Overexpression of Mxi1 inhibits the induction of the human ornithine decarboxylase gene by the Myc/Max protein complex.
We have previously shown that the Myc/Max protein complex plays a role in the growth-associated expression of the human ornithine decarboxylase gene. Mxi1 and Mad, novel Max-associated proteins have been identified and shown to form heterodimers with Max which bind efficiently to the Myc/Max consensus recognition sequence, CACGTG, in vitro. However, formation of Max/Mxi1 or Max/Mad heterodimers results in a reduction in Myc/Max dependent transcriptional activation of reporter plasmid constructs containing the consensus element. In light of the evidence that ODC is transcriptionally regulated in vitro and in vivo by the Myc/Max protein complex and the potential role of Mxi1 and Mad as antagonists of Myc transactivation activity, we set out to determine if one of these Max associated proteins, Mxi1, could affect the regulation of ODC expression by Myc/Max and if this regulation was correlated to growth status. Our results show that overexpression of Mxi1 does in fact inhibit ODC gene expression in a dose-dependent manner both in vivo and in vitro. In addition, evidence is presented which shows that levels of Mxi1 are up-regulated during long term quiescence and down-regulated following growth stimulation by serum. These results suggest that alterations in the levels of Max-associated proteins such as Mxi1 can modulate critical levels of functional Myc/Max protein complexes. This can alter transcriptional transactivation of Myc-regulated targets and as a consequence affect levels of genes essential for initiation and/or maintenance of growth.


Chloroplast thylakoid protein phosphatase is a membrane surface-associated activity.
Chloroplast thylakoid protein phosphatase activity was measured using (32)P-labeled histone as an exogenous substrate and an assay of the (32)Pi released involving formation of a phosphomolybdate complex and organic extraction. The activity was liberated from wheat (Triticum aestivum) thylakoids by washing the membranes in NaCl-containing solutions followed by centrifugation. The liberated phosphatase activity had a pH optimum of approximately 6.75, was inhibited by addition of 10 millimolar EDTA or EGTA, and was stimulated by addition of millimolar amounts of dithiothreitol, magnesium, manganese, or calcium ions. The rate of thylakoid protein dephosphorylation was decreased following liberation of a portion of the protein phosphatase activity and was increased by addition of salt-liberated phosphatase fraction. These results suggest that at least a portion of wheat thylakoid protein phosphatase is a peripheral, rather than an integral, membrane protein.


The relationship between job components, neighbourhood walkability and African academics' physical activity: a post-COVID-19 context.
Research to date suggests that physical activity (PA) among academics is insufficient globally. Academics in many African countries were recently required to resume work while observing social distancing protocols. Physical inactivity (PI) was, therefore, expected to increase in such academics. Interestingly, walkable neighbourhoods are resources that could discourage excessive sitting and PI in this situation. This study, therefore, assessed the moderating role of neighbourhood walkability in the relationship between core job components (i.e. on-site teaching, online teaching, research and student assessment) and PA among academics. The study adopted a cross-sectional design that utilized an online survey hosted by Google Forms to gather data. Participants were volunteer full-time academics in Nigeria, Ghana, Kenya and Tanzania. A total of 1064 surveys were analysed, with a sensitivity analysis utilized to select covariates for the ultimate hierarchical linear regression model. After controlling for the ultimate covariates (e.g. gender, education and income), PA was found to be positively associated with the job component 'research work' but negatively associated with student assessment. Neighbourhood walkability increased the positive relationship of research work with PA and reduced the negative relationship of student assessment with PA. The non-significant negative relationship between 'teaching online' and PA was made positively significant by neighbourhood walkability. We conclude that research as a job component is positively associated with PA, but online teaching is negatively associated with PA among African academics in a post-COVID-19 context.


Alchemical prediction of hydration free energies for SAMPL.
Hydration free energy calculations have become important tests of force fields. Alchemical free energy calculations based on molecular dynamics simulations provide a rigorous way to calculate these free energies for a particular force field, given sufficient sampling. Here, we report results of alchemical hydration free energy calculations for the set of small molecules comprising the 2011 Statistical Assessment of Modeling of Proteins and Ligands challenge. Our calculations are largely based on the Generalized Amber Force Field with several different charge models, and we achieved RMS errors in the 1.4-2.2 kcal/mol range depending on charge model, marginally higher than what we typically observed in previous studies (Mobley et al. in J Phys Chem B 111(9):2242-2254, 2007, J Chem Theory Comput 5(2):350-358, 2009, J Phys Chem B 115:1329-1332, 2011; Nicholls et al. in J Med Chem 51:769-779, 2008; Klimovich and Mobley in J Comput Aided Mol Design 24(4):307-316, 2010). The test set consists of ethane, biphenyl, and a dibenzyl dioxin, as well as a series of chlorinated derivatives of each. We found that, for this set, using high-quality partial charges from MP2/cc-PVTZ SCRF RESP fits provided marginally improved agreement with experiment over using AM1-BCC partial charges as we have more typically done, in keeping with our recent findings (Mobley et al. in J Phys Chem B 115:1329-1332, 2011). Switching to OPLS Lennard-Jones parameters with AM1-BCC charges also improves agreement with experiment. We also find a number of chemical trends within each molecular series which we can explain, but there are also some surprises, including some that are captured by the calculations and some that are not.


Suspected central anticholinergic syndrome in a 6-week-old infant.
A 6-wk-old male infant became unresponsive after an uneventful general anesthetic for hernia repair. His symptoms were consistent with central anticholinergic syndrome. He appeared to awaken after treatment with IV physostigmine in a dose of 0.04 mg/kg. Because of the recurrence of sedation, a second physostigmine infusion was administered, which again led to transient arousal. Finally, the patient awoke spontaneously after 24 h and recovered uneventfully.


Laparoscopic incisional hernia repair: our experience with 105 consecutive cases.
Conventional repair of incisional hernia is associated with significant complications and a high recurrence rate (30-50%). The laparoscopic approach offers an effective alternative and reduces the recurrences to less than 5%. The aim of this study was to review our experience with laparoscopic incisional hernia repair. Medical records of all patients who underwent laparoscopic incisional hernia repair from January 2002 to December 2006 were reviewed. Demographic and postoperative data were recorded. The study population consisted of 105 patients, 72 females (68.5%) and 33 males (31.5%); the mean age was 56 years (range: 17-83 years). The mean fascial defect size was 116.9 cm2 and the average mesh size used was 256 cm2. Operative time was 118 min and the average hospital stay was 5 days. An expanded polytetrafluoroethylene (ePTFE) prosthesis was used In all patients. Perioperative complications occurred in 33 patients (31.4%) including seroma, cellulitis at the trocar site and prolonged ileus. During the follow-up there were 3 hernia recurrences (2.8%). Our study shows that laparoscopic incisional hernia repair resulted in a moderate rate of perioperative complications, a short hospital stay and a low recurrence rate. Hence the laparoscopic technique should be considered an effective and safe alternative to conventional incisional hernia repair.


Mechanisms of Na transport at the basolateral pole of rat enterocyte.
Basolateral membranes isolated from rat jejunal enterocytes and enriched 14 times were found present as unsealed and sealed right side out (RSO) or inside out (IO) vesicles in the ratio 2:2:1. Entrance of 1 mM Na (JNa) into basolateral membrane vesicles was measured in the presence and in the absence of 5 mM ATP by a rapid filtration technique, under different experimental conditions. JNa across the basolateral membrane is cis-inhibited by K, transstimulated by K and further stimulated by ATP (activation of the Na pump). Both K- and ATP-positive effects are also obtained by other cations: the relative stimulation sequence is K greater than Rb = NH4 greater than Cs. The ATP effect can be suppressed by vanadate and strophanthidin; moreover the K effect on JNa is not influenced by blocking the mechanism of the Na pump with ouabain, strophanthidin and adenosine 5'-[beta,gamma-imido]triphosphate. The transmembrane potential does not influence the K-stimulated JNa. In addition to the Na pump this study demonstrates the existence of an exchange mechanism between Na and K, which seems to be different from the Na pump. There appears to be no Na-K cotransport.


Key role of congestion in natural history of heart failure.
The natural course of heart failure with decreased and preserved systolic function is almost identical. The current concept of heart failure where decreased cardiac output plays the major role does not explain this similarity. We suggest a revised concept of heart failure where congestion plays the leading role. While congestion is almost invariably present in heart failure with normal and with reduced systolic function, the low output syndrome is only present in heart failure with reduced systolic function. The small difference in morbidity and mortality in favor of heart failure with preserved systolic function reflects the contribution of low output syndrome to the natural course of the disease. Congestion can result from low output or from multiple other conditions, but severity of congestion is the major determinant of progression of heart failure.


Silver(I) and rhenium(I) metal complexes of a 2,2'-bipyridine-functionalized third-generation tris(pyrazolyl)methane ligand.
Heterotopic ligands offer the possibility of preparing polynuclear bimetallic complexes. Recent studies of heteroditopic ligands and their metal complexes have focused on novel supramolecular systems, biological activity, and the development of MRI contrast agents. The heteroditopic ligand Bipy-CH2-O-CH2-C(pz)3 (Bipy-L; Bipy is 2,2'-bipyridine and pz is pyrazolyl) reacts with AgBF4 to produce the coordination polymer catena-poly[[silver(I)-(μ-5-{[tris(pyrazol-1-yl)methoxy]methyl-κ2N,N'}-2,2'-bipyridine-κ2N,N')] diethyl ether hemisolvate], {[Ag(C22H20N8O)]BF4·0.5C4H10O}n, and with Re(CO)5Br to form the discrete compound bromidotricarbonyl(5-{[tris(pyrazol-1-yl)methoxy]methyl}-2,2'-bipyridine-κ2N,N')rhenium(I), [ReBr(C22H20N8O)(CO)3]. The silver(I) compound is a one-dimensional coordination polymer, built up by a κ2 coordination mode of the bipyridine group and a κ2-κ0 coordination mode of the -C(pz)3 donor set. In [ReBr(Bipy-L)(CO)3], the ligand coordinates only via the bipyridine end, leaving the -C(pz)3 donor set free for further coordination interactions.


