OTUB1 inhibits CNS autoimmunity by preventing IFN-γ-induced hyperactivation of astrocytes.
Astrocytes are critical regulators of neuroinflammation in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Growing evidence indicates that ubiquitination of signaling molecules is an important cell-intrinsic mechanism governing astrocyte function during MS and EAE Here, we identified an upregulation of the deubiquitinase OTU domain, ubiquitin aldehyde binding 1 (OTUB1) in astrocytes during MS and EAE Mice with astrocyte-specific OTUB1 ablation developed more severe EAE due to increased leukocyte accumulation, proinflammatory gene transcription, and demyelination in the spinal cord as compared to control mice. OTUB1-deficient astrocytes were hyperactivated in response to IFN-γ, a fingerprint cytokine of encephalitogenic T cells, and produced more proinflammatory cytokines and chemokines than control astrocytes. Mechanistically, OTUB1 inhibited IFN-γ-induced Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling by K48 deubiquitination and stabilization of the JAK2 inhibitor suppressor of cytokine signaling 1 (SOCS1). Thus, astrocyte-specific OTUB1 is a critical inhibitor of neuroinflammation in CNS autoimmunity.


Psychiatric care and health insurance reform.
Concerns about cost, access, and quality of health care in the United States have led to a variety of legislative proposals that would reform our health care system and its financing. Health insurance benefits for mental illness, including substance abuse, are treated differently from medical/surgical benefits, with stricter limits on outpatient visits and hospital days. Medicare, Medicaid, and most private health insurance plans contain this historic disparity of coverage for mental illness compared to general medical illness. Psychiatric services are also distinguishable because of the large public sector reimbursement for mental illness treatment and support. Principles for a more equitable design of mental health benefits include a non-discriminatory approach; payment on the basis of service rather than diagnosis; application of cost containment for care of mental illness on the same basis as care of general medical illness; retention of the public sector as a backup system for high-cost, long-term care; encouragement of lower-cost alternatives to the hospital through the development of a continuum of care; and a recognition of the distinction between psychotherapy and medical management. All current approaches to universal health care fall short of these principles. A research agenda is needed now more than ever in order to articulate the case for complete coverage of mental illness and substance abuse.


Insights into water-mediated ion clustering in aqueous CaSO4 solutions: pre-nucleation cluster characteristics studied by ab initio calculations and molecular dynamics simulations.
The molecular structure of growth units building crystals is a fundamental issue in the crystallization processes from aqueous solutions. In this work, a systematic investigation of pre-nucleation clusters and their hydration characteristics in aqueous CaSO4 solutions was performed using ab initio calculations and molecular dynamics (MD) simulations. The results of ab initio calculations and MD simulations indicate that the dominant species in aqueous CaSO4 solutions are monodentate ion-associated structures. Compared with charged ion clusters, neutral clusters are more likely to be present in an aqueous CaSO4 solution. Neutral (CaSO4)m clusters are probably the growth units involved in the pre-nucleation or crystallization processes. Meanwhile, hydration behavior around ion associated species in aqueous CaSO4 solutions plays an important role in related phase/polymorphism selections. Upon ion clustering, the residence of some water molecules around Ca2+ in ion-associated species is weakened while that of some bridging waters is enhanced due to dual interaction by Ca2+ and SO42-. Some phase/polymorphism selections can be achieved in aqueous CaSO4 solutions by controlling the hydration around pre-nucleation clusters. Moreover, the association trend between calcium and sulfate is found to be relatively strong, which hints at the low solubility of calcium sulfate in water.


Improved first Rayleigh-Sommerfeld method applied to metallic cylindrical focusing micro mirrors.
An improved first Rayleigh-Sommerfeld method (IRSM1) is intensively applied to analyzing the focal properties of metallic cylindrical focusing micro mirrors. A variety of metallic cylindrical focusing mirrors with different f-numbers, different polarization of incidence, or different types of profiles are investigated. The focal properties include the focal spot size, the diffraction efficiency, the real focal length, the total reflected power, and the normalized sidelobe power. Numerical results calculated by the IRSM1, the original first Rayleigh-Sommerfeld method (ORSM1), and the rigorous boundary element method (BEM) are presented for quantitative comparison. It is found that the IRSM1 is much more accurate than the ORSM1 in performance analysis of metallic cylindrical focusing mirrors, especially for cylindrical refractive focusing mirrors with small f-numbers. Moreover, the IRSM1 saves great amounts of computational time and computer memory in calculations, in comparison with the vectorial BEM.


Persantine and aspirin in coronary heart disease. The Persantine-Aspirin Reinfarction Study Research Group.
In the Persantine-Aspirin Reinfarction Study (PARIS) trial, 2026 persons who had recovered from myocardial infarction (MI) were randomized into three groups: Persantine plus aspirin (PR/A) (n = 810); aspirin alone (ASA) (n = 810); placebo (PLBO) (n = 406). The average length of follow-up study was 41 months. Results for the three specified primary end points were: total mortality 16% lower in PR/A and 18% lower in ASA compared with PLBO; coronary mortality 24% and 21% lower; incidence of nonfatal MI plus fatal coronary disease 25% and 24% lower. These differences were not satistically significant by the study criterion (Z greater than or equal to 2.6). By life-table analysis, the rates of coronary mortality and coronary incidence were about 50% lower in the PR/A group than in the PLBO group from 8-24 months, and for coronary incidence all Z values were greater than or equal to 2.6; ASA rates were about 30% lower than PLBO rates, and for coronary incidence, Z values were greater than or equal to 2.6 at two points. For these end points, from 8-20 months, PR/A rates were about 30% lower than ASA rates, but all Z values were less than 2.0 PR/A and ASA patients entering within 6 months of last MI showed the largest percentage reductions in mortality; only the difference between PR/A and PLBO groups for 3-year coronary mortality yielded a Z value of 2.6.


Effect of exosomes from plasma of dairy cows with or without an infected uterus on prostaglandin production by endometrial cell lines.
A contributing factor to declining fertility in dairy cows is an activated inflammatory system associated with uterine infection. Detecting uterine disease using biomarkers may allow earlier diagnosis and intervention with resultant improvements in fertility. Exosomes are known to participate in intercellular communication, paracrine, and endocrine signaling. Exosomes carry a cargo of proteins, lipids, and nucleic acids that represent specific cellular sources. Prostaglandins are lipids that are critical determinants of bovine fertility. In this study exosomes were isolated from the plasma of cows before (d 0) and during (d 10) the study in healthy animals or those with an induced uterine infection in a 2 × 2 factorial design. Exosomes were characterized for size and number (nanoparticle tracking analysis), exosomal marker expression (Western blot), and morphology (transmission electron microscopy). No significant differences were observed in exosome size or number. The abundance of exosome-enriched markers was confirmed in noninfected and infected animals. Transmission electron microscopy confirmed the morphology of the exosomes. These exosomes were co-incubated with bovine endometrial epithelial and stromal cells. Exosomes from d-10-infected animal plasma decreased PGF2α production in endometrial epithelial but not stromal cells. For future research, the identification of effectors in the cargo may provide a useful basis for early diagnosis of uterine infection using an exosomal characterization approach.


Vibrational energy transfer near a dissociative adsorption transition state: State-to-state study of HCl collisions at Au(111).
In this work we seek to examine the nature of collisional energy transfer between HCl and Au(111) for nonreactive scattering events that sample geometries near the transition state for dissociative adsorption by varying both the vibrational and translational energy of the incident HCl molecules in the range near the dissociation barrier. Specifically, we report absolute vibrational excitation probabilities for HCl(v = 0 → 1) and HCl(v = 1 → 2) scattering from clean Au(111) as a function of surface temperature and incidence translational energy. The HCl(v = 2 → 3) channel could not be observed-presumably due to the onset of dissociation. The excitation probabilities can be decomposed into adiabatic and nonadiabatic contributions. We find that both contributions strongly increase with incidence vibrational state by a factor of 24 and 9, respectively. This suggests that V-T as well as V-EHP coupling can be enhanced near the transition state for dissociative adsorption at a metal surface. We also show that previously reported HCl(v = 0 → 1) excitation probabilities [Q. Ran et al., Phys. Rev. Lett. 98, 237601 (2007)]-50 times smaller than those reported here-were influenced by erroneous assignment of spectroscopic lines used in the data analysis.


Genomic risk prediction of aromatase inhibitor-related arthralgia in patients with breast cancer using a novel machine-learning algorithm.
Many breast cancer (BC) patients treated with aromatase inhibitors (AIs) develop aromatase inhibitor-related arthralgia (AIA). Candidate gene studies to identify AIA risk are limited in scope. We evaluated the potential of a novel analytic algorithm (NAA) to predict AIA using germline single nucleotide polymorphisms (SNP) data obtained before treatment initiation. Systematic chart review of 700 AI-treated patients with stage I-III BC identified asymptomatic patients (n = 39) and those with clinically significant AIA resulting in AI termination or therapy switch (n = 123). Germline DNA was obtained and SNP genotyping performed using the Affymetrix UK BioBank Axiom Array to yield 695,277 SNPs. SNP clusters that most closely defined AIA risk were discovered using an NAA that sequentially combined statistical filtering and a machine-learning algorithm. NCBI PhenGenI and Ensemble databases defined gene attribution of the most discriminating SNPs. Phenotype, pathway, and ontologic analyses assessed functional and mechanistic validity. Demographics were similar in cases and controls. A cluster of 70 SNPs, correlating to 57 genes, was identified. This SNP group predicted AIA occurrence with a maximum accuracy of 75.93%. Strong associations with arthralgia, breast cancer, and estrogen phenotypes were seen in 19/57 genes (33%) and were functionally consistent. Using a NAA, we identified a 70 SNP cluster that predicted AIA risk with fair accuracy. Phenotype, functional, and pathway analysis of attributed genes was consistent with clinical phenotypes. This study is the first to link a specific SNP/gene cluster to AIA risk independent of candidate gene bias.


