Cervical cancer screening in Bali: a public health issue.
Cervical cancer is the most common cancer in women in developing countries. Regarding cervical cancer in Bali, we sought to determine the incidence, to evaluate existing preventive and screening programs, to identify the population being screened, and to examine the methods of testing. The records of the Udayana Teaching Hospital pathology laboratory and Cancer Registry were reviewed, retrospectively. The incidence of cervical cancer in Bali is 7/100,000. There has already been a substantial increase in the number of Papanicolaou tests (PT) from 767 in 1990 to 1,355 in 1992. In 63% of these tests the results were Class II, indicating a need for attention to infection. Cervical intraepithelial neoplasia has a statistically significant increase with age. The number of PT performed peaks in the 35-44 year age group, with a sharp decline thereafter. Fifty-four percent of PT are performed in the capital city, which has only 20% of the female population. Bali Hindu women make up 94% of the female population, but receive only 81% of PT, while Muslim women make up 5% of the population and receive 12% of PT. Seventy-eight percent of PT contain no endocervical cells. There has already been a promising increase in the number of PT performed in Bali. Public health promotion efforts as well as outreach programs should be expanded, perhaps using the Banjar system, to reach older and rural women. Collectors of Pap smears should be instructed on the importance of endocervical sampling.


Substrate Positioning Dynamics Involves a Non-Electrostatic Component to Mediate Catalysis.
Substrate positioning dynamics (SPD) orients the substrate in the active site, thereby influencing catalytic efficiency. However, it remains unknown whether SPD effects originate primarily from electrostatic perturbation inside the enzyme or can independently mediate catalysis with a significant non-electrostatic component. In this work, we investigated how the non-electrostatic component of SPD affects transition state (TS) stabilization. Using high-throughput enzyme modeling, we selected Kemp eliminase variants with similar electrostatics inside the enzyme but significantly different SPD. The kinetic parameters of these mutants were experimentally characterized. We observed a valley-shaped, two-segment linear correlation between the TS stabilization free energy (converted from kinetic parameters) and substrate positioning index (a metric to quantify SPD). The energy varies by approximately 2 kcal/mol. Favorable SPD was observed for the distal mutant R154W, increasing the proportion of reactive conformations and leading to the lowest activation free energy. These results indicate the substantial contribution of the non-electrostatic component of SPD to enzyme catalytic efficiency.


Retinal venous sheathing and neovascularization in disseminated sclerosis.
A 54-year-old black woman with no significant visual complaint and a diagnosis of disseminated sclerosis of 18 years' duration is presented because of marked bilateral sheathing of the retinal veins, and previously unreported dilated collateral vessels and early neovasularization secondary to peripheral vein occlusion.


TBL10 is required for O-acetylation of pectic rhamnogalacturonan-I in Arabidopsis thaliana.
O-Acetylated pectins are abundant in the primary cell wall of plants and growing evidence suggests they have important roles in plant cell growth and interaction with the environment. Despite their importance, genes required for O-acetylation of pectins are still largely unknown. In this study, we showed that TRICHOME BIREFRINGENCE LIKE 10 (AT3G06080) is involved in O-acetylation of pectins in Arabidopsis (Arabidopsis thaliana). The activity of the TBL10 promoter was strong in tissues where pectins are highly abundant (e.g. leaves). Two homozygous knock-out mutants of Arabidopsis, tbl10-1 and tbl10-2, were isolated and shown to exhibit reduced levels of wall-bound acetyl esters, equivalent of ~50% of the wild-type level in pectin-enriched fractions derived from leaves. Further fractionation revealed that the degree of acetylation of the pectin rhamnogalacturonan-I (RG-I) was reduced in the tbl10 mutant compared to the wild type, whereas the pectin homogalacturonan (HG) was unaffected. The degrees of acetylation in hemicelluloses (i.e. xyloglucan, xylan and mannan) were indistinguishable between the tbl10 mutants and the wild type. The mutant plants contained normal trichomes in leaves and exhibited a similar level of susceptibility to the phytopathogenic microorganisms Pseudomonas syringae pv. tomato DC3000 and Botrytis cinerea; while they displayed enhanced tolerance to drought. These results indicate that TBL10 is required for O-acetylation of RG-I, possibly as an acetyltransferase, and suggest that O-acetylated RG-I plays a role in abiotic stress responses in Arabidopsis.


Review: studies of ferric heme proteins with highly anisotropic/highly axial low spin (S = 1/2) electron paramagnetic resonance signals with bis-histidine and histidine-methionine axial iron coordination.
Six-coordinated heme groups are involved in a large variety of electron transfer reactions because of their ability to exist in both the ferrous (Fe(2+)) and ferric (Fe(3+)) state without any large differences in structure. Our studies on hemes coordinated by two histidines (bis-His) and hemes coordinated by histidine and methionine (His-Met) will be reviewed. In both of these coordination environments, the heme core can exhibit ferric low spin (electron paramagnetic resonance EPR) signals with large g(max) values (also called Type I, highly anisotropic low spin, or highly axial low spin, HALS species) as well as rhombic EPR (Type II) signals. In bis-His coordinated hemes rhombic and HALS envelopes are related to the orientation of the His groups with respect to each other such that (i) parallel His planes results in a rhombic signal and (ii) perpendicular His planes results in a HALS signal. Correlation between the structure of the heme and its ligands for heme with His-Met axial ligation and ligand-field parameters, as derived from a large series of cytochrome c variants, show, however, that for such a combination of axial ligands there is no clear-cut difference between the large g(max) and the "small g-anisotropy" cases as a result of the relative Met-His arrangements. Nonetheless, a new linear correlation links the average shift delta of the heme methyl groups with the g(max) values.


The complete N-terminal extension of heparin cofactor II is required for maximal effectiveness as a thrombin exosite 1 ligand.
Heparin cofactor II (HCII) is a circulating protease inhibitor, one which contains an N-terminal acidic extension (HCII 1-75) unique within the serpin superfamily. Deletion of HCII 1-75 greatly reduces the ability of glycosaminoglycans (GAGs) to accelerate the inhibition of thrombin, and abrogates HCII binding to thrombin exosite 1. While a minor portion of HCII 1-75 can be visualized in a crystallized HCII-thrombin S195A complex, the role of the rest of the extension is not well understood and the affinity of the HCII 1-75 interaction has not been quantitatively characterized. To address these issues, we expressed HCII 1-75 as a small, N-terminally hexahistidine-tagged polypeptide in E. coli. Immobilized purified HCII 1-75 bound active α-thrombin and active-site inhibited FPR-ck- or S195A-thrombin, but not exosite-1-disrupted γT-thrombin, in microtiter plate assays. Biotinylated HCII 1-75 immobilized on streptavidin chips bound α-thrombin and FPR-ck-thrombin with similar KD values of 330-340 nM. HCII 1-75 competed thrombin binding to chip-immobilized HCII 1-75 more effectively than HCII 54-75 but less effectively than the C-terminal dodecapeptide of hirudin (mean Ki values of 2.6, 8.5, and 0.29 μM, respectively). This superiority over HCII 54-75 was also demonstrated in plasma clotting assays and in competing the heparin-catalysed inhibition of thrombin by plasma-derived HCII; HCII 1-53 had no effect in either assay. Molecular modelling of HCII 1-75 correctly predicted those portions of the acidic extension that had been previously visualized in crystal structures, and suggested that an α-helix found between residues 26 and 36 stabilizes one found between residues 61-67. The latter region has been previously shown by deletion mutagenesis and crystallography to play a crucial role in the binding of HCII to thrombin exosite 1. Assuming that the KD value for HCII 1-75 of 330-340 nM faithfully predicts that of this region in intact HCII, and that 1-75 binding to exosite 1 is GAG-dependent, our results support a model in which thrombin first binds to GAGs, followed by HCII addition to the ternary complex and release of HCII 1-75 for exosite 1 binding and serpin mechanism inhibition. They further suggest that, in isolated or transferred form, the entire HCII 1-75 region is required to ensure maximal binding of thrombin exosite 1.


Acute transfusion reactions encountered in patients at a tertiary care center.
To determine the frequency and type of Acute Transfusion Reactions (ATRs) occurring in inpatients, reported to the transfusion service at Aga Khan University Hospital, Karachi, Pakistan. This was a three years and seven months (from January 2005 till July 2008) retrospective review of all the transfusion reactions that were reported to the transfusion service at Aga Khan University Hospital, Karachi, Pakistan. All the reactions were clinically evaluated by the blood bank physician. Transfusion reactions occurring during or within four hours after transfusion were evaluated and classified by standard and recognized definitions defined by American Association of Blood Banks. The acute transfusion reactions (ATRs) reported during the study period were 212. However, out of these 212 ATRs, 182 ATRs were confirmed by blood bank physician, and included febrile non haemolytic reactions [89 (41.9%)], allergic reaction [73 (34.4%)], isolated hypotension [3 (1.4%)], haemolytic reaction [4 (1.8%)] and bacterial contamination [2 (0.9%)]. Eleven (5.1%) ATRs were unclassifiable and were thus labeled as non specific reaction. The frequency of transfusion reactions in our patients was found to be 0.082%. Febrile non haemolytic reaction was the most frequent transfusion reaction followed by allergic reaction. This may be an under reported figure. There is a need for establishing a haemovigilance system for critical analysis of blood transfusion events.


CONSTITUTIVELY PHOTOMORPHOGENIC1 is required for the UV-B response in Arabidopsis.
CONSTITUTIVELY PHOTOMORPHOGENIC1 (COP1) is a negative regulator of photomorphogenesis in Arabidopsis thaliana. COP1 functions as an E3 ubiquitin ligase, targeting select proteins for proteasomal degradation in plants as well as in mammals. Among its substrates is the basic domain/leucine zipper (bZIP) transcription factor ELONGATED HYPOCOTYL5 (HY5), one of the key regulators of photomorphogenesis under all light qualities, including UV-B responses required for tolerance to this environmental threat. Here, we report that, in contrast with the situation in visible light, COP1 is a critical positive regulator of responses to low levels of UV-B. We show that in the cop1-4 mutant, flavonoid accumulation and genome-wide expression changes in response to UV-B are blocked to a large extent. COP1 is required for HY5 gene activation, and both COP1 and HY5 proteins accumulate in the nucleus under supplementary UV-B. SUPPRESSOR OF PHYTOCHROME A-105 family proteins (SPA1 to SPA4) that are required for COP1 function in dark and visible light are not essential in the response to UV-B. We conclude that COP1 performs a specific and novel role in the plants' photomorphogenic response to UV-B, coordinating HY5-dependent and -independent pathways, which eventually results in UV-B tolerance.