General pharmacology in experimental animals of gadobenate dimeglumine (MultiHance), a new magnetic resonance imaging contrast agent.
To assess in animals the pharmacological tolerability for intravascular gadobenate dimeglumine. Cardiovascular effects: In healthy animals no relevant effects were observed apart from slight and transient increases in cardiac output and decreases in systemic vascular resistance. In pigs with myocardial ischemia: doses up to 3.0 mmol/kg caused dose-dependent decreases in heart rate, systemic vascular resistance and mean arterial blood pressure along with transient increases in cardiac output. In vitro: Myocardial contractility was slightly depressed after direct exposure to a 30 mM solution. Respiratory effects in healthy pigs: no effects after 1.0 mmol/kg i.v. Effects on the central nervous system: In healthy animals: gadobenate dimeglumine, 1.0 mmol/kg i.v, did not penetrate nor impair the blood-brain barrier in rats and did not affect behavior, motor coordination or EEG. In pathological models: even in the presence of an osmotically disrupted blood-brain barrier, brain penetration of gadobenate was poor and no signs of epileptogenic potential were evident. Effects on blood: No hemolytic potential was observed. Plasma coagulation was slightly affected in vitro but not in vivo. Effects on kidney and liver function: Transient increases in diuresis, without effects on blood and urine enzymes were observed at doses of 1.25 and 2.5 mmol/kg. The clinical use of gadobenate dimeglumine as an intravascular magnetic resonance imaging contrast agent is strongly supported by the good tolerability of the product in healthy and pathological animal models.


Effect of number of clinics and panel size on patient continuity for medical residents.
Accreditation Council for Graduate Medical Education program requirements for internal medicine residency training include a longitudinal, continuity experience with a panel of patients. To determine whether the number of resident clinics, the resident panel size, and the supervising attending physician affect patient continuity. To determine the number of clinics and the panel size necessary to maximize patient continuity. We used linear regression modeling to assess the effect of number of attended clinics, the panel size, and the attending physician on patient continuity. Forty medicine residents in an academic medicine clinic. Percent patient continuity by the usual provider of care method. Unadjusted linear regression analysis showed that patient continuity increased 2.3% ± 0.7% for each additional clinic per 9 weeks or 0.4% ± 0.1% for each additional clinic per year (P = .003). Conversely, patient continuity decreased 0.7% ± 0.4% for every additional 10 patients in the panel (P = .04). When simultaneously controlling for number of clinics, panel size, and attending physician, multivariable linear regression analysis showed that patient continuity increased 3.3% ± 0.5% for each additional clinic per 9 weeks or 0.6% ± 0.1% for each additional clinic per year (P < .001). Conversely, patient continuity decreased 2.2% ± 0.4% for every additional 10 patients in the panel (P < .001). Thus, residents who actually attend at least 1 clinic per week with a panel size less than 106 patients can achieve 50% patient continuity. Interestingly, the attending physician accounted for most of the variability in patient continuity (51%). Patient continuity for residents significantly increased with increasing numbers of clinics and decreasing panel size and was significantly influenced by the attending physician.


Role of interleukin-23 (IL-23) receptor signaling for IL-17 responses in human Lyme disease.
Interleukin-23 (IL-23) is known to play a crucial role in the development and maintenance of T helper 17 cells. It has been previously demonstrated that IL-17 is involved in experimental Lyme arthritis, caused by Borrelia burgdorferi bacteria. However, the precise role of the IL-23 receptor (IL-23R) for the B. burgdorferi-induced IL-17 responses or human Lyme disease has not yet been elucidated. IL-23R single nucleotide polymorphism (SNP) rs11209026 was genotyped using the TaqMan assay. Functional studies were performed using peripheral blood mononuclear cells, and cytokines were measured using enzyme-linked immunosorbent assay (ELISA). Dose-dependent production of IL-23 and IL-17 by B. burgdorferi could be observed. Interestingly, when IL-23 bioactivity was inhibited by a specific antibody against IL-23p19, IL-17 production was significantly downregulated. In contrast, production of gamma interferon (IFN-γ) was not affected after the blockade of IL-23 activity. Moreover, individuals bearing a single nucleotide polymorphism in the IL-23R gene (Arg381Gln) produced significantly less IL-17 after B. burgdorferi stimulation compared with that of the individuals bearing the wild type. Despite lower IL-17 production, the IL-23R gene polymorphism did not influence the development of chronic Lyme disease in a cohort of patients with Lyme disease. This study demonstrates that IL-23R signaling is needed for B. burgdorferi-induced IL-17 production in vitro and that an IL-23R gene SNP leads to impaired IL-17 production. However, the IL-23R gene polymorphism is not crucial for the pathogenesis of chronic Lyme.


Membrane type 1-matrix metalloproteinase is regulated by chemokines monocyte-chemoattractant protein-1/ccl2 and interleukin-8/CXCL8 in endothelial cells during angiogenesis.
We have investigated the putative role and regulation of membrane type 1-matrix metalloproteinase (MT1-MMP) in angiogenesis induced by inflammatory factors of the chemokine family. The absence of MT1-MMP from null mice or derived mouse lung endothelial cells or the blockade of its activity with inhibitory antibodies resulted in the specific decrease of in vivo and in vitro angiogenesis induced by CCL2 but not CXCL12. Similarly, CCL2- and CXCL8-induced tube formation by human endothelial cells (ECs) was highly dependent on MT1-MMP activity. CCL2 and CXCL8 significantly increased MT1-MMP surface expression, clustering, activity, and function in human ECs. Investigation of the signaling pathways involved in chemokine-induced MT1-MMP activity in ECs revealed that CCL2 and CXCL8 induced cortical actin polymerization and sustained activation of phosphatidylinositol 3-kinase (PI3K) and the small GTPase Rac. Inhibition of PI3K or actin polymerization impaired CCL2-induced MT1-MMP activity. Finally, dimerization of MT1-MMP was found to be enhanced by CCL2 in ECs in a PI3K- and actin polymerization-dependent manner. In summary, we identify MT1-MMP as a molecular target preferentially involved in angiogenesis mediated by CCL2 and CXCL8, but not CXCL12, and suggest that MT1-MMP dimerization might be an important mechanism of its regulation during angiogenesis.


10-year survival rate in 92 patients with invasive bladder carcinoma treated by bladder sparing methods.
The 10-year survival rate was evaluated in 92 patients with invasive bladder cancer (stages T 2 to 4) who were treated between 1966 and 1985 using bladder-sparing methods such as intravesical instillation of antineoplastic agents, transurethral resection, partial cystectomy, arterial infusion chemotherapy, radiation and embolization of the internal iliac artery. The overall 5-year and 10-year survival rates were 68.1% and 53.9% respectively at a median follow-up period of 60 months. The 10-year survival rate for patients with clinical stage T 2, T3a, T3b and T 4 were 83.7%, 58.9%, 50.8% and 0%, respectively. Our data were comparable or superior to those following radical cystectomy combined with pre- and post-operative radiation or chemotherapy. In conclusion, our bladder-sparing conservative method is thought to be an alternative treatment for advanced bladder cancer and provides a favorable survival rate as well as an improved quality of life with preservation of bladder function.


The systematic error in the estimation of fetal weight and the underestimation of fetal growth restriction.
Fetal growth restriction (FGR) is associated with an increased risk of perinatal morbidity and mortality and has lifetime implications for the risk of chronic medical conditions. Antenatal diagnosis of FGR remains poor, with the majority of cases remaining undiagnosed. Although several factors contribute to the underdiagnosis of FGR, the error in ultrasound estimation of fetal weight (EFW) generally is not considered in clinical practice. In this commentary, we suggest that the intrinsic, or systematic, error in ultrasound EFW is a significant factor contributing to the underestimation of fetuses predicted to have FGR and should be incorporated into screening and surveillance recommendations. To illustrate this point, we present an analytic model of published data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies characterizing and quantifying the impact of the systematic error in ultrasound EFW on the underdiagnosis of FGR. Independent of the centile at which the risk of adverse outcome related to FGR begins, whether the 10th, 5th or 3rd percentile, our analysis suggests the need to modify to the current paradigm for identifying and responding to fetuses estimated to be at risk.


Crohn's Disease in which the Patient Developed Aortitis during Treatment with Adalimumab.
A 23-year-old woman developed aortitis during treatment with adalimumab (ADA) for ileocolic Crohn's disease (CD). The patient complained of a high fever, abdominal pain, diarrhea, hematochezia and arthralgia. Although the ADA therapy resulted in immediate symptom improvement, after six weeks, she again complained of a low-grade fever and abdominal pain, whereas the CD-related symptoms did not worsen. Contrast-enhanced computed tomography revealed thoracoabdominal aortitis, and we therefore started treatment with prednisolone, which immediately improved the fever and abdominal pain. We subsequently tapered the dose of prednisolone and resumed the administration of ADA in order to maintain the CD remission. No further episodes of aortitis relapse were noted after restarting ADA, and the CD currently remains in remission. This is the first report of the onset of aortitis during ADA therapy for CD.


Near-horizon conformal symmetry and black hole entropy.
Near an event horizon, the action of general relativity acquires a new asymptotic conformal symmetry. For two-dimensional dilaton gravity, this symmetry results in a chiral Virasoro algebra, and Cardy's formula for the density of states reproduces the Bekenstein-Hawking entropy. This lends support to the notion that black hole entropy is controlled universally by conformal symmetry near the horizon.


Anion influence on the structure and magnetic properties of a series of multidimensional pyrimidine-2-carboxylato-bridged copper(II) complexes.
Seven new polynuclear copper(II) complexes of formula [Cu(mu-pymca)2] (1) (pymca(-) = pyrimidine-2-carboxylato), [Cu(mu-pymca)Br] (2), [Cu(mu-pymca)Cl] (3), [Cu(mu-pymca)(SCN)(H2O)] x 4 H2O (4), [Cu(mu-pymca)N3] (5), [Cu2(mu1,5-dca)2(pymca)2] (6) (dca = dicyanamide), and K{[mu-Au(CN)2]2[(Cu(NH3)2)2(mu-pymca)]}[Au(CN)2]2 (7) have been synthesized by reactions of K-pymca with copper(II) ions in the presence of different counteranions. Compound 1 is a linear neutral chain with a carboxylato bridging ligand in a syn-anti coordination mode, whereas complexes 2 and 3 consist of cationic linear chains with cis and trans bis(chelating) pymca bridging ligands. Complex 4 adopts a helical pymca-bridged chain structure. In complex 5, zigzag pymca-bridged chains are connected by double end-on azide bridging ligands to afford a unique honeycomb layer structure. Complex 6 is a centrosymmetric dinuclear system with double mu 1,5-dicyanamide bridging ligands and pymca end-cap ligands. Complex 7 is made of pymca-bridged dinuclear [Cu(NH3)2(mu-pymca)Cu(NH3)2](3+) units connected by [Au(CN)2](-) anions to four other dinuclear units, giving rise to cationic (4,4) rectangular nets, which are linked by aurophilic interactions to afford a singular 3D network. Variable-temperature magnetic susceptibility measurements show that complex 1 exhibits a very weak antiferromagnetic coupling through the syn-anti (equatorial-axial) carboxylate bridge (J = -0.57 cm(-1)), whereas complexes 2-4 and 7 exhibit weak to strong antiferromagnetic couplings through the bis(chelating) pymca bridging ligand J = -17.5-276.1 cm(-1)). Quantum Monte Carlo methods have been used to analyze the experimental magnetic data for 5, leading to an antiferromagnetic coupling (J = -34 cm(-1)) through the pymca ligand and to a ferromagnetic coupling (J = 71 cm(-1)) through the azide bridging ligands. Complex 6 exhibits a very weak antiferromagnetic coupling through the dicyanamide bridging ligands (J = -5.1 cm(-1)). The magnitudes of the magnetic couplings in complexes 2-5 have been explained on the basis of the overlapping between magnetic orbitals and DFT theoretical calculations.


