocturnal apneic episodes, induced by repetitive choke sensation and physical efforts attempting to restore breathing. Different hemispheric roles into sleep processes and a possible thalamus key role in OSA neurophysiopathology are intriguing issues that future studies should attempt to clarify.


Effects of progesterone on pulsatile luteinizing hormone (LH) secretion and LH subunit messenger ribonucleic acid during lactation in the rat.
In ovarian-intact lactating rats, removal of the suckling stimulus leads to restoration of pituitary LH beta mRNA levels and pulsatile LH secretion after 72 h, which correlates with a sharp decrease in plasma progesterone concentrations to basal levels. In contrast, in ovariectomized lactating rats, the increase in pituitary LH function is observed by 24 h after pup removal. To determine if progesterone secretion from the ovary participates in the delayed recovery of LH secretion, we treated lactating rats with the progesterone antagonist RU 486 and determined the effects on the time course of recovery of pulsatile LH secretion and LH subunit mRNA after pup removal and on pituitary responsiveness to GnRH. In ovarian-intact lactating rats treated with RU 486, pulsatile LH secretion was observed in about 40% of the rats within 24 h after pup removal (LH interpulse interval, 43.7 +/- 8.3 min) and in about 90% of the rats within 48 h after pup removal (LH interpulse interval, 46.1 +/- 3.6 min). The mean plasma LH level in the RU 486-treated rats was 10.1 +/- 2.2 ng/ml 24 h after removal of pups (control, less than 5 ng/ml) and had increased to 35.1 +/- 6.4 ng/ml 48 h after pup removal (control, 9.1 +/- 2.5 ng/ml). However, RU 486 treatment had no significant effect on LH mRNA subunit levels. To determine whether progesterone acts at the pituitary to block GnRH stimulation of LH secretion, we tested the effects of RU 486 on LH secretion in response to 2- and 5-ng pulses of GnRH. Pituitary responsiveness was tested 24 h after pup removal. We found that both doses of GnRH were effective in stimulating pulsatile LH secretion, and treatment with RU 486 had no significant effect on this response. We conclude from these studies that progesterone secretion from the ovary contributes to the inhibition of LH secretion that occurs after pup removal, since antagonizing progesterone's action resulted in an earlier restoration of pulsatile LH secretion. The increase in LH secretion occurred in the absence of any significant changes in responsiveness of the pituitary to GnRH stimulation or in LH subunit mRNA levels. Therefore, the primary site of action of progesterone would appear to be at the hypothalamus to suppress pulsatile GnRH secretion.


Efficacy and safety of a once-yearly i.v. Infusion of zoledronic acid 5 mg versus a once-weekly 70-mg oral alendronate in the treatment of male osteoporosis: a randomized, multicenter, double-blind, active-controlled study.
Zoledronic acid (ZOL) has shown beneficial effects on bone turnover and bone mineral density (BMD) in postmenopausal osteoporosis. This study compared the efficacy and safety of a once-yearly i.v. infusion of ZOL with weekly oral alendronate (ALN) in men with osteoporosis. In this multicenter, double-blind, active-controlled, parallel-group study, participants (n = 302) were randomized to receive either once-yearly ZOL 5 mg i.v. or weekly oral ALN 70 mg for 24 months. Changes in BMD and bone marker levels were assessed. ZOL increased BMD at the lumbar spine, total hip, femoral neck, and trochanter and was not inferior to ALN at 24 months [least squares mean estimates of the percentage increases in lumbar spine BMD of 6.1% and 6.2%; difference approximately 0.13; 95% confidence interval (CI) 1.12-0.85 in the ZOL and ALN groups, respectively]. At month 12, the median change from baseline of markers for bone resorption [serum β-C-terminal telopeptide of type I collagen (β-CTx) and urine N-terminal telopeptide of type I collagen (NTx)] and formation [serum N-terminal propeptide of type I collagen (P1NP) and serum bone-specific alkaline phosphatase (BSAP)] were comparable between ZOL and ALN groups. Most men preferred i.v. ZOL over oral ALN. The incidence of adverse events and serious adverse events was similar in the treatment groups. It is concluded that a once-yearly i.v. infusion of ZOL 5 mg increased bone density and decreased bone turnover markers similarly to once-weekly oral ALN 70 mg in men with low bone density.


