The inhibitory spillover effect: Controlling the bladder makes better liars.
The Inhibitory-Spillover-Effect (ISE) on a deception task was investigated. The ISE occurs when performance in one self-control task facilitates performance in another (simultaneously conducted) self-control task. Deceiving requires increased access to inhibitory control. We hypothesized that inducing liars to control urination urgency (physical inhibition) would facilitate control during deceptive interviews (cognitive inhibition). Participants drank small (low-control) or large (high-control) amounts of water. Next, they lied or told the truth to an interviewer. Third-party observers assessed the presence of behavioral cues and made true/lie judgments. In the high-control, but not the low-control condition, liars displayed significantly fewer behavioral cues to deception, more behavioral cues signaling truth, and provided longer and more complex accounts than truth-tellers. Accuracy detecting liars in the high-control condition was significantly impaired; observers revealed bias toward perceiving liars as truth-tellers. The ISE can operate in complex behaviors. Acts of deception can be facilitated by covert manipulations of self-control.


Effect of the oncolytic ECHO-7 virus Rigvir® on the viability of cell lines of human origin in vitro.
Background: The role of oncolytic viruses in cancer treatment is increasingly studied. The first oncolytic virus (Rigvir®, ECHO-7) was registered in Latvia over a decade ago. In a recent retrospective study Rigvir® decreased mortality 4.39-6.57-fold in stage IB-IIC melanoma patients. The aims of the present study are to test the effect of Rigvir® on cell line viability in vitro and to visualize the cellular presence of Rigvir® by immunocytochemistry. Methods: The cytolytic effect of Rigvir® on the viability of FM-9, RD, AGS, A549, HDFa, HPAF‑II, MSC, MCF7, HaCaT, and Sk-Mel-28 cell lines was measured using live cell imaging. PBMC viability was measured using flow cytometry. The presence of ECHO-7 virus was visualized using immunocytochemistry. Statistical difference between treatment groups was calculated using two-way ANOVA. Results: Rigvir® (10%, volume/volume) reduced cell viability in FM-9, RD, AGS, A549, HDFa, HPAF‑II and MSC cell lines by 67-100%. HaCaT cell viability was partly affected while Rigvir® had no effect on MCF7, Sk-Mel-28 and PBMC viability. Detection of ECHO-7 by immunocytochemistry in FM-9, RD, AGS, A549, HDFa, HPAF-II and Sk-Mel-28 cell lines suggests that the presence of Rigvir® in the cells preceded or coincided with the time of reduction of cell viability. Rigvir® (10%) had no effect on live PBMC count. Conclusions: The results suggest that Rigvir® in vitro reduces the viability of cells of human melanoma, rhabdomyosarcoma, gastric adenocarcinoma, lung carcinoma, pancreas adenocarcinoma but not in PBMC. The presence of Rigvir® in the sensitive cells was confirmed using anti-ECHO-7 antibodies. The present results suggest that a mechanism of action for the clinical benefit of Rigvir® is its cytolytic properties. The present results suggest that the effect of Rigvir® could be tested in other cancers besides melanoma. Further studies of possible Rigvir® entry receptors are needed.


Suppressing Kv1.3 Ion Channel Activity with a Novel Small Molecule Inhibitor Ameliorates Inflammation in a Humanised Mouse Model of Ulcerative Colitis.
The potassium channel Kv1.3 is a potentially attractive therapeutic target in T cell-mediated inflammatory diseases, as the activity of antigen-activated T cells is selectively impeded by Kv1.3 inhibition. In this study, we examined Kv1.3 as a potential therapeutic intervention point for ulcerative colitis [UC], and studied the efficacy of DES1, a small-molecule inhibitor of Kv1.3, in vitro and in vivo. Kv1.3 expression on T cells in peripheral blood mononuclear cells [PBMCs] isolated from donors with and without UC was examined by flow cytometry. In biopsies from UC patients, Kv1.3-expressing CD4+ T cells were detected by flow cytometry and immunohistochemistry. In vitro, we determined the ability of DES1 to inhibit anti-CD3-driven activation of T cells. In vivo, the efficacy of DES1 was determined in a humanised mouse model of UC and compared with infliximab and tofacitinib in head-to-head studies. Kv1.3 expression was elevated in PBMCs from UC patients and correlated with the prevalence of TH1 and TH2 T cells. Kv1.3 expression was also detected on T cells from biopsies of UC patients. In vitro, DES1 suppressed anti-CD3-driven activation of T cells in a concentration-dependent manner. In vivo, DES1 significantly ameliorated inflammation in the UC model and most effectively so when PBMCs from donors with higher levels of activated T cells were selected for reconstitution. The efficacy of DES1 was comparable to that of either infliximab or tofacitinib. Inhibition of Kv1.3 [by DES1, for instance] appears to be a potential therapeutic intervention strategy for UC patients.


The p53QS transactivation-deficient mutant shows stress-specific apoptotic activity and induces embryonic lethality.
The role of transcriptional activation in p53 function is highly controversial. To define this role in vivo, we generated a Trp53 knock-in construct encoding a protein carrying mutations of two residues that are crucial for transactivation (L25Q,W26S). Here we show that these mutations have selective effects on the biological functions of p53. Although its ability to activate various p53 target genes is largely compromised, the p53(QS) protein retains the ability to transactivate the gene Bax. The ability of the p53(QS) mutant protein to elicit a DNA damage-induced G1 cell cycle-arrest response is also partially impaired. p53(QS) has selective defects in its ability to induce apoptosis: it is completely unable to activate apoptosis in response to DNA damage, is partially unable to do so when subjected to serum deprivation and retains substantial apoptotic activity upon exposure to hypoxia. These findings suggest that p53 acts through distinct, stimulus-specific pathways to induce apoptosis. The importance of the biological activity of p53(QS) in vivo is underscored by our finding that expression of p53(QS), which cannot bind mdm2, induces embryonic lethality. Taken together, these results suggest that p53 has different mechanisms of action depending on specific contextual cues, which may help to clarify the function of p53 in preventing cancer.


Four new metal-organic frameworks based on diverse secondary building units: sensing and magnetic properties.
Four new metal-organic frameworks (MOFs), {[Zn3(L)(OH)(H2O)5]·NMP·2H2O}n (1), {[H2N(Me)2][Zn2(L)(H2O)]·DMF·H2O}n (2), {[Co5(L)2(H2O)11]·2H2O}n (3) and {[Mn5(L)2(H2O)12]·6H2O}n (4), were assembled employing a symmetrical V-shaped rigid multicarboxylic acid ligand H5L (H5L = 2,4-di(3',5'-dicarboxylphenyl)benzoic acid) with different metal ions, resulting in versatile frameworks as well as various types of coordination modes of H5L. 1 forms a three-dimensional (3D) 4-connected sra net based on trinuclear [Zn3(μ3-OH)(μ2-COO)(μ1-COO)4] clusters, while 2 displays a 3D (4,6)-connected net based on two types of binuclear [Zn2(μ2-COO)2(μ1-COO)4] and [Zn2(μ2-COO)4] clusters. 3 and 4 contain similar [M3(μ2-COO)4(μ1-COO)2] (3, M = Co; 4, M = Mn) clusters but result in different 4-connected 3D and 2D frameworks, respectively. 1 and 2 show solid-state luminescence properties at ambient temperature. Meanwhile, 1 shows high selectivity and sensitivity for not only Fe3+ cations but also for CrO42-, Cr2O72- and MnO4- anions via a luminescence quenching effect with a low detection limit, which thus means that it could be a potential crystalline material for detecting these anions. The mechanisms of the quenching effect and sensing properties of 1 are discussed in detail. In addition, 3 and 4 have the presence of antiferromagnetic interactions between the metal ions.


The corepressors GPS2 and SMRT control enhancer and silencer remodeling via eRNA transcription during inflammatory activation of macrophages.
While the role of transcription factors and coactivators in controlling enhancer activity and chromatin structure linked to gene expression is well established, the involvement of corepressors is not. Using inflammatory macrophage activation as a model, we investigate here a corepressor complex containing GPS2 and SMRT both genome-wide and at the Ccl2 locus, encoding the chemokine CCL2 (MCP-1). We report that corepressors co-occupy candidate enhancers along with the coactivators CBP (H3K27 acetylase) and MED1 (mediator) but act antagonistically by repressing eRNA transcription-coupled H3K27 acetylation. Genome editing, transcriptional interference, and cistrome analysis reveals that apparently related enhancer and silencer elements control Ccl2 transcription in opposite ways. 4C-seq indicates that corepressor depletion or inflammatory signaling functions mechanistically similarly to trigger enhancer activation. In ob/ob mice, adipose tissue macrophage-selective depletion of the Ccl2 enhancer-transcribed eRNA reduces metaflammation. Thus, the identified corepressor-eRNA-chemokine pathway operates in vivo and suggests therapeutic opportunities by targeting eRNAs in immuno-metabolic diseases.


Attentional limitations in processing sequentially presented vibrotactile targets.
In seven experiments, participants experienced rapid, serially presented streams of vibrations and responded to specific targets in the streams. In visual (and sometimes auditory) streams presented in this manner, it is typical to find a deficit in reporting the second of two targets when both must be reported and the second appears within a short temporal interval of the first, but not when identical displays are presented but only the second target must be reported (e.g., the attentional blink, or AB). This conventional AB pattern was found in the last experiment, in which judgments were about target location. However in the first six experiments reported here, in which judgments were about frequency, intensity, duration, or location of targets, accuracy was dependent on target separation regardless of whether or not the first target was reported. This unconventional pattern could represent an AB if the first target was attended even when it was not reported. The evidence for this claim and an alternative possibility that location judgments are especially sensitive to attention manipulations are discussed.