The origin of hospices/hospitals.
Hospices/hospitals in Western civilization are primarily an outgrowth of the teachings of Jesus. Soon after Greek monastic orders constructed buildings for the sick and dying, noblewoman Fabiola established the first hospices in the western Mediterranean. The hospice/hospital movement spread widely in medieval Europe. In modern society a distinction has been made between hospitals and hospices. Hospitals are devoted mostly to curing patients while hospices are concerned with terminal care. St. Christopher's Hospice is the acclaimed model of what a hospice program should contain. Caring for the sick and dying has contributed greatly to the positive influence of Christianity.


Cell analysis for hematopoietic stem/progenitor cell transplantation.
Cytometric analysis has become an important aspect in the quality control of cells in all phases of hematopoietic cell transplantation. In the stage of donor conditioning the counting of stem and progenitor cells is important and several reliable single platform tests for CD34+ cells have become available recently. It has been shown, that the count of certain subsets of CD34 may predict best time for harvesting stem cells better than just CD34. In many cases manipulation of the cell sample after collection from the donor is necessary before the cells are adequate for transplantation. Characterization of the resulting cell preparations requires reliable quantitative analysis of a variety of cell types like the enumeration of T-cells at the level of one in ten thousand for some allogeneic transplantations. It is discussed how these clinical requirements will need a refinement of cytometric procedures to achieve adequate clinical decisions.


Haemodynamic changes measured by transthoracic bioimpedance during treatment with recombinant human erythropoietin.
Hypertension complicates the treatment of anaemia of chronic renal failure with recombinant human erythropoietin (EPO) in some patients. We conducted a prospective study measuring changes in cardiac index (CI) and systemic vascular resistance index (SVRI) in 29 patients from before commencement of EPO to attainment of target haemoglobin concentration. We used the operator-independent technique of trans-thoracic bioimpedance. The group of patients who developed EPO-induced hypertension (EpHT) were separately analysed and compared with the group who had no change in blood pressure (NC). Our results showed there was a significant rise in SVRI after treatment in EpHT group patients but in the NC group there was a small fall. CI increased significantly in the NC group after treatment but no change was recorded in the EpHT group. These findings clearly demonstrate how the cardiovascular changes differ in patients who develop EPO-induced hypertension.


Clinical pharmacy services in an ambulatory oncology clinic: Patient perception and satisfaction.
Studies have shown that patients rate pharmacists more favourably when the pharmacist expresses interest in the patient and attends to patients' perspectives. There is limited available evidence evaluating both patient perception and satisfaction regarding clinical pharmacy services provided in an ambulatory oncology clinic. This was a prospective mixed methods study involving surveys and patient interviews. Consenting participants completed a survey at their first visit evaluating their perceptions of the importance of the clinical pharmacy services offered in the ambulatory oncology clinic. They completed a second survey 6-8 weeks later to re-evaluate their perceptions and to measure satisfaction ratings. The final component of this study involved semi-structured one-on-one telephone interviews to gather qualitative data regarding the study objectives. A total of 35 participants completed the survey, of which eleven completed one-on-one patient telephone interviews. Patients perceived the clinical pharmacy services assessed as important to their care before receiving treatment. The ratings of the importance of the pharmacist in managing patients' nausea/vomiting significantly decreased when remeasured, whereas the importance of meeting the pharmacist in the clinic significantly increased. The importance of the role of the pharmacist was highlighted in patient interviews as well: patients particularly valued the pharmacist's initiative to meet them in the clinic, the education provided by pharmacist, and the pharmacist's accessibility throughout treatment. Overall, patients in the ambulatory oncology clinic perceived the services offered as important to their care and they were highly satisfied.


Assessment and nonpharmacological management for patients with cancer anorexia-cachexia syndrome: a best practice implementation project.
Cancer anorexia-cachexia syndrome (CACS) is a common multifactorial syndrome, which affects up to 80% patients with advanced cancer. At present, evidence to support the benefit of pharmacological intervention in the management of CACS is limited. Patients would benefit from standard procedures for early assessment and identification of cancer anorexia-cachexia, and using nonpharmacological strategies to manage patients with CACS. This best practice implementation project aimed to implement an evidence-based practice in assessing and managing patients with CACS, thereby improving the compliance of clinical practice with the best evidence and the quality of life of patients with CACS. This was an evidence-based audit and feedback project that used a three-phase approach at a public hospital in China. Phase 1 included the development of seven evidence-based audit criteria and carrying out a baseline audit on 30 patients using the JBI's Practical Application of Clinical Evidence System in the Department of Radiation Oncology of Nanfang Hospital. Phase 2 utilized the Getting Research into Practice component of the Practical Application of Clinical Evidence System to identify barriers to compliance with best practice principles and developed strategies and resources to improve compliance. Phase 3 involved conducting a follow-up audit using the same sample size and audit criteria to assess the results of interventions implemented to improve practice and identify issues that would be addressed in future audit. The compliance rates of audit criteria 1, 2 and 6 were 100% at both baseline and follow-up audit. After the application of evidence, the compliance rate increased from 0 to 100% for audit criterion 3, from 0 to 76.6% for audit criterion 4, from 23 to 70% for audit criterion 5, and from 0 to 40% for audit criterion 5. The best evidence for the assessment and nonpharmacological management of cancer patients with CACS can improve clinical practice, the quality of clinical nursing, and patient satisfaction. The application of electronic informatization promotes the implementation and maintenance of best practice.


Detection of Cryptosporidium parvum in raw milk by PCR and oligonucleotide probe hybridization.
Cryptosporidium spp. are potential contaminants of food. Suspected cases of food-borne cryptosporidiosis are rarely confirmed because of the limited numbers of oocysts in the samples and the lack of sensitive detection methods adaptable to food. PCR was investigated as a means of overcoming this problem. A PCR assay was designed for the specific amplification of a previously sequenced portion of an oocyst protein gene fragment of Cryptosporidium parvum (N. C. Lally, G. D. Baird, S. J. McQuay, F. Wright, and J. J. Oliver, Mol. Biochem. Parasitol. 56:69-78, 1992) and compared with the primer set of Laxer et al. (M. A. Laxer, B. K. Timblin, and R. J. Patel, Am. J. Trop. Med. Hyg. 45:688-694, 1991). The PCR products were hybridized with digoxigenin-labeled internal probes and detected by chemiluminescence to enhance sensitivity. The two sets of primers were compared with regard to their sensitivity and specificity by using a variety of human and animal isolates of C. parvum and related parasites. Both assays enabled the detection of 1 to 10 oocysts in 20 ml of artificially contaminated raw milk. The assay based on the PCR set and probe of Laxer et al. detected DNAs from Eimeria acervulina and Giardia intestinalis. The new assay has good specificity for C. parvum bovine isolates and hence has a better potential for monitoring the prevalence of C. parvum in raw milk and other environmental samples.


Body mass index in mid-life is associated with a first stroke in men: a prospective population study over 28 years.
Data on the association between obesity and stroke are still limited. We examined the possible association between mid-life body mass index (BMI) and risk of stroke in the prospective Multifactor Primary Prevention Study in Göteborg, Sweden. 7402 apparently healthy men aged 47 to 55 at baseline were followed-up over a 28-year period. Incidence of fatal and nonfatal stroke was recorded in a local stroke registry through the Swedish National Register on Cause of Death and the Swedish Hospital Discharge Registry. A total of 873 first strokes were recorded, including 495 ischemic, 144 hemorrhagic, and 234 unspecified strokes. Compared with men with low normal weight (BMI, 20.0 to 22.49 kg/m2), men with BMI >30.0 kg/m2 had a multiple adjusted hazard ratio of 1.93 (95% CI, 1.44 to 2.58) for total stroke, 1.78 (95% CI, 1.22 to 2.60) for ischemic stroke, and 3.91 (95% CI, 2.10 to 7.27) for unspecified stroke. There was no significant association between BMI and hemorrhagic stroke. Adjustment for potential mediators, eg, hypertension, diabetes and serum cholesterol levels, attenuated but did not eliminate the risk. In this prospective population-based study of men, increased BMI in mid-life was associated with an increased risk for total, ischemic, and unspecified stroke, but not with hemorrhagic stroke. The result supports the role of mid-life BMI as a risk factor for stroke later in life and suggests a differentiated effect on stroke subtypes.


Availability and capacity of substance abuse programs in correctional settings: A classification and regression tree analysis.
OBJECTIVE TO BE ADDRESSED: The purpose of this study was to investigate the structural and organizational factors that contribute to the availability and increased capacity for substance abuse treatment programs in correctional settings. We used classification and regression tree statistical procedures to identify how multi-level data can explain the variability in availability and capacity of substance abuse treatment programs in jails and probation/parole offices. The data for this study combined the National Criminal Justice Treatment Practices (NCJTP) Survey and the 2000 Census. The NCJTP survey was a nationally representative sample of correctional administrators for jails and probation/parole agencies. The sample size included 295 substance abuse treatment programs that were classified according to the intensity of their services: high, medium, and low. The independent variables included jurisdictional-level structural variables, attributes of the correctional administrators, and program and service delivery characteristics of the correctional agency. The two most important variables in predicting the availability of all three types of services were stronger working relationships with other organizations and the adoption of a standardized substance abuse screening tool by correctional agencies. For high and medium intensive programs, the capacity increased when an organizational learning strategy was used by administrators and the organization used a substance abuse screening tool. Implications on advancing treatment practices in correctional settings are discussed, including further work to test theories on how to better understand access to intensive treatment services. This study presents the first phase of understanding capacity-related issues regarding treatment programs offered in correctional settings.