The social and emotional impact of cardiac transplantation.
To date, there has been limited systematic research in the area of the emotional impact of cardiac transplantation. Since September 1984, a prospective study addressing this issue has been in progress at St. Vincent's Hospital, Sydney, Australia. Initial results suggest that anxiety, associated with declining health and adjustment to the prospect of transplantation, was the major issue at pre-transplantation. Follow-up at the time of their first hospital discharge after transplantation and again at 3 months showed improvement in all psychological measures and did not identify any psychological morbidity.


Polymorphism in an androgen-regulated mouse gene is the result of the insertion of a B1 repetitive element into the transcription unit.
The single-copy RP2 gene in mice produces three major mRNAs, the abundances of which are significantly increased in the kidneys by the administration of testosterone. S1 nuclease analysis of the kidney mRNAs indicated that they differ in the lengths of their 3' untranslated regions as a result of the use of different polyadenylation sites. When the mRNAs from different inbred mouse strains were examined by Northern blot analysis, it was observed that the largest mRNA varies in size, whereas the sizes of the other mRNAs remain the same. In DBA/LiHa and DBA/2J mice, the largest mRNA is approximately 2,150 nucleotides long, whereas the corresponding mRNA in C57BL/6J and BALB/cJ mice is only 1,950 nucleotides in length. All of these strains also have RP2 mRNAs that are 1,450 and 1,350 nucleotides long. By S1 nuclease mapping and comparison of the sequence of cDNA clones representing these mRNAs in DBA/LiHa and C57BL/6J mice, we determined that this size difference or polymorphism observed in the largest mRNA is the result of the insertion of a member of the B1 family of repeats into the 3' untranslated region of the RP2 gene in DBA mice. This particular B1 repeat is transcribed by RNA polymerase III in vitro, and its transcriptional orientation is opposite to that of the RP2 transcript. The polymorphism described here is evidence for the mobility of B1 repetitive elements within the genome.


Effect of anoxia on the electroretinogram of three anoxia-tolerant vertebrates.
To survive anoxia, neural ATP levels have to be defended. Reducing electrical activity, which accounts for 50% or more of neural energy consumption, should be beneficial for anoxic survival. The retina is a hypoxia sensitive part of the central nervous system. Here, we quantify the in vivo retinal light response (electroretinogram; ERG) in three vertebrates that exhibit varying degrees of anoxia tolerance: freshwater turtle (Trachemys scripta), epaulette shark (Hemiscyllium ocellatum) and leopard frog (Rana pipiens). A virtually total suppression of ERG in anoxia, probably resulting in functional blindness, has previously been seen in the extremely anoxia-tolerant crucian carp (Carassius carassius). Surprisingly, the equally anoxia-tolerant turtle, which strongly depresses brain and whole-body metabolism during anoxia, exhibited a relatively modest anoxic reduction in ERG: the combined amplitude of turtle ERG waves was reduced by approximately 50% after 2 h. In contrast, the shark b-wave amplitude practically disappeared after 30 min of severe hypoxia, and the frog b-wave was decreased by approximately 75% after 40 min in anoxia. The specific A(1) adenosine receptor antagonist CPT significantly delayed the suppression of turtle ERG, while the hypoxic shark ERG was unaffected by the non-specific adenosine receptor antagonist aminophylline, suggesting adenosinergic involvement in turtle but not in shark.


Bladder function preservation with brachytherapy, external beam radiation therapy, and limited surgery in bladder cancer patients: Long-term results [corrected].
To report long-term results of a bladder preservation strategy for muscle-invasive bladder cancer (MIBC) using external beam radiation therapy and brachytherapy/interstitial radiation therapy (IRT). Between May 1989 and October 2011, 192 selected patients with MIBC were treated with a combined regimen of preoperative external beam radiation therapy and subsequent surgical exploration with or without partial cystectomy and insertion of source carrier tubes for afterloading IRT using low dose rate and pulsed dose rate. Data for oncologic and functional outcomes were prospectively collected. The primary endpoints were local recurrence-free survival (LRFS), bladder function preservation survival, and salvage cystectomy-free survival. The endpoints were constructed according to the Kaplan-Meier method. The mean follow-up period was 105.5 months. The LRFS rate was 80% and 73% at 5 and 10 years, respectively. Salvage cystectomy-free survival at 5 and 10 years was 93% and 85%. The 5- and 10-year overall survival rates were 65% and 46%, whereas cancer-specific survival at 5 and 10 years was 75% and 67%. The distant metastases-free survival rate was 76% and 69% at 5 and 10 years. Multivariate analysis revealed no independent predictors of LRFS. Radiation Therapy Oncology Group grade ≥3 late bladder and rectum toxicity were recorded in 11 patients (5.7%) and 2 patients (1%), respectively. A multimodality bladder-sparing regimen using IRT offers excellent long-term oncologic outcome in selected patients with MIBC. The late toxicity rate is low, and the majority of patients preserve their functional bladder.


Notch signaling drives multiple myeloma induced osteoclastogenesis.
Multiple myeloma (MM) is closely associated with bone destruction. Once migrated to the bone marrow, MM cells unbalance bone formation and resorption via the recruitment and maturation of osteoclast precursors. The Notch pathway plays a key role in different types of cancer and drives several biological processes relevant in MM, including cell localization within the bone marrow, proliferation, survival and pharmacological resistance. Here we present evidences that MM can efficiently drive osteoclastogenesis by contemporaneously activating Notch signaling on tumor cells and osteoclasts through the aberrant expression of Notch ligands belonging to the Jagged family. Active Notch signaling in MM cells induces the secretion of the key osteoclastogenic factor, RANKL, which can be boosted in the presence of stromal cells. In turn, MM cells-derived RANKL causes the upregulation of its receptor, RANK, and Notch2 in pre-osteoclasts. Notch2 stimulates osteoclast differentiation by promoting autocrine RANKL signaling. Finally, MM cells through Jagged ligands expression can also activate Notch signaling in pre-osteoclast by direct contact. Such synergism between tumor cells and pre-osteoclasts in MM-induced osteoclastogenesis can be disrupted by silencing tumor-derived Jagged1 and 2. These results make the Jagged ligands new promising therapeutic targets in MM to contrast bone disease and the associated co-morbidities.


Molecular analyses of zebrafish V0v spinal interneurons and identification of transcriptional regulators downstream of Evx1 and Evx2 in these cells.
V0v spinal interneurons are highly conserved, glutamatergic, commissural neurons that function in locomotor circuits. We have previously shown that Evx1 and Evx2 are required to specify the neurotransmitter phenotype of these cells. However, we still know very little about the gene regulatory networks that act downstream of these transcription factors in V0v cells. To identify candidate members of V0v gene regulatory networks, we FAC-sorted wild-type and evx1;evx2 double mutant zebrafish V0v spinal interneurons and expression-profiled them using microarrays and single cell RNA-seq. We also used in situ hybridization to compare expression of a subset of candidate genes in evx1;evx2 double mutants and wild-type siblings. Our data reveal two molecularly distinct subtypes of zebrafish V0v spinal interneurons at 48 h and suggest that, by this stage of development, evx1;evx2 double mutant cells transfate into either inhibitory spinal interneurons, or motoneurons. Our results also identify 25 transcriptional regulator genes that require Evx1/2 for their expression in V0v interneurons, plus a further 11 transcriptional regulator genes that are repressed in V0v interneurons by Evx1/2. Two of the latter genes are hmx2 and hmx3a. Intriguingly, we show that Hmx2/3a, repress dI2 interneuron expression of skor1a and nefma, two genes that require Evx1/2 for their expression in V0v interneurons. This suggests that Evx1/2 might regulate skor1a and nefma expression in V0v interneurons by repressing Hmx2/3a expression. This study identifies two molecularly distinct subsets of zebrafish V0v spinal interneurons, as well as multiple transcriptional regulators that are strong candidates for acting downstream of Evx1/2 to specify the essential functional characteristics of these cells. Our data further suggest that in the absence of both Evx1 and Evx2, V0v spinal interneurons initially change their neurotransmitter phenotypes from excitatory to inhibitory and then, later, start to express markers of distinct types of inhibitory spinal interneurons, or motoneurons. Taken together, our findings significantly increase our knowledge of V0v and spinal development and move us closer towards the essential goal of identifying the complete gene regulatory networks that specify this crucial cell type.


Laboratory techniques for human viral encephalitis diagnosis.
Encephalitis is an inflammatory process involving the parenchyma of the brain. It typically presents as a clinical syndrome characterised by fever, headache and altered conscious level, often with focal neurological deficits and fits. The clinical presentation overlaps with other diseases of the central nervous system including viral and bacterial meningitis, and brain abscess. The causes of encephalitis are legion, and include principally viral but also bacterial, parasitic and fungal pathogens. Noninfectious aetiologies, especially autoimmune conditions such as potassium channel voltage gated antibodies and anti-NDMA receptor antibodies, are increasingly recognised. Diagnosis comes from clinical examination, neuroimaging and laboratory testing. With such a wide range of potential pathogens a syndromic approach to diagnosis is preferred, testing for a range of organisms. Traditional techniques such as cell culture and direct virus antigen detection have little or no role nowadays. Laboratory diagnosis of viral encephalitis is ideally based on examination of cerebrospinal fluid (CSF) for cells, protein and glucose, followed by nucleic acid amplification tests (NAAT) such as polymerase chain reaction (PCR) for a range of viral targets. Samples other than CSF sometimes give a definitive or probable aetiological diagnosis; examples include skin biopsy in rabies, and serum NAAT and antibody tests for some arboviruses and enteroviruses. Newer approaches to amplification and to multitarget detection are becoming increasingly important. Detection of intrathecal antibody production against specific viruses retains a place in diagnosis where NAAT is negative. Some of the laboratory techniques available will be discussed in this article.


Finding Street Gang Members on Twitter.
Most street gang members use Twitter to intimidate others, to present outrageous images and statements to the world, and to share recent illegal activities. Their tweets may thus be useful to law enforcement agencies to discover clues about recent crimes or to anticipate ones that may occur. Finding these posts, however, requires a method to discover gang member Twitter profiles. This is a challenging task since gang members represent a very small population of the 320 million Twitter users. This paper studies the problem of automatically finding gang members on Twitter. It outlines a process to curate one of the largest sets of verifiable gang member profiles that have ever been studied. A review of these profiles establishes differences in the language, images, YouTube links, and emojis gang members use compared to the rest of the Twitter population. Features from this review are used to train a series of supervised classifiers. Our classifier achieves a promising F1 score with a low false positive rate.


