p39 Is Responsible for Increasing Cdk5 Activity during Postnatal Neuron Differentiation and Governs Neuronal Network Formation and Epileptic Responses.
Two distinct protein cofactors, p35 and p39, independently activate Cyclin-dependent kinase 5 (Cdk5), which plays diverse roles in normal brain function and the pathogenesis of many neurological diseases. The initial discovery that loss of p35 impairs neuronal migration in the embryonic brain prompted intensive research exploring the function of p35-dependent Cdk5 activity. In contrast, p39 expression is restricted to the postnatal brain and its function remains poorly understood. Despite the robustly increased Cdk5 activity during neuronal differentiation, which activator is responsible for enhancing Cdk5 activation and how the two distinct activators direct Cdk5 signaling to govern neuronal network formation and function still remains elusive. Here we report that p39, but not p35, is selectively upregulated by histone acetylation-mediated transcription, which underlies the robust increase of Cdk5 activity during rat and mouse neuronal differentiation. The loss of p39 attenuates overall Cdk5 activity in neurons and preferentially affects phosphorylation of specific Cdk5 targets, leading to aberrant axonal growth and impaired dendritic spine and synapse formation. In adult mouse brains, p39 deficiency results in dysregulation of p35 and Cdk5 targets in synapses. Moreover, in contrast to the proepileptic phenotype caused by the lack of p35, p39 loss leads to deficits in maintaining seizure activity and induction of immediate early genes that control hippocampal excitability. Together, our studies demonstrate essential roles of p39 in neuronal network development and function. Furthermore, our data support a model in which Cdk5 activators play nonoverlapping and even opposing roles to govern balanced Cdk5 signaling in the postnatal brain. Neuronal network development requires tightly regulated activation of Cyclin-dependent kinase 5 (Cdk5) by two distinct cofactors, p35 and p39. Despite the well-known p35-dependent Cdk5 function, why postnatal neurons express abundant p39 in addition to p35 remained unknown for decades. In this study, we discovered that selective upregulation of p39 is the underlying mechanism that accommodates the increased functional requirement of Cdk5 activation during neuronal differentiation. In addition, we demonstrated that p39 selectively directs Cdk5 to phosphorylate protein substrates essential for axonal development, dendritic spine formation, and synaptogenesis. Moreover, our studies suggest opposing roles of p39 and p35 in synaptic Cdk5 function and epileptic responses, arguing that cooperation between Cdk5 activators maintains balanced Cdk5 signing, which is crucial for postnatal brain function.


Enantiomeric toxicokinetics of the new isoindoline anxiolytic pazinaclone in rats and dogs.
Enantiomeric toxicokinetics of the new isoindoline pazinaclone (CAS 103255-66-9, DN-2327) were studied in rats and dogs of both sexes after oral administration by gavage. Non-toxic doses in 4-week toxicity studies in rats are > or = 3000 mg/kg/d and 500 mg/kg/d for S- and R-pazinaclone, respectively; the corresponding doses in dogs are 10 and 4 mg/kg/d, respectively. R-Pazinaclone is more toxic in female rats than in male rats. In both rats and dogs, circulating enantiomer concentrations of pazinaclone and the active M-II metabolite increased with dose. Higher S- and R-pazinaclone concentrations were found in female rats than in male rats; the concentrations in dogs were sex independent. In rats, the AUCs for the parent compound after a 3000 mg/kg oral dose of S-pazinaclone were about 9-fold (males) and 4-fold (females) greater than those after dosing of R-pazinaclone at 500 mg/kg. In dogs, the AUC for the parent compound after a 10 mg/kg oral dose of S-pazinaclone was 33-fold greater than that after oral dosing of the R-enantiomer at 4 mg/kg. The toxic activity is thus likely to reside predominantly in the R-enantiomers of pazinaclone and M-II. The exposure of the R-enantiomers in humans, after administration of the anticipated clinical dose of the racemic drug, seemed to be no more than that in rats and dogs at nontoxic doses.