Retinopathy of prematurity risk factors: Does human milk prevent retinopathy of prematurity?
Akyüz-Ünsal Aİ, Key Ö, Güler D, Bekmez S, Sagus M, Akcan AB, Kurt-Omurlu İ, Anık A, Oruç-Dündar S, Türkmen M. Retinopathy of prematurity risk factors: Does human milk prevent retinopathy of prematurity? Turk J Pediatr 2019; 61: 13-19. The aim of this study was to investigate the risk factors for Retinopathy of Prematurity (ROP) development and the potential effect of human breast milk among these factors. For this purpose, infants admitted to a tertiary referral clinic for ROP screening and treatment between April 2013 and May 2015, were included in this retrospective study. The demographic data, accompanying diseases, previous surgery, type of feeding and duration of human breast milk intake were recorded. According to the ROP screening examination results, infants were divided into two groups as those with ROP (infants at any stage of ROP) and those without ROP. Relationship between the risk factors and ROP were evaluated. The comparison of 221 infants without ROP and 99 infants with ROP; revealed that gestational age at birth, birth weight, mechanical ventilation support, bronchopulmonary and cardiac diseases, hydrocephaly, any previous surgery, infections, steroid treatment percentages were high and human breast milk intake percentage was low among infants with ROP. Mean breast feeding time for infants with ROP (3.81 ± 2.33 month) was shorter than the infants without ROP (5.51 ± 1.43 month) (p < 0.001). In logistic regression analysis, the duration of breast feeding was inversely related with ROP (OR 0.744; 95% CI 0.621-0.891; p < 0,001). These results suggest that gestational age at birth and accompanying diseases are the main risk factors for the development of ROP. As the duration of the breast feeding of the infants without ROP was longer than the infants with ROP; breast feeding may have a preventive effect on ROP development.


Anti-Mesothelin Nanobodies for Both Conventional and Nanoparticle-Based Biomedical Applications.
Mesothelin, a cancer biomarker overexpressed in tumors of epithelial origin, is a target for nanotechnology-based diagnostic, therapeutic, and prognostic applications. The currently available anti-mesothelin antibodies present limitations, including low penetration due to large size and/or lack of in vivo stability. Single domain antibodies (sdAbs) or nanobodies (Nbs) provide powerful solutions to these specific problems. We generated a phage-display library of Nbs that were amplified from B cells of a llama that was immunized with human recombinant mesothelin. Two nanobodies (Nb A1 and Nb C6) were selected on the basis of affinity (K(D) = 15 and 30 nM, respectively). Nb A1 was further modified by adding either a cysteine to permit maleimide-based bioconjugations or a sequence for the site-specific metabolic addition of a biotin in vivo. Both systems of conjugation (thiol-maleimide and streptavidin/biotin) were used to characterize and validate Nb A1 and to functionalize nanoparticles. We showed that anti-mesothelin Nb A1 could detect native and denatured mesothelin in various diagnostic applications, including flow cytometry, western blotting, immunofluorescence, and optical imaging. In conclusion, anti-mesothelin Nbs are novel, cost-effective, small, and single domain reagents with high affinity and specificity for the tumor-associated antigen mesothelin, which can be simply bioengineered for attachment to nanoparticles or modified surfaces using multiple bioconjugation strategies. These anti-mesothelin Nbs can be useful in both conventional and nanotechnology-based diagnostic, therapeutic and prognostic biomedical applications.


Reliability and accuracy of the South African Triage Scale when used by nurses in the emergency department of Timergara Hospital, Pakistan.
Triage is one of the core requirements for the provision of effective emergency care and has been shown to reduce patient mortality. However, in low- and middle-income countries this strategy is underused, under-resourced and poorly researched. To assess the inter- and intra-rater reliability and accuracy of nurse triage ratings when using the South African Triage Scale (SATS) in an emergency department (ED) in Timergara, Pakistan. Fifteen ED nurses assigned triage ratings to a set of 42 reference vignettes (written case reports of ED patients) under classroom conditions. Inter-rater reliability was assessed by comparing these triage ratings; intra-rater reliability was assessed by asking the nurses to re-triage 10 random vignettes from the original set of 42 vignettes and comparing these duplicate ratings. Accuracy of the nurse ratings was measured against the reference standard. Inter-rater reliability was substantial (intraclass correlation coefficient 0.77; 95% confidence interval (CI) 0.69 - 0.85). The intra-rater agreement was also high with 87% exact agreement (95% CI 67 - 100) and 100% agreement allowing for a one-level discrepancy in triage ratings. Overall, the SATS had high specificity (97%) and moderate sensitivity (70%). Across all acuity levels the proportion of over-triage did not exceed the acceptable threshold of 30 - 50%. Under-triage was acceptable for all except emergency cases (66%). ED nurses in Pakistan can reliably use the SATS to assign triage acuity ratings. While the tool is accurate for 'very urgent' and 'routine' cases, importantly, it may under-triage 'emergency' cases requiring immediate attention. Approaches that will improve accuracy and validity are discussed.


Effects of alcohol and caloric restrictions on blood pressure and serum lipids in overweight men.
We have examined the independent and combined effects on blood pressure and blood lipids of alcohol restriction and weight loss in overweight male drinkers with a view to assessing overall effects on cardiovascular risk of two widely promoted nonpharmacological approaches for hypertension. Eighty-six men with a mean age of 44.3 years, a mean regular alcohol intake of 440 ml/wk (five or six standard drinks per day), a mean blood pressure of 137.4 mm Hg systolic and 84.8 mm Hg diastolic, and a mean body mass of 92.5 kg entered a controlled two-way factorial study. The subjects were randomly assigned to four groups for an 18-week intervention in which members of two groups drank only low-alcohol beer, thereby reducing their alcohol intake by 374 ml/wk, while those of the other two groups continued their normal alcohol intake. Within the low and normal alcohol intake groups subjects either continued their usual diet or reduced their caloric intake by 4,200-6,300 kJ/day (1,000-1,500 kcal/day) (with protein, fat, and carbohydrate provided as 15%, 30%, and 55% of total calories, respectively). Calorie reduction and alcohol restriction caused weight losses of 7.5 (p less than 0.001) and 2.1 (p less than 0.01) kg, respectively. Calorie reduction and alcohol restriction were associated with decreases in systolic blood pressure of 5.4 (p less than 0.001) and 4.8 (p less than 0.01) mm Hg, respectively, and in diastolic blood pressure of 4.2 (p less than 0.001) and 3.3 (p less than 0.01) mm Hg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Active Wnt proteins are secreted on exosomes.
Wnt signalling has important roles during development and in many diseases. As morphogens, hydrophobic Wnt proteins exert their function over a distance to induce patterning and cell differentiation decisions. Recent studies have identified several factors that are required for the secretion of Wnt proteins; however, how Wnts travel in the extracellular space remains a largely unresolved question. Here we show that Wnts are secreted on exosomes both during Drosophila development and in human cells. We demonstrate that exosomes carry Wnts on their surface to induce Wnt signalling activity in target cells. Together with the cargo receptor Evi/WIs, Wnts are transported through endosomal compartments onto exosomes, a process that requires the R-SNARE Ykt6. Our study demonstrates an evolutionarily conserved functional role of extracellular vesicular transport of Wnt proteins.


Relationship between malaria incidence and IgG levels to Plasmodium falciparum merozoite antigens in Malian children: impact of hemoglobins S and C.
Heterozygous hemoglobin (Hb) AS (sickle-cell trait) and HbAC are hypothesized to protect against Plasmodium falciparum malaria in part by enhancing naturally-acquired immunity to this disease. To investigate this hypothesis, we compared antibody levels to four merozoite antigens from the P. falciparum 3D7 clone (apical membrane antigen 1, AMA1-3D7; merozoite surface protein 1, MSP1-3D7; 175 kDa erythrocyte-binding antigen, EBA175-3D7; and merozoite surface protein 2, MSP2-3D7) in a cohort of 103 HbAA, 73 HbAS and 30 HbAC children aged 3 to 11 years in a malaria-endemic area of Mali. In the 2009 transmission season we found that HbAS, but not HbAC, significantly reduced the risk of malaria compared to HbAA. IgG levels to MSP1 and MSP2 at the start of this transmission season inversely correlated with malaria incidence after adjusting for age and Hb type. However, HbAS children had significantly lower IgG levels to EBA175 and MSP2 compared to HbAA children. On the other hand, HbAC children had similar IgG levels to all four antigens. The parasite growth-inhibitory activity of purified IgG samples did not differ significantly by Hb type. Changes in antigen-specific IgG levels during the 2009 transmission and 2010 dry seasons also did not differ by Hb type, and none of these IgG levels dropped significantly during the dry season. These data suggest that sickle-cell trait does not reduce the risk of malaria by enhancing the acquisition of IgG responses to merozoite antigens.


Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients.
To evaluate the long-term effect of angiotensin-converting enzyme inhibition on proteinuria and on the rate of decline in kidney function in patients with type II diabetes mellitus and microalbuminuria. Randomized, double-blind, placebo-controlled trial. Each patient was followed for 5 years. Six clinics for diabetes mellitus coordinated by a department of medicine in a university hospital in Israel. Ninety-four normotensive, type II diabetic patients with microalbuminuria and normal renal function. The patients were randomly assigned to receive enalapril, 10 mg per day, or placebo. Any increase in blood pressure was treated with long-acting nifedipine. Albuminuria, blood pressure, serum creatinine, fasting blood glucose, and glycosylated hemoglobin levels, every 3 to 4 months. In the patients treated with enalapril, albuminuria decreased from 143 +/- 64 (mean +/- SD) mg/24 h to 122 +/- 67 mg/24 h during the first year. Thereafter, we observed a slow increase to 140 +/- 134 mg/24 h after 5 years. In the placebo group, albuminuria increased from 123 +/- 58 mg/24 h to 310 +/- 167 mg/24 h after 5 years. (Difference in rate of change in proteinuria [P < 0.05]). Kidney function (expressed as mean reciprocal creatinine) declined by 13% in the placebo group and remained stable (-1%) in the enalapril group (P < 0.05). Control of blood glucose levels remained stable, in both groups, throughout the study. The mean blood pressure was stable in the enalapril group (initial group mean, 99 +/- 2.1 mm Hg; fifth-year mean, 100 +/- 3.2 mm Hg) and increased in the placebo group from an initial mean value of 97 +/- 3.2 mm Hg to 102 +/- 3.4 mm Hg at the end of the study period (P = 0.082). In normotensive patients with diabetes mellitus type II, the institution of angiotensin-converting enzyme inhibition during early stages of diabetic nephropathy results in long-term stabilization of plasma creatinine levels and of the degree of urinary loss of albumin. These effects are probably independent of the antihypertensive action of these agents.