Classifying asthma: disagreement among specialists.
The asthma practice guidelines developed by the National Institutes of Health include a system for classifying asthma severity. The goal of the present study was to assess the interrater reliability of this classification system by measuring agreement among pediatric asthma specialists. A survey containing eight case summaries was mailed to 24 board-certified pediatric allergists and pulmonologists, who were asked to classify each case according to the national guidelines. The case summaries included the patient's medical history, physical examination, and chest radiograph and pulmonary function test results. Physicians were also asked to interpret the pulmonary function tests, to indicate the main factors used to classify each case (daytime symptoms, nighttime symptoms, pulmonary function testing, or various combinations), and to make treatment recommendations. kappa statistics were used to measure agreement. Fourteen of 24 surveys mailed (58%) were completed and returned. Agreement was poor for classifying asthma (kappa = 0.29; 95% confidence interval [CI], 0.25 to 0.33) and for the main factors used to make the classifications (kappa = 0.19; 95% CI, 0.14 to 0.23). Specialists exhibited higher agreement in their interpretation of pulmonary function tests (no asthma, kappa = 0.66; asthma on baseline, kappa = 0.53; exercise-induced asthma, kappa = 0.65). While physicians' treatment recommendations were consistent with their severity classifications, the low level of agreement in those classifications led to substantial variability in the treatments recommended. The low level of agreement among pediatric asthma specialists in classifying asthma severity suggests the need to refine the classification system used in the national guidelines to help ensure the consistent application of those guidelines.


Impact of prior flavivirus immunity on Zika virus infection in rhesus macaques.
Studies have demonstrated cross-reactivity of anti-dengue virus (DENV) antibodies in human sera against Zika virus (ZIKV), promoting increased ZIKV infection in vitro. However, the correlation between in vitro and in vivo findings is not well characterized. Thus, we evaluated the impact of heterotypic flavivirus immunity on ZIKV titers in biofluids of rhesus macaques. Animals previously infected (≥420 days) with DENV2, DENV4, or yellow fever virus were compared to flavivirus-naïve animals following infection with a Brazilian ZIKV strain. Sera from DENV-immune macaques demonstrated cross-reactivity with ZIKV by antibody-binding and neutralization assays prior to ZIKV infection, and promoted increased ZIKV infection in cell culture assays. Despite these findings, no significant differences between flavivirus-naïve and immune animals were observed in viral titers, neutralizing antibody levels, or immune cell kinetics following ZIKV infection. These results indicate that prior infection with heterologous flaviviruses neither conferred protection nor increased observed ZIKV titers in this non-human primate ZIKV infection model.


Response of whole-body protein and urea turnover to exercise differs between patients with chronic obstructive pulmonary disease with and without emphysema.
Exercise is known to improve physical capacity and muscle mass in patients with chronic obstructive pulmonary disease (COPD). However, recent evidence suggests that exercise may also negatively influence metabolism in COPD. The objective was to investigate whether exercise influences whole-body protein metabolism differently in COPD patients and control subjects and to elucidate the effect of the specific underlying lung disease. Whole-body protein synthesis and breakdown and urea synthesis were measured by using stable-isotope methods in 14 male patients with severe COPD (forced expiratory volume in 1 s: 37 +/- 12% of predicted) and in 8 male control subjects during and after 20 min of exercise. Subjects were normal weight [body mass index (in kg/m2) of COPD patients and control subjects: 25.8 +/- 3.9 and 25.7 +/- 4.4, respectively]. The COPD group was selected to include patients with (Emph+, n = 7) and without (Emph-, n = 7) emphysema. Absolute workload was 35 +/- 5 W, corresponding to 17 +/- 2%, 33 +/- 9%, and 52 +/- 14% of the maximal obtained workload in the control, Emph-, and Emph+ groups. Exercise induced a 9% increase in protein synthesis and breakdown in the Emph- and control groups, which normalized postexercise. In the Emph+ group, protein turnover did not change significantly during exercise but decreased postexercise (+/- 10%). Exercise did not change net protein breakdown (protein breakdown - synthesis) or urea synthesis, except in the Emph+ group, which showed a 14% reduction in urea synthesis postexercise (P < 0.05). Low-intensity exercise suppresses whole-body protein and urea turnover in COPD patients with emphysema and needs to be considered when maximal anabolism is targeted through a combination of exercise and nutrition.


Dynamic multi-site phosphorylation by Fyn and Abl drives the interaction between CRKL and the novel scaffolding receptors DCBLD1 and DCBLD2.
Discoidin, CUB, and LCCL domain containing 2 (DCBLD2) is a neuropilin-like transmembrane scaffolding receptor with known and anticipated roles in vascular remodeling and neuronal positioning. DCBLD2 is also up-regulated in several cancers and can drive glioblastomas downstream of activated epidermal growth factor receptor. While a few studies have shown either a positive or negative role for DCBLD2 in regulating growth factor receptor signaling, little is known about the conserved signaling features of DCBLD family members that drive their molecular activities. We previously identified DCBLD2 tyrosine phosphorylation sites in intracellular YxxP motifs that are required for the phosphorylation-dependent binding of the signaling adaptors CRK and CRKL (CT10 regulator of kinase and CRK-like). These intracellular YxxP motifs are highly conserved across vertebrates and between DCBLD family members. Here, we demonstrate that, as for DCBLD2, DCBLD1 YxxP motifs are required for CRKL-SH2 (Src homology 2) binding. We report that Src family kinases (SFKs) and Abl differentially promote the interaction between the CRKL-SH2 domain and DCBLD1 and DCBLD2, and while SFKs and Abl each promote DCBLD1 and DCBLD2 binding to the CRKL-SH2 domain, the effect of Abl is more pronounced for DCBLD1. Using high-performance liquid chromatography coupled with tandem mass spectrometry, we quantified phosphorylation at several YxxP sites in DCBLD1 and DCBLD2, mapping site-specific preferences for SFKs and Abl. Together, these data provide a platform to decipher the signaling mechanisms by which these novel receptors drive their biological activities.


Medical aspects of the Confederacy (1861--1865).
In military philosophy injured soldiers are a greater liability to the opposition than dead men, and there was no greater example of this than during the War Between the States. The state of the art of Southern medicine in the 1860s, as well as the military circumstances and politics of the day are discussed to discern the effectiveness of the medical care provided. Useful medicomilitary procedures, as well as an increase in medical knowledge, did emerge from this struggle and deserve acknowledgment.


Ubiquitination regulates the plasma membrane expression of renal UT-A urea transporters.
The renal UT-A urea transporters UT-A1, UT-A2, and UT-A3 are known to play an important role in the urinary concentrating mechanism. The control of the cellular localization of UT-A transporters is therefore vital to overall renal function. In the present study, we have investigated the effect of ubiquitination on UT-A plasma membrane expression in Madin-Darby canine kidney (MDCK) cell lines expressing each of the three renal UT-A transporters. Inhibition of the ubiquitin-proteasome pathway caused an increase in basal transepithelial urea flux across MDCK-rat (r)UT-A1 and MDCK-mouse (m)UT-A2 monolayers (P < 0.01, n = 3, ANOVA) and also increased dimethyl urea-sensitive, arginine vasopressin-stimulated urea flux (P < 0.05, n = 3, ANOVA). Inhibition of the ubiquitin-proteasome pathway also increased basolateral urea flux in MDCK-mUT-A3 monolayers (P < 0.01, n = 4, ANOVA) in a concentration-dependent manner. These increases in urea flux corresponded to a significant increase in UT-A transporter expression in the plasma membrane (P < 0.05, n = 3, ANOVA). Further analysis of the MDCK-mUT-A3 cell line confirmed that vasopressin specifically increased UT-A3 expression in the plasma membrane (P < 0.05, n = 3, ANOVA). However, preliminary data suggested that vasopressin produces this effect through an alternative route to that of the ubiquitin-proteasome pathway. In conclusion, our study suggests that ubiquitination regulates the plasma membrane expression of all three major UT-A urea transporters, but that this is not the mechanism primarily used by vasopressin to produce its physiological effects.


Investigating Deferral Rates in Cochlear Implantation: How Often Do Candidates Defer and Why?
Evaluate the rate at which cochlear implant (CI) candidates decline surgery and identify associated factors. Retrospective cohort study. Tertiary referral center. Four hundred ninety-three CI candidates from July 1989 to December 2020 with complete demographic and socioeconomic data. Diagnostic. Age, sex, race, marital and employment status, median household income percentile, distance-to-CI-center, and residence in a medically underserved county. Of the 493 CI candidates included, 80 patients (16.2%) declined surgery. Based on chart checking, the most common reason patients did not receive the implant was due to loss of follow-up (38%). African American patients were 73% less likely to undergo implantation compared with White patients (odds ratio [OR], 0.27 [0.11-0.68]; p = 0.005). Asian patients were 95% less likely to undergo implantation (OR, 0.05 [0.009-0.25]; p = 0.0003) compared with White patients. For every 1-year age increase, patients were 4% less likely to undergo implantation (OR, 0.96 [0.94-0.98]; p < 0.0001) and for every 10-year age increase, the patients were 33% less likely. Compared with their single counterparts, married patients were more likely to undergo implantation (OR, 1.87 [1.12-3.15]; p = 0.02). No differences were observed when comparing implanted and nonimplanted CI candidates in sex, employment status, distance-to-CI-center, or median family income percentile. A χ2 test of independence showed no association between receiving CIs and living in medically underserved counties ( χ2 = 2; N = 493; 0.3891; p = 0.53). Not infrequently, CI candidates decline surgery. Although demographic factors (race, age, and marital status) were associated with the cochlear implantation decision, socioeconomic factors (median family income and residence in a medically underserved community) were not. Perhaps cultural components of a patient's race have a larger impact on whether or not the patients get implanted.