Impact of 12h shift patterns in nursing: a scoping review.
To provide a comprehensive scoping review of evidence of the impact and effectiveness of 12h shifts in the international nursing literature, supplemented by a review of evidence in other, non-nursing related industries. A search of the academic literature was undertaken in electronic databases (AMED, MEDLINE, CINAHL, PsychInfo, Scopus, HMIC, the Cochrane Library, Business Source Premier, Econ Lit, ASSIA and Social Policy and Practice). A total of 158 potentially relevant nursing research papers and reviews were published between 1973 and 2014. Two reviewers independently reviewed the articles, leaving 85 primary research studies and 10 review papers in the nursing field to be included in the scoping review. Thirty-one relevant primary research papers and reviews were also identified in the non-nursing related industries literature. Research into 12h nursing shifts fell within five broad themes: 'risks to patients', 'patient experience', 'risks to staff', 'staff experience' and 'impact on the organisation of work'. There was inconclusive evidence of the effects of 12h shift patterns in all five themes, with some studies demonstrating positive impacts and others negative or no impacts. This also mirrors the evidence in other, non-nursing related industries. The quality of research reviewed is generally weak and most studies focus on the risks, experience and work/life balance for staff, with few addressing the impact on patient outcomes and experience of care or work productivity. There is insufficient evidence to justify the widespread implementation or withdrawal of 12h shifts in nursing. It is not clearly understood where there are real benefits and where there are real and unacceptable risks to patients and staff. More research focusing on the impact of 12h nursing shifts on patient safety and experience of care and on the long term impact on staff and work organisation is required.


Homeostatic cytokines and expansion of regulatory T cells accompany thymic impairment in children with Down syndrome.
Down syndrome (DS), the most common chromosomal abnormality in humans, is characterized by precocious immunologic aging that results, among other things, in alterations of B and T lymphocyte subsets and natural killer cells, defective phagocytosis, and chemotaxis of polymorphonuclear leukocytes. We studied 30 children affected by DS, compared them to 29 healthy controls, and evaluated the functionality of the thymus (by measuring the amount of lymphocytes that express the signal-joint T cell receptor rearrangement excision circles [sj-TREC+]), the plasma levels of interleukin (IL)-7 and IL-15, the proliferative T cell response to these cytokines, the expression of the alpha chain of the IL-7 receptor (CD127), the extrathymic differentiation of T lymphocytes, and the presence of natural regulatory T cells (Tregs) in peripheral blood. We found that DS children had a significantly lower number of sj-TREC+ lymphocytes, the levels of which were strongly correlated with age. We found higher plasma levels of IL-7 and IL-15 than in healthy controls, and a higher proliferative T cell response to IL-15. DS children also showed a lower percentage of CD4(+) cells and profound alterations of T cell differentiation, along with increased amount of Tregs and of cells expressing markers of apoptosis. We can thus hypothesize that the precocious thymic involution occurring in DS is mirrored by a high production of IL-7 and IL-15, which is crucial for cell survival and proliferation. The complex alterations present in the periphery are likely the result of a compensatory mechanism: the overproduction of homeostatic cytokines could be a reaction to the impaired intrathymic production of T lymphocytes and/or to the expansion of Treg in the periphery, and could be required to allow the survival of T cells.


Clinical, cytogenetic and molecular characterization of a patient with combined succinic semialdehyde dehydrogenase deficiency and incomplete WAGR syndrome with obesity.
We describe the clinical course, as well as cytogenetic and molecular findings, of a 3-year-old obese boy with psychomotor retardation who exhibited two rare conditions: succinic semialdehyde dehydrogenase deficiency (SSADH deficiency, MIM 271980), a disorder of gamma-aminobutyric acid metabolism with a heterogeneous clinical spectrum, and partial Wilms' tumor, aniridia, genital abnormalities, and mental retardation (WAGR) syndrome, an association between Wilms' tumor, aniridia, genitourinary malformations, and mental retardation due to mutations involving the short arm of chromosome 11, particularly deletions at the chromosomal region 11p13 (MIM 194072). Diagnosis of SSADH deficiency in our patient was established by demonstration of absent enzyme activity in isolated leucocytes, and was associated with a novel missense mutation (c.587G>A; p.Gly196Asp) in the SSADH coding sequence. We further confirmed an incomplete WAGR syndrome in this boy [karyotype 46, XY, del (11) (p13p14.2)] with a normal WT1 (Wilms' tumor) gene and an absence of pathology in the genitourinary tract, but with obesity (WAGR syndrome with obesity, WAGRO syndrome). The patient also exhibited distinctive cerebral anomalies such as increased signals of the globi pallidi, internal hydrocephalus and cerebellar vermian atrophy. However, treatment options for this patient are limited, including supportive treatment, physiotherapy, special educational training, and vigabatrin. In summary, we report the first patient with the exceptional rare findings of both SSADH deficiency and partial WAGR/WAGRO syndrome.