Loss of trabecular bone mineral density in systemic lupus erythematosus.
To evaluate trabecular bone mineral density (BMD) in young ambulatory female patients with systemic lupus erythematosus (SLE). Bone mineral density (gm/cm2) at the lumbar vertebrae (L1-L4) and at the left femur (neck, trochanter, intertrochanter, and Ward's triangle) was measured by dual x-ray absorptiometry in 46 SLE patients (mean age 31 years, mean disease duration 76 months) and in 108 healthy female controls (mean age 32 years). Twenty-two of the SLE patients were receiving corticosteroids (CS) at the time of the study. Lumbar BMD in the SLE patients was less severely reduced than was BMD at the femoral sites, but the SLE group was closer to the lumbar fracture threshold of 0.812 gm/cm2 than was the control group (P = 0.0009). There were no significant differences between the SLE patients currently being treated with corticosteroids and those who were not (P > 0.3). BMD at Ward's triangle and at the femoral neck was not significantly reduced in the SLE patients. Total femoral BMD had a sensitivity of 76% and specificity of 62% in differentiating the SLE group from the controls. The positive predictive value was 61% and the negative predictive value was 89%. The prevalence of osteopenia in the SLE patients was 25%. SLE causes significant trabecular bone loss, which is not due to corticosteroid therapy.


Construction and validation of a 15-gene ferroptosis signature in lung adenocarcinoma.
Ferroptosis is a novel form of programmed cell death characterized by the excessive accumulation of intracellular iron and an increase in reactive oxygen species. Emerging studies have shown that ferroptosis plays a vital role in the progression of lung adenocarcinoma, but the effect of ferroptosis-related genes on prognosis has been poorly studied. The purpose of this study was to explore the prognostic value of ferroptosis-related genes. Lung adenocarcinoma samples were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The least absolute shrinkage and selection operator (LASSO) Cox regression algorithm was used to establish a predictive signature for risk stratification. Kaplan-Meier (K-M) survival analysis and receiver operating characteristic (ROC) curve analysis were conducted to evaluate the signature. We further explored the potential correlation between the risk score model and tumor immune status. A 15-gene ferroptosis signature was constructed to classify patients into different risk groups. The overall survival (OS) of patients in the high-risk group was significantly shorter than that of patients in the low-risk group. The signature could predict OS independent of other risk factors. Single-sample gene set enrichment analysis (ssGSEA) identified the difference in immune status between the two groups. Patients in the high-risk group had stronger immune suppression, especially in the antigen presentation process. The 15-gene ferroptosis signature identified in this study could be a potential biomarker for prognosis prediction in lung adenocarcinoma. Targeting ferroptosis might be a promising therapeutic alternative for lung adenocarcinoma.


Impact of etiology on the painful early stage of chronic pancreatitis: a long-term prospective study.
This prospective study aimed to investigate the impact of etiology on the pain profile in relation to alterations of function and morphology from early to advanced chronic pancreatitis (CP). Our mixed medico-surgical cohort comprised 265 patients with alcoholic (ACP), 21 with idiopathic "juvenile" (IJCP), 46 with idiopathic "senile" (ISCP) and 11 with hereditary CP (HPCP). The patients were followed regularly from onset of disease according to the protocol published previously. Males predominated in ACP, IJCP, ISCP (> 71%) but not in HP (46%). Age at onset (median) was 10, 23, 36 and 62 years in HP, IJCP, ACP and ISCP, respectively. Follow-up from disease onset ranged from 14 to 36 years. The progression to late-stage CP, documented by exocrine insufficiency (86-100%) and calcification (80-91%) lasted 2 to 5-fold longer in HP/IJCP compared to ACP. Early stage CP, characterized by recurrent pancreatitis prevailed in > or = 90% of patients, except for those with ISCP (48%), and lasted up to 5-fold longer in HP/IJCP compared to ACP. Surgery for severe pain was required for ACP/IJCP in 57% of the patients compared to < 27% in HP/ISCP. Permanent pain relief regularly occurred in late-stage CP irrespective of etiology and surgery. The clinical profile of the 4 "etiological" subgroups is predictably different in the painful early (precalcific) CP stage.