Clinical Course of Non-Traumatic Non-Aneurysmal Subarachnoid Hemorrhage: A Single Institution Experience over 10 Years and Review of the Contemporary Literature.
To report our experience with a relatively large series of patients with non-traumatic non-aneurysmal subarachnoid hemorrhage (NNSAH) to identify the prognosis associated with different bleeding patterns as well as a further diagnostic work-up to determine the underlying cause. Between January 2004 and December 2014, 81 patients with angiography-negative non-traumatic subarachnoid hemorrhage (SAH) were treated at our institution. Diagnosis was confirmed with a typical history of spontaneous SAH and cranial computed tomography (CT) scan or lumbar puncture (LP). The patients were grouped according to the bleeding pattern on the CT scan: Group 1: Perimesencephalic (PM) SAH (n=33, 40.7%); Group 2: Non-perimesencephalic (nPM) SAH (n=41, 50.6%); and Group 3: CT-negative NNSAH (n=7, 8.6%). The clinical course, hospitalization period, and complications were noted. All patients underwent an initial four-vessel digital subtraction angiography (DSA). Cranial magnetic resonance imaging (MRI), repeat DSA investigations and spinal MRI were performed in all patients. The mean hospital stays were 6.3, 14.7 and 10.1 days for patient groups 1, 2, and 3, respectively. The mortality rate was 1.2% (1 patient) in our series. Repeat DSA investigations were positive in two patients (2.5%), both from Group 2 (4.9%). Cranial MRI revealed 100% negative results. Spinal MRI revealed positive results in three patients from Group 2 (7.3%). We suggest our diagnostic work-up for patients with nPM-SAH, namely repeat DSA and spinal MRI, until an evidence-based guideline is established for the patient management.


Seizure-induced brain-borne inflammation sustains seizure recurrence and blood-brain barrier damage.
Epilepsy is a common neurological disorder characterized by recurrent seizures often unresponsive to pharmacological treatment. Brain inflammation is considered a crucial etiopathogenetic mechanism of epilepsy that could be targeted to control seizures. Specific inflammatory mediators overexpressed in human epileptogenic foci are known to promote seizures in animal models. We investigated whether seizures induce brain inflammation independently on extracerebral factors. We also investigated whether brain-borne inflammation is required and sufficient to maintain seizure activity and whether it causes blood-brain barrier (BBB) impairment. We addressed these questions by studying the relation between seizures, inflammation, and BBB permeability in a brain preparation isolated from extracerebral compartments. Epileptiform activity was induced by arterial perfusion of bicuculline in the in vitro isolated guinea pig brain. Seizure-induced brain inflammation was evaluated by quantitative immunohistochemical analysis of interleukin (IL)-1β in parenchymal cells. BBB damage was assessed by extravasation of intravascular fluorescein isothiocyanate-albumin. The effects of arterially perfused anakinra, a human recombinant IL-1β receptor antagonist, were investigated on epileptiform discharges, brain inflammation, and BBB damage. Seizure induction in the absence of extracerebral factors promoted the release of IL-1β from brain resident cells and enhanced its biosynthesis in astrocytes. Anakinra rapidly terminated seizures, prevented their recurrence, and resolved seizure-associated BBB breakdown. Seizures initiate brain inflammation in glia and promote BBB damage that is independent of either leukocytes or blood-borne inflammatory molecules. Brain inflammation contributes to the duration and recurrence of seizures. This study supports the use of specific anti-inflammatory drugs in clinical conditions that present with intractable recurrent seizures.


Evidence of collaboration, pooling of resources, learning and role blurring in interprofessional healthcare teams: a realist synthesis.
Interprofessional teamwork has become an integral feature of healthcare delivery in a wide range of conditions and services in many countries. Many assumptions are made in healthcare literature and policy about how interprofessional teams function and about the outcomes of interprofessional teamwork. Realist synthesis is an approach to reviewing research evidence on complex interventions which seeks to explore these assumptions. It does this by unpacking the mechanisms of an intervention, exploring the contexts which trigger or deactivate them and connecting these contexts and mechanisms to their subsequent outcomes. This is the second in a series of four papers reporting a realist synthesis of interprofessional teamworking. The paper discusses four of the 13 mechanisms identified in the synthesis: collaboration and coordination; pooling of resources; individual learning; and role blurring. These mechanisms together capture the day-to-day functioning of teams and the dependence of that on members' understanding each others' skills and knowledge and learning from them. This synthesis found empirical evidence to support all four mechanisms, which tentatively suggests that collaboration, pooling, learning, and role blurring are all underlying processes of interprofessional teamwork. However, the supporting evidence for individual learning was relatively weak, therefore there may be assumptions made about learning within healthcare literature and policy that are not founded upon strong empirical evidence. There is a need for more robust research on individual learning to further understand its relationship with interprofessional teamworking in healthcare.


Critical pathways.
A critical Pathway (CP) is a clinical management tool that helps medical care providers coordinate the delivery of patient care for a particular case type or condition. As a guide to usual treatment patterns, a CP gives a view of the "big picture." The CP usually recommends a total treatment regimen. Treatment regimens are formulated through the consensus of a multi-disciplinary collaboration of all those involved in a patient's care. If developed and implemented properly, critical paths can lead to desirable outcomes for the patient and improved operating effectiveness/efficiency for the healthcare facility. Components of CPs often include protocols, algorithms, and clinical practice guidelines. Metrics, bench-marks, compliance, and variances become common terms among members of the healthcare team. Although CPs have gained wide acceptance as inpatient management tools, they are rapidly being sought for outpatient settings as well. This article details the CP process and cites examples of two hospitals that have used CPs to reduce length of stay and cut costs.


Properties of exogenously added GPI-anchored proteins following their incorporation into cells.
Isolated glycosylphosphatidylinositol (GPI)-anchored proteins, when added to cells in vitro, incorporate into their surface membranes and, once incorporated, exert their native functions. Virtually any protein of interest, if expressed as a GPI-reanchored derivative, can be modified to acquire this capacity. Such transfer of proteins directly to cells, termed "protein engineering" or "painting" constitutes an alternative to conventional gene transfer for manipulating cell surface composition that has many potential applications. Previous studies with incorporated GPI-anchored proteins have focused almost entirely on their extracellular functions. In this study, biotinylated human erythrocyte (E(hu)) decay accelerating factor, E(hu) acetylcholinesterase, and GPI-reanchored murine B7-1 and B7-2 were used as GPI-anchored reporters to characterize their plasma membrane organization and cell signalling properties following addition to Hela or Chinese hamster ovary cells. For each reporter, three types of cell-association were documented; (1) nonphysiological attachment and/or incomplete insertion, (2) uncomplexed membrane integration, and (3) organization into TX-100-resistant microdomains. Transit from the first two compartments into the third, i.e., microdomains, progressed slowly, continuing even after 24 to 36 h and was associated with the acquisition of cell signalling capacity. All four reporters, incorporated in two different detergents, behaved similarly. When organized in microdomains, caveolin and other GPI proteins co-isolated with the incorporated reporter. These results have implications for protein engineering of cells in general, and in particular, for cells such as modified tumor cell immunogens administered to patients for therapeutic purposes.


Immunohistochemical detection and immunochemical analysis of type II collagen degradation in human normal, rheumatoid, and osteoarthritic articular cartilages and in explants of bovine articular cartilage cultured with interleukin 1.
Articular cartilage destruction and loss of function in arthritic diseases involves proteolytic degradation of the connective tissue matrix. We have investigated the degradation of cartilage collagen by developing immunochemical methods that permit the identification and analysis of type II collagen degradation in situ. Previously, a technique to specifically identify type II collagen degradation in situ in articular cartilage did not exist. These methods utilize a polyclonal antiserum (R181) that specifically reacts with unwound alpha-chains and CNBr-derived peptides, alpha 1(II)CB11 and alpha 1(II)CB8, of human and bovine type II collagens. The experimental approach is based on the fact that when fibrillar collagens are cleaved the helical collagen molecule unwinds, exposing hidden epitopes. Here we demonstrate the use of R181 in studying type II collagen degradation in bovine articular cartilage that has been cultured with or without IL-1 and in human normal, rheumatoid, and osteoarthritic articular cartilages. Compared to cartilages either freshly isolated or cultured without IL-1, bovine cartilage cultured with IL-1 for 3-5 d showed an increase in both pericellular and intercellular immunohistochemical staining. Extracts of these cartilages contained type II collagen alpha chains that were increased in amount after culture with IL-1 for 11 d. In addition, culture with IL-1 resulted in the appearance of alpha chain fragments of lower molecular weight. All human arthritic tissues examined showed areas of pronounced pericellular and territorial staining for collagen degradation as compared with non-diseased tissues, indicating that chondrocytes are responsible in part for this degradation as compared with non-diseased tissues. In most cases rheumatoid cartilage was stained most intensely at the articular surface and in the deep and mid-zones, whereas osteoarthritic cartilage usually stained more in the superficial and mid-zones, but less intensely. Distinct patterns of sites of collagen degradation reflect differences in collagen destruction in these diseases, suggesting possible different sources of chondrocyte activation. These experiments demonstrate the application of immunological methods to detect collagen degradation and demonstrate an increase of collagen degradation in human arthritides and in IL-1-treated viable bovine cartilage.


Clinical management of severe fluorosis in an adult.
Dental fluorosis is defined as hypomineralisation of enamel resulting from excessive ingestion of fluoride (more than 1 ppm) during tooth development. Mild-to-moderate forms of dental fluorosis are often unnoticed by the patients whereas severe fluorosis presents with dark brown-to-black discolouration of teeth along with enamel pitting and hypoplasia. Such discolouration results in an unpleasing appearance as well as psychological distress to the affected individual. Dental fluorosis can be managed by bleaching, micro/macroabrasion, veneering or crowning. The choice between different treatment options depends on the severity of fluorosis and patients' aesthetic demands. The aim of this case report was to describe the stepwise oral rehabilitation of an adult with severe fluorosis along with multiple carious teeth. After restoration of carious teeth and extraction of unsalvageable teeth, bleaching and full-coverage restorations were used for the management of fluorosis.


Stereotactic Body Radiation Therapy for Prostate Cancer: Review of Experience of a Multicenter Phase I/II Dose-Escalation Study.
Stereotactic body radiation therapy (SBRT) is an area of active investigation for treatment of prostate cancer. In our phase I dose-escalation study, maximum-tolerated dose (MTD) was not reached, and subsequently phase II study has been completed. The purpose of this article is to review our experiences of dose-escalated SBRT for localized prostate cancer. Patients enrolled to phase I/II study from 2006 to 2011 were reviewed. Prescription dose groups were 45, 47.5, and 50 Gray (Gy) in five fractions over 2.5 weeks. Toxicity and quality of life questionnaire data were collected and analyzed. Descriptive statistics were obtained in the form of means, medians, and ranges for the continuous variables, and frequencies and percentages for the categoric variables. Ninety-one patients were enrolled from five institutions. Median follow-up for prostate specific antigen (PSA) evaluation was 42 months. PSA control remains at 99%. While the MTD was not reached in the phase I study, excess high grade rectal toxicity (10.6%) was noted in the phase II study. The 13 patients treated to 50 Gy in the phase I study that did not have high grade rectal toxicity, in retrospect met these parameters and have not had further events on longer follow-up. Prostate specific antigen control rate, even for patients with intermediate risk, is thus far excellent at these dose levels. This study provides a platform for exploration of SBRT based clinical trials aimed at optimizing outcome for intermediate and high risk patients. High grade toxicities specifically related to the rectum were observed in a small but meaningful minority at the highest dose level. Dose constraints based on physiologic parameters have been defined to mitigate this risk, and strategies to minimize rectal exposure to such doses are being explored.