Carpal tunnel syndrome: ultrasound, neurophysiology, clinical and patient-oriented assessment.
The aim of this study is twofold. First, to assess the relationships between the cross-sectional area (CSA) of the median nerve (MN) calculated at ultrasound (US) and: (1) patient's perception of his/her symptoms and hand function; (2) clinical severity of CTS; (3) neurophysiological classification; (4) hand distribution of symptoms. Second, to assess the sensitivity of ultrasonography (US) and neurophysiology in the diagnosis of CTS using clinical measures as gold standard. We performed a prospective study by using multidimensional assessment: clinical (Historic and Objective scale, Hi-Ob), neurophysiological, patient-oriented measures (Boston Carpal Tunnel Questionnaire, BCTQ) and high-resolution US. The dominant hands of 54 consecutive patients who were referred to our neurophysiologic laboratory with clinical signs of CTS (43 females, mean age 53.3, range 30-80, SD: 13.1) were examined. A statistically significant correlation was found between the CSA of the MN at wrist and (1) hand function (according to BCTQ, r=0.35, p=0.01), (2) clinical scale (Hi-Ob scale, r=0.51, p<0.00007), (3) neurophysiologic classification (r=0.80, p<0.0000001), and (4) hand distribution of symptoms (p=0.017). Neurophysiology showed higher sensitivity than US but in one of 3 cases with normal neurophysiological results, US showed data suggestive of CTS. A positive correlation exists between US findings and all the conventional measures of CTS severity. The sensitivity of the combination of US and neurophysiology is higher than the sensitivity of neurophysiology or US alone. US is a useful complementary tool for CTS assessment. Information on the contribution of US in CTS and the interpretation of severity measurements in CTS.


Eruptive xanthomas masquerading as molluscum contagiosum.
Eruptive xanthomas are cutaneous manifestations of hyperlipidemias in which lipids accumulate in large foam cells within the skin. They classically present as crops of 1- to 4-mm yellow-orange papules and are often associated with extreme hypertriglyceridemia. We describe a 12-year-old boy with autism who was thought to have widespread molluscum contagiosum for a year before dermatologic consultation was obtained. Recognition of eruptive xanthomas led to the discovery of massive hypertriglyceridemia (serum triglycerides 6853 mg/dL) and diabetes mellitus. Through medical intervention, including insulin and fenofibrate therapy, and dietary modification with weight loss, the xanthomas cleared during the subsequent months, and his serum triglyceride levels nearly normalized.


Prevention of experimental colitis by parenteral administration of a pathogen-derived immunomodulatory molecule.
Filamentous haemagglutinin (FHA) of Bordetella pertussis subverts host immune responses by inhibiting interleukin (IL)12 and enhancing IL10 production by macrophages and dendritic cells, and promoting the induction of regulatory T cells. Injection of FHA would ameliorate disease in a T cell-dependent model of colitis via the induction of anti-inflammatory cytokines and regulatory T cells. Colitis was induced by injection of CD4CD45RB(high) naive T cells into severe combined immunodeficient (SCID) mice. Mice were treated with four subcutaneous injections of FHA or buffer alone. Parenteral injection of FHA stimulated IL10 and/or transforming growth factor beta production in local and mesenteric lymph nodes and Peyer's patches of mice 2-6 h after administration. Compared with phosphate-buffered saline-treated mice, FHA-treated SCID mice had significantly (p<0.01) less weight loss, lower colon weight, less colon shrinkage and reduced inflammatory lesions. The therapeutic effect of FHA was associated with enhanced IL10 and reduced type 1 and type 2 T helper cytokine production by spleen cells. Finally, FHA also attenuated the symptoms of colitis in SCID mice transferred with CD4CD45RB(high) T cells from IL10-deficient mice. Our finding shows that FHA suppresses type 1 T helper and pro-inflammatory cytokines, and ameliorates disease activity in a chronic T cell-dependent model of colitis, an effect that was not dependent on IL10 production by T cells, but was associated with induction of anti-inflammatory cytokines in vivo. Having already been used as a pertussis vaccine component in children, FHA is a promising candidate for clinical testing in patients with Crohn's disease.


Presence of multiple HIV subtypes and a high frequency of subtype chimeric viruses in heterosexually infected women.
The HIV-1 subtype distribution was determined in 41 HIV-positive women (-8% of all HIV-infected women in Denmark) belonging to different risk groups. HIV p17 gag and env gene subtypes were determined by DNA sequence analysis. Five different HIV subtypes were detected across all patients. Most HIV-1-positive women of Danish origin carried subtype B viruses, and a minority had virus belonging to subtypes A or C. All injecting drug users (IDUs) were infected with HIV subtype B viruses, whereas all non-B subtypes were present in cases linked to heterosexual transmission. In contrast, all women of African origin carried non-B HIV subtypes (subtypes A, C, D, or G) regardless of transmission mode. Of these women, 21% infected with non-B HIV subtypes appeared to be infected by subtype chimeric viruses and 7% were jointly infected with viruses belonging to two different subtypes (A and C). Data demonstrate a preferential representation of non-B HIV subtypes in women infected through heterosexual contact, as well as a high degree of recombination between viruses derived from endemic areas in which several HIV subtypes predominate. Combined with the increased incidence of heterosexual transmission of HIV, the results imply that an increased subtype diversity can be anticipated in newly infected individuals.


Trematocranus pachychilus, a new endemic cichlid from Lake Malawi (Teleostei, Cichlidae).
A new species of Trematocranus, T. pachychilussp. n., is described from Lake Malawi. So far, it has only been found at Jafua Bay, Mozambique. It can easily be distinguished from T. labifer by its molariform pharyngeal dentition. A morphometric study, including 24 measurements and 15 counts, was done to compare the new species with T. microstoma and T. placodon. Trematocranus pachychilus is characterised by its thick lips. This species further differs from T. microstoma by its bicuspid (vs. unicuspid) outer oral teeth, wide (vs. small) pharyngeal bone, and its head shape. It resembles T. placodon, from which it can be distinguished by its straight to concave head profile (vs. rounded), less-developed pharyngeal bones (vs. hypertrophied), and the presence of small to minute teeth on the lateral parts of the dentigerous area on the lower pharyngeal bone. A key to the species of Trematocranus is provided.


The genetic diversity of multiple sclerosis risk among Hispanic and African American populations living in the United States.
Substantial progress has been made toward unraveling the genetic architecture of multiple sclerosis (MS) within populations of European ancestry, but few genetic studies have focused on Hispanic and African American populations within the United States. We sought to test the relevance of common European MS risk variants outside of the major histocompatibility complex (n = 200) within these populations. Genotype data were available on 2652 Hispanics (1298 with MS, 1354 controls) and 2435 African Americans (1298 with MS, 1137 controls). We conducted single variant, pathway, and cumulative genetic risk score analyses. We found less replication than statistical power suggested, particularly among African Americans. This could be due to limited correlation between the tested and causal variants within the sample or alternatively could indicate allelic and locus heterogeneity. Differences were observed between pathways enriched among the replicating versus all 200 variants. Although these differences should be examined in larger samples, a potential role exists for gene-environment or gene-gene interactions which alter phenotype differentially across racial and ethnic groups. Cumulative genetic risk scores were associated with MS within each study sample but showed limited diagnostic capability. These findings provide a framework for fine-mapping efforts in multi-ethnic populations of MS.


Acute and subacute effect of rheopheresis on microvascular endothelial function in patients suffering from age-related macular degeneration.
This study was performed on seven patients affected by the atrophic form of age-related macular degeneration (AF-ARMD). The patients under investigation belonged to a larger study aimed at evaluating the efficacy of rheopheresis treatment (RT) on the visual function of AF-ARMD patients. Following the protocol of the larger study, patients received RT twice a week, every two weeks, for a total of ten treatments, as well as high-dose supplementation with zinc and vitamins A, E and beta-carotene. Recruited patients underwent skin laser Doppler flowmetry coupled with skin iontophoresis of the endothelium-dependent vasodilator acetylcholine (ACh) and a test of skin post-ischemic reactive hyperemia, before and after the first RT (time 1: all seven patients) and the fifth RT (time 2: six patients). A significantly higher absolute (anova for repeated measures) and relative (percentage change from the baseline) skin blood flux response (SBFR) to ACh iontophoresis was observed after RT, compared to before RT at time 1 (679 +/- 43% and 436 +/- 78%, respectively; P < 0.05), as well as before RT at time 2 compared to before RT at time 1 (683 +/- 74% and 436 +/- 78%, respectively; P < 0.05). Absolute and relative SBFR to ischemia did not differ either after RT compared to before RT at time 1, or before RT at time 2 compared to before RT at time 1. These findings are consistent with an acute and subacute beneficial effect of RT on skin microvascular endothelial function in the studied AF-ARMD patients.


Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: a meta-analysis.
The epidermal growth factor receptor (EGFR) signaling pathway is crucial for regulating tumorigenesis and cell survival and may be important in the development and progression of non-small cell lung cancer (NSCLC). We examined the impact of EGFR-tyrosine kinase inhibitors (TKIs) on progression-free survival (PFS) and overall survival (OS) in advanced NSCLC patients with and without EGFR mutations. Randomized trials that compared EGFR-TKIs monotherapy or combination EGFR-TKIs-chemotherapy with chemotherapy or placebo were included. We used published hazard ratios (HRs), if available, or derived treatment estimates from other survival data. Pooled estimates of treatment efficacy of EGFR-TKIs for the EGFR mutation-positive (EGFRmut(+)) and EGFR mutation-negative (EGFRmut(-)) subgroups were calculated with the fixed-effects inverse variance weighted method. All statistical tests were two-sided. We included 23 eligible trials (13 front-line, 7 second-line, 3 maintenance; n = 14570). EGFR mutation status was known in 31% of patients. EGFR-TKIs treatment prolonged PFS in EGFRmut(+) patients, and EGFR mutation was predictive of PFS in all settings: The front-line hazard ratio for EGFRmut(+) was 0.43 (95% confidence interval [CI] = 0.38 to 0.49; P < .001), and the front-line hazard ratio for EGFRmut(-) was 1.06 (95% CI = 0.94 to 1.19; P = .35; P interaction < .001). The second-line hazard ratio for EGFRmut(+) was 0.34 (95% CI = 0.20 to 0.60; P < .001), and the second-line hazard ratio for EGFRmut(-) was 1.23 (95% CI = 1.05 to 1.46; P = .01; P interaction < .001). The maintenance hazard ratio for EGFRmut(+) was 0.15 (95% CI = 0.08 to 0.27; P < .001), and the maintenance hazard ratio for EGFRmut(-) was 0.81 (95% CI = 0.68 to 0.97; P = .02; P interaction < .001). EGFR-TKIs treatment had no impact on OS for EGFRmut(+) and EGFRmut(-) patients. EGFR-TKIs therapy statistically significantly delays disease progression in EGFRmut(+) patients but has no demonstrable impact on OS. EGFR mutation is a predictive biomarker of PFS benefit with EGFR-TKIs treatment in all settings. These findings support EGFR mutation assessment before initiation of treatment. EGFR-TKIs should be considered as front-line therapy in EGFRmut(+) advanced NSCLC patients.