Multiple gene targeting siRNAs for down regulation of Immediate Early-2 (Ie2) and DNA polymerase genes mediated inhibition of novel rat Cytomegalovirus (strain All-03).
Cytomegalovirus (CMV) is an opportunistic pathogen that causes severe complications in congenitally infected newborns and non-immunocompetent individuals. Developing an effective vaccine is a major public health priority and current drugs are fronting resistance and side effects on recipients. In the present study, with the aim of exploring new strategies to counteract CMV replication, several anti-CMV siRNAs targeting IE2 and DNA polymerase gene regions were characterized and used as in combinations for antiviral therapy. The rat embryo fibroblast (REF) cells were transfected with multi siRNA before infecting with CMV strain ALL-03. Viral growth inhibition was measured by tissue culture infectious dose (TCID50), cytopathic effect (CPE) and droplet digital PCR (ddPCR) while IE2 and DNA polymerase gene knockdown was determined by real-time PCR. Ganciclovir was deployed as a control to benchmark the efficacy of antiviral activities of respective individual siRNAs. There was no significant cytotoxicity encountered for all the combinations of siRNAs on REF cells analyzed by MTT colorimetric assay (P > 0.05). Cytopathic effects (CPE) in cells infected by RCMV ALL-03 had developed significantly less and at much slower rate compared to control group. The expression of targeted genes was downregulated successfully resulted in significant reduction (P < 0.05) of viral mRNA and DNA copies (dpb + dpc: 79%, 68%; dpb + ie2b: 68%, 60%; dpb + dpc + ie2b: 48%, 42%). Flow cytometry analysis showed a greater percentage of viable and early apoptosis of combined siRNAs-treated cells compared to control group. Notably, the siRNAs targeting gene regions were sequenced and mutations were not encountered, thereby avoiding the formation of mutant with potential resistant viruses. In conclusion. The study demonstrated a tremendous promise of innovative approach with the deployment of combined siRNAs targeting at several genes simultaneously with the aim to control CMV replication in host cells.


Involving human resources in strategic planning.
Too often, human-resources departments are not fully involved in strategic planning. However, any plan that neglects work-force recruitment, structure and motivation is incomplete. The author explains how a human-resources department can strengthen its function and become part of the planning process from the beginning.


Oscillations in the human brain during walking execution, imagination and observation.
Gait is an essential human activity which organizes many functional and cognitive behaviors. The biomechanical constraints of bipedalism implicating a permanent control of balance during gait are taken into account by a complex dialog between the cortical, subcortical and spinal networks. This networking is largely based on oscillatory coding, including changes in spectral power and phase-locking of ongoing neural activity in theta, alpha, beta and gamma frequency bands. This coding is specifically modulated in actual gait execution and representation, as well as in contexts of gait observation or imagination. A main challenge in integrative neuroscience oscillatory activity analysis is to disentangle the brain oscillations devoted to gait control. In addition to neuroimaging approaches, which have highlighted the structural components of an extended network, dynamic high-density EEG gives non-invasive access to functioning of this network. Here we revisit the neurophysiological foundations of behavior-related EEG in the light of current neuropsychological theoretic frameworks. We review different EEG rhythms emerging in the most informative paradigms relating to human gait and implications for rehabilitation strategies.


Usefulness of real-time tissue elastography for detecting the border of basal cell carcinomas.
Preoperative evaluation of tumor thickness and silhouette in basal cell carcinoma (BCC) is one of the important assessments to be done. However, evaluation is not always sufficient even utilizing sonography and magnetic resonance imaging. Recently, a new technique called real-time tissue elastography (RTE) was developed that can display the hardness of tissue as a color overlay of a sonographic image. Therefore, RTE could be used as a tool for detecting the tumor border according to differences in tissue rigidity. In the present study, the correlation between histopathological and RTE tumor thickness measurements was evaluated for BCC. Eleven BCC (six nodular, three superficial, and two adenoid or cystic) from individual patients were evaluated. Tumor silhouette and thickness were detected using conventional B-mode sonography and RTE. All lesions were surgically excised and tumor thickness was also examined histologically. In the six nodular BCC, the tumor silhouette determined by RTE showed a close correlation with the results of histopathology. Particularly, for four out of the six cases, the correlation was excellent. In addition, the mean difference in tumor thickness measurements between histology and RTE (-0.368 mm) was lower than that between histology and B-mode sonography (-0.835 mm). As for the superficial BCC, tumor thickness was too thin to evaluate. Tumor thickness measured by B-mode sonography and RTE was identical for two cases of adenoid or cystic BCC. In conclusion, RTE is useful in the preoperative assessment of tumor thickness, especially with the nodular type of BCC, and allows us to determine adequate surgical margins.