Macrocirculation is not the sole determinant of respiratory induced variations in the reflection mode photoplethysmographic signal.
Photoplethysmography (PPG) is a non-invasive optical technique sensitive to variations in blood volume and perfusion in the tissue. Reflection mode PPG may have clinical advantages over transmission mode PPG. To improve clinical usefulness and further development of the reflection mode PPG, studies on factors that modify the signal are warranted. We studied the coherence between the respiratory induced intensity variations (RIIV) of the PPG signal and respiratory synchronous pressure variations in central venous pressure (CVP), peripheral venous pressure (PVP) and arterial blood pressure (ABP) during positive pressure ventilation on 12 patients under anaesthesia and on 12 patients with spontaneous breathing. During positive pressure ventilation the coherence between all signals was high. Inspiration was followed first by an increase in CVP, then by increases in ABP and PVP and lastly by RIIV indicating less back-scattered light. In spontaneously breathing patients the coherence was high, but the phases between the signals were changed. During inspiration, ABP decreased slightly before CVP, followed by a decrease in RIIV and PVP. The phase relation between RIIV and respiratory induced variation in macrocirculation changed with ventilatory mode, but not in a uniform way, indicating the influence of mechanisms other than macrocirculation involved in generating the RIIV signal.


Demographic processes drive increases in wildlife disease following population reduction.
Population reduction is often used as a control strategy when managing infectious diseases in wildlife populations in order to reduce host density below a critical threshold. However, population reduction can disrupt existing social and demographic structures leading to changes in observed host behaviour that may result in enhanced disease transmission. Such effects have been observed in several disease systems, notably badgers and bovine tuberculosis. Here we characterise the fundamental properties of disease systems for which such effects undermine the disease control benefits of population reduction. By quantifying the size of response to population reduction in terms of enhanced transmission within a generic non-spatial model, the properties of disease systems in which such effects reduce or even reverse the disease control benefits of population reduction are identified. If population reduction is not sufficiently severe, then enhanced transmission can lead to the counter intuitive perturbation effect, whereby disease levels increase or persist where they would otherwise die out. Perturbation effects are largest for systems with low levels of disease, e.g. low levels of endemicity or emerging disease. Analysis of a stochastic spatial meta-population model of demography and disease dynamics leads to qualitatively similar conclusions. Moreover, enhanced transmission itself is found to arise as an emergent property of density dependent dispersal in such systems. This spatial analysis also shows that, below some threshold, population reduction can rapidly increase the area affected by disease, potentially expanding risks to sympatric species. Our results suggest that the impact of population reduction on social and demographic structures is likely to undermine disease control in many systems, and in severe cases leads to the perturbation effect. Social and demographic mechanisms that enhance transmission following population reduction should therefore be routinely considered when designing control programmes.


The effect of lattice strain on the catalytic properties of Pd nanocrystals.
The effect of lattice strain on the catalytic properties of Pd nanoparticles is systematically studied. Synthetic strategies for the preparation of a series of shape-controlled Pd nanocrystals with lattice strain generated from different sources has been developed. All of these nanocrystals were created with the same capping agent under similar reaction conditions. First, a series of Pd nanoparticles was synthesized that were enclosed in {111} surfaces: Single-crystalline Pd octahedra, single-crystalline AuPd core-shell octahedra, and twinned Pd icosahedra. Next, various {100}-terminated particles were synthesized: Single-crystalline Pd cubes and single-crystalline AuPd core-shell cubes. Different extents of lattice strain were evident by comparing the X-ray diffraction patterns of these particles. During electrocatalysis, decreased potentials for CO stripping and increased current densities for formic-acid oxidation were observed for the strained nanoparticles. In the gas-phase hydrogenation of ethylene, the activities of the strained nanoparticles were lower than those of the single-crystalline Pd nanoparticles, perhaps owing to a larger amount of cetyl trimethylammonium bromide on the surface.


Urban public parks and mental health in adult women: Mediating and moderating factors.
The association of green spaces such as urban public parks and mental health might vary according to personal characteristics and characteristics of the park and be mediated by the use of the park. We investigate the association between urban public park coverage and mental health in adult women, the moderation of this association by personal and park-related characteristics, and the mediation of the association by use of public space. Combining data from a cross-sectional survey of the adult female population of Tijuana (Mexico) in 2014, and a study of public spaces in 2013, we analyzed the association between park coverage in buffers of 400 and 800 m from participants' homes and score in the Center for Epidemiologic Studies-Depression scale (CES-D). We tested for mediation by use of park and interaction of urban park coverage with personal and park characteristics. Urban public park coverage in the 400-m buffer had an inverse association with CES-D score that was moderated by age (significant only for younger participants), with no evidence of mediation. Park coverage in the 800-m buffer also had an inverse association with CES-D score, moderated by age and occupation (significant for younger participants and homemakers), and a mediated association was also observed. There was no interaction between park coverage and park characteristics in their association with CES-D score. Our results confirm the potential of public parks to improve mental health and suggest that this effect could be more important at some stages in the life course for women. The upper-middle-income, Latin American country setting adds to the current knowledge that is mostly based on high-income countries.


Anticancer effects of α-Bisabolol in human non-small cell lung carcinoma cells are mediated via apoptosis induction, cell cycle arrest, inhibition of cell migration and invasion and upregulation of P13K/AKT signalling pathway.
Non-small lung cancer (NSLC) is one of the leading causes of cancer-related deaths world over. Excempting operable cases the treatments for NSCLC mainly include chemotherapy and radiotherapy. However, the survival rate for NSCLC is still far from satsifactory. Moreover, chemotherapy has lot of associated side effects. Therefore, there is an urgent need to look for novel and more viable treatment options. Against this background, the present study was designed to evaluate the anticancer activity of α-Bisabolol against NSCLC. Cell viability was assessed by MTT assay. Apoptosis was determined by DAPI and annexin V/propidium iodide (PI) staining. Mitochondrial membrane potential (MMP) and cell cycle analysis were determined by flow cytometry. Cell migration was investigated by wound healing assay and protein expression was evaluated by western blotting. α-Bisabolol exerted significant anticancer activity on A549 NSCLC cells with IC50 of 15 μM. The anticancer effects of α-Bisabolol were found to be due to G2/M cell cycle arrest and mitochondrial apoptosis. α-Bisabolol also inhibited cell migration of A549 cells dose-dependently. Moreover, the results showed that α-Bisabolol could inhibit the PI3K/AKT signalling pathway in a dose-dependent manner. The results of the present study indicate that α-Bisabolol exerted selective anticancer effects on A549 cells via induction of cell cycle arrest, mitochondrial apoptosis and inhibition of PI3K/Akt signalling pathways. This molecule showed promising anticancer features and could be developed as a potent lead candidate for the management and treatment of NSCLC.


Postoperative nausea and vomiting after total intravenous anesthesia with propofol and remifentanil or alfentanil: how important is the opioid?
To compare the frequency and duration of postoperative nausea and vomiting (PONV) following total intravenous anesthesia (TIVA) with propofol and either remifentanil or alfentanil in outpatients undergoing arthroscopic surgery of the extremities. Randomized, third-party blinded study. University medical center. 100 ASA physical status I and II patients scheduled for arthroscopic surgery of the knee or shoulder. The anesthesia regimen consisted of a bolus followed by continuous infusion of propofol (2 mg/kg followed by 120 microg/kg/min) and the opioid (remifentanil 0.5 microg/kg followed by 0.1 microg/kg/min or alfentanil 10 microg/kg followed by 0.25 microg/kg/min). Patients breathed 100% oxygen spontaneously through a Laryngeal Mask Airway (or an endotracheal tube when medically indicated). Opioids were titrated to maintain blood pressure and heart rate within 20% of baseline and a respiratory rate of 10 to 16 breaths/min. Propofol was titrated downward as low as possible without permitting patient movement. Nausea was determined by an 11-point categorical scale and was recorded before surgery and multiple time points thereafter. The times of emetic episodes were recorded. Treatment of PONV was at the discretion of the postanesthesia care unit (PACU) nurses who were blinded to the identity of the opioid used. Nausea scores were 0 at all time points in over 70% of the patients in each group. None of the 100 patients vomited while in the hospital, and only one patient required antiemetic therapy. When propofol-based TIVA is used for arthroscopic surgery, short-acting opioids do not significantly affect the risk of PONV.


The in vitro pharmacology of chloroquine and quinacrine.
The effects of guanethidine, chloroquine and quinacrine on noradrenergic nerves have been compared in vitro using the isolated expansor secundariorum muscle of chicks. The effect of chloroquine on alpha-methyl-noradrenaline uptake by noradrenergic nerve terminals in various tissues were studied. The inhibitory action of guanethidine and quinacrine on noradrenergic nerves appeared to be mediated intraneuronally. The inhibitory action of chloroquine was readily reversible and unaffected by dexamphetamine. Chloroquine caused supersensitivity of the expansor muscle to noradrenaline by blocking its neuronal reuptake since the supersensitivity caused by denervation was not further increased by chloroquine. This was confirmed by the finding that chloroquine inhibited alpha-methylnoradrenaline uptake (Uptake1). Quinacrine did not cause supersensitivity to noradrenaline, possibly due to its direct depressant action on the expansor secundariorum muscle.


OpenChem: A Deep Learning Toolkit for Computational Chemistry and Drug Design.
Deep learning models have demonstrated outstanding results in many data-rich areas of research, such as computer vision and natural language processing. Currently, there is a rise of deep learning in computational chemistry and materials informatics, where deep learning could be effectively applied in modeling the relationship between chemical structures and their properties. With the immense growth of chemical and materials data, deep learning models can begin to outperform conventional machine learning techniques such as random forest, support vector machines, and nearest neighbor. Herein, we introduce OpenChem, a PyTorch-based deep learning toolkit for computational chemistry and drug design. OpenChem offers easy and fast model development, modular software design, and several data preprocessing modules. It is freely available via the GitHub repository.


Economic evaluation of typhoid vaccination in a prolonged typhoid outbreak setting: the case of Kasese district in Uganda.
Vaccination has been increasingly promoted to help control epidemic and endemic typhoid fever in high-incidence areas. Despite growing recognition that typhoid incidence in some areas of sub-Saharan Africa is similar to high-incidence areas of Asia, no large-scale typhoid vaccination campaigns have been conducted there. We performed an economic evaluation of a hypothetical one-time, fixed-post typhoid vaccination campaign in Kasese, a rural district in Uganda where a large, multi-year outbreak of typhoid fever has been reported. We used medical cost and epidemiological data retrieved on-site and campaign costs from previous fixed-post vaccination campaigns in Kasese to account for costs from a public sector health care delivery perspective. We calculated program costs and averted disability-adjusted life years (DALYs) and medical costs as a result of vaccination, to calculate the cost of the intervention per DALY and case averted. Over the 3 years of projected vaccine efficacy, a one-time vaccination campaign was estimated to avert 1768 (90%CI: 684-4431) typhoid fever cases per year and a total of 3868 (90%CI: 1353-9807) DALYs over the duration of the immunity conferred by the vaccine. The cost of the intervention per DALY averted was US$ 484 (90%CI: 18-1292) and per case averted US$ 341 (90%CI: 13-883). We estimated the vaccination campaign in this setting to be highly cost-effective, according to WHO's cost-effective guidelines. Results may be applicable to other African settings with similar high disease incidence estimates.