Introduction: Stimulate the mitochondria! A Bonington approach to improving assisted reproductive technology outcomes or a call to action?
This introduction reviews the background of mitochondrial transplantation. Its goals are to provide both basic and clinical insights into mitochondria and reproduction. The articles will review the biology of mitochondria, mitochondrial DNA, mitochondrial dynamics, and mitochondrial stress (unfolded protein response), discuss novel imaging technology, fluorescent lifetime imaging microscopy to visualize mitochondria and their function in oocytes and early embryos, provide a critical and objective review of the data suggesting and refuting the possible use of mitochondrial DNA as well as other emerging technologies as a biomarker for embryo viability and finally to review the use of mitochondria as a rejuvenation tool in human in vitro fertilization.


Pulse transmission coefficient: a novel nonhyperemic parameter for assessing the physiological significance of coronary artery stenoses.
We sought to test the hypothesis that the pulse transmission coefficient (PTC) can serve as a nonhyperemic physiologic marker for the severity of coronary artery stenosis in humans. Coronary lesions may impair the transmission of pressure waves across a stenosis, potentially acting as a low-pass filter. The PTC is a novel nonhyperemic parameter that calculates the transmission of high-frequency components of the pressure signal through a stenosis. Thus, it may reflect the severity of the coronary artery stenosis. This study was designed to examine the correlation between PTC and fractional flow reserve (FFR) in patients with coronary artery disease. Pressure signals were obtained by pressure guidewire in 56 lesions (49 patients) in the nonhyperemic state and were analyzed with a new algorithm that identifies the high-frequency components in the pressure signal. The PTC was calculated as the ratio between the distal and proximal high-frequency components of the pressure waveform across the lesion. The FFR measurements were assessed with intracoronary adenosine. There was a significant correlation between PTC and FFR (r = 0.81, p < 0.001). By using a receiver operating characteristic analysis, we identified a PTC < 0.60 (sensitivity 100%, specificity 98%) to be the optimal cutoff value for predicting an FFR < 0.75. Pulse transmission coefficient is a novel nonhyperemic parameter for the physiologic assessment of coronary artery stenoses. It correlates significantly with FFR and may predict an FFR < 0.75 with high accuracy. Pulse transmission coefficient may be useful as an adjunct measurement to FFR, especially in patients with microcirculatory disease and impaired maximal hyperemia.


Tibial plafond fractures. How do these ankles function over time?
The intermediate outcome of fractures of the tibial plafond treated with current techniques has not been reported, to our knowledge. The purpose of this study, performed at a minimum of five years after injury, was to determine the effect of these fractures on ankle function, pain, and general health status and to determine which factors predict favorable and unfavorable outcomes. Fifty-six ankles (fifty-two patients) with a tibial plafond fracture were treated with a uniform technique consisting of application of a monolateral hinged transarticular external fixator coupled with screw fixation of the articular surface. Thirty-one patients with thirty-five involved ankles returned between five and twelve years after the injury for a physical examination, assessment of ankle pain and function with the Iowa Ankle Score and Ankle Osteoarthritis Scale, assessment of general health status with the Short Form-36 (SF-36), and radiographic examination of the ankle. Arthrodesis had been performed on five of the forty ankles for which the outcome was known at a minimum of five years after the injury. Other than removal of prominent screws (two patients), no other surgical procedure had been performed on any patient. The average Iowa Ankle Score was 78 points (range, 28 to 96 points). The scores on the SF-36 and Ankle Osteoarthritis Scale demonstrated a long-term negative effect of the injury on general health and on ankle pain and function when compared with those parameters in age-matched controls. The degree of osteoarthrosis was grade 0 in three ankles, grade 1 in six, grade 2 in twenty, and grade 3 in six. The majority of patients had some limitation with regard to recreational activities, with an inability to run being the most common complaint (twenty-seven of the thirty-one patients). Fourteen patients changed jobs because of the ankle injury. Fifteen ankles were rated by the patient as excellent; ten, as good; seven, as fair; and one, as poor. Nine patients with previously recorded ankle scores had better scores after the longer follow-up interval. The patients perceived that their condition had improved for an average of 2.4 years after the injury. Although tibial plafond fractures have an intermediate-term negative effect on ankle function and pain and on general health, few patients require secondary reconstructive procedures and symptoms tend to decrease for a long time after healing.


Vesicular stomatitis virus-based ebola vaccine is well-tolerated and protects immunocompromised nonhuman primates.
Ebola virus (EBOV) is a significant human pathogen that presents a public health concern as an emerging/re-emerging virus and as a potential biological weapon. Substantial progress has been made over the last decade in developing candidate preventive vaccines that can protect nonhuman primates against EBOV. Among these prospects, a vaccine based on recombinant vesicular stomatitis virus (VSV) is particularly robust, as it can also confer protection when administered as a postexposure treatment. A concern that has been raised regarding the replication-competent VSV vectors that express EBOV glycoproteins is how these vectors would be tolerated by individuals with altered or compromised immune systems such as patients infected with HIV. This is especially important as all EBOV outbreaks to date have occurred in areas of Central and Western Africa with high HIV incidence rates in the population. In order to address this concern, we evaluated the safety of the recombinant VSV vector expressing the Zaire ebolavirus glycoprotein (VSVDeltaG/ZEBOVGP) in six rhesus macaques infected with simian-human immunodeficiency virus (SHIV). All six animals showed no evidence of illness associated with the VSVDeltaG/ZEBOVGP vaccine, suggesting that this vaccine may be safe in immunocompromised populations. While one goal of the study was to evaluate the safety of the candidate vaccine platform, it was also of interest to determine if altered immune status would affect vaccine efficacy. The vaccine protected 4 of 6 SHIV-infected macaques from death following ZEBOV challenge. Evaluation of CD4+ T cells in all animals showed that the animals that succumbed to lethal ZEBOV challenge had the lowest CD4+ counts, suggesting that CD4+ T cells may play a role in mediating protection against ZEBOV.


You can't touch this: touch-free navigation through radiological images.
Keyboards, mice, and touch screens are a potential source of infection or contamination in operating rooms, intensive care units, and autopsy suites. The authors present a low-cost prototype of a system, which allows for touch-free control of a medical image viewer. This touch-free navigation system consists of a computer system (IMac, OS X 10.6 Apple, USA) with a medical image viewer (OsiriX, OsiriX foundation, Switzerland) and a depth camera (Kinect, Microsoft, USA). They implemented software that translates the data delivered by the camera and a voice recognition software into keyboard and mouse commands, which are then passed to OsiriX. In this feasibility study, the authors introduced 10 medical professionals to the system and asked them to re-create 12 images from a CT data set. They evaluated response times and usability of the system compared with standard mouse/keyboard control. Users felt comfortable with the system after approximately 10 minutes. Response time was 120 ms. Users required 1.4 times more time to re-create an image with gesture control. Users with OsiriX experience were significantly faster using the mouse/keyboard and faster than users without prior experience. They rated the system 3.4 out of 5 for ease of use in comparison to the mouse/keyboard. The touch-free, gesture-controlled system performs favorably and removes a potential vector for infection, protecting both patients and staff. Because the camera can be quickly and easily integrated into existing systems, requires no calibration, and is low cost, the barriers to using this technology are low.


Rapid-response systems as a patient safety strategy: a systematic review.
Rapid-response systems (RRSs) are a popular intervention in U.S. hospitals and are supported by accreditors and quality improvement organizations. The purpose of this review is to evaluate the effectiveness and implementation of these systems in acute care settings. A literature search was performed between 1 January 2000 through 30 October 2012 using PubMed, PsycINFO, CINAHL, and the Cochrane Central Register of Controlled Trials. Studies published in any language evaluating outcome changes that occurred after implementing an RRS and differences between groups using and not using an RRS (effectiveness) or describing methods used by RRSs (implementation) were reviewed. A single reviewer (checked by a second reviewer) abstracted data and rated study quality and strength of evidence. Moderate-strength evidence from a high-quality meta-analysis of 18 studies and 26 lower-quality before-and-after studies published after that meta-analysis showed that RRSs are associated with reduced rates of cardiorespiratory arrest outside of the intensive care unit and reduced mortality. Eighteen studies examining facilitators of and barriers to implementation suggested that the rate of use of RRSs could be improved.


Pareto-path multitask multiple kernel learning.
A traditional and intuitively appealing Multitask Multiple Kernel Learning (MT-MKL) method is to optimize the sum (thus, the average) of objective functions with (partially) shared kernel function, which allows information sharing among the tasks. We point out that the obtained solution corresponds to a single point on the Pareto Front (PF) of a multiobjective optimization problem, which considers the concurrent optimization of all task objectives involved in the Multitask Learning (MTL) problem. Motivated by this last observation and arguing that the former approach is heuristic, we propose a novel support vector machine MT-MKL framework that considers an implicitly defined set of conic combinations of task objectives. We show that solving our framework produces solutions along a path on the aforementioned PF and that it subsumes the optimization of the average of objective functions as a special case. Using the algorithms we derived, we demonstrate through a series of experimental results that the framework is capable of achieving a better classification performance, when compared with other similar MTL approaches.


Challenges in defining surgical-site infections following hydrocephalus surgeries.
Multiple organizations track neurosurgical surgical-site infection (SSI) rates, but significant variation exists among reporting criteria. We report our center's experience with the variation in cases captured by 2 major definitions. Standardization could support improvement activities and SSI reduction.