Role of T cells in inflammation caused by adenovirus vectors in the brain.
In many organs, E1-deleted human adenovirus vectors trigger antiviral T cell responses which limit the duration of vector-encoded gene expression. When injected into the brain, however, long-term expression is possible in spite of the ensuing inflammatory response. To examine the role of T cells in the immune response in the brain, monoclonal antibodies were used to systemically deplete CD4+ and/or CD8+ T cell subsets from mice at the time of vector injection. The early phase of the inflammatory response, characterized by high MHC I expression and recruitment of mononuclear cells, was unaffected by T cell depletion. Six days after injection, however, inflammation was markedly reduced by CD8-depletion and eliminated by CD4-depletion. Vector expression of the marker protein beta-galactosidase did not differ between depleted and undepleted mice. In contrast, when mice had been previously exposed to adenovirus vector in the periphery, beta-galactosidase expression in the brain was transient, showing that T cells can effectively target vector-transduced cells in this organ. We conclude that adenovirus vectors are able to achieve long-term expression in the brain because such a route of injection triggers an ineffective T cell response.


Characterization of NE81, the first lamin-like nucleoskeleton protein in a unicellular organism.
Lamins build the nuclear lamina and are required for chromatin organization, gene expression, cell cycle progression, and mechanical stabilization. Despite these universal functions, lamins have so far been found only in metazoans. We have identified protein NE81 in Dictyostelium, which has properties that justify its denomination as a lamin-like protein in a lower eukaryote. This is based on its primary structure, subcellular localization, and regulation during mitosis, and its requirement of the C-terminal CaaX box as a posttranslational processing signal for proper localization. Our knockout and overexpression mutants revealed an important role for NE81 in nuclear integrity, chromatin organization, and mechanical stability of cells. All our results are in agreement with a role for NE81 in formation of a nuclear lamina. This function is corroborated by localization of Dictyostelium NE81 at the nuclear envelope in human cells. The discovery of a lamin-like protein in a unicellular organism is not only intriguing in light of evolution, it may also provide a simple experimental platform for studies of the molecular basis of laminopathies.


Evaluating the Effectiveness of ACT for Anxiety Disorders in a Self-Help Context: Outcomes From a Randomized Wait-List Controlled Trial.
Rigorous evaluations of cognitive behavioral self-help books for anxiety in pure self-help contexts are lacking. The present study evaluated the effectiveness of an Acceptance and Commitment Therapy (ACT) self-help workbook for anxiety-related concerns, with no therapist contact, in an international sample. Participants (N=503; 94% mental health diagnosis) were randomized to an immediate workbook (n=256) or wait-list condition (n=247). Assessments at pretreatment, 12weeks, 6months, and 9months evaluated anxiety and related symptoms, quality of life, and ACT treatment processes (e.g., psychological flexibility). Participants in the wait-list arm crossed over to the workbook following the 12-week assessment. The workbook condition yielded significant improvements on all assessments from pre- to posttreatment relative to wait-list, and these gains were maintained at follow-ups. The pattern observed in the wait-list condition was virtually identical to the active treatment arm after receiving the workbook, but not before. Attrition was notable, but supplemental analyses suggested dropout did not influence treatment effects for all but one measure. Overall, findings provide preliminary support for the effectiveness of this self-help workbook and suggest ACT-based self-help bibliotherapy might be a promising low-cost intervention for people experiencing significant anxiety-related concerns.


Structure and function of the global topsoil microbiome.
Soils harbour some of the most diverse microbiomes on Earth and are essential for both nutrient cycling and carbon storage. To understand soil functioning, it is necessary to model the global distribution patterns and functional gene repertoires of soil microorganisms, as well as the biotic and environmental associations between the diversity and structure of both bacterial and fungal soil communities1-4. Here we show, by leveraging metagenomics and metabarcoding of global topsoil samples (189 sites, 7,560 subsamples), that bacterial, but not fungal, genetic diversity is highest in temperate habitats and that microbial gene composition varies more strongly with environmental variables than with geographic distance. We demonstrate that fungi and bacteria show global niche differentiation that is associated with contrasting diversity responses to precipitation and soil pH. Furthermore, we provide evidence for strong bacterial-fungal antagonism, inferred from antibiotic-resistance genes, in topsoil and ocean habitats, indicating the substantial role of biotic interactions in shaping microbial communities. Our results suggest that both competition and environmental filtering affect the abundance, composition and encoded gene functions of bacterial and fungal communities, indicating that the relative contributions of these microorganisms to global nutrient cycling varies spatially.


Patterns of regional lymph node metastasis of nasopharyngeal carcinoma: a meta-analysis of clinical evidence.
The characteristics of cervical lymphatic metastasis in nasopharyngeal carcinoma (NPC) are not completely understood. As such, radiotherapy to the entire lymphatic of the neck bilaterally has been empirically practiced even in early stage disease, although not supported by clinical evidence. We studied the pattern and probability of nodal metastasis through a meta-analysis of published evidences, with an aim to establish an evidence-based guideline for selecting and delineation of clinical target volume of neck lymphatics for conformation radiation for NPC. A literature search yielded an initial 411 original articles, and 13 studies with 2920 NPC cases staged via MRI were included in this analysis. The occurrence of nodal metastasis was calculated and analyzed according to the respective regional nodal levels. 85% of NPC cases presented with lymphadenopathy. The most commonly involved regions include retropharyngeal (69%) and level II lymph nodes (70%). The overall probability of levels III, IV, and V nodal involvement are 45%, 11%, and 27%, respectively. Low-risk node groups included the supraclavicular, levels IA/IB and VI nodes, and parotid nodes with involvement rates at 3%, 0%, 3%, 0%, and 1%, respectively. Nodal metastases followed an orderly pattern and the probability of "skip" metastasis between levels varied between 0.5-7.9%. Lymph node metastasis in NPC follows a predictable and orderly pattern. The rarity of metastasis in certain nodal groups and "skip" metastasis suggest that reduced treatment volume is feasible in conformal radiotherapy for NPC.


The migration of Ascaris suum larvae, and the associated pulmonary inflammatory response in susceptible C57BL/6j and resistant CBA/Ca mice.
Ascariasis is an important infection in humans (Ascaris lumbricoides) and pigs (Ascaris suum) and individuals appear to be predisposed to either heavy or light worm burdens. These extremes of susceptibility and resistance are represented in a mouse model by 2 strains of mice, CBA mice showing high resistance to infection and C57BL/6 which are highly susceptible, as reflected in worm burdens in the lungs 6-7 days after infection. In an attempt to identify the point at which the difference between these 2 strains is first manifested, we quantified worm burdens at key stages during infection leading up to the pulmonary stage of development. Thus mice were inoculated with fully embryonated A. suum eggs and larval burdens were enumerated in the large intestine and rectum, liver and lungs of the 2 strains at 6 h post-inoculation (p.i.) and on each of days 1-8 p.i. inclusively. A higher percentage of the total inoculum was recovered from the intestine/rectum of C57BL/6j mice in contrast to CBA/Ca mice at 6 h p.i. Larvae were recovered from the intestinal contents and also whilst actively migrating through the large intestinal wall. The number of larvae recovered was significantly reduced in CBA/Ca mice in contrast to C57BL/6j mice between the phase of migration from the liver and arrival in the lungs. The combined results of the inoculation of mice with corticosteroids and the examination of the change in profile and number of leukocytes present in bronchoalveolar lavage fluid suggested that the pulmonary inflammatory immune response was not prominently involved in primary protection of mice to A. suum infection in the latter days of infection in the lungs. The susceptible C57BL/6j mice produced a BAL response almost twice as intense as that of resistant CBA/Ca mice with stronger neutrophil, lymphocyte and eosinophil but not macrophage components, suggesting that the difference in worm burdens between the strains was generated earlier in the course of infection. These results were further corroborated by a histological examination of the lung tissues which showed that the passage of the larval stages of A. suum through the mouse lungs was associated with a marked inflammatory response in both strains. Again, C57BL/6j mice exhibited increased inflammation relative to CBA/Ca mice. Hence some hepatic/post-hepatic factor that varies between the 2 strains, but exerts its effect before the lung phase plays a critical role in determining the success of larvae through the host tissues. The possible sites of this host defence are reviewed.


Hard Superconducting Gap and Diffusion-Induced Superconductors in Ge-Si Nanowires.
We show a hard superconducting gap in a Ge-Si nanowire Josephson transistor up to in-plane magnetic fields of 250 mT, an important step toward creating and detecting Majorana zero modes in this system. A hard gap requires a highly homogeneous tunneling heterointerface between the superconducting contacts and the semiconducting nanowire. This is realized by annealing devices at 180 °C during which aluminum interdiffuses and replaces the germanium in a section of the nanowire. Next to Al, we find a superconductor with lower critical temperature (TC = 0.9 K) and a higher critical field (BC = 0.9-1.2 T). We can therefore selectively switch either superconductor to the normal state by tuning the temperature and the magnetic field and observe that the additional superconductor induces a proximity supercurrent in the semiconducting part of the nanowire even when the Al is in the normal state. In another device where the diffusion of Al rendered the nanowire completely metallic, a superconductor with a much higher critical temperature (TC = 2.9 K) and critical field (BC = 3.4 T) is found. The small size of these diffusion-induced superconductors inside nanowires may be of special interest for applications requiring high magnetic fields in arbitrary direction.


Temporal aspects of orientation pooling using visual noise stimuli.
Previous psychophysical studies have shown that oriented signals are pooled over space to support better perceptual performance. We have investigated whether oriented signals may also be pooled over time. Using an orientation-in-noise paradigm, the threshold to discriminate large orientation differences was measured as the minimum amount of signal required to discriminate an oriented stimulus from unoriented noise. Discrimination thresholds were better with dynamic stimuli, containing multiple independent samples over time, than with static stimuli presented for an equal duration. Thresholds for dynamic stimuli showed gradual improvement from very brief (12 ms) to remarkably long presentation times (>4 s). Spatial integration of orientation signals is very efficient and can be understood in terms of a model based on signal detection theory, with performance limited by early and late stages of intrinsic noise. The nature of temporal integration is different, however, and is more consistent with probability summation of the outputs from low-level orientation detectors operating at a very brief timescale but whose outputs can be combined over a very long duration to yield better perceptual performance.