Congenital Spinal Lipomatous Malformations. Part 2. Differentiation from Selected Closed Spinal Malformations.
Congenital spinal lipomatous malformations (spinal lipomas, lipomyeloceles, and lipomyelomeningoceles) are closed neural tube defects over the lower back. Differentiation from some other closed neural tube defects in this region can be problematic for pathologists. This review is based on PubMed searches of the embryology, gross and histopathologic findings, and laboratory reporting requisites for retained medullary spinal cords, coccygeal medullary vestiges and cysts, myelocystoceles, true human vestigial tails, and pseudotails for comparison with congenital spinal lipomatous malformations. Embryology, imaging, gross and histopathology of these closed neural tube lesions have different but overlapping features compared to congenital spinal lipomatous malformations, requiring context for diagnosis. The lipomyelocele spectrum and to some degree all of the malformations discussed, even though they may not share gross appearance, anatomic site, surgical approach, or prognosis, require clinical and histopathologic correlation for final diagnosis.


Effects of hemodialysis, dialyser type and iron infusion on oxidative stress in uremic patients.
Uremic patients undergoing hemodialysis (HD) are considered to face an elevated risk for atherosclerosis and cancer. This has been attributed in part to an increased oxidative stress. In this pilot study, oxidative cell damage in blood of HD-patients was compared to those of controls: total DNA damage (basic and specific oxidative DNA damage), modulation of glutathione levels (total and oxidized glutathione) and of lipid peroxidation were monitored via the Comet assay (with and without FPG), a kinetic photometric assay and HPLC quantification of plasma malondialdehyde (MDA), respectively. In some samples, leukocytes were analysed for malondialdehyde-deoxyguanosine-adducts (M1dG) with an immunoslot blot technique. HD-patients (n=21) showed a significant increase of total DNA damage (p<10(-12)), compared to controls (n=12). In a subset of patients and controls, GSSG levels and M1dG, however, only increased slightly, while tGSH and MDA levels did not differ. The influence of different low flux HD-membranes was tested in a pilot study with nine patients consecutively dialysed on three membrane types for four weeks each. In addition to the individual disposition of the patient, the dialyser membrane had a significant impact on oxidative stress. Total DNA damage was found to be almost identical for polysulfone and vitamin E coated cellulosic membranes, whereas a slight, but significant increase was observed with cellulose-diacetate (p<0.001). In patients receiving iron infusion during HD, MDA-formation (n=11) and total DNA damage (n=10) were additionally increased (p<0.005). Our results show an increased oxidative damage in HD-patients, compared to healthy volunteers. Significant influences were found for the dialyser membrane type and iron infusion.


Bipartite binding of a kinase activator activates Cdc7-related kinase essential for S phase.
Dfp1/Him1 protein of fission yeast, Schizosaccharomyces pombe, encodes the regulatory subunit for Hsk1 kinase, a homologue of budding yeast Cdc7 kinase essential for initiation and progression of the S phase of the cell cycle. This protein binds and activates Hsk1 kinase, which phosphorylates the MCM2 protein. Comparison of the amino acid sequences of the Cdc7 regulatory subunits from various eukaryotes revealed the presence of three small stretches of conserved amino acid sequences, namely Dbf4 motifs N, M, and C. We report here that the Dbf4 motif M, a unique proline-rich motif, and the Dbf4 motif C, a C(2)H(2)-type zinc finger motif, are essential for mitotic functions of Dfp1/Him1 protein as well as for full-level activation of Hsk1 kinase. In vitro, a small segment containing the Dbf4 motif M or C alone binds to and partially activates Hsk1. Co-expression of these two segments augments the extent of activation. Furthermore, a fused polypeptide containing only Dbf4 motifs M and C without any spacer can activate Hsk1 and is capable of rescuing the growth defect of him1 null cells. Insertion of a long stretch of amino acids between the motif M and motif C can be tolerated for mitotic functions. On the other hand, internal deletion of Dbf4 motif N, which has some similarity with the BRCA C-terminal domain motif, results in a defect in hydroxyurea-induced checkpoint responses and sensitivity to methyl methane sulfonate, yet mitotic functions and kinase activation are intact. In one-hybrid assays with budding yeast Dbf4, motif N mutants exhibit reduced interaction with a replication origin. Our observations suggest the molecular architecture of Cdc7.Dbf4-related kinase complexes at the origins, in which they are tethered to replication machinery through Dbf4 motif N and the catalytic subunits are activated through bipartite binding of Dbf4 motifs M and C of the regulatory subunits.


A novel carbon source-dependent genetic transformation system for the versatile cell factory Hypocrea jecorina (anamorph Trichoderma reesei).
Genetic transformation is an indispensable tool for basic fungal research, as well as a useful technique for directed improvement of industrial strains. Here we describe a simple and reproducible transformation system for the filamentous fungus Hypocrea jecorina. The system is based on hxk1 (encoding hexokinase) as selectable marker, a hexokinase-negative strain and D-mannitol, which is used as selective carbon source and osmotic stabilizer. Following transformation with the hxk1 gene, the obtained transformants were able to grow on D-mannitol as sole carbon source. Transformation efficiency achieved using D-mannitol as carbon source and osmotic stabilizer was roughly five times higher than that using D-sorbitol. The utility of this system was further demonstrated by transformation of H. jecorina with the egfp (encoding the enhanced green fluorescent protein) gene. Fluorescence microscopy revealed EGFP fluorescence in positive transformants. Our results demonstrated the feasibility of exploiting a carbon source metabolic pathway for the development of promising fungal transformation systems, which provides a new molecular toolbox for genetic modifications of the cell factory H. jecorina.


Specificity of learning a sport skill to the visual condition of acquisition.
The authors' main purpose was to determine whether learning of a real-world sport skill (basketball free throws) is specific to the sources of afferent visual information available during practice. Twenty-eight male high school students (inexperienced in the experimental task) were randomly assigned to a full vision or target only vision group. Participants trained under full vision or target only condition for 15 sessions. Following training, in immediate tests, they were examined under full vision and then under target only conditions. Ten days later, in delayed tests, they performed the task under full vision and then under target only conditions. Results showed both groups performed the task similarly across the experimental period. Interestingly, it was found that immediate and delayed retention performance is specific to the training visual context. The groups' performances dropped significantly when we tested them at a visual condition that differed from what they had experienced while learning the task. Performance of the task seemed to have integrated with the visual information available during the task acquisition. These findings provide evidence for the specificity of practice hypothesis in the field of motor learning and control.


Combined salicyclic acid and ultrasound treatments for reducing the chilling injury on peach fruit.
The effects of salicylic acid (SA; 1 mmol L(-1)) and ultrasound treatment (40 kHz, 10 min) either separately or combined on the chilling injury (CI) in cold-stored peach fruit ( Prunus persica Batsch cv. Baifeng) were investigated. The results showed that SA treatment alone alleviated CI during storage. Ultrasound alone had no influence, but when it was combined with SA, it resulted in greater inhibition of CI than SA alone. The activities of antioxidant enzymes, such as catalase, ascorbate peroxidase, monodehydroascorbate reductase, dehydroascorbate reductase, and glutathione reductase, were induced by a combination of SA with ultrasound. In addition, the combined treatment also increased the endogenous SA concentrations in peaches. These results suggested that the induced tolerance against CI by the combination of ultrasound and SA treatment in cold-stored peach fruit was related to the induction of antioxidant enzymes and the increase in the SA concentration.


Patterns of cerebral perfusion in patients with asymptomatic internal carotid artery disease.
The perfusion profile of patients with asymptomatic internal carotid artery (ICA) disease has not been well studied. The purpose of this study is to describe the perfusion patterns of patients with asymptomatic ICA disease using computed tomography perfusion (CTP) and its potential value in identifying patients at higher risk for transient ischemic attacks (TIAs) or strokes. We analyzed 32 patients with asymptomatic high grade ICA disease who had CTP and computed tomography angiography (CTA) of the head and neck. Twenty-four patients had severe ICA stenosis and eight had ICA occlusion. The degree of ipsilateral external carotid artery (ECA) and contralateral ICA stenosis, patency of the anterior communicating artery (ACOM), A1 segment and posterior communicating artery (PCOM) were evaluated in all patients. Sixteen patients had normal CTP and the other 16 patients had cerebral hypoperfusion, characterized by abnormalities in one or more of the three perfusion maps. Ipsilateral hypoplastic A1 segment was more frequent in the group with cerebral hypoperfusion (p = 0.025). Ipsilateral TIAs occurred in two patients, both with cerebral hypoperfusion. Cerebral hypoperfusion is present in half of the patients with asymptomatic ICA disease, predominantly in patients with a hypoplastic ipsilateral A1 segment. These patients likely represent a higher-risk group for symptomatic brain ischemia.


Diketopyrrolopyrrole (DPP)-Based Materials and Its Applications: A Review.
Diketopyrrolopyrrole (DPP) and its derivatives have been widely studied in the past few years due to its intrinsic physical and chemical properties, such as strong electron-withdrawing, deep color, high charge carrier mobility, strong aggregation, good thermal-/photo-stability. In the 1970s, DPP was developed and used only in inks, paints, and plastics. Later, DPP containing materials were found to have potential other applications, typically in electronic devices, which attracted the attention of scientists. In this feature article, the synthesis pathway of DPP-based materials and their applications in organic field-effect transistors, photovoltaic devices, sensors, two photo-absorption materials, and others are reviewed, and possible future applications are discussed. The review outlines a theoretical scaffold for the development of conjugated DPP-based materials, which have multiple potential applications.


[Experimental middle ear cholesteatoma originated from free skin graft of the external ear].
The pathogenesis of middle ear cholesteatoma has been thought to be invasion of squamous epithelium originated from the external ear skin including the tympanic membrane. There is no evidence, however, that the external ear skin has more potential to form cholesteatoma than that of other sites. In this report experimental middle ear cholesteatoma of guinea pigs originated from the external ear skin was histologically compared with that originated from the auricular skin. Cholesteatoma as dermal cyst was seen in the middle ear of almost all animals (25/28 = 89.3%), using a free skin graft (3 x 3 mm), regardless of the skin taken from superior (group A) or inferior (group B) part of the external ear, or the auricle (group C) eight weeks after skin implantation. The activity of epithelium such as keratinization was evident in group C. There is, however, no obvious difference in surrounding granulation tissues among group A, B, and C. In a half of this series, cyst wall was broken and its contents (debris) mainly consisted of keratin were put on surrounding granulation tissues three weeks after skin implantation. Striking keratinized epithelium and subepithelial inflammations in relation to the amount of debris were observed at the eighth week. These findings suggest that the external ear skin does not have specific potential to form cholesteatoma and keratin plays some roles in growth of cholesteatoma.