Differential susceptibility of reef-building corals to deoxygenation reveals remarkable hypoxia tolerance.
Ocean deoxygenation threatens the persistence of coastal ecosystems worldwide. Despite an increasing awareness that coastal deoxygenation impacts tropical habitats, there remains a paucity of empirical data on the effects of oxygen limitation on reef-building corals. To address this knowledge gap, we conducted laboratory experiments with ecologically important Caribbean corals Acropora cervicornis and Orbicella faveolata. We tested the effects of continuous exposure to conditions ranging from extreme deoxygenation to normoxia (~ 1.0 to 6.25 mg L-1 dissolved oxygen) on coral bleaching, photophysiology, and survival. Coral species demonstrated markedly different temporal resistance to deoxygenation, and within a species there were minimal genotype-specific treatment effects. Acropora cervicornis suffered tissue loss and mortality within a day of exposure to severe deoxygenation (~ 1.0 mg L-1), whereas O. faveolata remained unaffected after 11 days of continuous exposure to 1.0 mg L-1. Intermediate deoxygenation treatments (~ 2.25 mg L-1, ~ 4.25 mg L-1) elicited minimal responses in both species, indicating a low oxygen threshold for coral mortality and coral resilience to oxygen concentrations that are lethal for other marine organisms. These findings demonstrate the potential for variability in species-specific hypoxia thresholds, which has important implications for our ability to predict how coral reefs may be affected as ocean deoxygenation intensifies. With deoxygenation emerging as a critical threat to tropical habitats, there is an urgent need to incorporate deoxygenation into coral reef research, management, and action plans to facilitate better stewardship of coral reefs in an era of rapid environmental change.


KNEE JOINT STRUCTURAL CHANGES IN OSTEOARTHRITIS AND INJECTIONS OF PLATELET RICH PLASMA AND BONE MARROW ASPIRATE CONCENTRATE.
The article presents the results of an experimental study on the knee joint structural changes and morphometric evaluation of articular cartilage with the injections of platelet rich plasma (PRP) and bone marrow aspirate concentrate (BMAC). Cartilage defect, anterior cruciate ligament intersection and medial meniscus resection were performed for the induction of osteoarthritis in rabbits. After 28 days, 0.9% NaCl, PRP or BMAC was administered intra-articularly; 0.9% NaCl or PRP was injected intra-articularly within 14 days. After 2 months, histological and morphometric examination of the epiphyseal surface of the femur and tibia was performed. Animal models showed identical diameter of epiphyseal cartilage defect, chondrocyte reduction (by 55.1%), reduction of perifocal articular surface thickness (by 53.2%) and relative bone density of epiphysis (by 44.3%). Modeling of the joint defect was not limited to the area of damage and caused degenerative changes of the articular cartilage of the tibia. Statistical analysis showed that the introduction of PRP had no preventive effect on the degenerative changes in the articular surface. In the BMAC group, the thickness of the hyaline cartilage of the tibia was found to be 23.1% (P<0.05) greater compared with the 0.9% NaCl group and the double PRP group. However, the relative density of subchondral bone tissue in the experimental groups with osteoarthritis had no differences.