Human serum amyloid A protein. Behaviour in aqueous and urea-containing solutions and antibody production.
Human serum amyloid A protein (apo-SAA) can be prepared by gel filtration of delipidated acute-phase high-density lipoprotein in the presence of urea. The resultant apo-SAA is soluble (greater than 90% solubility) in a wide range of buffer solutions, with all of the six major isoforms of apo-SAA being equally soluble. In urea-containing solutions the isoforms behave qualitatively differently in various urea concentrations, probably reflecting subtle primary-structure variations. The higher-pI isoforms are only completely unfolded at greater than 7 M-urea. By immunizing with apo-SAA adsorbed to acid-treated bacteria (Salmonella minnesota R595), high-titre antibodies can easily be elicited in rabbits.


Overexpression of Gα11 in Osteoblast Lineage Cells Suppresses the Osteoanabolic Response to Intermittent PTH and Exercise.
Intermittent parathyroid hormone (iPTH) treatment and mechanical loading are osteoanabolic stimuli that are partially mediated through actions on G protein-coupled receptors (GPCRs). GPCR signaling can be altered by heterotrimeric G protein Gα subunits levels, which can therefore lead to altered responses to such stimuli. Previous studies have suggested that enhanced signaling through the Gαq/11 pathway inhibits the osteoanabolic actions of PTH. The influence of Gαq/11 signaling on mechanotransduction, however, has not been reported in vivo. Using transgenic mice that specifically overexpress Gα11 in osteoblast lineage cells (G11-Tg mice), we investigated the skeletal effects of elevated Gα11 levels on iPTH and mechanical loading by treadmill exercise. Both regimens increased trabecular and cortical bone in Wild-Type (WT) mice as a result of increased bone formation. In G11-Tg mice, there was no change in trabecular or cortical bone and no increase in bone formation in response to iPTH or exercise. While exercise reduced osteoclast parameters in WT mice, these changes were diminished in G11-Tg mice as expression of M-csf and Trap remained increased. Collectively, our results suggest that osteoblastic upregulation of Gα11 is inhibitory to osteoanabolic actions of both PTH and exercise, and that its suppression may be a promising target for treating bone loss.


Initial experience with a robotically operated video optical telescopic-microscope in cranial neurosurgery: feasibility, safety, and clinical applications.
OBJECTIVE The move toward better, more effective optical visualization in the field of neurosurgery has been a focus of technological innovation. In this study, the authors' objectives are to describe the feasibility and safety of a new robotic optical platform, namely, the robotically operated video optical telescopic-microscope (ROVOT-m), in cranial microsurgical applications. METHODS A prospective database comprising patients who underwent a cranial procedure between April 2015 and September 2016 was queried, and the first 200 patients who met the inclusion criteria were selected as the cohort for a retrospective chart review. Only adults who underwent microsurgical procedures in which the ROVOT-m was used were considered for the study. Preoperative, intraoperative, and postoperative data were retrieved from electronic medical records. The authors address the feasibility and safety of the ROVOT-m by studying various intraoperative variables and by reporting perioperative morbidity and mortality, respectively. To assess the learning curve, cranial procedures were categorized into 6 progressively increasing complexity groups. The main categories of pathology were I) intracerebral hemorrhages (ICHs); II) intraaxial tumors involving noneloquent regions or noncomplex extraaxial tumors; III) intraaxial tumors involving eloquent regions; IV) skull base pathologies; V) intraventricular lesions; and VI) cerebrovascular lesions. In addition, the entire cohort was evenly divided into early and late cohorts. RESULTS The patient cohort comprised 104 female (52%) and 96 male (48%) patients with a mean age of 56.7 years. The most common pathological entities encountered were neoplastic lesions (153, 76.5%), followed by ICH (20, 10%). The distribution of cases by complexity categories was 11.5%, 36.5%, 22%, 20%, 3.5%, and 6.5% for Categories I, II, II, IV, V, and VI, respectively. In all 200 cases, the surgical goal was achieved without the need for intraoperative conversion. Overall, the authors encountered 3 (1.5%) major neurological morbidities and 6 (3%) 30-day mortalities. Four of the 6 deaths were in the ICH group, resulting in a 1% mortality rate for the remainder of the cohort when excluding these patients. None of the intraoperative complications were considered to be attributable to the visualization provided by the ROVOT-m. When comparing the early and late cohorts, the authors noticed an increase in the proportion of higher-complexity surgeries (Categories IV-VI), from 23% in the early cohort, to 37% in the late cohort (p = 0.030). In addition, a significant reduction in operating room setup time was demonstrated (p < 0.01). CONCLUSIONS The feasibility and safety of the ROVOT-m was demonstrated in a wide range of cranial microsurgical applications. The authors report a gradual increase in case complexity over time, representing an incremental acquisition of experience with this technology. A learning curve of both setup and execution phases should be anticipated by new adopters of the robot system. Further prospective studies are required to address the efficacy of ROVOT-m. This system may play a role in neurosurgery as an integrated platform that is applicable to a variety of cranial procedures.


Involvement of chalcone reductase in the soybean isoflavone metabolon: identification of GmCHR5, which interacts with 2-hydroxyisoflavanone synthase.
Soybean (Glycine max) 5-deoxyisoflavonoids (daidzein and its conjugates) are precursors of glyceollin phytoalexins. They are also converted to equol by microbes in the human intestine, resulting in health benefits. 5-Deoxyisoflavonoids accumulate in the roots (93% mol/mol of the total root isoflavonoids) and seeds of unstressed soybean plants. Chalcone reductase (CHR) is a key enzyme mediating 5-deoxyisoflavonoid biosynthesis because it catalyzes the production of 6'-deoxychalcone through its effects on the chalcone synthase (CHS)-catalyzed reaction. The soybean genome encodes at least 11 CHR-related homologs, but it is unclear which ones are functionally important for daidzein accumulation in unstressed plants. Among the CHR homologs, the temporal and spatial expression patterns of GmCHR5 were the most correlated with the distribution patterns of 5-deoxyisoflavonoids. The CHR activity of GmCHR5 was confirmed in vitro and in planta. In the in vitro assays, the ratio of CHR products (6'-deoxychalcone) to total CHS products (R value) was dependent on GmCHR5 and CHS concentrations, with higher concentrations resulting in higher R values (i.e. approaching 90%). Subcellular localization analyses revealed that GmCHR5 was present in the cytoplasm and nucleus. Protein-protein interaction assays indicated that GmCHR5, but not GmCHR1 and GmCHR6, interacted with 2-hydroxyisoflavanone synthase (IFS) isozymes. The CHS isozymes also interacted with IFS isozymes but not with GmCHR5. The proposed micro-compartmentalization of isoflavone biosynthesis through the formation of an IFS-mediated metabolon is probably involved in positioning GmCHR5 close to CHS, resulting in an R value that is high enough for the accumulation of abundant 5-deoxyisoflavonoids in soybean roots.


Progestin and breast cancer. The missing pieces of a puzzle.
The previous assumption that progestin does not promote breast cancer development needs to be re-examined since a growing body of evidence indicates the opposite. Data from recent experimental trials and results from clinical and epidemiological studies on hormonal contraceptives and hormone replacement therapy (HRT) have been confronted with breast cancer cases known from the German database of adverse drug reactions (ADR), reported in association with the use of progestin only contraceptives (POC) and combined oral contraceptives (COC). Also cases reported in association with HRT have been analysed. The available data complement one another showing a tumour promoting potential of progestin, possibly higher than that of a combination of estrogen and progestin. These assumptions are based on the following facts: 1) in estrogen-supplemented animals, progesterone has been shown to reactivate the growth of regressed tumour xenograft obtained from breast cancer cell lines, expressing both estrogen and progesterone receptor; 2) antiprogestin has been revealed to suppress the reactivation of the growth of tumour xenograft and to fully suppress the development of breast cancer in an animal model for BRCA1 gene mutation; 3) metabolites of progesterone have been recognised as potent regulators of cell proliferation, cell detachment and apoptosis; 4) progesterone has been shown to inhibit, in a dose-dependent manner, apoptosis in breast cancer cell lines and apoptosis induced by doxorubicin and 5-fluorouracyl (drugs used in breast cancer treatment); 5) an association between breast cancer and HRT was suspected upon the addition of progestin on a regular basis for the prevention of endometrial cancer; 6) in a randomised placebo-controlled trial on HRT an increased risk of breast cancer was shown for the combination of estrogen and progestin, but not for estrogen alone; 7) in epidemiological studies on POC the recognition of an increased breast cancer risk was most probably impeded due to previously unrecognised systematic selection bias; 8) in a large epidemiological study on the risk of early-onset breast cancer in association with COC an increased risk was detected for COC use up to 1975, but no increased, even a slightly decreased, risk was shown for users of low-dose COC, applied since 1976; 9) a considerably higher number of breast cancer cases have been reported from Germany on POC than on the widespread used COC [corrected] (111 versus 12); 10) the big resemblance among the breast cancers reported for POC and their similarity with breast malignancies diagnosed in pregnancy suggest the existence of a pattern rather than pure coincidence [corrected]


Metal-organic-framework derived Co-Pd bond is preferred over Fe-Pd for reductive upgrading of furfural to tetrahydrofurfuryl alcohol.
Combined noble-transition metal catalysts have been used to produce a wide range of important non-petroleum-based chemicals from biomass-derived furfural (as a platform molecule) and have garnered colossal research interest due to the urgent demand for sustainable and clean fuels. Herein, we report the palladium-modified metal-organic-framework (MOF) assisted preparation of PdCo3O4 and PdFe3O4 nanoparticles encapsulated in a graphitic N-doped carbon (NC) matrix via facile in situ thermolysis. This provides a change in selectivity with superior catalytic activity for the reductive upgrading of biomass-derived furfural (FA). Under the optimized reaction conditions, the newly designed PdCo3O4@NC catalyst exhibited highly efficient catalytic performance in the hydrogenation of furfural, providing 100% furfural conversion with 95% yield of tetrahydrofurfuryl alcohol (THFAL). In contrast, the as-synthesized Pd-Fe3O4@NC afforded a THFAL yield of 70% after an 8 h reaction with four consecutive recycling tests. Based on different characterization data (XPS, H2-TPR) for nanohybrids, we can conclude that the presence of PdCo-Nx active sites, and the multiple synergistic effects between Co3O4 and Pd(ii), Co3O4 and Pd0, as well as the presence of N in the carbonaceous matrix, are responsible for the superior catalytic activity and improved catalyst stability. Our strategy provides a facile design and synthesis process for a noble-transition metal alloy as a superior biomass refining, robust catalyst via noble metal modified MOFs as precursors.