Dual interaction of ADP ribosylation factor 1 with Sec7 domain and with lipid membranes during catalysis of guanine nucleotide exchange.
Sec7 domains catalyze the replacement of GDP by GTP on the G protein ADP-ribosylation factor 1 (myrARF1) by interacting with its switch I and II regions and by destabilizing, through a glutamic finger, the beta-phosphate of the bound GDP. The myristoylated N-terminal helix that allows myrARF1 to interact with membrane lipids in a GTP-dependent manner is located some distance from the Sec7 domain-binding region. However, these two regions are connected. Measuring the binding to liposomes of functional or abortive complexes between myrARF1 and the Sec7 domain of ARNO demonstrates that myrARF1, in complex with the Sec7 domain, adopts a high affinity state for membrane lipids, similar to that of the free GTP-bound form. This tight membrane attachment does not depend on the release of GDP induced by the Sec7 domain but is partially inhibited by the uncompetitive inhibitor brefeldin A. These results suggest that the conformational switch of the N-terminal helix of myrARF1 to the membrane-bound form is an early event in the nucleotide exchange pathway and is a prerequisite for a structural rearrangement at the myrARF1-GDP/Sec7 domain interface that allows the glutamic finger to expel GDP from myrARF1.


MedMiner: an Internet text-mining tool for biomedical information, with application to gene expression profiling.
The trend toward high-throughput techniques in molecular biology and the explosion of online scientific data threaten to overwhelm the ability of researchers to take full advantage of available information. This problem is particularly severe in the rapidly expanding area of gene expression experiments, for example, those carried out with cDNA microarrays or oligonucleotide chips. We present an Internet-based hypertext program, MedMiner, which filters and organizes large amounts of textual and structured information returned from public search engines like GeneCards and PubMed. We demonstrate the value of the approach for the analysis of gene expression data, but MedMiner can also be extended to other areas involving molecular genetic or pharmacological information. More generally still, MedMiner can be used to organize the information returned from any arbitrary PubMed search.


Three ways social identity shapes climate change adaptation.
Adaptation to climate change is inescapably influenced by processes of social identity-how people perceive themselves, others, and their place in the world around them. Yet there is sparse evidence into the specific ways in which identity processes shape adaptation planning and responses. This paper proposes three key ways to understand the relationship between identity formation and adaptation processes: (a) how social identities change in response to perceived climate change risks and threats; (b) how identity change may be an objective of adaptation; and (c) how identity issues can constrain or enable adaptive action. It examines these three areas of focus through a synthesis of evidence on community responses to flooding and subsequent policy responses in Somerset county, UK and the Gippsland East region in Australia, based on indepth longitudinal data collected among those experiencing and enacting adaptation. The results show that adaptation policies are more likely to be effective when they give individuals confidence in the continuity of their in-groups, enhance the self-esteem of these groups, and develop their sense of self-efficacy. These processes of identity formation and evolution are therefore central to individual and collective responses to climate risks.


Methylation-induced silencing of ASC and the effect of expressed ASC on p53-mediated chemosensitivity in colorectal cancer.
Tumor suppressor p53 is known to play a crucial role in chemosensitivity in colorectal cancer. We previously demonstrated that an apoptosis-associated speck-like protein, ASC, is a p53-target gene which regulates p53-Bax mitochondrial apoptotic pathway. ASC is also known to be a target of methylation-induced gene silencing. An inactivation of ASC might thus cause resistance to chemotherapy, and if this is the case, then the expression of ASC would restore the chemosensitivity. The aim of this study was to clarify this hypothesis. ASC was methylated in 25% of all resected specimens in patients with colorectal cancer; however, ASC methylation did not always correspond to a lack of ASC protein. When expressed in colon cancer cells, in which ASC is absent due to methylation, ASC was found to enhance the chemosensitivity in a p53-dependent manner. In p53-null cells, ASC increased the p53-mediated cell death induced by p53-expressing adenovirus infection. Our data suggest that the methylation-induced silencing of ASC might cause resistance to p53-mediated chemosensitivity in colorectal cancer. The gene introduction of ASC may thus restore such chemosensitivity, and this modality may therefore be a useful new treatment strategy for colorectal cancer.


Immersive Virtual Reality Applications in Schizophrenia Spectrum Therapy: A Systematic Review.
(1) Background: Virtual Reality (VR) is a fully immersive computer simulated experience consisting of a three-dimensional interactive virtual environment, through a head-mounted display (HMD) and controller. The use of virtual reality has recently been proposed for the treatment of various psychiatric conditions, including the spectrum of schizophrenia. Our review aims to investigate the current available evidence regarding the use of immersive virtual reality in the treatment of psychotic symptoms. (2) Methods: From April 2019 to June 2020, we conducted a systematic review aimed at identifying therapeutic applications in immersive virtual reality for the spectrum of schizophrenia, searching for relevant studies on Web of Science, EMBASE, PsycINFO and CINHAL. (3) Results: We identified a total of 2601 unique records. Of these, 64 full-text articles were assessed for eligibility, and six out of these met the inclusion criteria and were included in the final systematic review. (4) Conclusions: The available data on immersive virtual reality are currently limited due to the few studies carried out on the topic; however, it has demonstrated its effectiveness and versatility in successfully treating various psychotic symptoms including delusions, hallucinations, or cognitive and social skills. Existing literature agrees on safe, tolerable, and long-term persistence of the therapeutic effects obtained by immersive VR. No serious side effects have been reported. In some specific cases, VR therapy was found to be very effective compared to usual treatment, allowing effective drug free interventions, and therefore without side effects for patients, even in those resistant to normal drug therapies.


Exploring gender dysphoria and related outcomes in a prospective cohort study: protocol for the Swedish Gender Dysphoria Study (SKDS).
There has been a drastic increase in the reported number of people seeking help for gender dysphoria in many countries over the last two decades. Yet, our knowledge of gender dysphoria and related outcomes is restricted due to the lack of high-quality studies employing comprehensive approaches. This longitudinal study aims to enhance our knowledge of gender dysphoria; different aspects will be scrutinised, focusing primarily on the psychosocial and mental health outcomes, prognostic markers and, secondarily, on the underlying mechanisms for its origin. The Swedish Gender Dysphoria Study is an ongoing multicentre longitudinal cohort study with 501 registered participants with gender dysphoria who are 15 years old or older. Participants at different phases of their clinical evaluation process can enter the study, and the expected follow-up duration is three years. The study also includes a comparison group of 458 age- and county-matched individuals without gender dysphoria. Data on the core outcomes of the study, which are gender incongruence and experienced gender dysphoria, body satisfaction and satisfaction with gender-affirming treatments, as well as other relevant outcomes, including mental health, social functioning and life satisfaction, are collected via web surveys. Two different research visits, before and after starting on gender-affirming hormonal treatment (if applicable), are planned to collect respective biological and cognitive measures. Data analysis will be performed using appropriate biostatistical methods. A power analysis showed that the current sample size is big enough to analyse continuous and categorical outcomes, and participant recruitment will continue until December 2022. The ethical permission for this study was obtained from the Local Ethical Review Board in Uppsala, Sweden. Results of the study will be presented at national and international conferences and published in peer-reviewed journals. Dissemination will also be implemented through the Swedish Gender Dysphoria Study network in Sweden.


Current research on transcultural psychiatry in the Anglophone Caribbean: epistemological, public policy, and epidemiological challenges.
In this article, we review recent research on mental health in the Caribbean. Three major themes emerge: (a) the effects of colonialism on the Caribbean psyche; (b) decolonization of psychiatric public policy, including innovative treatment approaches, deinstitutionalization, and community and policy responses to mental health issues; and (c) the nature and epidemiology of psychiatric pathology among contemporary Caribbean people, with particular focus on migration, genetic versus social causation of psychosis and personality disorders, and mechanisms of resilience and social capital. Caribbean transcultural psychiatry illustrates the principles of equipoise unique to developing countries that protect the wellness and continued survival of postcolonial Caribbean people.


Analysis of lung multiple indicator data with an effective diffusivity model of capillary exchange.
In this study, we have compared an effective diffusivity model with several models previously used to describe lung microvascular exchange of small molecules (multiple indicator curves): the Crone integral extraction model, the Sangren-Sheppard model, and the Rowlett-Harris model. The parameters of each model were adjusted to achieve a best fit of multiple-tracer data from six isolated dog lung preparations perfused under zone III conditions at three flows and from five awake sheep before and after histamine infusion. The effective diffusivity model was the best at matching the data and the unique falling extraction pattern observed in the lung. When the isolated lung data was analyzed, the permeability-surface area products (PS) of three models were all significantly lower at lower flows. However, the effective diffusivity model parameter (D 1/2 S, an effective diffusivity-surface area product) was not significantly affected by flow reduction. Lung lymph flow and lymph-to-plasma protein ratios from the awake sheep indicated that PS and D 1/2 S should have increased, and except for the Sangren-Sheppard model, all models predicted significantly increased values. By use of sensitivity analysis, the parameters of the effective diffusivity model were found to be more independently determined than those of the Sangren-Sheppard model, but data collected at longer times were necessary to reliably identify the extravascular volume parameter (LS, diffusing distance-surface area product) of the effective diffusivity model. We conclude that the effective diffusivity model is a better descriptor of multiple tracer data from the lung, that its parameters are more reliably and independently determined, and that it more reliably describes the effects of flow and histamine infusion on capillary-tissue exchange.


Electrospun Polyethylene Terephthalate Nonwoven Reinforced Polypropylene Separator: Scalable Synthesis and Its Lithium Ion Battery Performance.
A novel polyethylene terephthalate nonwoven reinforced polypropylene composite separator (PET/PP) with high thermal stability and low thermal shrinkage characteristic is developed through a scalable production process. In the composite separator, the electronspun polyethylene terephthalate nonwoven layer improves the electrolyte affinity and can sustain as the barrier layer after the shutdown of the polypropylene layer. Due to its high ionic conductivity, the PET/PP separator shows an excellent discharge capacity. In addition, the superior thermal stability of the separator significantly enhances the safety performance of the separator. Considering the feasibility of the large-scale production of the PET/PP separator and its superior battery performance, we expect that the novel separator could be a promising alternative to the existing commercial separators.