Emergency department screening and intervention for patients with alcohol-related disorders: a pilot study.
Physicians in emergency departments (EDs) treat more patients with alcohol-related disorders than do those in primary care settings. To implement an effective screening, brief intervention, and referral (SBIR) program for use in EDs. Further, to evaluate the impact of the program on alcohol-consumption levels. A prospective cohort pilot study was conducted at a suburban community teaching hospital using a convenience sample of ED patients and an original seven-question screening tool based on well-known guidelines. Subjects screening positive for possible alcohol abuse were given treatment referrals. Follow-up telephone interviews were conducted 6 months later. Of the 1556 enrolled subjects, 251 (16%) were classified as at-risk drinkers. Seventy-nine at-risk subjects (32% [95% CI, 26%-37%]) screened positive on CAGE-based questions (Cut down, Annoyed, Guilty, Eye opener). At follow-up, 20 (25% [95% CI, 16%-35%]) were successfully contacted. Of these 20 subjects, 5 (25%) refused to participate in follow-up screening. For the remaining 15 individuals, follow-up screening indicated that the mean (SD) number of drinks consumed per week decreased from 28 (14) on study enrollment to 10 (10) at 6-month follow-up (P<.001). Maximum number of drinks per occasion decreased from 12 (8) at enrollment to 6 (7) on follow-up (P=.008). Subject scores on the CAGE-based questions decreased from pre- to postintervention, though not significantly, with an average of 2.1 (1) affirmative answers on enrollment and 1.5 (1.4) at follow-up (P=.108). Implementation of an effective SBIR program for alcohol-related disorders can be accomplished in the ED.


An update on adjuvant systemic therapy for elderly patients with early breast cancer.
Elderly women with early breast cancer require an individualized approach to risk assessment and treatment. Unfortunately, there are limited data to inform optimal adjuvant therapy decisions in this population. Cytotoxic chemotherapy, biologic treatments and endocrine agents, while important in reducing breast cancer recurrence and mortality, are associated with the potential for adverse effects that may be of particular significance to elderly patients. In this review, we summarize the evidence for geriatric assessment in elderly patients with early breast cancer, outline special considerations for the use of chemotherapy and trastuzumab in older adults, and describe the age-specific risks of endocrine therapy in the adjuvant breast cancer setting. The treatment of elderly women with early breast cancer should take into account cancer risk, life expectancy, comorbidities, functional status, physiologic changes, and patient values. Formal geriatric assessment may better inform treatment recommendations for individual patients. In general, there is no strong evidence to suggest that older women benefit less from standard adjuvant therapies than do their younger counterparts. When choosing between endocrine therapies, the differential risks associated with each agent should be considered and particular attention to the fracture risk on aromatase inhibitors (AIs) is warranted. Enrolment of women over 70 years of age into breast cancer clinical trials should be encouraged to better inform treatment guidelines.


Mouse models in endocrine tumors.
Endocrine and neuroendocrine tumors comprise a highly heterogeneous group of neoplasms that can arise from (neuro)endocrine cells, either from endocrine glands or from the widespread diffuse neuroendocrine system, and, consequently, are widely distributed throughout the body. Due to their diversity, heterogeneity and limited incidence, studying in detail the molecular and genetic alterations that underlie their development and progression is still a highly elusive task. This, in turn, hinders the discovery of novel therapeutic options for these tumors. To circumvent these limitations, numerous mouse models of endocrine and neuroendocrine tumors have been developed, characterized and used in pre-clinical, co-clinical (implemented in mouse models and patients simultaneously) and post-clinical studies, for they represent powerful and necessary tools in basic and translational tumor biology research. Indeed, different in vivo mouse models, including cell line-based xenografts (CDXs), patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMs), have been used to delineate the development, progression and behavior of human tumors. Results gained with these in vivo models have facilitated the clinical application in patients of diverse breakthrough discoveries made in this field. Herein, we review the generation, characterization and translatability of the most prominent mouse models of endocrine and neuroendocrine tumors reported to date, as well as the most relevant clinical implications obtained for each endocrine and neuroendocrine tumor type.


Phylogenetic relationships of Burmeistera (Campanulaceae: Lobelioideae): Combining whole plastome with targeted loci data in a recent radiation.
The field of molecular systematics has benefited greatly with the advent of high-throughput sequencing (HTS), making large genomic datasets commonplace. However, a large number of targeted Sanger sequences produced by many studies over the last two decades are publicly available and should not be overlooked. In this study, we elucidate the phylogenetic relationships of the plant genus Burmeistera (Campanulaceae: Lobelioideae), while investigating how to best combine targeted Sanger loci with HTS data. We sequence, annotate, and analyze complete to nearly complete plastomes for a subset of the genus. We then combine these data with a much larger taxonomic dataset for which only Sanger sequences are available, making this the most comprehensively sampled study in the genus to date. We show that using a phylogeny inferred from the species with plastome data as a topological constraint for the larger dataset increases the resolution of our data and produces a more robust evolutionary hypothesis for the group. We then use the resulting phylogeny to study the evolution of morphological traits thought to be important in Burmeistera, and assess their usefulness in the current taxonomic classification of the genus. The main morphological character used to delimit subgeneric sections, the presence or absence of hairs on the apex of the two ventral anthers, shows a complex evolutionary history with many changes in the tree, suggesting that this character should not be used for taxonomic classification. Although it is too soon to propose a new subgeneric classification for Burmeistera, our results highlight some morphological traits shared by whole clades that could potentially be used in future taxonomic work.


Increased susceptibility of erythrocyte membrane lipids to peroxidation in sickle cell disease.
Erythrocytes from normal subjects and from cases of sickle cell disease were exposed to hydrogen peroxide and the extent of membrane lipid peroxidation studied. Significantly increased peroxidation was observed in intact erythrocytes, isolated lipids from intact erythrocytes or their ghosts compared with normal controls. However, the extent of lipid peroxidation was less for isolated lipids of intact erythrocytes or their ghosts. This difference may be due to loss of factors enhancing peroxidation in intact erythrocytes in the extraction procedure. It is likely that damage to erythrocyte membranes caused by increased susceptibility to lipid peroxidation may be a factor in some of the haematological features of sickle cell disease.


Increased saliva cortisol awakening response in patients with mild cognitive impairment.
It is unknown whether HPA-axis dysfunction is present in patients with mild cognitive impairment (MCI). The aim of the present study was to investigate whether cortisol levels are elevated among patients with MCI and/or whether the individuals have adequate feedback control of their HPA axis. 27 patients with MCI and 15 healthy controls were included in the study. Saliva samplings were performed 5 times a day before intake of 0.5 mg dexamethasone, and 5 times a day after intake of dexamethasone, respectively. Significantly higher cortisol levels were found 15 min after awakening among patients with MCI in comparison with the controls, both before and after dexamethasone administration (p<0.05). Also, the ratio between cortisol at awakening time and 15 min after awakening was lower in the patient group after dexamethasone administration (p<0.05). There were no significant differences in basal cortisol levels before or after dexamethasone between groups. The results indicate that there is an HPA-axis disturbance, with normal basal cortisol levels and increased awakening response among patients with MCI. The dissociation between basal values and the awakening response may be of pathophysiological importance for the cognitive impairment.


Peripheral blood mononuclear cell membrane fluidity and disease outcome in patients with multiple sclerosis.
Immune cell membrane lipids are important determinants of membrane fluidity, eicosanoid production and phagocytosis and fatty acid metabolic abnormalities have been reported in immune cells from patients with multiple sclerosis. The aim of this study was to investigate the relationship between peripheral blood mononuclear cell membrane fluidity, permeability status, and disease outcome as measured by the Kurtzke expanded disability status scale. Phospholipids, fatty acids and cholesterol composition in peripheral blood mononuclear cells from 26 patients diagnosed with multiple sclerosis and 25 healthy control subjects were determined by colorimetric assay, gas chromatography and enzymatic assays, respectively. Membrane fluidity was calculated according to previously established formulae and correlated with C-reactive protein and the Kurtzke expanded disability status scale. There were no significant differences in membrane lipids in peripheral blood mononuclear cells from patients and controls. However, correlation studies showed lipid metabolic abnormalities, which were reflected in significant correlations between membrane fluidity as measured by both its fatty acid and phospholipid compositions, and the functional system scores. C-reactive protein showed positive correlations with phosphatidylcholine, phosphatidylserine, phosphatidylinositol and total phospholipids in membranes from control subjects. Metabolic abnormalities, as well as correlations between membrane fluidity and the functional system scores, suggested the involvement of these immune cell membranes in the disease progression. Furthermore, the changed relationship between membrane phospholipids and C-reactive protein, which has been shown to correlate with infectious episodes and clinical relapse, could be an indication of immune cell dysfunction in patients with multiple sclerosis.


Effects of immunological sensitization on the responses and sensitivity of guinea pig airways to bronchoconstrictors. Modulation by selective inhibition of arachidonic acid metabolism.
The force generated by tracheal spirals and lung parenchymal strips from normal and ovalbumin-sensitized guinea pigs was measured in vitro, after challenge with histamine, carbachol, leukotriene (LT) C4, LTD4, or a prostaglandin endoperoxide analog (U-44069). The responses and sensitivity of airway tissues to the above agonists were identical in normal and sensitized animals. Treatment of tracheal spirals with indomethacin (8.5 microM), phenidone (185 microM), and nordihydroguaiaretic acid (NDGA: 30 microM) reduced resting tension (tone) equally in both normal and sensitized trachea, but did not affect lung parenchymal strips from either group. The responses of tracheal spirals from normal and sensitized animals to low concentrations of histamine, carbachol, LTC4, and LTD4 were reduced or abolished by treatment with the above inhibitors. Responses to higher concentrations of the same agonists were significantly enhanced. In contrast, treatment of normal and sensitized trachea with indomethacin (2.8 and 8.5 microM) did not abolish or reduce the effects of low concentrations of U-44069. However, an enhancement of the effect of high concentrations occurred only on normal tracheal spirals, even though the control tissues from each group responded identically with U-44069 in the absence of any inhibitor. Parenchymal strips increased in sensitivity to histamine, but not carbachol, as a result of time, vehicle, or prior exposure to the drug. Inhibitor treatment did not affect sensitivity or responsiveness of parenchyma to histamine, carbachol, and U-44069, but the contractile activity of LTD4 on both normal and sensitized lung parenchymal strips was reduced by indomethacin, NDGA, and phenidone. We conclude that ovalbumin sensitization does not induce hyperreactivity of guinea pig airways.