Function and evolution of the long noncoding RNA circuitry orchestrating X-chromosome inactivation in mammals.
X-chromosome inactivation (XCI) is a chromosome-wide regulatory process that ensures dosage compensation for X-linked genes in Theria. XCI is established during early embryogenesis and is developmentally regulated. Different XCI strategies exist in mammalian infraclasses and the regulation of this process varies also among closely related species. In Eutheria, initiation of XCI is orchestrated by a cis-acting locus, the X-inactivation center (Xic), which is particularly enriched in genes producing long noncoding RNAs (lncRNAs). Among these, Xist generates a master transcript that coats and propagates along the future inactive X-chromosome in cis, establishing X-chromosome wide transcriptional repression through interaction with several protein partners. Other lncRNAs also participate to the regulation of X-inactivation but the extent to which their function has been maintained in evolution is still poorly understood. In Metatheria, Xist is not conserved, but another, evolutionary independent lncRNA with similar properties, Rsx, has been identified, suggesting that lncRNA-mediated XCI represents an evolutionary advantage. Here, we review current knowledge on the interplay of X chromosome-encoded lncRNAs in ensuring proper establishment and maintenance of chromosome-wide silencing, and discuss the evolutionary implications of the emergence of species-specific lncRNAs in the control of XCI within Theria. WIREs RNA 2016, 7:702-722. doi: 10.1002/wrna.1359 For further resources related to this article, please visit the WIREs website.


Quantitative Magnetic Resonance Imaging Analysis of the Common Site of Acute Achilles Tendon Rupture: 5 to 8 cm Above the Distal End of the Calcaneal Insertion.
Previous studies have not quantitatively analyzed the site of acute Achilles tendon rupture. To investigate the site of acute Achilles tendon rupture via magnetic resonance imaging (MRI). Cross-sectional study; Level of evidence, 4. The medical records and MRIs of 195 patients with acute Achilles tendon rupture were retrospectively reviewed. The rupture site was measured as the distance from the most distal fibers of the Achilles tendon at the calcaneal insertion to the proximal end of the distal stump. The relationship between the site of rupture and patient characteristics was analyzed, and the intra- and interobserver reliability of the measurements was assessed using intraclass correlation coefficients. The rupture site had a mean distance of 6.4 cm (SD, 1.5) and the 10th to 90th percentile range was 5.0 to 8.4 cm. There was no significant difference in location of the rupture according to patient characteristics and the time of imaging. The intra- and interobserver reliability of measurements was excellent. Most acute Achilles tendon ruptures visible on MRI occurred 5 to 8 cm above the distal end of the calcaneal insertion, which is more proximal than the previously reported 2 to 6 cm location.


A proteinaceous fraction of wheat bran may interfere in the attachment of enterotoxigenic E. coli K88 (F4+) to porcine epithelial cells.
Wheat bran (WB) from Triticum aestivum has many beneficial effects on human health. To the best of our knowledge, very little has been published about its ability to prevent pathogenic bacterial adhesion in the intestine. Here, a WB extract was fractionated using different strategies, and the obtained fractions were tested in different in vitro methodologies to evaluate their interference in the attachment of enterotoxigenic Escherichia coli (ETEC) K88 to intestinal porcine epithelial cells (IPEC-J2) with the aim of identifying the putative anti-adhesive molecules. It was found that a proteinaceous compound in the >300-kDa fraction mediates the recognition of ETEC K88 to IPEC-J2. Further fractionation of the >300-kDa sample by size-exclusion chromatography showed several proteins below 90 kDa, suggesting that the target protein belongs to a high-molecular-weight (MW) multi-component protein complex. The identification of some relevant excised bands was performed by mass spectrometry (MS) and mostly revealed the presence of various protease inhibitors (PIs) of low MW: Serpin-Z2B, Class II chitinase, endogenous alpha-amylase/subtilisin inhibitor and alpha-amylase/trypsin inhibitor CM3. Furthermore, an incubation of the WB extract with ETEC K88 allowed for the identification of a 7S storage protein globulin of wheat, Globulin 3 of 66 kDa, which may be one of the most firmly attached WB proteins to ETEC K88 cells. Further studies should be performed to gain an understanding of the molecular recognition of the blocking process that takes place. All gathered information can eventually pave the way for the development of novel anti-adhesion therapeutic agents to prevent bacterial pathogenesis.


Marrow stromal cells as stem cells for nonhematopoietic tissues.
Marrow stromal cells can be isolated from other cells in marrow by their tendency to adhere to tissue culture plastic. The cells have many of the characteristics of stem cells for tissues that can roughly be defined as mesenchymal, because they can be differentiated in culture into osteoblasts, chondrocytes, adipocytes, and even myoblasts. Therefore, marrow stromal cells present an intriguing model for examining the differentiation of stem cells. Also, they have several characteristics that make them potentially useful for cell and gene therapy.


Limbic system pathologies associated with deficiencies and excesses of the trace elements iron, zinc, copper, and selenium.
Deficiencies of nutrients such as amino acids, vitamins, lipids, and trace elements during gestation and early infanthood have strong deleterious effects on the development of the limbic system; these effects may be irreversible, even when adequate supplementation is provided at later developmental stages. Recent advances in the neurochemistry of biometals are increasingly establishing the roles of the trace elements iron, copper, zinc, and selenium in a variety of cell functions and are providing insight into the repercussions of deficiencies and excesses of these elements on the development of the central nervous system, especially the limbic system. The limbic system comprises diverse areas with high metabolic demands and differential storage of iron, copper, zinc, and selenium. This review summarizes available evidence suggesting the involvement of these trace elements in pathological disorders of the limbic system.


Use of an ecologically relevant modelling approach to improve remote sensing-based schistosomiasis risk profiling.
Schistosomiasis is a widespread water-based disease that puts close to 800 million people at risk of infection with more than 250 million infected, mainly in sub-Saharan Africa. Transmission is governed by the spatial distribution of specific freshwater snails that act as intermediate hosts and the frequency, duration and extent of human bodies exposed to infested water sources during human water contact. Remote sensing data have been utilized for spatially explicit risk profiling of schistosomiasis. Since schistosomiasis risk profiling based on remote sensing data inherits a conceptual drawback if school-based disease prevalence data are directly related to the remote sensing measurements extracted at the location of the school, because the disease transmission usually does not exactly occur at the school, we took the local environment around the schools into account by explicitly linking ecologically relevant environmental information of potential disease transmission sites to survey measurements of disease prevalence. Our models were validated at two sites with different landscapes in Côte d'Ivoire using high- and moderate-resolution remote sensing data based on random forest and partial least squares regression. We found that the ecologically relevant modelling approach explained up to 70% of the variation in Schistosoma infection prevalence and performed better compared to a purely pixel-based modelling approach. Furthermore, our study showed that model performance increased as a function of enlarging the school catchment area, confirming the hypothesis that suitable environments for schistosomiasis transmission rarely occur at the location of survey measurements.


Human transgene-free amniotic-fluid-derived induced pluripotent stem cells for autologous cell therapy.
The establishment of a reliable prenatal source of autologous, transgene-free progenitor cells has enormous potential in the development of regenerative-medicine-based therapies for infants born with devastating birth defects. Here, we show that a largely CD117-negative population of human amniotic fluid mesenchymal stromal cells (AF-MSCs) obtained from fetuses with or without prenatally diagnosed anomalies are readily abundant and have limited baseline differentiation potential when compared with bone-marrow-derived MSCs and other somatic cell types. Nonetheless, the AF-MSCs could be easily reprogrammed into induced pluripotent stem cells (iPSCs) using nonintegrating Sendai viral vectors encoding for OCT4, SOX2, KLF4, and cMYC. The iPSCs were virtually indistinguishable from human embryonic stem cells in multiple assays and could be used to generate a relatively homogeneous population of neural progenitors, expressing PAX6, SOX2, SOX3, Musashi-1, and PSA-NCAM, for potential use in neurologic diseases. Further, these neural progenitors showed engraftment potential in vivo and were capable of differentiating into mature neurons and astrocytes in vitro. This study demonstrates the usefulness of AF-MSCs as an excellent source for the generation of human transgene-free iPSCs ideally suited for autologous perinatal regenerative medicine applications.


Evaluation of C-reactive protein measurement for assessing the risk and prognosis in ischemic stroke: a statement for health care professionals from the CRP Pooling Project members.
Several studies have shown, in different populations, that modest elevation of plasma C-reactive protein (CRP) in the range seen in apparently healthy individuals is a strong predictor of future vascular events. Elevated plasma CRP concentrations are also associated with an increased risk of cerebrovascular events and an increased risk of fatal and nonfatal cardiovascular events in ischemic stroke patients. These epidemiological and clinical observations suggest that determination of plasma CRP concentrations could be used as an adjunct for risk assessment in primary and secondary prevention of cerebrovascular disease and be of prognostic value. The aim of this review is to summarize the evidence for CRP as an independent predictor of cerebrovascular events in at-risk individuals and ischemic stroke patients and to consider its usefulness in evaluating prognosis after stroke. CRP fulfils most of the requirements of a new risk and prognostic predictor, but several issues await further confirmation and clarification before this marker can be included in the routine evaluation of stroke patients and subjects at risk for cerebrovascular disease. Potentially important associations have been established between elevated plasma CRP concentrations and increased efficacy of established therapies, particularly lipid-lowering therapy with statins. At present, there is not sufficient evidence to recommend measurement of CRP in the routine evaluation of cerebrovascular disease risk in primary prevention, because there is insufficient evidence as to whether early detection, or intervention based on detection, improves health outcomes, although shared risk of cardiovascular disease indicates this may be of value. In secondary prevention of stroke, elevated CRP adds to existing prognostic markers, but it remains to be established whether specific therapeutic options can be derived from this.


Correction of random exponential band transmissions for Doppler effects.
The transmission of a randomly spaced array of Lorentz lines whose intensities are exponentially distributed may be simply corrected for doppler effects. Evaluation of the correction exponent requires an integration over the Voigt line profile, which may be done once and for all. The integration is described and results presented in a table. From these results, the mean curve of growth of a single Voigt line in such an array may easily be calculated. Curtis' approximation, applied to such a band, gives equivalent widths several tens of percent too large in many situations.