THE RELATIONS OF THE NORTH AMERICAN FLORA TO THAT OF SOUTH AMERICA.
Reviewing the floral relations of North and South America as illustrated in the foregoing instances, we may say that the phenomena of distribution agree fairly with the record of physical conditions which have succeeded each other and those which still exist, and upon which we might almost a priori have predicted an analogous set of distribution phenomena. In this relationship we may distinguish three categories of distribution: (1) Those due to the conditions of human civilization, commerce, etc. This has resulted in placing the same species in similar regions of both continents, as, for example, Fagonia cretica in Lower California and Chile; Munroa squarrosa, western plains of North America, plains of Argentine and high plateaus of Chile and Bolivia; Frankenia grandiflora, Southern California and Arizona, coast lands of Chile; Oxytheca dendroidea, Lastarricea chilensis, and Chorizanthe comrnmissuralis, all in Southern California and Western Chile. (2) Those due to the operation of natural causes acting unde present conditions of climate, geology, etc. Under this head may be cited such species as sida leprosa, hastata, anomala, Cienfugosia sulphurea, Spergulariaplattensis and, in general, elements of Gulf zone distribution; also certain elements which still find a pathway along the continental axis, including some alpine and mountain xerophilous genera. (3) The third category of distribution would include those phenomena due to geological and climatic changes acting through long periods. Under this head are included the elements of greatest significance in the relationsip of the North and South America floras. The endemic boreal flora of the Andes, the equally endemic boreal flora of the Mexican Cordilleras, and genera with sharply distinct species or sub-genera in the arid extra-tropical regions of both continents, which may be called remnant elements.


Endocrine FGFs and their signaling in the brain: Relevance for energy homeostasis.
Since their discovery in 2000, there has been a continuous expansion of studies investigating the physiology, biochemistry, and pharmacology of endocrine fibroblast growth factors (FGFs). FGF19, FGF21, and FGF23 comprise a subfamily with attributes that distinguish them from typical FGFs, as they can act as hormones and are, therefore, referred to as endocrine FGFs. As they participate in a broad cross-organ endocrine signaling axis, endocrine FGFs are crucial lipidic, glycemic, and energetic metabolism regulators during energy availability fluctuations. They function as powerful metabolic signals in physiological responses induced by metabolic diseases, like type 2 diabetes and obesity. Pharmacologically, FGF19 and FGF21 cause body weight loss and ameliorate glucose homeostasis and energy expenditure in rodents and humans. In contrast, FGF23 expression in mice and humans has been linked with insulin resistance and obesity. Here, we discuss emerging concepts in endocrine FGF signaling in the brain and critically assess their putative role as therapeutic targets for treating metabolic disorders.


Statistical issues in tumor marker studies.
Inferences from tumor marker studies are complicated by a variety of statistical concerns, which can make proper interpretation of results difficult. This article focuses on important issues that should be addressed when designing, conducting, and analyzing tumor marker studies. To highlight the importance of considering statistical significance, risk ratios, statistical power, reproducibility, multiple testing, confirmatory studies, and missing data in the design of marker studies used for prognosis. Suggestions are provided for more effectively conducting marker studies. These include more careful attention to adequacy of the number of subjects for a marker study and improved documentation and standardization of assay methods. The importance of complete reporting of study results and description of the statistical analysis methods used is also emphasized. Cooperation among clinicians, laboratory scientists, and statisticians will be required to conduct statistically sound tumor marker studies and to facilitate prioritizing markers for new and confirmatory studies in an environment of limited patient and specimen resources.


Spectral Bandedness in High-Fidelity Computational Fluid Dynamics Predicts Rupture Status in Intracranial Aneurysms.
Recent studies using high-fidelity computational fluid dynamics (CFD) have revealed high-frequency flow instabilities consistent with clinical reports of bruits and "musical murmurs", which have been speculated to contribute to aneurysm growth and rupture. We hypothesized that harmonic flow instabilities ("spectral bandedness") in aneurysm CFD data may be associated with rupture status. Before testing this hypothesis, we first present a novel method for quantifying and visualizing spectral bandedness in cardiovascular CFD datasets based on musical audio-processing tools. Motivated by previous studies of aneurysm hemodynamics, we also computed a selection of existing metrics that have demonstrated association with rupture in large studies. In a dataset of 50 bifurcation aneurysm geometries modeled using high-fidelity CFD, our spectral bandedness index (SBI) was the only metric significantly associated with rupture status (AUC = 0.76, p = 0.002), with a specificity of 79% (correctly predicting 19/24 unruptured cases) and sensitivity of 65% (correctly predicting 17/26 ruptured cases). Three-dimensional flow visualizations revealed coherent regions of high SBI to be associated with strong near-wall inflow jets and vortex-shedding/flutter phenomena in the aneurysm sac. We speculate that these intracycle, coherent flow instabilities may preferentially contribute to the progressive degradation of the aneurysm wall through flow-induced vibrational mechanisms, and that their absence in high-fidelity CFD may be useful for identifying intracranial aneurysms at lower risk of rupture.


Preparation and characterization of films from pea protein.
The conditions for protein film preparation from an alkaline dispersion of a pea protein isolate were investigated in the presence of polyols as plasticizers. Mechanical and barrier properties of resulting films were studied as a function of protein dispersion conditions, protein and plasticizer concentrations and ratios, chain length of the plasticizer, and pH and composition of the alkaline medium. Neither the mode of protein hydration nor the pea isolate origin had a significant effect on the mechanical properties of pea protein films. However, increasing the plasticizer chain length induced slightly higher surface hydrophobicity but poor mechanical properties. Addition of monoglycerides to film-forming solution allowed a significant improvement of the films during aging. Both tensile strength and surface hydrophobicity increased when ammonium hydroxide was used as protein dispersing agent instead of sodium hydroxide.


Characterization of tetanus toxin binding to rat brain membranes. Evidence for a high-affinity proteinase-sensitive receptor.
Binding of 125I-labelled tetanus toxin to rat brain membranes in 25 mM-Tris/acetate, pH 6.0, was saturable and there was a single class of high-affinity site (KD 0.26-1.14 nM) present in high abundance (Bmax. 0.9-1.89 nmol/mg). The sites were largely resistant to proteolysis and heating but were markedly sensitive to neuraminidase. Trisialogangliosides were effective inhibitors of toxin binding (IC50 10 nM) and trisialogangliosides inserted into membranes lacking a toxin receptor were able to bind toxin with high affinity (KD 2.6 nM). The results are consistent with previous studies and the hypothesis that di- and trisialogangliosides act as the primary receptor for tetanus toxin under these conditions. In contrast, when toxin binding was assayed in Krebs-Ringer buffer, pH 7.4, binding was greatly reduced, was non-saturable and competition binding studies showed evidence for a small number of high-affinity sites (KD 0.42 nM, Bmax. 0.90 pmol/mg) and a larger number of low-affinity sites (KD 146 nM, Bmax. 179 pmol/mg). Treatment of membranes with proteinases, heat, and neuraminidase markedly reduced binding. Trisialogangliosides were poor inhibitors of toxin binding (IC50 11.0 microM), and trisialogangliosides inserted into membranes bound toxin with low affinity. The results suggest that in physiological buffers tetanus toxin binds with high affinity to a protein receptor, and that gangliosides represent only a low-affinity site.


Alignator: a GPU powered software package for robust fiducial-less alignment of cryo tilt-series.
The robust alignment of tilt-series collected for cryo-electron tomography in the absence of fiducial markers, is a problem that, especially for tilt-series of vitreous sections, still represents a significant challenge. Here we present a complete software package that implements a cross-correlation-based procedure that tracks similar image features that are present in several micrographs and explores them implicitly as substitutes for fiducials like gold beads and quantum dots. The added value compared to previous approaches, is that the algorithm explores a huge number of random positions, which are tracked on several micrographs, while being able to identify trace failures, using a cross-validation procedure based on the 3D marker model of the tilt-series. Furthermore, this method allows the reliable identification of areas which behave as a rigid body during the tilt-series and hence addresses specific difficulties for the alignment of vitreous sections, by correcting practical caveats. The resulting alignments can attain sub-pixel precision at the local level and is able to yield a substantial number of usable tilt-series (around 60%). In principle, the algorithm has the potential to run in a fully automated fashion, and could be used to align any tilt-series directly from the microscope. Finally, we have significantly improved the user interface and implemented the source code on the graphics processing unit (GPU) to accelerate the computations.


[Networks of care for ST-elevation myocardial infarction in Italy. Results of the RETE IMA WEB survey].
The organization of a regional system of care (RSC) for ST-elevation myocardial infarction (STEMI) is recommended by the Italian Federation of Cardiology (FIC) and international guidelines in order to increase the number of patients treated with primary coronary angioplasty and, more in general, with reperfusion therapy, speed up the diagnostic and therapeutic processes, and ultimately improve the outcome. The "RETE IMA WEB" survey was launched in 2007 from the Italian Society of Invasive Cardiology (SICI-GISE) in collaboration with the FIC, with the aim of evaluating the current state of RSC for STEMI in Italy. The personnel of the 118 Emergency System participated in the survey. Data collection was made using different electronic forms with access limited by personal passwords. We assessed the organization of the RSC together with local resource availability, with specific attention to the distance from a Hub center. The survey ended in December 31, 2008. We censored 701 hospitals admitting STEMI patients, 157 (22.4%) with uninterrupted access (h24/7 days) to the catheterization laboratory (2.67 per million inhabitants). An operative network was present in 36/103 (35.9%) provinces, with important geographic variability. Among hospitals without a full-time primary angioplasty facility, only 46% was within a RSC. ECG was available in 72% of the national territory, telemedicine in 50%. Prehospital fibrinolysis was available in 16% of the country. Overall, 92.4% of the Italian population resides within 60 min of a Hub center. In 2008, despite an adequate framework, the RSC for STEMI in Italy was heterogeneous and still suboptimal. Healthcare administrators, scientific societies and all operators involved in the process of care for STEMI should make efforts to implement current guidelines.