Tangeretin Protects Mice from Alcohol-Induced Fatty Liver by Activating Mitophagy through the AMPK-ULK1 Pathway.
Alcoholic beverages are widely consumed all over the world, but continuous ethanol exposure leads to hepatic steatosis that, without proper treatment, will later develop into severe liver disorders. In this study, we investigated the potential protective effect of tangeretin, a flavonoid derived from citrus peel, against alcoholic fatty liver. The in vivo effects of tangeretin were analyzed by oral intake in a chronic-binge alcohol feeding C57BL/6j mouse model, while the underlying mechanism was explored by in vitro studies performed on ethanol-treated hepatic AML-12 cells. Ethanol feeding increased the serum alanine aminotransferase and aspartate aminotransferase levels, the liver weight, and the serum and liver triacylglycerol contents, whereas 20 and 40 mg/kg tangeretin treatment promoted a dose-dependent suppression of these effects. Interestingly, tangeretin prevented increases in the liver oxidative stress level and protected the hepatocyte mitochondria from ethanol-induced morphologic abnormalities. A mechanistic study showed that 20 μM tangeretin treatment activated mitophagy through an AMP-activated protein kinase (AMPK)-uncoordinated 51-like kinase 1 (Ulk1) pathway, thereby restoring mitochondria respiratory function and suppressing steatosis. By contrast, blocking the AMPK-Ulk1 pathway with compound C reversed the hepatoprotective effect of tangeretin. Overall, tangeretin activated mitophagy and protected against ethanol-induced hepatic steatosis through an AMPK-Ulk1-dependent mechanism.


Sleep problems as a risk factor for suicide: Are certain specific sleep domains associated with increased suicide risk?
The purpose of this study was to examine the relationship between sleep problems and suicidal ideation in depressive patients. Evidence from diverse settings and populations indicates that sleep problems are associated with suicidal ideation. However, relationships between them are not well defined. This study was conducted in order to explore whether poor sleep was associated with suicidal ideation above and beyond depression and whether specific domains of sleep were related to suicidal ideation. We also determined whether the association between sleep problems and suicidal ideation was mediated by depression. Patients aged 18-65 years from an outpatient clinic at Seoul St. Mary's Hospital were recruited for this study. From September 2010 to November 2017, a total of 909 participants were included in the final sample. The Beck Depression Inventory (BDI) and Pittsburgh Sleep Quality Index (PSQI) were used to assess psychiatric symptoms. Independent samples t-test, chi-square test, Pearson correlation analyses, hierarchical multiple regression analyses, and mediation analyses were performed using SPSS PROCESS macro. The majority of participants with suicidal ideation also had sleep problems (94.9%). After controlling for age, marital status, and depressive symptoms, total sleep problems estimated by the PSQI global score were also significant associated with suicidal ideation. Among seven sleep components derived from the PSQI, several components including cough or snore loudly, have bad dreams, and use sleep medication were associated with increased suicide risk. Also, the relationship between sleep problems and suicidal ideation was mediated by depressive symptoms indirectly. There was no convincing direct relationship between sleep problems and suicidal ideation. Investigating the pathways which connect sleep problems and suicidality is fundamental to the development of suicide prevention. While it might be premature to suggest specific interventions, it would be important for clinicians to consider evaluating and managing sleep problems in the context of suicidality.


Influence of mother's intestinal microbiota on gut colonization in the infant.
The aim here was to elucidate the mother-infant association in the gut colonization of 1-6 month-old infants and to establish whether probiotics can influence this process. Fecal samples from 80 mother-infant pairs were analyzed at 1 month (mothers and infants) and 6 months (infants) by real-time polymerase chain reaction to assess bacterial numbers. This double-blind placebo-controlled trial involved 2 different probiotic combinations (1. Lactobacillus rhamnosus + Bifidobacterium longum and 2. Lactobacillus paracasei + Bifidobacterium longum) given to the mothers 2 months prior to and 2 months after delivery. Bifidobacterium bifidum colonization in the mothers significantly increased the infants' probability of being colonized by B. bifidum and their bifidobacterial diversity indexes (DI) and the mother-infant similarity indexes (SI) both at 1 and 6 months of age. The counts of Bifidobacterium genus (at 1 month) and Bifidobacterium longum (at 6 months) correlated between mothers and infants. At 6 months, a significant effect of the probiotic intervention was found in the mother-infant association of fecal bifidobacterial counts but not in the colonization frequencies, DI or SI. In conclusion, a clear association between mother and infant was found in gut colonization by bifidobacteria. Maternal colonization by B. bifidum had the most consistent effects on the infant's bifidobacterial microbiota. Maternal probiotic treatment had little effect on this mother-infant association.


Finding the missing stimulus mismatch negativity (MMN): emitted MMN to violations of an auditory gestalt.
Deviations from repetitive auditory stimuli evoke a mismatch negativity (MMN). Counterintuitively, omissions of repetitive stimuli do not. Violations of patterns reflecting complex rules also evoke MMN. To detect a MMN to missing stimuli, we developed an auditory gestalt task using one stimulus. Groups of six pips (50 ms duration, 330 ms stimulus onset asynchrony [SOA], 400 trials), were presented with an intertrial interval (ITI) of 750 ms while subjects (n=16) watched a silent video. Occasional deviant groups had missing 4th or 6th tones (50 trials each). Missing stimuli evoked a MMN (p<.05). The missing 4th (-0.8 µV, p<.01) and the missing 6th stimuli (-1.1 µV, p<.05) were more negative than standard 6th stimuli (0.3 µV). MMN can be elicited by a missing stimulus at long SOAs by violation of a gestalt grouping rule. Patterned stimuli appear more sensitive to omissions and ITI than homogenous streams.


QT hysteresis index improves the power of treadmill exercise test in the screening of coronary artery disease.
QT hysteresis phenomenon exists in healthy subjects, and is more exaggerated in patients with coronary artery disease (CAD) and long QT syndrome. The purpose of this study was to establish an appropriate method to evaluate the magnitude of QT hysteresis, and assess the value of QT hysteresis index in the treadmill exercise test (TET) in predicting CAD. METHODS AND RESULTS: A total of 138 subjects with suspected CAD and referred for TET and selective coronary angiography (SCA) were divided into positive (n=77) and negative (n=61) SCA groups. Dynamic ECG were recorded during TET. QT/RR curves were constructed and QTp (Q-Tpeak) and QTe (Q-Tend) hysteresis indices were calculated for each subject. SYNTAX score in the positive SCA group was determined. The QTp and QTe hysteresis indices in the positive SCA group were significantly higher than in the negative SCA group. The combination of QTe hysteresis index and conventional TET criteria had the highest sensitivity and negative predictive value according to receiver operating characteristic curve, and was an independent predictor on multivariate logistic regression. QT hysteresis indices significantly correlated with SYNTAX score in the positive SCA group. QTe hysteresis index enhances the specificity of predicting CAD in TET. It improves the diagnostic value of TET for CAD significantly when combined with conventional criteria and is associated with the severity of CAD.


Double common bile duct: report of a case.
We report a case of double common bile duct. A 51-year-old woman was examined for abdominal pain. Ultrasound revealed a stone of approximately 7 mm in the gallbladder, and abdominal computed tomography revealed air in the intrahepatic bile duct and gallbladder. The endoscopic retrograde cholangiography showed that the contrast medium flowed into the duodenal bulbus from the gallbladder. The diagnosis was inflammatory cholecystoduodenal fistula, and a cholecystectomy was performed. There were no inflammatory changes surrounding the gallbladder. The resected specimen showed that the fistula was covered by a mucous membrane with Brunner's glands. The muscle layer of the fistula was continuous to the duodenum from the gallbladder, and no new connective tissue or inflammatory adhesion between the muscles could be seen. A double common bile duct was diagnosed in this patient. The postoperative course was uneventful.


Malignant triton tumor of the pelvis in a 2-year-old boy.
We report a 2-year-old boy who had a family history of neurofibromatosis, multiple cafe-au-lait spots on the trunk, tibial pseudarthrosis, and was diagnosed with a malignant triton tumor of the pelvis. To our knowledge our case is one of the youngest patients reported with a malignant triton tumor and the second pediatric case with a pelvic malignant triton tumor.


School-to-work program participation and the post-high school employment of young adults with disabilities.
Previous research on the education-to-employment transition for students with disabilities has suggested that participation in school-to-work programs is positively associated with post-high school success. This article utilizes data from the National Longitudinal Survey of Youth 1997 (NLSY97) to extend these findings in several ways. First, we assess the efficacy of specific types of school-based and work-based initiatives, including job shadowing, mentoring, cooperative education, school-sponsored enterprise, technical preparation, internships, and career major. Next, we extend the usual focus on the employment outcomes of work status and financial compensation to consider job-specific information on the receipt of fringe benefits. Overall, results from longitudinal multivariate analyses suggest that transition initiatives are effective in facilitating vocational success for this population; however, different aspects of school-to-work programs are beneficial for different aspects of employment. School-based programs are positively associated with stable employment and full-time work while work-based programs most consistently increase the likelihood that youth with disabilities will be employed in jobs that provide fringe benefits. Analyses also indicate that - once individuals with disabilities are stably employed - they can be employed in "good" jobs that provide employee benefits.


Calibration of fluorescence intensities to quantify antibody binding surface determinants of cell subpopulations by flow cytometry.
Quantitative indirect immunofluorescence analysis by flow cytometry was used to determine the mean number of antibody binding sites per cell in a small subpopulation of rat brain cells expressing low levels of a cell surface differentiation antigen recognized by monoclonal antibody (Mab) RB13-6 (Kindler-Röhrborn et al.: Differentiation 30:53-60, 1985). For these non-disjunct distributions of fluorescence intensities, the cut-off border between antigen-positive and antigen-negative cells was defined by a statistical test. To eliminate the influence of accidental disturbances leading to incorrect statistical decisions, the curves for antigen-negative cells were fitted according to cell number and shape. The flow cytometer was calibrated with the use of a clonal cell line for which the average number of Mab RB13-6 binding sites per cell had previously been determined by radioimmunoassay and Scatchard-plot analysis. Using this analytical procedure, both the proportion of Mab binding brain cells and the mean number of Mab binding sites per Mab binding cell could be determined as a function of developmental stage.