[Hematological, hemostatic and biochemical alterations induced by clofazimine and clarithromycin, in single and multiple doses, in rats].
Clarithromycin and clofazimine have been used to treat leprosy, tuberculosis and infections caused by the Mycobacterium avium complex. Since there is a scarcity of data on the toxicity of therapeutic regimens that include these drugs, this study had the aim of determining the adverse effects of these therapies, through evaluation of hematological, hemostatic and biochemical parameters. The drugs were administered to male Wistar rats, as monotherapy, in regimens of single and multiple doses. Clarithromycin caused increases in the numbers of mononuclear and polymorphonuclear leukocytes. Both of the drugs inverted the proportions between mononuclear and polymorphonuclear cells and increased the numbers of polymorphonuclear cells and degenerating cells. Clofazimine and clarithromycin prolonged the prothrombin time and clarithromycin also prolonged the activated partial thromboplastin time. Clarithromycin caused increases in total and direct bilirubin. Both of the drugs increased the plasma levels of gamma-glutamyltransferase. Therefore, clofazimine and clarithromycin induce hematological, hemostatic and hepatic changes.


Activity-dependent FUS dysregulation disrupts synaptic homeostasis.
The RNA-binding protein fused-in-sarcoma (FUS) has been associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two neurodegenerative disorders that share similar clinical and pathological features. Both missense mutations and overexpression of wild-type FUS protein can be pathogenic in human patients. To study the molecular and cellular basis by which FUS mutations and overexpression cause disease, we generated novel transgenic mice globally expressing low levels of human wild-type protein (FUS(WT)) and a pathological mutation (FUS(R521G)). FUS(WT) and FUS(R521G) mice that develop severe motor deficits also show neuroinflammation, denervated neuromuscular junctions, and premature death, phenocopying the human diseases. A portion of FUS(R521G) mice escape early lethality; these escapers have modest motor impairments and altered sociability, which correspond with a reduction of dendritic arbors and mature spines. Remarkably, only FUS(R521G) mice show dendritic defects; FUS(WT) mice do not. Activation of metabotropic glutamate receptors 1/5 in neocortical slices and isolated synaptoneurosomes increases endogenous mouse FUS and FUS(WT) protein levels but decreases the FUS(R521G) protein, providing a potential biochemical basis for the dendritic spine differences between FUS(WT) and FUS(R521G) mice.


What Are the Effects of Irreversible Electroporation on a Staphylococcus aureus Rabbit Model of Osteomyelitis?
The treatment of osteomyelitis can be challenging because of poor antibiotic penetration into the infected bone and toxicities associated with prolonged antibiotic regimens to control infection. Irreversible electroporation (IRE), a percutaneous image-guided ablation technology in which the targeted delivery of high-voltage electrical pulses permanently damages the cell membrane, has been shown to effectively control bacterial growth in various settings. However, IRE for the management of bone infections has yet to be evaluated. We aimed to evaluate IRE for treating osteomyelitis by assessing (1) the efficacy of IRE to suppress the in vitro growth of a clinical isolate of S. aureus, alone or combined with cefazolin; and (2) the effects of IRE on the in vivo treatment of a rabbit model of osteomyelitis. S. aureus strain UAMS-1 expanded in vitro to the log phase was subjected to an electric field of 2700 V/cm, which was delivered in increasing numbers of pulses. Immediately after electroporation, bacteria were plated on agar plates with or without cefazolin. The number of colony-forming units (CFUs) was scored the following day. ANOVA tests were used to analyze in vitro data. In a rabbit osteomyelitis model, we inoculated the same bacterial strain into the radius of adult male New Zealand White rabbits. Three weeks after inoculation, all animals (n = 32) underwent irrigation and débridement, as well as wound culture of the infected forelimb. Then, they were randomly assigned to one of four treatment groups (n = eight per group): untreated control, cefazolin only, IRE only, or combined IRE + cefazolin. Serial radiography was performed to assess disease progression using a semiquantitative grading scale. Bone and soft-tissue specimens from the infected and contralateral forelimbs were collected at 4 weeks after treatment for bacterial isolation and histologic assessment using a semiquantitative scale. The in vitro growth of S. aureus UAMS-1 was impaired by IRE in a pulse-dependent fashion; the number of CFUs/mL was different among seven pulse levels, namely 0, 10, 30, 60, 90, 120, and 150 pulses. With the number of CFUs/mL observed in untreated controls set as 100%, 10 pulses rendered a median of 50.2% (range 47.1% to 58.2%), 30 pulses rendered a median of 2.7% (range 2.5% to 2.8%), 60 pulses rendered a median of 0.014% (range 0.012% to 0.015%), 90 pulses rendered a median of 0.004% (range 0.002% to 0.004%), 120 pulses rendered a median of 0.001% (range 0.001% to 0.001%), and 150 pulses rendered a median of 0.001% (range 0.000% to 0.001%) (Kruskal-Wallis test: p = 0.003). There was an interaction between the effect of the number of pulses and the concentration of cefazolin (two-way ANOVA: F [8, 30] = 17.24; p < 0.001), indicating that combining IRE with cefazolin is more effective than either treatment alone at suppressing the growth of S. aureus UAMS-1. Likewise, the clinical response in the rabbit model (the percentage of animals without detectable residual bacteria in the bone and surrounding soft tissue after treatment) was better in the combination group than in the other groups: control, 12.5% (one of eight animals); IRE only, 12.5% (one of eight animals); cefazolin only, 25% (two of eight animals); and IRE + cefazolin, 75% (six of eight animals) (two-sided Fisher's exact test: p = 0.030). IRE effectively suppressed the growth of S. aureus UAMS-1 and enhanced the antibacterial effect of cefazolin in in vitro studies. When translated to a rabbit osteomyelitis model, the addition of IRE to conventional parenteral antibiotic treatment produced the strongest response, which supports the in vitro findings. Our results show that IRE may improve the results of standard parenteral antibiotic treatment, thus setting the stage for models with larger animals and perhaps trials in humans for validation.


Detecting breaches in defensive barriers using in situ simulation for obstetric emergencies.
In Reason's safety model, high-reliability healthcare organisations are characterised by multiple layers of defensive barriers in depth associated with increased levels of safety in the care delivery system. However, there is very little empirical evidence describing and defining defensive barriers in healthcare settings or systematic analysis documenting the nature of breaches in these barriers. This study uses in situ simulation to identify defensive barriers and classify the nature of active and latent breaches in these barriers. An in situ simulation methodology was used to study team performance during obstetrics emergencies. The authors conducted 46 trials of in situ simulated obstetrics emergencies in two phases at six different hospitals involving 823 physicians, nurses and support staff from January 2006 to February 2008. These six hospitals included a university teaching hospital, two suburban community hospitals and three rural hospitals. The authors created a high-fidelity simulation by developing scenarios based on actual sentinel events. A total of 965 breaches were identified by participants in 46 simulation trials. Of the 965 breaches, 461 (47.8%) were classified as latent conditions, and 494 (51.2%) were classified as active failures. In Reason's model, all sentinel events involve a breached protective layer. Understanding how protective layers breakdown is the first step to ensure patient safety and establish a high reliability. These findings suggest where to invest resources to help achieve a high reliability. In situ simulation helps recognise and remedy both active failures and latent conditions before they combine to cause bad outcomes.


Self-association of the Lentivirus protein, Nef.
The HIV-1 pathogenic factor, Nef, is a multifunctional protein present in the cytosol and on membranes of infected cells. It has been proposed that a spatial and temporal regulation of the conformation of Nef sequentially matches Nef's multiple functions to the process of virion production. Further, it has been suggested that dimerization is required for multiple Nef activities. A dimerization interface has been proposed based on intermolecular contacts between Nefs within hexagonal Nef/FynSH3 crystals. The proposed dimerization interface consists of the hydrophobic B-helix and flanking salt bridges between R105 and D123. Here, we test whether Nef self-association is mediated by this interface and address the overall significance of oligomerization. By co-immunoprecipitation assays, we demonstrated that HIV-1Nef exists as monomers and oligomers with about half of the Nef protomers oligomerized. Nef oligomers were found to be present in the cytosol and on membranes. Removal of the myristate did not enhance the oligomerization of soluble Nef. Also, SIVNef oligomerizes despite lacking a dimerization interface functionally homologous to that proposed for HIV-1Nef. Moreover, HIV-1Nef and SIVNef form hetero-oligomers demonstrating the existence of homologous oligomerization interfaces that are distinct from that previously proposed (R105-D123). Intracellular cross-linking by formaldehyde confirmed that SF2Nef dimers are present in intact cells, but surprisingly self-association was dependent on R105, but not D123. SIV(MAC239)Nef can be cross-linked at its only cysteine, C55, and SF2Nef is also cross-linked, but at C206 instead of C55, suggesting that Nefs exhibit multiple dimeric structures. ClusPro dimerization analysis of HIV-1Nef homodimers and HIV-1Nef/SIVNef heterodimers identified a new potential dimerization interface, including a dibasic motif at R105-R106 and a six amino acid hydrophobic surface. We have demonstrated significant levels of intracellular Nef oligomers by immunoprecipitation from cellular extracts. However, our results are contrary to the identification of salt bridges between R105 and D123 as necessary for self-association. Importantly, binding between HIV-1Nef and SIVNef demonstrates evolutionary conservation and therefore significant function(s) for oligomerization. Based on modeling studies of Nef self-association, we propose a new dimerization interface. Finally, our findings support a stochastic model of Nef function with a dispersed intracellular distribution of Nef oligomers.


Screening and diagnosis of chronic kidney disease in people with type 2 diabetes attending Australian general practice.
Australian guidelines recommend annual screening and monitoring of chronic kidney disease (CKD) in people with type 2 diabetes (T2D). A cross-sectional study utilising data from NPS MedicineWise MedicineInsight program from June 2015 to May 2016 was undertaken to explore: (1) the proportion of patients with T2D attending general practice who have had screening for, or ongoing monitoring of, CKD; (2) the proportion of patients without a documented diagnosis of CKD who have pathology consistent with CKD diagnosis; and (3) the patient factors associated with screening and the recording of a diagnosis of CKD. Of 90550 patients with T2D, 44394 (49.0%) were appropriately screened or monitored. There were 8030 (8.9%) patients with a recorded diagnosis of CKD, whereas 6597 (7.3%) patients had no recorded diagnosis of CKD despite pathology consistent with a diagnosis. Older age and diagnosis of hypertension or hyperlipidaemia were associated with increased odds of CKD diagnosis being recorded. Older patients, males, those with recorded diagnoses of hypertension or hyperlipidaemia and those who had their medical record opened more frequently were more likely to be screened appropriately. Screening and monitoring of CKD appears suboptimal. Research to explore barriers to screening, recording and monitoring of CKD, and strategies to address these, is required.