Use of singular value decomposition to characterize age and gender differences in SPECT cerebral perfusion.
The main objective of this study was to characterize changes in brain perfusion associated with normal aging and gender. Perfusion SPECT images using 99mTc-hexamethyl propyleneamine oxime (HMPAO) were obtained from 152 healthy subjects (67 men, 85 women) aged 50-92 yr. An automated method was developed to objectively assess image data from a large number of brain regions. Image data were reduced with singular value decomposition (SVD), which produced 20 eigenvectors capturing 97.05% of the total information content of 4320 regions from each subject. Subjects were scored individually on each vector. Multivariate analyses demonstrated that there were no significant differences in whole-brain HMPAO uptake with age, but age-related regional declines were seen in lateral ventricular regions. Women had higher HMPAO uptake than men in estimates of global perfusion and regional perfusion in the midcingulate/corpus callosum, inferior temporal and inferior parietal areas. These discriminations demonstrate that singular value deomposition of SPECT data may be used to assess differences in perfusion patterns between groups of subjects. They replicate several previous findings, both with respect to age-related changes in perfusion and with respect to gender differences. In addition, they identify a previously unreported gender difference in biparietal regions.


Catalytic Enantioselective Synthesis of Axially Chiral Imidazoles by Cation-Directed Desymmetrization.
Axially chiral five-membered heterobiaryls synthesized by enantioselective catalysis typically feature large ortho-substituents or a heteroatom in the chiral axis to maintain a stable configuration. Herein we report a cation-directed catalytic enantioselective desymmetrization method that enables rapid access to axially chiral imidazoles with the basic nitrogen at the ortho position and efficiently integrates π-stacking moieties to ensure a stable axial configuration for further applications. The process is operationally simple, is highly enantioselective, and can be performed on the gram scale. The majority of the products are obtained in >90% ee, but interestingly even those with only moderate ee can readily be enriched to near optical purity by selective racemate crystallization. Together with a mild phosphine oxide reduction method, axially chiral imidazoles such as StackPhos and its derivatives are readily prepared in high yield and excellent enantioselectivity on the gram scale. The method also enables the preparation of new chiral non-phosphine-bearing imidazoles.


Adaptive developmental plasticity in rhesus macaques: the serotonin transporter gene interacts with maternal care to affect juvenile social behaviour.
Research has increasingly highlighted the role that developmental plasticity-the ability of a particular genotype to produce variable phenotypes in response to different early environments-plays as an adaptive mechanism. One of the most widely studied genetic contributors to developmental plasticity in humans and rhesus macaques is a serotonin transporter gene-linked polymorphic region (5-HTTLPR), which determines transcriptional efficiency of the serotonin transporter gene in vitro and modifies the availability of synaptic serotonin in these species. A majority of studies to date have shown that carriers of a loss-of-function variant of the 5-HTTLPR, the short (s) allele, develop a stress-reactive phenotype in response to adverse early environments compared with long (l) allele homozygotes, leading to the prevalent conceptualization of the s-allele as a vulnerability allele. However, this framework fails to address the independent evolution of these loss-of-function mutations in both humans and macaques as well as the high population prevalence of s-alleles in both species. Here we show in free-ranging rhesus macaques that s-allele carriers benefit more from supportive early social environments than l-allele homozygotes, such that s-allele carriers which receive higher levels of maternal protection during infancy demonstrate greater social competence later in life. These findings provide, to our knowledge, the first empirical support for the assertion that the s-allele grants high undirected biological sensitivity to context in primates and suggest a mechanism through which the 5-HTTLPR s-allele is maintained in primate populations.


Characterization of heavy particles of adeno-associated virus type 1.
The temperature-sensitive mutant ts4 of adenovirus type 2 (Ad-2) is capable of complementing adeno-associated virus type 1 (AAV-1) in HEp2, KB and HEK cells at 34 degrees C and 39 degrees C when used as a helper virus. Heavy non-infectious AAV-1 particles can be generated by using the mutant ts4 in HEp2 cells. When AAV-1 is grown in serial passages in HEp2 cells, both the wild-type Ad-2 and the mutant ts4 give rise to heavy, less infectious AAV-1 particles. The heavy AAV-1 particles generated by Ad-2 in advanced serial passages retain the property of having CF and IF antigens, but the AAV-1 generated by the mutant in advanced serial passages lose this property. There is no appreciable difference in the particle counts made by electron microscopy of AAV-1 preparations generated either by Ad-2 or the mutant ts4. Analysis by polyacrylamide gel electrophoresis of purified heavy AAV generated by ts4 indicates that in late passage an additional polypeptide of higher mol. wt. than the three structural polypeptides is detected.


Interpenetrating network hydrogel beads of carboxymethylcellulose and egg albumin for controlled release of lipid lowering drug.
Novel interpenetrating network hydrogel beads of sodium carboxymethylcellulose and egg albumin loaded with a lipid lowering drug, simvastatin, were prepared by ionotropic gelation and covalent cross-linking method. The IPN beads were characterized by differential scanning colorimetric analysis, X-ray diffractometry to understand the crystalline nature of the drug after entrapment into IPN matrix. Fourier transform infrared spectroscopy was used to find the chemical stability of drug in the polymer matrix and scanning electron microscopy was performed to study the surface morphology. The ionically cross-linked beads were capable of releasing drug up to 7 h, whereas the drug release was extended up to 12 h in case of dual cross-linked beads. The beads which were prepared with higher concentration of glutaraldehyde released the drug more slowly. The release data were fitted to an empirical equation to determine the transport mechanism, which indicated the non-Fickian trend for drug transport.


Optimal and acceptable technical facilities involving risks.
Economic cost-benefit optimization of technical facility requires suitable "life saving cost" and/or an appropriate acceptance criterion if human life and limb are at risk. Traditionally, acceptance criteria implicit in codes of practice, standards, or regulations for well-defined fields of application are calibrated against past and present practice. This is all but satisfying. It is unclear whether present rules are already optimal. Extrapolations into new fields of application are extremely difficult. Direct cost-benefit analysis is proposed as an alternative. Based on the recently proposed "life quality index" (LQI), a rational acceptance criterion and so-called life saving cost are derived. The classical life quality index is reviewed, modified, and imbedded in modern economics theory. The results are then applied to technical facilities. The relation between optimization and the LQI-based acceptance criterion is discussed. The relevant economics literature is reviewed with respect to discount rates applicable for long-term investments into risk reduction. They should be as low as possible according to a recent mathematical result. Modern economic growth theory decomposes the output growth rate into the rate of time preference of consumption and the rate of economical growth multiplied by the elasticity of marginal utility of consumption. It is found that the rate of time preference of consumption should be a little larger than the long-term population growth rate. The public benefit rate (output growth rate) on the other hand should be smaller than the sum of the population growth rate and the long-term growth rate of a national economy, which is around 2% for most industrial countries. Accordingly, the rate of time preference of consumption is about 1%, which is also intergenerationally acceptable from an ethical point of view. Given a certain output growth rate there is a corresponding maximum financial interest rate in order to maintain nonnegativity of the objective function at the optimum. Finally, a simple demonstration example is added.


Too short to spawn? Implications of small body size and swimming distance on successful migration and maturation of the European eel Anguilla anguilla.
Individual net fat reserves after migration and reproductive investments were calculated for migrating female silver eels Anguilla anguilla (n = 387) collected in the outlet region of the Baltic Sea during the autumn run. It is estimated that 20·4% of the A. anguilla had completely exhausted all initial fat reserves and that 45·0% of A. anguilla were within 90% of complete energy depletion after migration and reproduction. This study concludes that a combination of body size and distance (6900 km) to the spawning area in the Sargasso Sea explains the results. An increase in the costs of migration due to heavy infection with Anguillicoloides crassus was also evaluated in an additional scenario with results showing that 26·4% of the A. anguilla had completely depleted all fat reserves. It is hypothesized that a large proportion of female silver A. anguilla from the Baltic Sea catchment area will have inadequate or suboptimal reserves for successful migration and reproduction.


Transcriptional profiling identifies novel regulators of macrophage polarization.
Macrophages are key inflammatory immune cells that display dynamic phenotypes and functions in response to their local microenvironment. Major advances have occurred in understanding the transcriptional, epigenetic, and functional differences in various macrophage subsets by in vitro modeling and gene expression and epigenetic profiling for biomarker discovery. However, there is still no standardized protocol for macrophage polarization largely due to the lack of thorough validation of macrophage phenotypes following polarization. In addition, transcriptional regulation is recognized as a major mechanism governing differential macrophage polarization programs and as such, many genes have been identified to be associated with each macrophage subset. However, the functional role of many of these genes in macrophage polarization is still unknown. Moreover, the role of other regulatory mechanisms, such as DNA methylation, in macrophage polarization remains poorly understood. Here, we employed an optimized model of human M1 and M2 macrophage polarization which we used for large-scale transcriptional and DNA methylation profiling. We were unable to demonstrate a role for DNA methylation in macrophage polarization, as no significant changes were identified. However, we observed significant changes in the transcriptomes of M1 and M2 macrophages. Additionally, we identified numerous novel differentially regulated genes involved in macrophage polarization, including CYBB and DHCR7 which we show as important regulators of M1 and M2 macrophage polarization, respectively. Taken together, our improved in vitro human M1 and M2 macrophage model provides new understandings of the regulation of macrophage polarization and candidate macrophage biomarkers.


Eye care outreach to an underserved rural population in Oyo State.
This paper is essentially an initial assessment of work done through a rural community outreach programme based in the ophthalmology department of a large teaching hospital. It evaluates the accessibility, acceptability, and initial effectiveness of the programme by presenting information on selected variables. The evaluation is used to assess the initial achievements of the programme against the planned objectives.


[Human vulnerability to Trypanosoma cruzi vector transmission through health-disease processes and social appropriation of the territory].
Risk studies of Trypanosoma cruzi vector transmission have classically overlooked the role of social behaviors and subjectivities within the natural landscape and social environment. A review and analysis of the literature on relevant biological, eco-epidemiological and sociocultural factors was combined with an ethnographic study in order to develop a risk model framework identifying the components of hazard and human vulnerability. Social practices, representations and knowledge regarding the health-disease-care process and the social appropriation of the territory are considered as elements explicative of human vulnerability. Exploring these components within an ethnographic analysis allows new options and more adequate prevention or comprehensive risk control measures to be identified.