An atom in molecules study of infrared intensity enhancements in fundamental donor stretching bands in hydrogen bond formation.
Vibrational modes ascribed to the stretching of X-H bonds from donor monomers (HXdonor) in complexes presenting hydrogen bonds (HF···HF, HCl···HCl, HCN···HCN, HNC···HNC, HCN···HF, HF···HCl and H2O···HF) exhibit large (4 to 7 times) infrared intensity increments during complexation according to CCSD/cc-pVQZ-mod calculations. These intensity increases are explained by the charge-charge flux-dipole flux (CCFDF) model based on multipoles from the Quantum Theory of Atoms in Molecules (QTAIM) as resulting from a reinforcing interaction between two contributions to the dipole moment derivatives with respect to the vibrational displacements: charge and charge flux. As such, variations that occur in their intensity cross terms in hydrogen bond formation correlate nicely with the intensity enhancements. These stretching modes of HXdonor bonds can be approximately modeled by sole displacement of the positively charged hydrogens towards the acceptor terminal atom with concomitant electronic charge transfers in the opposite direction that are larger than those occurring for the H atom displacements of their isolated donor molecules. This analysis indicates that the charge-charge flux interaction reinforcement on H-bond complexation is associated with variations of atomic charge fluxes in both parent molecules and small electronic charge transfers between them. The QTAIM/CCFDF model also indicates that atomic dipole flux contributions do not play a significant role in these intensity enhancements.


Correction of hyperbilirubinemia in gunn rats using clinically relevant low doses of helper-dependent adenoviral vectors.
Crigler-Najjar syndrome type I is a severe inborn error of bilirubin metabolism caused by a complete deficiency of uridine diphospho-glucuronosyl transferase 1A1 (UGT1A1) and results in life-threatening unconjugated hyperbilirubinemia. Lifelong correction of hyperbilirubinemia by liver-directed gene therapy using a helper-dependent adenoviral (HDAd) vector has been previously reported in the Gunn rat, a model of Crigler-Najjar syndrome, but was only achieved using high doses (≥ 3 × 10(12) viral particles [vp]/kg), which are likely to elicit a severe toxic response in humans. Therefore, in this study, we investigate strategies to achieve correction of hyperbilirubinemia in the Gunn rat using clinically relevant low HDAd doses. We have found that correction of hyperbilirubinemia in the Gunn rat can be achieved with a low dose of 5 × 10(11) vp/kg by using an HDAd vector bearing a more potent UGT1A1 expression cassette. Furthermore, by using hydrodynamic injection of the improved HDAd vector, correction of hyperbilirubinemia in the Gunn rat can be achieved using an even lower dose of 5 × 10(10) vp/kg. Although hydrodynamic injection as performed in rats is not acceptable in humans, clinically attractive, minimally invasive methods have been successfully developed to mimic hydrodynamic injection of HDAd vector in non-human primates. Therefore, using an improved expression cassette combined with a more efficient method of vector delivery permits correction of hyperbilirubinemia in the Gunn rat using clinically relevant low HDAd doses and may thus pave the way to clinical application of HDAd vectors for Crigler-Najjar syndrome gene therapy.


Human PTH gene regulation in vivo using transgenic mice.
To study the regulation of the human PTH (hPTH) gene in vivo, we generated transgenic mice with the hPTH gene expressed in the mouse parathyroid using a bacterial artificial chromosome (BAC) containing the hPTH gene within its 144-kb chromosomal region. The BAC construct maintains the native hPTH gene surrounding sequences and isolates it from positional effects. The transgenic mice had normal levels of serum mouse PTH (mPTH) in addition to both intact and bioactive hPTH. Despite the presence of both mPTH and hPTH, serum calcium and 1,25(OH)(2) vitamin D levels were normal. The lack of response to hPTH may be due to tachyphylaxis of the mPTH receptor (PTH1R) and/or impaired recognition of the mPTH1R. In contrast, the regulation of hPTH levels in the mouse was intact. A calcium-depleted diet increased serum mPTH and both intact and bioactive hPTH. mPTH and hPTH mRNA levels were also markedly increased. The calcimimetic R-568 dramatically decreased mPTH and hPTH serum levels. Administered recombinant fibroblast growth factor (FGF)23 decreased hPTH. Therefore, the regulation of hPTH gene expression and serum hPTH levels is intact in the transgenic mice, indicating preservation of the signal transduction of the parathyroid calcium receptor and the Klotho-FGF receptor between mouse and man.


Trauma of the hand from circular saw table: a series of a 130 cases.
Trauma of the hand from a circular saw table is a common occurrence in developing countries it tends to occur in young hand working people and it causes a serious lesions. It was a retrospective series about a 130 cases of hand trauma from circular saw table. Epidemiological features, treatment, and permanent disabilities left by hand trauma from circular saw table were studied to identify ways to prevent such an accident. The average age was 31.24 years, these patients were exclusively men, 62% were apprentice wood workers, and the left hand was twice more injured than the right hand. Regarding clinical aspects, in 77% of cases, two or more fingers were injured, tip amputations of the left fingers predominated (49%), in 50% of the cases of hand wounds occurred to the dorsum of the hand, and extensor tendon injuries were observed twice more than flexor tendon injuries. Regarding the surgical treatment, performing an amputation stump was the most practiced primary surgery (107 cases i.e. 82% of primary surgeries). Arthrodesis, reconstructive flap surgery, and spongy bone grafts were the most practiced secondary surgeries (79% of secondary surgeries). Joint stiffness was the most observed complication (26%). Hand injuries from circular saw table such as those described in this study will continue to challenge the skill of surgeons devoted to the restoration of function and form to the damaged hand. Prevention, of course, should be the goal because of the severe functional and psychological impairment that may result from them.


Diffusion weighted MRI and 18F-FDG PET/CT in non-small cell lung cancer (NSCLC): does the apparent diffusion coefficient (ADC) correlate with tracer uptake (SUV)?
To investigate the potential correlation of the apparent diffusion coefficient assessed by diffusion-weighted MRI (DWI) and glucose metabolism determined by the standardized uptake value (SUV) at 18F-FDG PET/CT in non-small cell lung cancer (NSCLC). 18F-FDG PET/CT and DWI (TR/TE, 2000/66 ms; b-values, 0 and 500 s/mm(2)) were performed in 41 consecutive patients with histologically verified NSCLC. Analysing the PET-CT data calculation of the mean (SUV(mean)) and maximum (SUV(max)) SUV was performed. By placing a region-of-interest (ROI) encovering the entire tumor mean (ADC(mean)) and minimum ADC (ADC(min)) were determined by two independent radiologists. Results of 18F-FDG PET-CT and DWI were compared on a per-patient basis. For statistical analysis Pearson's correlation coefficient, Bland-Altman and regression analysis were assessed. Data analysis revealed a significant inverse correlation of the ADC(min) and SUV(max) (r=-0.46; p=0.032). Testing the correlation of the ADC(min) and SUV(max) for each histological subtype separately revealed that the inverse correlation was good for both adenocarcinomas (r=-0.47; p=0.03) and squamouscell carcinomas (r=-0.71; p=0.002), respectively. No significant correlation was found for the comparison of ADC(min) and SUV(mean) (r=-0.29; p=0.27), ADC(mean) vs. SUV(mean) (r=-0.28; p=0.31) or ADC(mean) vs. SUV(max) (r=-0.33; p=0.23). The κ-value of 0.88 indicated a good agreement between both observers. This preliminary study is the first to verify the relation between the SUV and the ADC in NSCLC. The significant inverse correlation of these two quantitative imaging approaches points out the association of metabolic activity and tumor cellularity. Therefore, DWI with ADC measurement might represent a new prognostic marker in NSCLC.


Computer and internet use in vascular outpatients--ready for interactive applications?
Exploring patients' computer and internet use, their expectations and attitudes is mandatory for successful introduction of interactive online health-care applications in Angiology. We included 165 outpatients suffering from peripheral arterial disease (PAD; n = 62) and chronic venous and / or lymphatic disease (CVLD; n = 103) in a cross-sectional-study. Patients answered a paper-based questionnaire. Patients were predominantly female (54.5%). 142 (86.1%) reported regular computer use for 9.7 +/- 5.8 years and 134 (81.2 %) used the internet for 6.2 +/- 3.6 years. CVLD-patients and internet-user were younger and higher educated, resulting in a significant difference in computer and internet use between the disease groups (p < 0.01 for both). Time spent online summed up to 4.3 +/- 2.2 days per week and 1.44 +/- 1.2 hours per day for all internet users without significant differences between the groups. The topics retrieved from the internet covered a wide spectrum and searches for health information were mentioned by 41.2 %. Although confidence in the internet (3.3 +/- 1.1 on a 1-6 Likert scale) and reliability in information retrieved from the internet (3.1 +/- 1.1) were relatively low, health-related issues were of high actual and future interest. 42.8% of the patients were even interested in interactive applications like health educational programs, 37.4% in self-reported assessments and outcome questionnaires and 26.9% in chatforums; 50% demanded access to their medical data on an Internetserver. Compared to older participants those < 50 yrs. used the internet more often for shopping, chatting, and e-mailing, but not for health information retrieval and interactive applications. Computers are commonly used and the internet has been adopted as an important source of information by patients suffering from PAD and CVLD. Besides, the internet offers great potentials and new opportunities for interactive disease (self-)management in angiology. To increase confidence and reliability in the medium a careful introduction and evaluation of these new online applications is mandatory.


Marked increase in incidence for bloodstream infections due to Escherichia coli, a side effect of previous antibiotic therapy in the elderly.
We conducted a survey including 3334 bloodstream infections (BSIs) due to E. coli diagnosed in 2005-2014 at a stable cohort of hospitals. Marked increases in incidence were observed for community-acquired (CA) BSIs in patients aged >75 years, CA-BSIs of digestive origin in patients aged 60-74 years, healthcare-associated BSIs, and BSIs associated with ESBL (extended-spectrum B-lactamase)-producing E. coli (ESBLEc). Using MLST, we studied the genetic diversity of 412 BSI isolates recovered during the 2014 survey: 7 major sequence type complexes (STCs) were revealed in phylogenetic group B2, 3 in group A/B1 and 2 in group D. Among the 31 ESBLEc isolates, 1/3 belonged to STC 131. We searched for possible associations between clonal groups, clinical determinants and characteristics of BSIs: isolates from groups B2 (except STC 131) and D were susceptible to antibiotics and associated with BSIs of urinary origin in patients <60 years. STC 131 and group A/B1 isolates were multi-drug resistant and associated with CA-BSIs of digestive origin in patients aged 60-74 with a recent history of antibiotic treatment. STC 131 isolates were associated with HCA-BSIs in patients with recent/present hospitalization in a long-stay unit. We provide a unique population-based picture of the epidemiology of E. coli BSI. The aging nature of the population led to an increase in the number of cases caused by the B2 and D isolates generally implicated in BSIs. In addition, the association of a trend toward increasing rates of gut colonization with multi drug-resistant isolates revealed by the rise in the incidence of BSIs of digestive origin caused by STC 131 and A/B1 (STCs 10, 23, and 155) isolates, and a significant increase in the frequency of BSIs in elderly patients with recent antibiotic treatment suggested that antibiotic use may have contributed to the growing incidence of BSI.