Semen collection from mice: electroejaculation.
The effects of device type (electrostimulator, function generator or computer-generated waveforms), waveform (square, triangle or sine wave), probe type (ring or strip) and anaesthetic compound (ketamine/xylazine combination or pentobarbitone sodium) were investigated on electroejaculation (EEJ) responses of C57B1 x CBA and C57Bl/6J mice. Ejaculates were analysed for total sperm count and motility variables using computer-assisted sperm analyses. Automated computer-generated waveforms delivered through a sound card were more effective and reproducible compared with waveforms generated by function generator and electrostimulator. Sine waves and triangle waves were found to be more effective in producing ejaculate than square waves. As an anaesthetic, pentobarbitone sodium tended to outperform ketamine/xylazine across waveforms and strains. Strip probes failed to produce any ejaculate regardless of the device or waveform employed. Sperm obtained by EEJ exhibited poor motility and C5B1/6J mice had lower motility variables than C57BI x CBA mice.


Evaluation of cost-effectiveness from the funding body's point of view of ultrasound-guided central venous catheter insertion compared with the conventional technique.
To evaluate the cost-effectiveness, from the funding body's point of view, of real-time ultrasound-guided central venous catheter insertion compared to the traditional method, which is based on the external anatomical landmark technique. A theoretical simulation based on international literature data was applied to the Brazilian context, i.e., the Unified Health System (Sistema Único de Saúde - SUS). A decision tree was constructed that showed the two central venous catheter insertion techniques: real-time ultrasonography versus external anatomical landmarks. The probabilities of failure and complications were extracted from a search on the PubMed and Embase databases, and values associated with the procedure and with complications were taken from market research and the Department of Information Technology of the Unified Health System (DATASUS). Each central venous catheter insertion alternative had a cost that could be calculated by following each of the possible paths on the decision tree. The incremental cost-effectiveness ratio was calculated by dividing the mean incremental cost of real-time ultrasound compared to the external anatomical landmark technique by the mean incremental benefit, in terms of avoided complications. When considering the incorporation of real-time ultrasound and the concomitant lower cost due to the reduced number of complications, the decision tree revealed a final mean cost for the external anatomical landmark technique of 262.27 Brazilian reals (R$) and for real-time ultrasound of R$187.94. The final incremental cost of the real-time ultrasound-guided technique was -R$74.33 per central venous catheter. The incremental cost-effectiveness ratio was -R$2,494.34 due to the pneumothorax avoided. Real-time ultrasound-guided central venous catheter insertion was associated with decreased failure and complication rates and hypothetically reduced costs from the view of the funding body, which in this case was the SUS.


Varying Dose of Atropine in Slowing Myopia Progression in Children Over Different Follow-Up Periods by Meta-Analysis.
Purpose: To evaluate the efficacy and safety of atropine for slowing myopia progression and to investigate whether the treatment effect remains constant with continuing treatment. Method: Studies were retrieved from MEDLINE, EMBASE, and the Cochrane Library from their inception to May 2021, and the language was limited to English. Randomized controlled trials (RCTs) and cohort studies involving atropine in at least one intervention and placebo/non-atropine treatment in another as the control were included and subgroup analysis based on low dose (0.01%), moderate dose (0.01%-<0.5%), and high dose (0.5-1.0%) were conducted. The Cochrane Collaboration and Newcastle-Ottawa Scale were used to evaluate the quality of RCTs and cohort studies, respectively. Results: Twelve RCTs and fifteen cohort studies involving 5,069 children aged 5 to 15 years were included. The weighted mean differences in myopia progression between the atropine and control groups were 0.73 diopters (D), 0.67 D, and 0.35 D per year for high-dose, moderate-dose, and low-dose atropine, respectively (χ2 = 13.76; P = 0.001, I 2 = 85.5%). After removing studies that provided extreme findings, atropine demonstrated a significant dose-dependent effect on both refractive change and axial elongation, with higher dosages of atropine resulting in less myopia progression (r = 0.85; P = 0.004) and less axial elongation (r = -0.94; P = 0.005). Low-dose atropine showed less myopia progression (-0.23 D; P = 0.005) and less axial elongation (0.09 mm, P < 0.001) in the second year than in the first year, whereas in high-dose atropine more axial elongation (-0.15 mm, P = 0.003) was observed. The higher dose of atropine was associated with a higher incidence of adverse effects, such as photophobia with an odds ratio (OR) of 163.57, compared with an OR of 6.04 for low-dose atropine and 8.63 for moderate-dose atropine (P = 0.03). Conclusion: Both the efficacy and adverse effects of atropine are dose-dependent in slowing myopia progression in children. The efficacy of high-dose atropine was reduced after the first year of treatment, whereas low-dose atropine had better efficacy in a longer follow-up period.