Vaccination can drive an increase in frequencies of antibiotic resistance among nonvaccine serotypes of Streptococcus pneumoniae.
The bacterial pathogen Streptococcus pneumoniae is a major public health concern, being responsible for more than 1.5 million deaths annually through pneumonia, meningitis, and septicemia. Available vaccines target only a subset of serotypes, so vaccination is often accompanied by a rise in the frequency of nonvaccine serotypes. Epidemiological studies suggest that such a change in serotype frequencies is often coupled with an increase of antibiotic resistance among nonvaccine serotypes. Building on previous multilocus models for bacterial pathogen population structure, we have developed a theoretical framework incorporating variation of serotype and antibiotic resistance to examine how their associations may be affected by vaccination. Using this framework, we find that vaccination can result in a rapid increase in the frequency of preexisting resistant variants of nonvaccine serotypes due to the removal of competition from vaccine serotypes.


Treatment of generalized anxiety disorder with citalopram.
Serotonin reuptake inhibitors (SSRI), such as venalafaxine and paroxetine, are used in the treatment of generalized anxiety disorder (GAD). Patients with GAD frequently have comorbid psychiatric disorders, such as depression. SSRIs are effective in the treatment of a variety of anxiety disorders and depression. Citalopram, a newer SSRI used in the treatment of depression, has not been studied for GAD. This is the first report of the use of citalopram, the most selective SSRI, for the treatment of GAD in a retrospective case observation study. Thirteen patients diagnosed with GAD were treated with citalopram at an academic outpatient clinic. The main outcome measures were the Hamilton Rating Scale for Anxiety (HAM-A), Hamilton Depression Rating Scale (HAM-D) and Clinical Global Impressions of Severity (CGI-S; at baseline) and Improvement (CGI-I). The mean age of the patients was 38 years. The mean dose of citalopram at endpoint was 33 mg/day (range 10-60 mg/day). After 12 weeks of treatment with citalopram, all 13 patients experienced full or partial improvement in GAD and depressive symptoms leading to meaningful improvement in social and occupational functioning. Mean baseline HAM-A scores (mean+/-SEM) decreased from 22.2+/-1.3 to 6.2+/-0.9 after citalopram treatment. The mean CGI-I score was 1.8+/-0.2 with 11 of the 13 patients responding (CGI-I of 1 or 2). These data suggest that citalopram may be an effective treatment for GAD. Several patients who had failed previous treatment with other SSRIs responded to citalopram, suggesting that a second SSRI, such as citalopram, may be beneficial in this population. A larger placebo-controlled study of citalopram is warranted in GAD.


Chylous ascites.
Chylous ascites is the accumulation of milky chyle in the peritoneal cavity. Chylous ascites has been reported after surgeries like abdominal aortic aneurysm repair, radical gastrectomy, duodenectomy, nephrectomy and Wilm's tumor resection. Our literature search did not reveal any reports of chylous ascites after a gastric ulcer resection. We report about an elderly woman with a rare complication of chylous ascites after an emergent surgery for a perforated gastric ulcer. A 70-year-old woman developed sudden respiratory distress on 5(th) post-operative day after an elective C3-C7 cervical discectomy and fusion. Her past medical history was significant for cervical spondylosis. The Computed Tomography (CT) scan of the chest revealed air under the diaphragm suspicious for hollow viscus perforation. She underwent an emergent surgery for drainage of hematoma in the neck along with an emergent laparotomy to repair a large perforated gastric ulcer distal to the gastro-esophageal junction. The patient had worsening of abdominal distention on 4(th) post-operative day. The CT scan of abdomen showed fluid collection in the abdomen. The abdominal drain revealed large amount of serous milky fluid at the rate of 1500 ml per day. The fluid analysis showed that the triglyceride level was 170 mg/dl and cholesterol level was 15 mg/dl. The fluid cultures did not grow any organism. She responded to treatment with octreotide and a diet of medium chain triglyceride oil. Any obstruction or damage to the lymphatic channels results in chylous ascites. Lymphomas, metastatic malignancies, and abdominal surgeries commonly cause chylous ascites. Ascitic fluid triglyceride level greater than 110 mg/dl is diagnostic of chylous ascites. Chylous ascites is a rare complication of a peptic ulcer resection which can be managed effectively with octreotide.


Minimal Sign Representation of Boolean Functions: Algorithms and Exact Results for Low Dimensions.
Boolean functions (BFs) are central in many fields of engineering and mathematics, such as cryptography, circuit design, and combinatorics. Moreover, they provide a simple framework for studying neural computation mechanisms of the brain. Many representation schemes for BFs exist to satisfy the needs of the domain they are used in. In neural computation, it is of interest to know how many input lines a neuron would need to represent a given BF. A common BF representation to study this is the so-called polynomial sign representation where [Formula: see text] and 1 are associated with true and false, respectively. The polynomial is treated as a real-valued function and evaluated at its parameters, and the sign of the polynomial is then taken as the function value. The number of input lines for the modeled neuron is exactly the number of terms in the polynomial. This letter investigates the minimum number of terms, that is, the minimum threshold density, that is sufficient to represent a given BF and more generally aims to find the maximum over this quantity for all BFs in a given dimension. With this work, for the first time exact results for four- and five-variable BFs are obtained, and strong bounds for six-variable BFs are derived. In addition, some connections between the sign representation framework and bent functions are derived, which are generally studied for their desirable cryptographic properties.


Has income-related inequity in health care utilization and expenditures been improved? Evidence from the Korean National Health and Nutrition Examination Survey of 2005 and 2010.
The purpose of this study is to examine and explain the extent of income-related inequity in health care utilization and expenditures to compare the extent in 2005 and 2010 in Korea. We employed the concentration indices and the horizontal inequity index proposed by Wagstaff and van Doorslaer based on one- and two-part models. This study was conducted using data from the 2005 and 2010 Korean National Health and Nutrition Examination Survey. We examined health care utilization and expenditures for different types of health care providers, including health centers, physician clinics, hospitals, general hospitals, dental care, and licensed traditional medical practitioners. The results show the equitable distribution of overall health care utilization with pro-poor tendencies and modest pro-rich inequity in the amount of medical expenditures in 2010. For the decomposition analysis, non-need variables such as income, education, private insurance, and occupational status have contributed considerably to pro-rich inequality in health care over the period between 2005 and 2010. We found that health care utilization in Korea in 2010 was fairly equitable, but the poor still have some barriers to accessing primary care and continuing to receive medical care.


Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo.
Plant-derived cannabinoids (phytocannabinoids) are compounds with emerging therapeutic potential. Early studies suggested that cannabidiol (CBD) has anticonvulsant properties in animal models and reduced seizure frequency in limited human trials. Here, we examine the antiepileptiform and antiseizure potential of CBD using in vitro electrophysiology and an in vivo animal seizure model, respectively. CBD (0.01-100 muM) effects were assessed in vitro using the Mg(2+)-free and 4-aminopyridine (4-AP) models of epileptiform activity in hippocampal brain slices via multielectrode array recordings. In the Mg(2+)-free model, CBD decreased epileptiform local field potential (LFP) burst amplitude [in CA1 and dentate gyrus (DG) regions] and burst duration (in all regions) and increased burst frequency (in all regions). In the 4-AP model, CBD decreased LFP burst amplitude (in CA1 only at 100 muM CBD), burst duration (in CA3 and DG), and burst frequency (in all regions). CBD (1, 10, and 100 mg/kg) effects were also examined in vivo using the pentylenetetrazole model of generalized seizures. CBD (100 mg/kg) exerted clear anticonvulsant effects with significant decreases in incidence of severe seizures and mortality compared with vehicle-treated animals. Finally, CBD acted with only low affinity at cannabinoid CB(1) receptors and displayed no agonist activity in [(35)S]guanosine 5'-O-(3-thio)triphosphate assays in cortical membranes. These findings suggest that CBD acts, potentially in a CB(1) receptor-independent manner, to inhibit epileptiform activity in vitro and seizure severity in vivo. Thus, we demonstrate the potential of CBD as a novel antiepileptic drug in the unmet clinical need associated with generalized seizures.


TgSUB2 is a Toxoplasma gondii rhoptry organelle processing proteinase.
All parasites in the phylum Apicomplexa, including Toxoplasma gondii and Plasmodium falciparum, contain rhoptries, specialized secretory organelles whose contents are thought to be essential for successful invasion of host cells. Serine proteinase inhibitors have been reported to block host cell invasion by both T. gondii and P. falciparum. We describe the cloning and characterization of TgSUB2, a subtilisin-like serine proteinase, from T. gondii. Like its closest homologue P. falciparum PfSUB-2, TgSUB2 is predicted to be a type I transmembrane protein. Disruption of TgSUB2 was unsuccessful implying that TgSUB2 is an essential gene. TgSUB2 undergoes autocatalytic processing as it traffics through the secretory pathway. TgSUB2 localizes to rhoptries and associates with rhoptry protein ROP1, a potential substrate. A sequence within TgSUB2 with homology to the ROP1 cleavage site (after Glu) was identified and mutated by site-directed mutagenesis. This mutation abolished TgSUB2 autoprocessing suggesting that TgSUB2 is a rhoptry protein maturase with similar specificity to the ROP1 maturase. Processing of secretory organelle contents appears to be ubiquitous among the Apicomplexa. As subtilases are present in genomes of all the Apicomplexa sequenced to date, subtilases may represent a novel chemotherapeutic target.


Sex-specific gray matter volume differences in females with developmental dyslexia.
Developmental dyslexia, characterized by unexpected reading difficulty, is associated with anomalous brain anatomy and function. Previous structural neuroimaging studies have converged in reports of less gray matter volume (GMV) in dyslexics within left hemisphere regions known to subserve language. Due to the higher prevalence of dyslexia in males, these studies are heavily weighted towards males, raising the question whether studies of dyslexia in females only and using the same techniques, would generate the same findings. In a replication study of men, we obtained the same findings of less GMV in dyslexics in left middle/inferior temporal gyri and right postcentral/supramarginal gyri as reported in the literature. However, comparisons in women with and without dyslexia did not yield left hemisphere differences, and instead, we found less GMV in right precuneus and paracentral lobule/medial frontal gyrus. In boys, we found less GMV in left inferior parietal cortex (supramarginal/angular gyri), again consistent with previous work, while in girls differences were within right central sulcus, spanning adjacent gyri, and left primary visual cortex. Our investigation into anatomical variants in dyslexia replicates existing studies in males, but at the same time shows that dyslexia in females is not characterized by involvement of left hemisphere language regions but rather early sensory and motor cortices (i.e., motor and premotor cortex, primary visual cortex). Our findings suggest that models on the brain basis of dyslexia, primarily developed through the study of males, may not be appropriate for females and suggest a need for more sex-specific investigations into dyslexia.