Endomyocardial biopsy in heterotopic heart transplant recipients via the femoral vein.
The results of endomyocardial biopsy (EMB) via the femoral vein in heterotopic heart transplant recipients were retrospectively analyzed and compared with those obtained using the right internal jugular vein approach. A total of 139 EMB were performed in 8 patients using the femoral (35) or the jugular (104) approach. Twenty three (64.7%) of the procedures performed via the femoral vein were part of the yearly hemodynamic and coronary artery study, and 12 (35.3%) constituted a routine postoperative evaluation of the myocardium rejection state in patients with imperviousness of the right internal jugular vein. Comparing the results obtained with the femoral approach, we observed a higher overall success rate (94.3 vs 88.5%, NS) and obtained more samples that were useful for histologic evaluation (95.5 vs 85.9%, NS); with the jugular procedure, the fragments were significatively larger in diameter (1.28 +/- 0.55 vs 1.61 +/- 0.85 mm, mean +/- SD) and in area (1.49 +/- 1.16 vs 2.28 +/- 2.24 mm2, mean +/- SD). No cardiac or local complications were noted when the femoral approach was used, while two attempts to perform biopsy via the jugular vein resulted in obstruction of this vessel. Our data suggest that the femoral venous approach for endomyocardial biopsy in heterotopic heart transplant recipients is a valid alternative to the more commonly used routes.


Shared Genetics of Multiple System Atrophy and Inflammatory Bowel Disease.
Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by intracellular accumulations of α-synuclein and nerve cell loss in striatonigral and olivopontocerebellar structures. Epidemiological and clinical studies have reported potential involvement of autoimmune mechanisms in MSA pathogenesis. However, genetic etiology of this interaction remains unknown. We aimed to investigate genetic overlap between MSA and 7 autoimmune diseases and to identify shared genetic loci. Genome-wide association study summary statistics of MSA and 7 autoimmune diseases were combined in cross-trait conjunctional false discovery rate analysis to explore overlapping genetic background. Expression of selected candidate genes was compared in transgenic MSA mice and wild-type mice. Genetic variability of candidate genes was further investigated using independent whole-exome genotyping data from large cohorts of MSA and autoimmune disease patients and healthy controls. We observed substantial polygenic overlap between MSA and inflammatory bowel disease and identified 3 shared genetic loci with leading variants upstream of the DENND1B and RSP04 genes, and in intron of the C7 gene. Further, the C7 gene showed significantly dysregulated expression in the degenerating midbrain of transgenic MSA mice compared with wild-type mice and had elevated burden of protein-coding variants in independent MSA and inflammatory bowel disease cohorts. Our study provides evidence of shared genetic etiology between MSA and inflammatory bowel disease with an important role of the C7 gene in both phenotypes, with the implication of immune and gut dysfunction in MSA pathophysiology. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Morphological variations of the deltoid ligament of the medial ankle.
Morphological variations of the deltoid ligament were investigated in this study, with the aim of classifying the different types on the basis of their components. Sixty ankles from 39 cadavers were dissected. The origin and insertion sites of the deltoid ligament were identified, and its length, width, and thickness were measured. The deltoid ligament was divided into two layers, superficial and deep, which respectively comprised four components (tibionavicular, tibiospring, tibiocalcaneal, and superficial posterior tibiotalar ligaments) and two components (anterior tibiotalar and deep posterior tibiotalar ligaments). The tibiospring and tibiocalcaneal ligaments were found in 100% of the specimens, while the prevalence rates of other components lay within the range 63.3-96.7%. The tibionavicular and deep posterior tibiotalar ligaments were the thinnest and thickest, respectively, while the other ligaments had similar thicknesses. The deltoid ligament was classified into types I-IV according to the combinations of these components: all components were present in type I (48.3%), the tibionavicular ligament was absent in type II (36.7%), only the superficial posterior tibiotalar ligament was absent in type III (6.7%), and only the anterior tibiotalar ligament was absent in type IV (8.3%). In conclusion, these results improve knowledge of the morphological and morphometric characteristics of the deltoid ligament and thus provide helpful information for surgical procedures in this region. Clin. Anat. 29:1059-1065, 2016. © 2016 Wiley Periodicals, Inc.


Uncharged tRNA, protein synthesis, and the bacterial stringent response.
Uncharged tRNA has been shown in vivo to have an active role both in the stringent response, and in modulating the rate of translational elongation. Both of these effects appear to be mediated by codon-anticodon interactions on the ribosome. Although the involvement of uncharged tRNA in the stringent response was expected from in vitro experiments, it has only recently been confirmed in vivo. Inhibition of translation by cognate uncharged tRNA was not expected, and a model is proposed in which excess uncharged tRNA competes with charged tRNA (in ternary complex) for the 30S component of the ribosomal A site. When uncharged tRNA is in sufficient excess over charged tRNA, interaction of uncharged tRNA with the 50S component of the A site occurs as well, leading to a stringent response. The cell has a continuum of responses to decreasing aminoacyl-tRNA levels: in moderately limited conditions, the proportion of uncharged tRNA increases, and the translation rate is slowed; under more severe limitations, uncharged tRNA provokes a stringent response, with pleiotropic consequences for the cell.


The epidemiology of malaria in the Wosera area, East Sepik Province, Papua New Guinea, in preparation for vaccine trials. I. Malariometric indices and immunity.
The epidemiological features of malaria were studied through seven community-based surveys in a population of 4000 in the Wosera area, East Sepik Province, Papua New Guinea. Prevalence of parasitaemia (all species, all ages) was 60%. Plasmodium falciparum was the predominant species in all surveys (55%), followed by P. vivax (25%) and P. malariae (20%). The highest prevalence for asexual forms of P. falciparum occurred in the 5-9-year age group, whereas P. falciparum gametocytaemia and P. vivax parasitaemia were observed most frequently in the 1-4-year age group and P. malariae in the 10-15-year age group. Mean densities of all species decreased with age except for that of P. malariae, which was lower in children aged < 1 year than in those aged 1-4 years. The prevalence of enlarged spleen was 57% in children and 10% in adults and closely matched the corresponding age-related parasite rate. Seroprevalence of antibody to the major merozoite surface antigen 2 rapidly increased with age, with > 90% of individuals older than 5 years being positive. Malariological indices showed irregular changes over time but there was no clear-cut seasonal pattern. The geographical distribution of these indices and immune responses was not uniform within the study area. Bednet use and drug consumption were negatively correlated with malariometric indices. Identification of significant temporal and local variations in malaria endemicity is important for the design and evaluation of intervention studies, including field trials of an antimalarial vaccine.


Conjunction of vocal production and perception regulates expression of the immediate early gene ZENK in a novel cortical region of songbirds.
The cortical nucleus LMAN (lateral magnocellular nucleus of the anterior nidopallium) provides the output of a basal ganglia pathway that is necessary for acquisition of learned vocal behavior during development in songbirds. LMAN is composed of two subregions, a core and a surrounding shell, that give rise to independent pathways that traverse the forebrain in parallel. The LMAN(shell) pathway forms a recurrent loop that includes a cortical region, the dorsal region of the caudolateral nidopallium (dNCL), hitherto unknown to be involved with learned vocal behavior. Here we show that vocal production strongly induces the IEG product ZENK in dNCL of zebra finches. Hearing tutor song while singing is more effective at inducing expression in dNCL of juvenile birds during the auditory-motor integration stage of vocal learning than is hearing conspecific song. In contrast, hearing conspecific song is relatively more effective at inducing expression in adult birds, regardless of whether they are producing song. Furthermore, ZENK+ neurons in dNCL include projection neurons that are part of the LMAN(shell) recurrent loop and a high proportion of dNCL projection neurons express ZENK in singing juvenile birds that hear tutor song. Thus juvenile birds that are actively refining their vocal pattern to imitate a tutor song show high levels of ZENK induction in dNCL neurons when they are singing while hearing the song of their tutor and low levels when they hear a novel conspecific. This pattern indicates that dNCL is a novel brain region involved with vocal learning and that its function is developmentally regulated.


Targeting therapeutic molecules to sites of disease.
Extract: The holy grail of drug development is to design a magic bullet that will deliver a therapeutic agent only to the site of disease with minimal side effects. This is of great importance in particular when it refers to biological agents such as cytokines that have pleiotropic actions in different tissues. Cytokines are local mediators of cell-to-cell communication. Their expression is transient and they have a short half-life. Therefore, to overcome the pharmacokinetic limitations of cytokines, they are given subcutaneously to reduce side effects. However, by this route they lose their potency. In order to use cytokines for therapeutic purposes they have to be administered frequently at high doses to achieve biologically active concentrations locally at the required sites of a disease.


Positron Emission Tomography in Animal Models of Alzheimer's Disease Amyloidosis: Translational Implications.
Animal models of Alzheimer's disease amyloidosis that recapitulate cerebral amyloid-beta pathology have been widely used in preclinical research and have greatly enabled the mechanistic understanding of Alzheimer's disease and the development of therapeutics. Comprehensive deep phenotyping of the pathophysiological and biochemical features in these animal models is essential. Recent advances in positron emission tomography have allowed the non-invasive visualization of the alterations in the brain of animal models and in patients with Alzheimer's disease. These tools have facilitated our understanding of disease mechanisms and provided longitudinal monitoring of treatment effects in animal models of Alzheimer's disease amyloidosis. In this review, we focus on recent positron emission tomography studies of cerebral amyloid-beta accumulation, hypoglucose metabolism, synaptic and neurotransmitter receptor deficits (cholinergic and glutamatergic system), blood-brain barrier impairment, and neuroinflammation (microgliosis and astrocytosis) in animal models of Alzheimer's disease amyloidosis. We further propose the emerging targets and tracers for reflecting the pathophysiological changes and discuss outstanding challenges in disease animal models and future outlook in the on-chip characterization of imaging biomarkers towards clinical translation.