Conformational and aggregational states of omega-aminoacylmelittin derivatives.
Melittin, a 26-residue peptide from bee venom, is known to change from a largely random to a largely alpha-helical conformation as a function of peptide concentration, pH, and ionic strength. In this report, we have determined the effect of displacing the positive charges of the amino groups of N-terminal glycine and lysine residues away from the backbone of melittin in coil-to-helix transitions by using omega-aminoacyl derivatives of melittin. These were prepared by acylating the amino groups of melittin with omega-amino acids to yield the melittin derivatives glycylmelittin (MLT-2), (4-aminobutanoyl)melittin (MLT-4), and (5-aminopentanoyl)melittin (MLT-5), respectively. At pH 7.2, there is a chain-length-dependent increase in helicity from MLT to MLT-5. The omega-aminoacylmelittin derivatives also show a concentration-dependent increase in helicity at pH 7.2. However, at pH 2.3, a concentration-independent, but chain length-dependent increase in helicity was observed. A hydrophilic derivative glycylglycylmelittin (MLT-GG) and a hydrophobic derivative MLT-5, which have side chains of equal length, show similar helicity, at pH 7.2, but at pH 2.3 MLT-GG shows almost no helicity, while MLT-5 is about 60% helical. The lysyl derivative (MLT-K), which has additional positive charges compared to melittin, behaves much like MLT-2. At pH 7.2, all the derivatives exhibit both cold- and heat-induced denaturation; a significant amount of residual structure is retained in the temperature range 80-100 degrees C. These results are discussed in terms of the electrostatic and hydrophobic interactions involving the side chains.


Finding an appropriate order for a hierarchy based on probabilistic dominance.
Methods of ranking individuals in a dominance hierarchy that use transitivity of relationships may obscure irregularities. Furthermore, these methods use only a small proportion of the information available from dominance encounters. This paper presents an intuitively appealing and easily implemented alternative to existing methods for ordering dominance data, developed from the work of Batchelder et al. (1992 Journal of Mathematical Psychology36, 185-212). The procedure presented here is based on a mathematical model of paired comparisons and it involves only simple estimation procedures. We illustrate its use with data on dominance among red deer Cervus elaphus, stags. The results indicate that dominance relationships are well characterized by the scale values that the model provides, and, because the method provides predictions for all pairings of animals, dominance predictions also exist for pairs of animals that have yet to be observed. Moreover, the dominance outcomes predicted by the model using the order scale are highly correlated with actual dominance observations at all levels. Overall, the procedure described provides a solution to the problem of identifying an appropriate order for a near-linear dominance hierarchy. Copyright 1999 The Association for the Study of Animal Behaviour.


Comparative effectiveness of dalteparin and enoxaparin in a hospital setting.
This study compared the effectiveness of a change from enoxaparin to dalteparin for the prophylaxis of patients at risk of venous thromboembolism (VTE). A retrospective cohort study identified hospitalized patients with VTE risk admitted at Wellmont Health System between August 1, 2008 and July 31, 2009. On February 1, 2009, a therapeutic interchange from enoxaparin to dalteparin occurred. All patient records were reviewed from billing data collected 6 months prior and following conversion. Statistical tests of heterogeneity compared distributions of demography between study cohorts and Cochran tests were used to compare pre- versus postchange in the outcomes. A total of 3557 and 3465 patient discharges were analyzed in the 6 months prior and following the interchange, respectively. Of these discharges, 1870 were administered enoxaparin and 1639 dalteparin. VTE rates were similar between the 2 groups. Data showed no significant difference in-hospital length of stay (LOS), readmittance, and bleeding rates in the populations. The system achieved a $40 788 savings over 6 months following the conversion using approved prophylactic dosing per patient indication. Dalteparin is similarly effective as enoxaparin and an alternative for the prophylaxis of VTE in a hospital setting while providing cost savings.