A bounded and adaptive memory-based approach to mine frequent patterns from very large databases.
Most of the existing methods to solve the problem of association rules mining (ARM) rely on special data structures to project the database (either totally or partially) in the primary memory. Traditionally, these data structures reside in the main memory and rely on the existing paging mechanism of the virtual memory manager (VMM) to handle the storage problem when they go out of the primary memory. Typically, VMM stores the overloaded data into the secondary memory based on some preassumed memory usage criteria. However, this direct and unplanned use of virtual memory results in an unpredictable behavior or thrashing, as depicted by some of the works described in the literature. This problem is tackled in this paper by presenting an ARM model capable of mining a transactional database, regardless of its size and without relying on the underlying VMM; the proposed approach could use only a bounded portion of the primary memory and this gives the opportunity to assign other parts of the main memory to other tasks with different priority. In other words, we propose a specialized memory management system which caters to the needs of the ARM model in such a way that the proposed data structure is constructed in the available allocated primary memory first. If at any point the structure grows out of the allocated memory quota, it is forced to be partially saved on secondary memory. The secondary memory version of the structure is accessed in a block-by-block basis so that both the spatial and temporal localities of the I/O access are optimized. Thus, the proposed framework takes control of the virtual memory access and hence manages the required virtual memory in an optimal way to the best benefit of the mining process to be served. Several clever data structures are used to facilitate these optimizations. Our method has the additional advantage that other tasks of different priorities may run concurrently with the main mining task with as little interference as possible because we do not rely on the default paging mechanism of the VMM. The reported test results demonstrate the applicability and effectiveness of the proposed approach.


RNAi-independent heterochromatin nucleation by the stress-activated ATF/CREB family proteins.
At the silent mating-type interval of fission yeast, the RNA interference (RNAi) machinery cooperates with cenH, a DNA element homologous to centromeric repeats, to initiate heterochromatin formation. However, in RNAi mutants, heterochromatin assembly can still occur at low efficiency. Here, we report that Atf1 and Pcr1, two ATF/CREB family proteins, act in a parallel mechanism to the RNAi pathway for heterochromatin nucleation. Deletion of atf1 or pcr1 alone has little effect on silencing at the mating-type region, but when combined with RNAi mutants, double mutants fail to nucleate heterochromatin assembly. Moreover, deletion of atf1 or pcr1 in combination with cenH deletion causes loss of silencing and heterochromatin formation. Furthermore, Atf1 and Pcr1 bind to the mating-type region and target histone H3 lysine-9 methylation and the Swi6 protein essential for heterochromatin assembly. These analyses link ATF/CREB family proteins, involved in cellular response to environmental stresses, to nucleation of constitutive heterochromatin.


Frequency domain near-infrared spectroscopy of the uterine cervix during cervical ripening.
Preterm labor is a common obstetric complication. Clinical evaluation of cervical ripening to predict preterm labor has a substantial inter- and intraobserver variability. We used frequency domain near-infrared spectroscopy (FD-NIRS) to non-invasively investigate the changes of the optical properties (i.e., absorption and scattering of light) in the uterine cervix during drug-induced cervical ripening. Ten volunteers scheduled for abortion were examined. Optical properties of the uterine cervix were measured and physiological parameters were calculated prior to and after induction of cervical ripening using topical misoprostol. Mean relative changes, +/-standard error of the mean as well as statistical significance using the t-test were calculated for oxy- and deoxyhemoglobin, total hemoglobin, oxygen-saturation, and water. The wavelength-dependent decrease of scattering (scatter power) was calculated by an exponential fit and tested with the Wilcoxon test. Misoprostol induced a decrease in total hemoglobin of 21 +/- 6% (P < 0.05), a decrease in oxyhemoglobin of 22 +/- 6% (P < 0.05), a decrease in deoxyhemoglobin of 16 +/- 11% and an increase of 36 +/- 8% (P < 0.005) in water content. The scatter power was significantly lower (P < 0.05) after cervical ripening. Our results show that FD-NIRS is a promising diagnostic tool to detect changes in cervical concentrations of hemoglobin and water. A severe tissue edema, probably due to a hormone-induced inflammatory process, seems to be important for cervical ripening. The reduction in total hemoglobin is likely to be a consequence of the increased water content of the tissue resulting in a dramatic increase of the distance between vessels. We propose this technology to assess the cervical ripening and eventually to predict preterm labor.