Childhood lichen planus: a report of 23 cases.
Lichen planus (LP) in children is a rare entity. We report 23 cases of childhood LP seen over a period of 7 years. Ninety-six percent of the children were of Arab ancestry. There were 52% boys and 48% girls. Classic LP was the most common clinical variant (70%), followed by eruptive generalized LP (13%). A majority of the patients had mild, localized disease. Oral involvement was seen in 39% of patients. Topical steroids were the mainstay of treatment in most of the cases. Children with chronic and recurrent disease responded to dapsone therapy, whereas in those with eruptive and widespread disease, UVB phototherapy was found to be safe and effective. The present report highlights the salient clinical features, treatment, and course of LP in children in Kuwait compared to those reported in children of other countries as well as those of adults.


3β-Methyl-Neurosteroid Analogs Are Preferential Positive Allosteric Modulators and Direct Activators of Extrasynaptic δ-Subunit γ-Aminobutyric Acid Type A Receptors in the Hippocampus Dentate Gyrus Subfield.
Neurosteroids are powerful modulators of γ-aminobutyric acid (GABA)-A receptors. Ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one, GX) and synthetic analogs of the neurosteroid allopregnanolone (AP) are designed to treat epilepsy and related conditions. However, their precise mechanism of action in native neurons remains unclear. Here, we sought to determine the mode of action of GX and its analogs at GABA-A receptors in native hippocampal neurons by analyzing extrasynaptic receptor-mediated tonic currents and synaptic receptor-mediated phasic currents. Concentration-response profiles of GX were determined in two cell types: δ-containing dentate gyrus granule cells (DGGCs) and γ2-containing CA1 pyramidal cells (CA1PCs). GX produced significantly greater potentiation of the GABA-A receptor-activated chloride currents in DGGCs (500%) than CA1PCs (200%). In the absence of GABA, GX evoked 2-fold greater inward currents in DGGCs than CA1PCs, which were 2-fold greater than AP within DGGCs. In hippocampus slices, GX potentiated and directly activated tonic currents in DGGCs. These responses were significantly diminished in DGGCs from δ-subunit knockout (δKO) mice, confirming GX's selectivity for δGABA-A receptors. Like AP, GX potentiation of tonic currents was prevented by protein kinase C inhibition. Furthermore, GX's protection against hippocampus-kindled seizures was significantly diminished in δKO mice. GX analogs exhibited greater potency and efficacy than GX on δGABA-A receptor-mediated tonic inhibition. In summary, these results provide strong evidence that GX and its analogs are preferential allosteric modulators and direct activators of extrasynaptic δGABA-A receptors regulating network inhibition and seizures in the dentate gyrus. Therefore, these findings provide a mechanistic rationale for the clinical use of synthetic neurosteroids in epilepsy and seizure disorders.


Evaluation of a Novel Stool Antigen Rapid Test Kit for Detection of Helicobacter pylori Infection.
The Quick Chaser H. pylori (QCP), which is a novel antigen detection kit for Helicobacter pylori, was developed recently. The previous examination kits targeted the catalase of H. pylori; however, this new test kit, to the best of our knowledge, is the first kit to target the flagellar protein of H. pylori The present study aimed to evaluate the efficacy of QCP compared with that of the already commercially available rapid test kit Testmate Rapid Pylori Antigen (TRP). TRP and QCP were utilized in 71 participants. The positive and negative concordance ratios of QCP to TRP were 100% (57/57) and 92.9% (13/14), respectively. Sensitivity based on the rapid urease test and culture test was 92.3%. Results of the dilution sensitivity test showed that QCP was eight times more sensitive to an H. pylori standard strain and the clarithromycin (CAM)-resistant clinical isolate and four times more sensitive to a CAM-susceptible clinical isolate than TRP. For the cross-reactivity test, 27 strains that exist in human feces, such as the Helicobacter genus, Bifidobacterium genus, Lactobacillus genus, and other resident bacteria, were selected. The results obtained using QCP were all negative, and no cross-reaction was observed. In conclusion, compared with TRP, QCP can detect H. pylori using clinical specimens with high sensitivity, regardless of CAM susceptibility and tolerance. No cross-reactivity was observed with other intestinal bacteria in humans. The kit is considered extremely useful in clinical settings.


Malignant melanoma in southern Arizona. Increasing incidence and sunlight as an etiologic factor.
This study demonstrated an increasing incidence of malignant melanoma during the past ten years and a very high incidence of this tumor in southern Arizona. During the ten-year period, 533 melanomas were removed from white patients. Of these, 52% were male and 48% were female. The number of melanomas increased yearly, from 20 in 1969 to 120 in 1978, a crude rate incidence of 6.49 to 28.57 (27.20 standardized) per 100,000, respectively. This reflects an average annual increase of 34% to 37% and a 340% increase for the period. The highest incidence of tumor was in the 50 to 59 year and 60 to 69 year age groups. The most common site of occurrence was the back, with twice as many tumors arising there in males. The legs were involved in 13% of patients, with an occurrence rate eight times higher in females. The extremely high incidence of melanomas in southern Arizona is probably due to meteorologic and geographic factors allowing large amounts of ultraviolet light to reach the earth's surface.


Hepatitis B virus HBx protein activation of cyclin A-cyclin-dependent kinase 2 complexes and G1 transit via a Src kinase pathway.
Numerous studies have demonstrated that the hepatitis B virus HBx protein stimulates signal transduction pathways and may bind to certain transcription factors, particularly the cyclic AMP response element binding protein, CREB. HBx has also been shown to promote early cell cycle progression, possibly by functionally replacing the TATA-binding protein-associated factor 250 (TAF(II)250), a transcriptional coactivator, and/or by stimulating cytoplasmic signal transduction pathways. To understand the basis for early cell cycle progression mediated by HBx, we characterized the molecular mechanism by which HBx promotes deregulation of the G0 and G1 cell cycle checkpoints in growth-arrested cells. We demonstrate that TAF(II)250 is absolutely required for HBx activation of the cyclin A promoter and for promotion of early cell cycle transit from G0 through G1. Thus, HBx does not functionally replace TAF(II)250 for transcriptional activity or for cell cycle progression, in contrast to a previous report. Instead, HBx is shown to activate the cyclin A promoter, induce cyclin A-cyclin-dependent kinase 2 complexes, and promote cycling of growth-arrested cells into G1 through a pathway involving activation of Src tyrosine kinases. HBx stimulation of Src kinases and cyclin gene expression was found to force growth-arrested cells to transit through G1 but to stall at the junction with S phase, which may be important for viral replication.


Highly selective sorption and unique packing geometries of unsaturated hydrocarbons and CO2 in a fluorine-substituted organic-inorganic ionic crystal.
An ionic crystal [Cr3O(OOCCF3)6(H2O)3]3[α-PW12O40]·8CH3COCH3·8H2O·CHCl3 [Ia] was synthesized by the complexation of a fluorine-substituted macrocation with a phosphododecatungstate. Compound Ia possessed a layered structure with an interlayer distance of ca. 3.5 Å, and the inner surface of the layer was decorated with CF3 groups of the macrocations. The solvent molecules (acetone and chloroform) spontaneously desorbed and exchanged with water under an ambient atmosphere and a hydrated phase [Cr3O(OOCCF3)6(H2O)3]3[α-PW12O40]·25H2O [Ib] was formed. The water molecules were partially desorbed by the treatment of Ibin vacuo or under a dry N2 or He flow at 298-303 K, and [Cr3O(OOCCF3)6(H2O)3]3[α-PW12O40]·15H2O [Ic] was formed. The powder XRD pattern of Ic well agreed with that calculated for Ia, showing that the structure was maintained after the exchange and partial desorption of guests. Compound Ic sorbed CO2 and unsaturated hydrocarbons, while saturated hydrocarbons such as ethane and methane were almost excluded despite the similar kinetic diameters. Acetylene/methane, CO2/methane, and ethylene/ethane sorption ratios were 13, 15, and 4.9, respectively, at 198 K and 100 kPa. Typical Monte Carlo-based optimized geometries of acetylene and CO2 showed different alignments in the structure of Ic despite the similar amounts of sorption and molecular sizes. Acetylene and CO2 were aligned mainly parallel and perpendicular, respectively, to the layer, which is probably due to the differences in the electron density distributions of the HOMO orbitals.


The crystal structure of RsSymEG1 reveals a unique form of smaller GH7 endoglucanases alongside GH7 cellobiohydrolases in protist symbionts of termites.
Glycoside hydrolase family 7 (GH7) cellulases are key enzymes responsible for carbon cycling on earth through their role in cellulose degradation, and constitute highly important industrial enzymes as well. Although these enzymes are found in a wide variety of evolutionarily distant organisms across eukaryotes, they exhibit remarkably conserved features within two groups: exo-acting cellobiohydrolases, and endoglucanases. However, recently reports have emerged of a separate clade of GH7 endoglucanases from protist symbionts of termites that are 60-80 amino acids shorter. In this work, we describe the first crystal structure of a short GH7 endoglucanase, RsSymEG1, from a symbiont of the lower termite Reticulitermes speratus. A more open flat surface and shorter loops around the non-reducing end of the cellulose-binding cleft indicate enhanced access to cellulose chains on the surface of cellulose microfibrils. Additionally, when comparing activities on polysaccharides to a typical fungal GH7 endoglucanase (Trichoderma longibrachiatum Cel7B), RsSymEG1 showed significantly faster initial hydrolytic activity. We also examine the prevalence and diversity of GH7 enzymes that the symbionts provide to the termite host, compare overall structures and substrate binding between cellobiohydrolase and long and short endoglucanase, and highlight the presence of similar short GH7s in other organisms.


Metabolic syndrome in Turkish children and adolescents.
The aim of this study was to determine the prevalence and phenotype of metabolic syndrome in Turkish children and adolescents. We adapted the National Cholesterol Education Program Adult Treatment Panel III criteria of metabolic syndrome to children and adolescents. Using the international cutoff points and percentiles, we determined 10- to 17-year-old Turkish children and adolescents with high blood pressure, high triglyceride (TG), low high-density lipoprotein cholesterol (HDL-C), fasting glucose of 100 mg/dL or greater, and elevated body mass index corresponding to overweight or obesity. We examined 1385 apparently healthy students between the ages of 10 to 17 years from Ankara, Turkey: 4.9% of the subjects were overweight or obese; 29.2% had either low HDL-C and/or high TG levels; and 15.7% had either systolic or diastolic blood pressure above the 95th age-, sex-, and height-specific percentile. Thirty students (2.2%) had metabolic syndrome by having 3 or more risk variables. Metabolic syndrome was nearly 10 times more common among overweight and obese students (21%), compared with lean students. Components of metabolic syndrome such as high blood pressure and high TG, and low HDL-C levels were common among Turkish children and adolescents. Strategies should focus on early detection and treatment of these risk variables in Turkish children.