Comparison of protocols and registry entries to published reports for randomised controlled trials.
Publication of complete trial results is essential if people are to be able to make well-informed decisions about health care. Selective reporting of randomised controlled trials (RCTs) is a common problem. To systematically review studies of cohorts of RCTs to compare the content of trial reports with the information contained in their protocols, or entries in a trial registry. We conducted electronic searches in Ovid MEDLINE (1950 to August 2010); Ovid EMBASE (1980 to August 2010); ISI Web of Science (1900 to August 2010) and the Cochrane Methodology Register (Issue 3, 2010), checked reference lists, and asked authors of eligible studies to identify further studies. Studies were not excluded based on language of publication or our assessment of their quality. Published or unpublished cohort studies comparing the content of protocols or trial registry entries with published trial reports. Data were extracted by two authors independently. Risk of bias in the cohort studies was assessed in relation to follow up and selective reporting of outcomes. Results are presented separately for the comparison of published reports to protocols and trial registry entries. We included 16 studies assessing a median of 54 RCTs (range: 2 to 362). Twelve studies compared protocols to published reports and four compared trial registry entries to published reports. In two studies, eligibility criteria differed between the protocol and publication in 19% and 100% RCTs. In one study, 16% (9/58) of the reports included the same sample size calculation as the protocol. In one study, 6% (4/63) of protocol-report pairs gave conflicting information regarding the method of allocation concealment, and 67% (49/73) of blinded studies reported discrepant information on who was blinded. In one study unacknowledged discrepancies were found for methods of handling protocol deviations (44%; 19/43), missing data (80%; 39/49), primary outcome analyses (60%; 25/42) and adjusted analyses (82%; 23/28). One study found that of 13 protocols specifying subgroup analyses, 12 of these 13 trials reported only some, or none, of these. Two studies found that statistically significant outcomes had a higher odds of being fully reported compared to nonsignificant outcomes (range of odds ratios: 2.4 to 4.7). Across the studies, at least one primary outcome was changed, introduced, or omitted in 4-50% of trial reports. Discrepancies between protocols or trial registry entries and trial reports were common, although reasons for these were not discussed in the reports. Full transparency will be possible only when protocols are made publicly available or the quality and extent of information included in trial registries is improved, and trialists explain substantial changes in their reports.


V beta 6-bearing T cells are involved in resistance to Trypanosoma cruzi infection in XID mice.
BALB.xid mice, carrying an X-linked mutation leading to the absence of CD5+ B cells, are highly resistant to Trypanosoma cruzi infection. These mice clear blood parasites in the acute phase of infection and do not develop the inflammatory infiltration characteristically observed in the chronic phase of susceptible strains of mice. We have shown that the resistance of BALB.xid is dependent on the production of high levels of IFN-gamma. Natural (adoptive foster) or artificial (in vivo injection of blocking antibodies) treatments of BALB.xid induced deletion of CD4+ and CD8+ cells bearing V beta 6 TCR. The absence of V beta 6 lymphocytes considerably reduced resistance to infection. Furthermore, in BALB.xid lacking this minor fraction of the T cell repertoire, almost 50% of the IFN-gamma production is lost. This indicates that V beta 6-bearing T cells are either directly or indirectly involved in the production of IFN-gamma and, thus, important for an effective immune response during the acute phase of experimental Chagas' disease.


Combining movement kinematics, efficiency functions, and Brinley plots to study age-related slowing of sensorimotor processes: insights from Fitts' task.
Measurement of changes in human information-processing capacities underlying slowing of sensorimotor processes is an important challenge for aging research. Methods exist to estimate the magnitude of slowing and variability coefficients, but attempts to apply them in motor tasks have been scarce. In the present experiment we combined movement kinematic analysis, efficiency functions and Brinley plot to assess age-related slowing and variability of sensorimotor processes in a discrete Fitts' aiming task. (1) Quantifying slowing and variability for the different sensorimotor processes involved in aiming movements, and (2) determining whether changes occurred continuously over time by comparing different age groups. 29 participants (24-90 years) divided into four age groups were tested. Target size manipulation resulted in three levels of difficulty. Total movement time, durations of the first and secondary movement phases and related variability were analyzed. Fitts and Brinley regression functions were calculated on the basis of the different movement variables. Only older participants were slower than the three younger age groups. For this group, age-difficulty effect was observed for total movement times, but analyses showed that only the secondary movement phase slowed multiplicatively. Additive and proportional increases in variability were also observed in older participants for the first and secondary movement phases, respectively. For the secondary movement phase, estimated slowing coefficients were comparable to those reported in cognitive literature. In addition, Brinley analyses showed that variability increased more than movement time in the secondary movement phase. Combination of the different methods of analysis allowed a precise assessment of the locus of slowing and variability of sensorimotor processes in the different movement phases. Results showed that significant changes in both slowing and variability of the different processes occurred late in life. Our findings also suggest that slowing could result from age-induced increase in noise produced by the neural system. Finally, the present results raise the question of whether age-related slowing and increase in variability observed in both cognitive and sensorimotor domains share common causes in the central nervous system.


Regulation of ribulose-1,5-bisphosphate carboxylase/oxygenase (rubisco) activase: product inhibition, cooperativity, and magnesium activation.
In many photosynthetic organisms, tight-binding Rubisco inhibitors are released by the motor protein Rubisco activase (Rca). In higher plants, Rca plays a pivotal role in regulating CO2 fixation. Here, the ATPase activity of 0.005 mm tobacco Rca was monitored under steady-state conditions, and global curve fitting was utilized to extract kinetic constants. The kcat was best fit by 22.3 ± 4.9 min(-1), the Km for ATP by 0.104 ± 0.024 mm, and the Ki for ADP by 0.037 ± 0.007 mm. Without ADP, the Hill coefficient for ATP hydrolysis was extracted to be 1.0 ± 0.1, indicating noncooperative behavior of homo-oligomeric Rca assemblies. However, the addition of ADP was shown to introduce positive cooperativity between two or more subunits (Hill coefficient 1.9 ± 0.2), allowing for regulation via the prevailing ATP/ADP ratio. ADP-mediated activation was not observed, although larger amounts led to competitive product inhibition of hydrolytic activity. The catalytic efficiency increased 8.4-fold upon cooperative binding of a second magnesium ion (Hill coefficient 2.5 ± 0.5), suggesting at least three conformational states (ATP-bound, ADP-bound, and empty) within assemblies containing an average of about six subunits. The addition of excess Rubisco (24:1, L8S8/Rca6) and crowding agents did not modify catalytic rates. However, high magnesium provided for thermal Rca stabilization. We propose that magnesium mediates the formation of closed hexameric toroids capable of high turnover rates and amenable to allosteric regulation. We suggest that in vivo, the Rca hydrolytic activity is tuned by fluctuating [Mg(2+)] in response to changes in available light.


Cost-effectiveness of skin-barrier-enhancing emollients among preterm infants in Bangladesh.
To evaluate the cost-effectiveness of topical emollients, sunflower seed oil (SSO) and synthetic Aquaphor, versus no treatment, in preventing mortality among hospitalized preterm infants (< 33 weeks gestation) at a tertiary hospital in Bangladesh. Evidence from a randomized controlled efficacy trial was evaluated using standard Monte Carlo simulation. Programme costs were obtained from a retrospective review of activities. Patient costs were collected from patient records. Health outcomes were calculated as deaths averted and discounted years of life lost (YLLs) averted. Results were deemed cost-effective if they fell below a ceiling ratio based on the per capita gross national income of Bangladesh (United States dollars, US$ 470). Aquaphor and SSO were both highly cost-effective relative to control, reducing neonatal mortality by 26% and 32%, respectively. SSO cost US$ 61 per death averted and US$ 2.15 per YLL averted (I$ 6.39, international dollars, per YLL averted). Aquaphor cost US$ 162 per death averted and US$ 5.74 per YLL averted (I$ 17.09 per YLL averted). Results were robust to sensitivity analysis. Aquaphor was cost-effective relative to SSO with 77% certainty: it cost an incremental US$ 26 more per patient treated, but averted 1.25 YLLs (US$ 20.74 per YLL averted). Topical therapy with SSO or Aquaphor was highly cost-effective in reducing deaths from infection among the preterm neonates studied. The choice of emollient should be made taking into account budgetary limitations and ease of supply. Further research is warranted on additional locally available emollients, use of emollients in community-based settings and generalizability to other geographic regions.


Full-Shift Trunk and Upper Arm Postures and Movements Among Aircraft Baggage Handlers.
The present study assessed full-shift trunk and upper arm postural exposure amplitudes, frequencies, and durations among Swedish airport baggage handlers and aimed to determine whether exposures differ between workers at the ramp (loading and unloading aircraft) and baggage sorting areas. Trunk and upper arm postures were measured using inclinometers during three full work shifts on each of 27 male baggage handlers working at a large Swedish airport. Sixteen of the baggage handlers worked on the ramp and 11 in the sorting area. Variables summarizing postures and movements were calculated, and mean values and variance components between subjects and within subject (between days) were estimated using restricted maximum likelihood algorithms in a one-way random effect model. In total, data from 79 full shifts (651h) were collected with a mean recording time of 495min per shift (range 319-632). On average, baggage handlers worked with the right and left arm elevated >60° for 6.4% and 6.3% of the total workday, respectively. The 90th percentile trunk forward projection (FP) was 34.1°, and the 50th percentile trunk movement velocity was 8° s(-1). For most trunk (FP) and upper arm exposure variables, between-subject variability was considerable, suggesting that the flight baggage handlers were not a homogeneously exposed group. A notable between-days variability pointed to the contents of the job differing on different days. Peak exposures (>90°) were higher for ramp workers than for sorting area workers (trunk 0.6% ramp versus 0.3% sorting; right arm 1.3% ramp versus 0.7% sorting). Trunk and upper arm postures and movements among flight baggage handlers measured by inclinometry were similar to those found in other jobs comprising manual material handling, known to be associated with increased risks for musculoskeletal disorders. The results showed that full-shift trunk (FP) and, to some extent, peak arm exposures were higher for ramp workers compared with sorting workers.