Inner retinal thickening affects microperimetry thresholds in the presence of photoreceptor thinning in patients with RPGR retinitis pigmentosa.
Loss of photoreceptors cause degeneration in areas of the retina beyond the photoreceptors. The pattern of changes has implications for disease monitoring and measurement of functional changes. The aim of the study was to study the changes in inner retinal structure associated with photoreceptor disease, and the impact of these on microperimetry threshold. This retrospective cohort study was conducted on optical coherence tomography (OCT) images and microperimetry tests collected between 2013 and 2019. 22 eyes with RPGR retinitis pigmentosa completed both OCT imaging and microperimetry assessment. 18 control eyes underwent OCT imaging. Photoreceptor layer and inner retinal thickness calculated for different eccentric areas were obtained. The relationship between the photoreceptor layer and inner retinal thickness, and microperimetry threshold was explored. Central 1° photoreceptor layer and inner retinal thickness were 96±34 and 139±75 μm in RPGR patients, and 139±15 and 62±14 μm in controls. Photoreceptor layer thickness differed between patient and control groups across increasing visual field areas (p<0.01, Kruskal-Wallis 1-way ANOVA), whereas the inner retinal thickness significantly differed between groups for the central 1° and 3° only. Microperimetry thresholds were explained by a combination of photoreceptor thickness (coefficient 0.15, 95% CI 0.13 to 0.18) and inner retinal thickness (coefficient 0.05, 95% CI 0.03 to 0.06). OCT shows evidence of remodelling in the inner retinal layers secondary to photoreceptor disease. This appears to have an impact on microperimetry threshold measurements.


Open-chest cardiac massage without major thoracotomy: metabolic indicators of coronary and cerebral perfusion.
To compare the coronary and cerebral perfusion achieved using a novel method of minimally-invasive, direct cardiac massage to that obtained using bimanual, open-chest cardiac massage. Prospective, controlled animal study with repeated measures. University research laboratory. Large domestic swine. Aortic, coronary sinus, jugular venous and pulmonary artery catheters were placed. Following an equilibration period, ventricular fibrillation was induced. After 4 min of untreated ventricular fibrillation, animals underwent bimanual, open-chest cardiac massage (N = 6) or minimally-invasive, direct cardiac massage using a novel device for direct cardiac compression (N = 6). Adrenaline was administered at a dose of 1 mg intravenously every 5 min. Systemic metabolic parameters, (arterial PO2, PCO2 and lactate concentration) and coronary sinus and jugular venous metabolic parameters (pH, PVO2, SVO2, PVCO2 and lactate concentration) were measured and calculated (coronary sinus/jugular-arterial SVO2, coronary sinus/jugular-arterial PCO2 and lactate differences) at baseline and at 10, 20 and 30 min following induction of ventricular fibrillation. Animals were euthanised after 30 min with no attempt at defibrillation. Oxygen tension and oxygen saturation of coronary sinus blood declined significantly during the experimental period, but no differences were noted between treatment groups. The coronary sinus-arterial oxygen saturation difference increased during the study with no significant differences between groups. Coronary sinus PCO2 and the coronary sinus-arterial PCO2 difference increased significantly in both experimental groups during cardiac massage. No inter-group differences were noted. A similar relationship was noted in coronary sinus lactate values. The coronary sinus-arterial lactate difference displayed a positive balance at all intervals with no differences noted between group values. The oxygen tension and oxygen saturation of jugular venous blood, were reduced from baseline levels with both treatments. The jugular-arterial oxygen saturation difference increased in both groups compared to baseline values. Between group values were significantly different only at the 20 min interval. Both the jugular venous PCO2 and the jugular-arterial PCO2 gradient were elevated at all intervals, but no inter-group differences were noted. Jugular venous lactate concentration rose steadily with time in both groups. No significant increase in the jugular-arterial lactate gradient was noted at any time point. Minimally-invasive, direct cardiac massage provides coronary and cerebral perfusion similar to that achieved using standard open-chest cardiac massage. This method may provide a more effective substitute for standard, closed-chest cardiac massage in cases of refractory cardiac arrest.