The BET inhibitor CPI203 promotes ex vivo expansion of cord blood long-term repopulating HSCs and megakaryocytes.
Although cytokine-mediated expansion of human hematopoietic stem cells (HSCs) can result in high yields of hematopoietic progenitor cells, this generally occurs at the expense of reduced bone marrow HSC repopulating ability, thereby limiting potential therapeutic applications. Because bromodomain-containing proteins (BCPs) have been demonstrated to regulate mouse HSC self-renewal and stemness, we screened small molecules targeting various BCPs as potential agents for ex vivo expansion of human HSCs. Of 10 compounds tested, only the bromodomain and extra-terminal motif inhibitor CPI203 enhanced the expansion of human cord blood HSCs without losing cell viability in vitro. The expanded cells also demonstrated improved engraftment and repopulation in serial transplantation assays. Transcriptomic and functional studies showed that the expansion of long-term repopulating HSCs was accompanied by synchronized expansion and maturation of megakaryocytes consistent with CPI203-mediated reprogramming of cord blood hematopoietic stem and progenitor cells. This approach may therefore prove beneficial for ex vivo gene editing, for enhanced platelet production, and for the improved usage of cord blood for transplantation research and therapy.


Cost-Utility Analysis of Geriatric Assessment and Management in Older Adults With Cancer: Economic Evaluation Within 5C Trial.
Geriatric assessment (GA) is a guideline-recommended approach to optimize cancer management in older adults. We conducted a cost-utility analysis alongside the 5C randomized controlled trial to compare GA and management (GAM) plus usual care (UC) against UC alone in older adults with cancer. The economic evaluation, conducted from societal and health care payer perspectives, used a 12-month time horizon. The Canadian 5C study randomly assigned patients to receive GAM or UC. Quality-adjusted life-years (QALYs) were measured using the EuroQol five dimension-5L questionnaire and health care utilization using cost diaries and chart reviews. We evaluated the incremental net monetary benefit (INMB) for the full sample and preselected subgroups. A total of 350 patients were included, of whom 173 received GAM and 177 UC. At 12 months, the average QALYs per patient were 0.728 and 0.751 for GAM and UC, respectively (ΔQALY, -0.023 [95% CI, -0.076 to 0.028]). Considering a societal perspective, the total average costs (in 2021 Canadian dollars) per patient were $46,739 and $45,177 for GAM and UC, respectively (ΔCost, $1,563 [95% CI, -$6,583 to $10,403]). At a cost-effectiveness threshold of $50,000/QALY, GAM was not cost-effective compared with UC (INMB, -$2,713 [95% CI, -$11,767 to $5,801]). The INMB was positive ($2,984 [95% CI, -$7,050 to $14,179]; probability of being cost-effective, 72%) for patients treated with curative intent, but remained negative for patients treated with palliative intent (INMB, -$9,909 [95% CI, -$24,436 to $4,153]). Findings were similar considering a health care payer perspective. To our knowledge, this is the first cost-utility analysis of GAM in cancer. GAM was cost-effective for patients with cancer treated with curative but not with palliative intent. The study provides further considerations for future adoption of GAM in practice.


Gambling: Electronic friends or a threat to one's health and personal development?
Gambling has become quite common in Sweden. The Swedish National Institute of Public Health (2010) has reported that about 70% of the Swedish population has gambled at least once during the last 12 months. Half of the population had gambled with money by 18 years of age and about 11% had gambled for the first time when they were 12-years-old or younger. In the report from the Swedish National Institute of Public Health, gambling problems are related to health problems and risky alcohol consumption. The highest problem rate is found among men aged 18 to 24; almost 1 in 10 had some gambling problems. The share of problem gamblers is found to be twice as high among the under-age gamblers as it is among the population as a whole. Young people gamble less but develop gambling problems to a larger extent than adult gamblers. In this article young people's gambling and their gambling careers are analysed as a natural part of their internalisation of other adult habits.


Impact of Astrocyte Depletion upon Inflammation and Demyelination in a Murine Animal Model of Multiple Sclerosis.
Astrocytes play a key role in demyelinating diseases, like multiple sclerosis (MS), although many of their functions remain unknown. The aim of this study was to investigate the impact of astrocyte depletion upon de- and remyelination, inflammation, axonal damage, and virus distribution in Theiler`s murine encephalomyelitis (TME). Groups of two to six glial fibrillary acidic protein (GFAP)-thymidine-kinase transgenic SJL mice and SJL wildtype mice were infected with TME virus (TMEV) or mock (vehicle only). Astrocyte depletion was induced by the intraperitoneal administration of ganciclovir during the early and late phase of TME. The animals were clinically investigated while using a scoring system and a rotarod performance test. Necropsies were performed at 46 and 77 days post infection. Cervical and thoracic spinal cord segments were investigated using hematoxylin and eosin (H&E), luxol fast blue-cresyl violet (LFB), immunohistochemistry targeting Amigo2, aquaporin 4, CD3, CD34, GFAP, ionized calcium-binding adapter molecule 1 (Iba1), myelin basic protein (MBP), non-phosphorylated neurofilaments (np-NF), periaxin, S100A10, TMEV, and immunoelectron microscopy. The astrocyte depleted mice showed a deterioration of clinical signs, a downregulation and disorganization of aquaporin 4 in perivascular astrocytes accompanied by vascular leakage. Furthermore, astrocyte depleted mice showed reduced inflammation and lower numbers of TMEV positive cells in the spinal cord. The present study indicates that astrocyte depletion in virus triggered CNS diseases contributes to a deterioration of clinical signs that are mediated by a dysfunction of perivascular astrocytes.


Challenge of pigs with classical swine fever viruses after C-strain vaccination reveals remarkably rapid protection and insights into early immunity.
Pre-emptive culling is becoming increasingly questioned as a means of controlling animal diseases, including classical swine fever (CSF). This has prompted discussions on the use of emergency vaccination to control future CSF outbreaks in domestic pigs. Despite a long history of safe use in endemic areas, there is a paucity of data on aspects important to emergency strategies, such as how rapidly CSFV vaccines would protect against transmission, and if this protection is equivalent for all viral genotypes, including highly divergent genotype 3 strains. To evaluate these questions, pigs were vaccinated with the Riemser® C-strain vaccine at 1, 3 and 5 days prior to challenge with genotype 2.1 and 3.3 challenge strains. The vaccine provided equivalent protection against clinical disease caused by for the two challenge strains and, as expected, protection was complete at 5 days post-vaccination. Substantial protection was achieved after 3 days, which was sufficient to prevent transmission of the 3.3 strain to animals in direct contact. Even by one day post-vaccination approximately half the animals were partially protected, and were able to control the infection, indicating that a reduction of the infectious potential is achieved very rapidly after vaccination. There was a close temporal correlation between T cell IFN-γ responses and protection. Interestingly, compared to responses of animals challenged 5 days after vaccination, challenge of animals 3 or 1 days post-vaccination resulted in impaired vaccine-induced T cell responses. This, together with the failure to detect a T cell IFN-γ response in unprotected and unvaccinated animals, indicates that virulent CSFV can inhibit the potent antiviral host defences primed by C-strain in the early period post vaccination.


Abnormalities in CNS monoamine metabolism in anorexia nervosa.
Patients with anorexia nervosa have disturbances of mood, appetite, and neuroendocrine function. Central nervous system monoamine pathways modulate these systems, and alterations in function of these systems may occur in anorexia nervosa. Because monoamine metabolism can be influenced by nutritional intake, we studied anorectics before and at intervals after correction of weight loss. Underweight anorectics had a 30% decrease in CSF homovanillic acid level and a 20% decrease in CSF 5-hydroxyindoleacetic acid concentration; these values returned to normal shortly after weight recovery. The CSF level of norepinephrine (NE) in underweight anorectics and in these patients a few weeks after weight restoration was similar to that in normal subjects. Long-term weight-recovered (20 +/- 7 months) anorectics, however, had a 50% decrease in CSF NE level compared with that of controls. Underweight anorectics have state-associated disturbances in dopamine and serotonin metabolism. Changes in NE metabolism are more complex and state independent. These abnormalities in neurotransmitter metabolism are part of the neurobiological syndrome of anorexia nervosa and may contribute to the characteristic changes in mood, behavior, and neuroendocrine function.


Cause-specific inequalities in mortality in Scotland: two decades of change. A population-based study.
Socioeconomic inequalities in mortality have increased in recent years in many countries. We examined age-, sex-, and cause-specific mortality rates for social groups in and regions of Scotland to understand the patterning of inequalities and the causes contributing to these inequalities. We used death records for 1980-82, 1991-92 and 2000-02 together with mid-year population estimates for 1981, 1991 and 2001 covering the whole of Scotland to calculate directly standardised mortality rates. Deaths and populations were coded to small areas (postcode sectors and data zones), and deprivation was assessed using area based measures (Carstairs scores and the Scottish Index of Multiple Deprivation). We measured inequalities using rate ratios and the Slope Index of Inequality (SII). Substantial overall decreases in mortality rates disguised increases for men aged 15-44 and little change for women at the same ages. The pattern at these ages was mostly attributable to increases in suicides and deaths related to the use of alcohol and drugs. Under 65 a 49% fall in the mortality of men in the least deprived areas contrasted with a fall of just 2% in the most deprived. There were substantial increases in the social gradients for most causes of death. Excess male mortality in the Clydeside region was largely confined to more deprived areas, whilst for women in the region mortality was in line with the Scottish experience. Relative inequalities for men and women were greatest between the ages of 30 and 49. General reductions in mortality in the major causes of death (ischaemic heart disease, malignant neoplasms) are encouraging; however, such reductions were socially patterned. Relative inequalities in mortality have increased and are greatest among younger adults where deaths related to unfavourable lifestyles call for direct social policies to address poverty.