White matter tractography in bipolar disorder and schizophrenia.
Abnormalities of white matter integrity have been repeatedly demonstrated in both schizophrenia and bipolar disorder with voxel based methods. Because these methods are limited in their ability to localize deficits to specific tracts, we sought to investigate alterations in fractional anisotropy (FA) in the uncinate fasciculus and anterior thalamic radiation with probabilistic tractography. Individuals with schizophrenia (n = 25) or bipolar disorder (n = 40) were recruited from families with two or more affected members and age-matched to a control group (n = 49). All participants underwent diffusion tensor magnetic resonance imaging that was subsequently analyzed with probabilistic tractography. Mean FA was calculated bilaterally for the uncinate and anterior thalamic radiation and compared between groups with repeated measures analysis of variance. Patients with schizophrenia or bipolar disorder showed common reductions in the uncinate fasciculus and anterior thalamic radiation. These reductions were unrelated to age, duration of illness, current medication, or current psychiatric symptoms in all patients or the lifetime presence of psychotic symptoms in bipolar subjects. Patients with schizophrenia or bipolar disorder show common abnormalities in the uncinate fasciculus and anterior thalamic radiation that fail to respect traditional diagnostic boundaries. These deficits might be related to shared risk factors and disease mechanisms common to both disorders.


Interventions Designed to Improve the Learning Environment in the Health Professions: A Scoping Review.
This article was migrated. The article was marked as recommended. Purpose: To identify and describe interventions designed to affect the learning environment (LE) in health professions education, summarize factors that influence the LE, and determine gaps that require additional research. The LE can be thought of as a dynamic and complex construct co-created by people in a particular setting. A positive LE represents a welcoming climate for learning, which enhances satisfaction, well-being, academic performance and collaboration, while a negative LE restricts participation and learning, leading to emotional exhaustion, depersonalization and burnout. Method: A six-step scoping review methodology was followed to identify and report on literature that describes interventions affecting the LE in the health professions education: 1. Identify the research question, 2. Identify relevant studies, 3. Select studies to be included, 4. Chart the data, 5. Collate, summarize and report results, and 6. Consult with stakeholders. Results: 2,201 unique citations were identified and reviewed using titles and abstracts. 240 full-text articles were retained for detailed review, resulting in the inclusion of 68 articles. Study results are reported in relation to essential components of the LE: personal, social, organizational, physical and virtual spaces. Results of four different types to the studies of the LE are described: specific interventionsimpacting the LE, comparisonsof perceptions of the LE by two or more different groups, associations with other variable such as well-being with the LE, and descriptivestudies of the LE. Major influences included accreditation regulations, curricular interventions, faculty/staff development grading practices, instructional interventions, placements, physical and virtual spaces, and support services; and are reported along with specific interventions. Conclusion: These results reflect the complexity of the LE and the need for conceptual clarity. Since the quality of the evidence was not evaluated, the identified influences should be viewed as potential opportunities to improve the LE.


A closer look at academic probation and attrition: what courses are predictive of nursing student success?
The purpose of this retrospective study was to identify undergraduate courses that serve as predictors of success for nursing students completing a BSN program. The sample included records of 327 students placed on probation or dismissed from a Midwest school of nursing between 2002 and 2010. Though previous research has shown that science courses can be used as predictors of nursing student success, our results suggest that non-science courses can serve in this capacity as well. In particular, an across-the-life-span fundamental psychology course was found to be an important predictor in determining whether or not probationary students eventually completed the program. These results suggest that nursing programs need to evaluate their programs not only reviewing students success in nursing courses but also in prerequisites beyond just science courses such as chemistry and biology.


Differential expression of ABCB5 in BRAF inhibitor-resistant melanoma cell lines.
More than 50% of metastatic melanoma patients have a specific mutation in the serine/threonine kinase BRAF. This results in constitutive activation of the RAS-RAF-MEK-ERK-MAP kinase pathway, which causes uncontrolled cell growth. Vemurafenib (PLX4032) is an oral chemotherapeutic agent that targets the specific mutation V600E in the BRAF protein. Initial response rates are high in patients with BRAF mutant melanoma treated with a BRAF inhibitor such as vemurafenib, but resistance nearly always develops and disease progression ensues. There are several different mechanisms by which melanoma develops BRAF inhibitor resistance. One potential component of resistance is increased drug efflux. Overexpressed ABCB5 (ATP-binding cassette transporter, subfamily B, member 5) has been shown to efflux anti-cancer drugs from cancer cells. The purpose of this study is to determine whether ABCB5 is highly expressed in BRAF inhibitor-resistant melanoma cells and to evaluate whether ABCB5 is involved in the development of resistance to BRAF inhibitors in cutaneous melanoma. We established three BRAF inhibitor-resistant melanoma cell lines with BRAF mutation. The expression level of ABCB5 in PLX-resistant cell lines was checked by real-time PCR and Western blot analysis. SK-MEL-2 melanoma cells with wild-type BRAF were used for comparison. The association of different levels of ABCB5 with the changes of ERK, p-ERK, Akt and p-Akt was also assessed by Western blotting. Re-sensitization of melanoma cells to PLX was tested by p-ERK inhibitor PD58059 and ABCB5 knockdown by ABCB5 siRNA, respectively. We showed that ABCB5 was overexpressed in SK-MEL-28PLXr and A2058PLXr cells but not in A375PLXr cells. ABCB5 overexpression is associated with activation of p-ERK status but not Akt. Inhibition of p-ERK re-sensitized SK-MEL-28PLXr and A2058PLXr cells to PLX treatment, but knockdown of ABCB5 did not re-sensitize A2058 PLXr and SK-MEL-28 PLXr cells to PLX treatment. These results confirm that, even though ABCB5 was overexpressed in SK-MEL-28 and A2058 melanoma cells that develop resistance to BRAF inhibitors, ABCB5 may not be a major targetable contributor to BRAF resistance. p-ERK inhibition may play important roles in BRAF resistance in these two melanoma cell lines.


[Unusual cause of tetraparesis in an adult].
A 61 year old male developed progressive spastic tetraparesis and paresis of the lower cranial nerves (IX, X and XI) after a minor spine-head trauma. Magnetic resonance depicted a partially cystic IV ventricular mass, extending to C1/C2 level. Neuropathology was compatible with choroids plexus papilloma (CCP). This case shows a rare clinical presentation of an infrequent adult tumour.


[Cardiovascular risk and dyslipidemias].
The relationship between plasma lipid abnormalities and the risk for cardiovascular disease is now clearly established. In addition to quantitative abnormalities such as increased plasma LDL-cholesterol and decreased HDL-cholesterol levels, lipid qualitative abnormalities are likely to play an important role in the pathogenesis of atherosclerosis. Indeed, dense triglyceride-rich LDL particles are atherogenic. Moreover, oxidized LDL are associated with increased cardiovascular risk and may play a central role in the pathogenesis of the atherosclerotic plaque. Fasting triglyceride level has rarely been shown to be an independent risk factor for cardiovascular disease, in the general population, but plasma triglyceride levels, following an oral fat load, seem to be a better marker. Recent intervention studies have shown an early effect of HMGCoA-reductase inhibitors in reducing cardiovascular morbidity and mortality, suggesting possible additive actions of statins on the atherosclerotic plaque, on the endothelial function and on thrombosis. The Care study shows that a clinical benefit with pravastatin treatment, in secondary prevention, can be obtained in patients with LDL-cholesterol above 125 mg/dl. If all the primary and secondary intervention studies have shown reduction of cardiovascular morbidity and mortality with hypolipidemic drugs, we also have to keep in mind the positive results from the dietary intervention studies, showing beneficial actions of diets rich in vitamins, fibers and omega 3 fatty acids. In clinical practice, compliance of the patient to his treatment is often difficult to achieve and many studies have shown that control of hyperlipidemia is frequently inaccurate and needs to be reinforced. A comprehensive education of the hyperlipidemic patient is urgently needed in order to improve his knowledge about hypolipidemic diet and to obtain his motivation which is essential for a long term compliance.


Effects of bed-rest on urea and creatinine: correlation with changes in fat-free mass.
Bed-rest experiments are designed for investigation on catabolic effects of hypokinetic conditions and/or for microgravity simulation in on-ground aerospace research. Bed-rest effects include a reduction in fat-free mass and muscle mass. Urea and creatinine are catabolites of endogenous protein and of muscular energetic metabolism which are excreted mainly by the kidney. The study investigated on urea, creatinine, and kidney function during bed-rest. Twenty healthy young men underwent a 7-day adaptation period (day-6 to day-0) and a 35-day bed-rest experiment (day1 to day35) during normocaloric diet. Urine were collected from day-3 to day0 (baseline) and from day1 to day35. Blood samples and anthropometrical data were collected at day0 (baseline) and bed-rest days 7, 14, 21, 28, and 35. Bed-rest reduced plasma volume, weight, fat-free mass, and muscle mass (P<0.001). During bed-rest there was a transient increase in plasma and urinary urea, a decrease in plasma creatinine, and no change in urinary creatinine. The overall integral of changes from day0 to day35 was on average +101.7 mg/dL for plasma urea (95%CI = +43.4/+159.9), +82.2 g/24 h for urinary urea (95%CI = +55.8/+108.7), -2.5 mg/dL for plasma creatinine (95%CI = -3.1/-1.9). Bed-rest reduced plasma cistatyn C also, which was used as mass-independent marker of glomerular filtration rate (-13.1%, P<0.05). Correlations with final reduction in fat-free mass and muscle mass were significant for the overall integral of changes in urinary urea from day0 to day35 (R = 0.706, P<0.001) and for early changes in urinary urea and plasma urea from day0 to day7 (R = 0.566, P = 0.009 and R = 0.715, P<0.001, respectively). Study results shows that urea is a marker of catabolic conditions secondary to hypokinetic conditions.


Ensuring adequate return on investment for primary care networks.
Developing and managing a successful primary care network requires a vision of what that network must accomplish, realistic performance objectives, well-designed management and support systems, and methods to reverse adverse performance trends if they occur. This article offers suggestions for fulfilling each of these requirements to help a healthcare organization achieve its long-term financial goal in a healthcare environment dominated by managed care.