Small ubiquitin-related modifiers: A novel and independent class of autoantigens in primary biliary cirrhosis.
Serum autoantibodies against components of nuclear dots (anti-NDs), namely PML and Sp100, are specifically detected in 20% to 30% of patients with primary biliary cirrhosis (PBC). Although anti-ND antibodies are nonpathogenic, the mechanisms that lead to this unique reactivity are critical to understanding the loss of immune tolerance in PBC. Importantly, Sp100 and PML are both covalently linked to small ubiquitin-related modifiers (SUMOs). Therefore, we investigated whether SUMO proteins are independent autoantigens in PBC and studied 99 PBC sera samples for reactivity against NDs, PML, and Sp100, as well as against SUMO-2 and SUMO-1 recombinant proteins. Autoantibodies against SUMO-2 and SUMO-1 were found in 42% and 15% of anti-ND-positive PBC sera, respectively. Anti-SUMO reactivity was not observed in anti-ND-negative sera. Anti-SUMO-2 autoantibodies were found in 58% of sera containing autoantibodies against both PML and Sp100 and were detected exclusively in sera containing anti-Sp100 autoantibodies. In conclusion, SUMO proteins constitute a novel and independent class of autoantigens in PBC. Furthermore, we believe our data emphasize the post-translational modification of lysine by either lipoylation in the case of AMA or SUMOylation in the case of specific anti-ND autoantibodies as the pivotal site for autoantibody generation in PBC.


Communicating Tobacco Product Information to the Public.
The 2009 Family Smoking Prevention and Tobacco Control Act (TCA) requires tobacco companies to disclose information about the harmful chemicals in their products to the U.S. Food and Drug Administration (FDA). The law requires the FDA, in turn, to communicate this information to the public "in a format that is understandable and not misleading to a lay person." But how should the FDA comply with this requirement? What does it mean for information about complex chemicals to be "understandable and not misleading to a lay person"? These questions are not easy ones to answer. Disclosures about the amount of harmful chemicals (constituents) in different tobacco products may help to inform consumers, but may also conversely prompt consumers to reach incorrect or unsupported conclusions about products' relative health risks. This paper first analyzes the FDA's legal obligation to publish tobacco constituent information so that it is "understandable and not misleading to a layperson." Second, it discusses how that legal analysis has guided scientific research examining how members of the public interpret messages regarding tobacco constituents. Lastly, this paper concludes with policy recommendations for the FDA as it considers how to comply with the law's constituent disclosure requirement while still furthering its overall objective of promoting public health.


Determination of free and total bisphenol A in human milk samples from Canadian women using a sensitive and selective GC-MS method.
A sensitive and selective GC-MS method was developed and used to analyse human milk samples for both free and total bisphenol A (BPA). Total BPA was detected in 72 of the 278 human milk samples (25.9%) at concentrations from < 0.036 to 2.5 ng g(-1) with a geometric mean (GM) of 0.13 ng g(-1) and median of 0.11 ng g(-1), while free BPA was detected in fewer samples, 46 of the 278 samples (16.5%) at concentrations ranging from < 0.036 to 2.3 ng g(-1) with a GM of 0.11 ng g(-1) and median of 0.10 ng g(-1). Ratios of [free BPA]/[total BPA] for the positive samples ranged from 7.9% to 100% with a GM of 57.2% and median of 70.3%. Concentrations of free and total BPA in most samples were low with 0.39 and 0.65 ng g(-1) at the 95th percentile for free and total BPA, respectively, and they are also lower than those reported in other countries. Based on the low frequency of detection of free BPA in human milk samples, in general, dietary exposure to BPA for Canadian breast-fed infants is expected to be somewhat lower compared with exposure among formula-fed infants.


A real-world approach to Evidence-Based Medicine in general practice: a competency framework derived from a systematic review and Delphi process.
Evidence-Based Medicine (EBM) skills have been included in general practice curricula and competency frameworks. However, GPs experience numerous barriers to developing and maintaining EBM skills, and some GPs feel the EBM movement misunderstands, and threatens their traditional role. We therefore need a new approach that acknowledges the constraints encountered in real-world general practice. The aim of this study was to synthesise from empirical research a real-world EBM competency framework for general practice, which could be applied in training, in the individual pursuit of continuing professional development, and in routine care. We sought to integrate evidence from the literature with evidence derived from the opinions of experts in the fields of general practice and EBM. We synthesised two sets of themes describing the meaning of EBM in general practice. One set of themes was derived from a mixed-methods systematic review of the literature; the other set was derived from the further development of those themes using a Delphi process among a panel of EBM and general practice experts. From these two sets of themes we constructed a real-world EBM competency framework for general practice. A simple competency framework was constructed, that acknowledges the constraints of real-world general practice: (1) mindfulness - in one's approach towards EBM itself, and to the influences on decision-making; (2) pragmatism - in one's approach to finding and evaluating evidence; and (3) knowledge of the patient - as the most useful resource in effective communication of evidence. We present a clinical scenario to illustrate how a GP might demonstrate these competencies in their routine daily work. We have proposed a real-world EBM competency framework for general practice, derived from empirical research, which acknowledges the constraints encountered in modern general practice. Further validation of these competencies is required, both as an educational resource and as a strategy for actual practice.