Evidence that a Ca2+ sparks/STOCs coupling mechanism is responsible for the inhibitory effect of caffeine on electro-mechanical coupling in guinea pig ureteric smooth muscle.
Recent studies have highlighted the role of the sarcoplasmic reticulum (SR) in controlling excitability, Ca2+ signalling and contractility in smooth muscle. Caffeine, an agonist of ryanodine receptors (RyRs) on the SR has been previously shown to effect Ca2+ signalling but its effects on excitability and contractility are not so clear. We have studied the effects of low concentration of caffeine (1 mM) on Ca2+ signalling, action potential and contractility of guinea pig ureteric smooth muscle. Caffeine produced reversible inhibition of the action potentials, Ca2+ transients and phasic contractions evoked by electrical stimulation. It had no effect on the inward Ca2+ current or Ca2+ transient but increased the amplitude and the frequency of spontaneous transient outward currents (STOCs) in voltage clamped ureteric myocytes, suggesting Ca2+-activated K+ channels (BK) are affected by it. In isolated cells and cells in situ caffeine produced an increase in the frequency and the amplitude of Ca2+ sparks as well the number of spark discharging sites per cell. Inhibition of Ca2+ sparks by ryanodine (50 microM) or SR Ca2+-ATPase (SERCA) cyclopiazonic acid (CPA, 20 microM) or BKCa channels by iberiotoxin (200 nM) or TEA (1 mM), fully reversed the inhibitory effect of caffeine on Ca2+ transients and force evoked by electrical field stimulation (EFS). These data suggest that the inhibitory effect of caffeine on the action potential, Ca2+ transients and force in ureteric smooth muscle is caused by activation of Ca2+ sparks/STOCs coupling mechanism.


Family-centred interventions for Indigenous early childhood well-being by primary healthcare services.
Primary healthcare, particularly Indigenous-led services, are well placed to deliver services that reflect the needs of Indigenous children and their families. Important characteristics identified by families for primary health care include services that support families, accommodate sociocultural needs, recognise extended family child-rearing practices, and Indigenous ways of knowing and doing business. Indigenous family-centred care interventions have been developed and implemented within primary healthcare services to plan, implement, and support the care of children, immediate and extended family and the home environment. The delivery of family-centred interventions can be through environmental, communication, educational, counselling, and family support approaches. To evaluate the benefits and harms of family-centred interventions delivered by primary healthcare services in Canada, Australia, New Zealand, and the USA on a range of physical, psychosocial, and behavioural outcomes of Indigenous children (aged from conception to less than five years), parents, and families. We used standard, extensive Cochrane search methods. The latest search date was 22 September 2021. We included randomised controlled trials (RCTs), cluster RCTs, quasi-RCTs, controlled before-after studies, and interrupted time series of family-centred care interventions that included Indigenous children aged less than five years from Canada, Australia, New Zealand, and the USA. Interventions were included if they met the assessment criteria for family-centred interventions and were delivered in primary health care. Comparison interventions could include usual maternal and child health care or one form of family-centred intervention versus another. We used standard Cochrane methods. Our primary outcomes were 1. overall health and well-being, 2. psychological health and emotional behaviour of children, 3. physical health and developmental health outcomes of children, 4. family health-enhancing lifestyle or behaviour outcomes, 5. psychological health of parent/carer. 6. adverse events or harms. Our secondary outcomes were 7. parenting knowledge and awareness, 8. family evaluation of care, 9. service access and utilisation, 10. family-centredness of consultation processes, and 11. economic costs and outcomes associated with the interventions. We used GRADE to assess the certainty of the evidence for our primary outcomes. We included nine RCTs and two cluster-RCTs that investigated the effect of family-centred care interventions delivered by primary healthcare services for Indigenous early child well-being. There were 1270 mother-child dyads and 1924 children aged less than five years recruited. Seven studies were from the USA, two from New Zealand, one from Canada, and one delivered in both Australia and New Zealand. The focus of interventions varied and included three studies focused on early childhood caries; three on childhood obesity; two on child behavioural problems; and one each on negative parenting patterns, child acute respiratory illness, and sudden unexpected death in infancy. Family-centred education was the most common type of intervention delivered. Three studies compared family-centred care to usual care and seven studies provided some 'minimal' intervention to families such as education in the form of pamphlets or newsletters. One study provided a minimal intervention during the child's first 24 months and then the family-centred care intervention for one year. No studies had low or unclear risk of bias across all domains. All studies had a high risk of bias for the blinding of participants and personnel domain. Family-centred care may improve overall health and well-being of Indigenous children and their families, but the evidence was very uncertain. The pooled effect estimate from 11 studies suggests that family-centred care improved the overall health and well-being of Indigenous children and their families compared no family-centred care (standardised mean difference (SMD) 0.14, 95% confidence interval (CI) 0.03 to 0.24; 2386 participants). We are very uncertain whether family-centred care compared to no family-centred care improves the psychological health and emotional behaviour of children as measured by the Infant Toddler Social Emotional Assessment (ITSEA) (Competence domain) (mean difference (MD) 0.04, 95% CI -0.03 to 0.11; 2 studies, 384 participants). We assessed the evidence as being very uncertain about the effect of family-centred care on physical health and developmental health outcomes of children. Pooled data from eight trials on physical health and developmental outcomes found there was little to no difference between the intervention and the control groups (SMD 0.13, 95% CI -0.00 to 0.26; 1961 participants). The evidence is also very unclear whether family-centred care improved family-enhancing lifestyle and behaviours outcomes. Nine studies measured family health-enhancing lifestyle and behaviours and pooled analysis found there was little to no difference between groups (SMD 0.16, 95% CI -0.06 to 0.39; 1969 participants; very low-certainty evidence). There was very low-certainty evidence of little to no difference for the psychological health of parents and carers when they participated in family-centred care compared to any control group (SMD 0.10, 95% CI -0.03 to 0.22; 5 studies, 975 parents/carers). Two studies stated that there were no adverse events as a result of the intervention. No additional data were provided. No studies reported from the health service providers perspective or on outcomes for family's evaluation of care or family-centredness of consultation processes. There is some evidence to suggest that family-centred care delivered by primary healthcare services improves the overall health and well-being of Indigenous children, parents, and families. However, due to lack of data, there was not enough evidence to determine whether specific outcomes such as child health and development improved as a result of family-centred interventions. Seven of the 11 studies delivered family-centred education interventions. Seven studies were from the USA and centred on two particular trials, the 'Healthy Children, Strong Families' and 'Family Spirit' trials. As the evidence is very low certainty for all outcomes, further high-quality trials are needed to provide robust evidence for the use of family-centred care interventions for Indigenous children aged less than five years.


Two PKC consensus sites on human acid-sensing ion channel 1b differentially regulate its function.
Human acid-sensing ion channel 1b (hASIC1b) is a H(+)-gated amiloride-sensitive cation channel. We have previously shown that glioma cells exhibit an amiloride-sensitive cation conductance. Amiloride and the ASIC1 blocker psalmotoxin-1 decrease the migration and proliferation of glioma cells. PKC also abolishes the amiloride-sensitive conductance of glioma cells and inhibits hASIC1b open probability in planar lipid bilayers. In addition, hASIC1b's COOH terminus has been shown to interact with protein interacting with C kinase (PICK)1, which targets PKC to the plasma membrane. Therefore, we tested the hypothesis that PKC regulation of hASIC1b at specific PKC consensus sites inhibits hASIC1b function. We mutated three consensus PKC phosphorylation sites (T26, S40, and S499) in hASIC1b to alanine, to prevent phosphorylation, and to glutamic acid or aspartic acid, to mimic phosphorylation. Our data suggest that S40 and S499 are critical sites mediating the modulation of hASIC1b by PKC. We expressed mutant hASIC1b constructs in Xenopus oocytes and measured acid-activated currents by two-electrode voltage clamp. T26A and T26E did not exhibit acid-activated currents. S40A was indistinguishable from wild type (WT), whereas S40E, S499A, and S499D currents were decreased. The PKC activators PMA and phorbol 12,13-dibutyrate inhibited WT hASIC1b and S499A, and PMA had no effect on S40A or on WT hASIC1b in oocytes pretreated with the PKC inhibitor chelerythrine. Chelerythrine inhibited WT hASIC1b and S40A but had no effect on S499A or S40A/S499A. PKC activators or the inhibitor did not affect the surface expression of WT hASIC1b. These data show that the two PKC consensus sites S40 and S499 differentially regulate hASIC1b and mediate the effects of PKC activation or PKC inhibition on hASIC1b. This will result in a deeper understanding of PKC regulation of this channel in glioma cells, information that may help in designing potentially beneficial therapies in their treatment.


Trends in cigarette smoking and physicians' advice to quit smoking among people with diabetes in the U.S.
This study describes changes in the distribution of cigarette smoking and in physicians' advice to quit smoking among the U.S. population with and without diabetes from the mid-1970s to 1990. Data on self-reported smoking status, physicians' advice to quit smoking, history of diabetes, and demographic characteristics were obtained from the 1974, 1985, and 1990 National Health Interview Surveys. We examined the age-adjusted prevalence of smoking and physicians' advice to quit smoking by race, sex, and educational level among individuals with diabetes and those without diabetes. The prevalence of smoking decreased 9.8 percentage points from 1974 to 1990 among individuals with diabetes (from 35.6 to 25.8%, P < 0.01) and 11.7 percentage points among those without diabetes (from 37.3 to 25.6%, P < 0.01). For all years, younger individuals, men, and people with less than a high school education were more likely to smoke, regardless of diabetes status. Among individuals who had ever smoked, those with diabetes were more likely to have received advice to quit than those without diabetes; from 1974 to 1990, the percentage advised to quit smoking by a physician increased from 35.1 to 58.4% for smokers with diabetes and from 26.8 to 46.0% for smokers without diabetes. Despite decreases in smoking prevalence over time, people with diabetes are still as likely to smoke as those without diabetes. More than 40% of smokers with diabetes currently report never having received advice from a physician to quit smoking. Health care providers should increase their efforts to reduce smoking among people with diabetes.


Effects of inter- and intra-aggregate magnetic dipolar interactions on the magnetic heating efficiency of iron oxide nanoparticles.
Iron oxide nanoparticles have found an increasing number of biomedical applications as sensing or trapping platforms and therapeutic and/or diagnostic agents. Most of these applications are based on their magnetic properties, which may vary depending on the nanoparticle aggregation state and/or concentration. In this work, we assess the effect of the inter- and intra-aggregate magnetic dipolar interactions on the heat dissipation power and AC hysteresis loops upon increasing the nanoparticle concentration and the hydrodynamic aggregate size. We observe different effects produced by inter- (long distance) and intra-aggregate (short distance) interactions, resulting in magnetizing and demagnetizing effects, respectively. Consequently, the heat dissipation power under alternating magnetic fields strongly reflects such different interacting phenomena. The intra-aggregate interaction results were successfully modeled by numerical simulations. A better understanding of magnetic dipolar interactions is mandatory for achieving a reliable magnetic hyperthermia response when nanoparticles are located into biological matrices.


Measurement of viscosity of lyotropic liquid crystals by means of rotating laser-trapped microparticles.
We describe a simple microrheology method to measure the viscosity coefficients of lyotropic liquid crystals. This approach is based on the use of a rotating laser-trapped optically anisotropic microsphere. In aligned liquid crystals that have negligible effect on trapping beam's polarization, the optical torque is transferred from circularly polarized laser trapping beam to the optically anisotropic microparticle and creates the shear flow in the liquid crystalline fluid. The balance of optical and viscous torques yields the local effective viscosity coefficients of the studied lyotropic systems in cholesteric and lamellar phases. This simple yet powerful method is capable of probing viscosity of complex anisotropic fluids for small amounts of sample and even in the presence of defects that obstruct the use of conventional rheology techniques.


Functionalized magnetic nanoparticles: Synthesis, characterization, catalytic application and assessment of toxicity.
Cost-effective water cleaning approaches using improved treatment technologies, for instance based on catalytic processes with high activity catalysts, are urgently needed. The aim of our study was to synthesize efficient Fenton-like photo-catalysts for rapid degradation of persistent organic micropollutants in aqueous medium. Iron-based nanomaterials were chemically synthesized through simple procedures by immobilization of either iron(II) oxalate (FeO) or iron(III) citrate (FeC) on magnetite (M) nanoparticles stabilized with polyethylene glycol (PEG). Various investigation techniques were performed in order to characterize the freshly prepared catalysts. By applying advanced oxidation processes, the effect of catalyst dosage, hydrogen peroxide concentration and UV-A light exposure were examined for Bisphenol A (BPA) conversion, at laboratory scale, in mild conditions. The obtained results revealed that BPA degradation was rapidly enhanced in the presence of low-concentration H2O2, as well as under UV-A light, and is highly dependent on the surface characteristics of the catalyst. Complete photo-degradation of BPA was achieved over the M/PEG/FeO catalyst in less than 15 minutes. Based on the catalytic performance, a hierarchy of the tested catalysts was established: M/PEG/FeO > M/PEG/FeC > M/PEG. The results of cytotoxicity assay using MCF-7 cells indicated that the aqueous samples after treatment are less cytotoxic.


Bedside nurses' perceptions of intensive care unit telemedicine.
Intensive care unit telemedicine is an innovative approach to providing critical care services for a broad geographic area, but its success may depend on acceptance by bedside providers. To determine critical care nurses' attitudes toward and perceptions about the use of telemedicine in critical care. A total of 179 nurses in 3 critical care units in 2 university-affiliated academic hospitals that use telemedicine intensivists and nurses were surveyed via the Internet about their practice and perceptions of telemedicine. Among the 93 respondents (response rate, 52%), 72 worked at least 1 night shift and therefore had experience with the telemedicine unit. Reported contact with the telemedicine unit was relatively infrequent: 31% reported being called by the unit 3 or more times in the preceding 6 months. A total of 44% reported regularly incorporating interventions suggested by the telemedicine staff. A majority (72%) thought that telemedicine increases patients' survival, but fewer thought that telemedicine prevents medical errors (47%) or improves the satisfaction of patients' families (42%). Some respondents thought that telemedicine interrupted work flow (9%), was intrusive (11%), or resulted in a feeling of being spied upon (13%). Most nurses thought that personally knowing the telemedicine physician was important (79%), and nurses were more likely to contact the telemedicine unit if they knew the physician on call (61%). Practicing bedside nurses with experience in telemedicine generally support its use, but concerns about privacy issues and the desire to personally know the telemedicine physician may hinder broader application of the technology.


Digital vs 35-mm photography. To convert or not to convert?
To compare the quality of images generated from a conventional 35-mm camera with those generated from various digital cameras; and to note the costs of the cameras and ease of use. A prospective, randomised, independent analysis of specific facial images taken with a 35-mm camera and 3 digital cameras by 3 facial plastic surgeons who were blinded to camera type. An academic medical center. Thirteen volunteer subjects ranging from age 27 to 58 years. The overall quality, focus, distortion, trueness of color, resolution, contrast, and presence of shadows were evaluated for each image. Attributes were scored on an ordinal scale of 1 to 5. A 1-way analysis of variance was used to test whether the average scores across cameras were significantly different. Results using analysis of variance did not differ from the results using a nonparametric Kruskal-Wallis test. When significant differences were found, the Duncan multiple range test was used to group significantly different scores. The null hypothesis that there is no difference between photographs taken with the various cameras was rejected (P < .001) for each of the image attributes. The images produced by the 35-mm camera (Nikon 6006) had the best overall quality, followed by the Olympus D600L, Kodak DCS 315, and Olympus D320L digital cameras. Differences in individual attributes between several of the cameras in each category were statistically significant (P < .05). The 35-mm camera produced the best overall image quality and ranked first for each of the individual attributes analyzed in this study. The Olympus D600L digital camera placed second in overall quality, but there was no statistically significant difference in focus, distortion, and resolution compared with the images generated by the 35-mm camera. The Olympus D600L digital camera also ranked second in color, contrast, and shadow. The Kodak DCS 315 and D320L digital cameras finished well behind the 35-mm camera in most categories. Although the 35-mm photographs were superior to the digital images, the surgeon should also consider other factors before selecting a system for photodocumentation of surgical results.


Pathways of ion movement in the canine tracheal epithelium.
The pathways of ion movement across canine tracheal epithelium, a Cl-secreting tissue, were examined by three techniques. First, the measurement of simultaneous, unidirectional fluxes of Na or Cl and mannitol, a large hydrophilic molecule that serves as a marker of the paracellular pathway, indicated that a significant fraction of both the Na flux from submucosa to mucosa (J Na sm) and the flux of Cl from mucosa to submucosa (J Cl ms) traverse the cellular pathway. The ratio of the Na-to-Cl diffusion coefficients through the paracellular pathway was 0.23, in contrast to the free solution ratio of 0.63. Second, in voltage-clamp experiments we examined the effect of transepithelial voltage differences on the unidirectional fluxes of Na and Cl. The results agree with the previous findings, suggesting that there are voltage-independent, or transcellular, backfluxes of Na and Cl, and that the relative permeability of Na to Cl through the voltage-dependent (presumably paracellular) pathway was 0.28. Third, measurement of transepithelial diffusion potentials gave a Na-to-Cl permeability ratio of 0.31 +/- 0.02 (mean +/- SE). These results suggest that there are significant transcellular backfluxes of Na and Cl and that the paracellular pathway in the canine trachea is anion selective. An anion-selective pathway would tend to shunt the secreted Cl back through the paracellular pathway, thus minimizing the net ion and fluid movement across the tissue in the open-circuit condition.


Thermal Analyses of Nanowarming-Assisted Recovery of the Heart From Cryopreservation by Vitrification.
This study explores thermal design aspects of nanowarming-assisted recovery of the heart from indefinite cryogenic storage, where nanowarming is the volumetric heating effect of ferromagnetic nanoparticles excited by a radio frequency electromagnet field. This study uses computational means while focusing on the human heart and the rat heart models. The underlying nanoparticle loading characteristics are adapted from a recent, proof-of-concept experimental study. While uniformly distributed nanoparticles can lead to uniform rewarming, and thereby minimize adverse effects associated with ice crystallization and thermomechanical stress, the combined effects of heart anatomy and nanoparticle loading limitations present practical challenges which this study comes to address. Results of this study demonstrate that under such combined effects, nonuniform nanoparticles warming may lead to a subcritical rewarming rate in some parts of the domain, excessive heating in others, and increased exposure potential to cryoprotective agents (CPAs) toxicity. Nonetheless, the results of this study also demonstrate that computerized planning of the cryopreservation protocol and container design can help mitigate the associated adverse effects, with examples relating to adjusting the CPA and/or nanoparticle concentration, and selecting heart container geometry, and size. In conclusion, nanowarming may provide superior conditions for organ recovery from cryogenic storage under carefully selected conditions, which comes with an elevated complexity of protocol planning and optimization.


The onset site of rheumatoid arthritis: the joints or the lung?
The etiopathogenesis of rheumatoid arthritis (RA) is not yet fully elucidated and the site of inflammation onset is still a matter of debate. The presence of autoantibodies as well as clinical manifestations, such as interstitial lung disease, before the onset of arthritis seems to be in favour of the hypothesis that initial pathogenic events take place in tissues other than the joint. In this review article we summarize the most recent literature on extra-synovial autoimmunity triggers eventually leading to RA, with particular focus on the role of the lung. To date, anti-cyclic citrullinated peptide antibodies (ACPAs) are considered central players in RA pathogenesis and represent the gold-standard for disease diagnosis. Lungs and mucosae are exposed to environmental stimuli such as dusts and smoke which have been shown to foster citrullination of peptides in lungs thereby triggering the production of ACPA. In addition, other mechanisms of disease pathogenesis independent of citrullination play an important role. Deeper knowledge of these processes could represent a huge step forward in the management of RA, with dramatic impact on diagnosis, prevention, prognostic stratification and treatment of the disease.


Selection and development of preclinical models in fracture-healing research.
Animal fracture models have been extensively applied to preclinical research as a platform to identify and characterize normal and abnormal physiological processes and to develop specific maneuvers that alter the biology and biomechanics being examined. The choice of animal model employed in a study bears a direct relationship to the specific intervention being analyzed. The animal models employed should be described clearly, control-group data should be established, and reproducibility should be defined from experiment to experiment and from institution to institution so that quantitative and qualitative outcomes can be reliably compared and contrasted to other related studies.