Olanzapine serum concentrations in psychiatric patients given standard doses: the influence of comedication.
We recorded steady state serum concentrations of olanzapine in 56 psychiatric patients under routine conditions. Twenty-two patients (39%) underwent monotherapy; the rest received additional psychotropic drugs. Doses were given once daily in the evening, and serum olanzapine levels were measured 12 hours later. For the whole group, the concentration-to-dose ratio (C/D) varied 26-fold, with a median value of 4.8 (nmol/L)/(mg/24 hours), but 80% of the patients had C/D values within the range 2 to 10 (nmol/L)/(mg/24 hours). All but three patients received standard doses (5-20 mg/24 hours), of whom 80% had serum concentrations of olanzapine within the range 22 to 146 nmol/L. Patients comedicated with potential inhibitors of CYP2D6 and other drugs displayed a median C/D approximately 40% higher than the group undergoing monotherapy. Patients comedicated with carbamazepine had a median C/D 36% lower than that of the monotherapy group. Therefore, the serum concentration range (12-hour values) of 25 to 150 nmol/L can be expected for patients receiving a standard daily dose.


New triterpene aldehydes, lucialdehydes A-C, from Ganoderma lucidum and their cytotoxicity against murine and human tumor cells.
Three new lanostante-type triterpene aldehydes, named lucialdehydes A-C (1-3), were isolated from the fruiting bodies of Ganoderma lucidum, together with ganodermanonol (4), ganodermadiol (5), ganodermanondiol (6), ganodermanontriol (7), ganoderic acid A (8), ganoderic acid B8 (9), and ganoderic acid C1 (10). The structures of the new triterpenes were determined as (24E)-3 beta-hydroxy-5 alpha-lanosta-7,9(11),24-trien-26-al (1), (24E)-3,7-dioxo-5 alpha-lanosta-8,24-dien-26-al (2), and (24E)-3 beta-hydroxy-7-oxo-5 alpha-lanosta-8,24-dien-26-al (3), respectively, by spectroscopic means. The cytotoxicity of the compounds isolated from the ganoderma mushroom was tested in vitro against Lewis lung carcinoma (LLC), T-47D, Sarcoma 180, and Meth-A tumor cell lines. Lucialdehydes B, C (2, 3), ganodermanonol (4) and ganodermanondiol (6) showed cytotoxic effects on tested tumor cells. Of the compounds, lucialdehyde C (3) exhibited the most potent cytotoxicity against LLC, T-47D, Sarcoma 180, and Meth-A tumor cells with ED(50) values of 10.7, 4.7, 7.1, and 3.8 microg/ml, respectively.


Effects of omapatrilat on the renin-angiotensin system in salt-sensitive hypertension.
The contribution of angiotensin-(1-7) [Ang-(1-7)] to the antihypertensive actions of omapatrilat, a novel vasopeptidase inhibitor, was evaluated in 22 salt-sensitive, low renin, hypertensive subjects as a substudy of a multicenter randomized, double-blind, parallel study of 4 weeks duration. A total of 25 other subjects received lisinopril as the active control. Omapatrilat (40 mg) produced sustained control of blood pressure (BP) (as assessed by 24-h ambulatory BP measurements) that was significantly greater than that produced by 20 mg daily of lisinopril. The antihypertensive response to either drug was accompanied by similar sustained inhibition of angiotensin converting enzyme activity. Plasma levels of angiotensin I (Ang I), angiotensin II (Ang II) and Ang-(1-7) were not altered by treatment with either omapatrilat or lisinopril, even though both regimens produced a modest rise in plasma renin activity. In contrast, urinary excretion rates of Ang I and Ang-(1-7) but not Ang II increased significantly throughout the dosing period of subjects who were given omapatrilat, whereas the smaller antihypertensive response produced by lisinopril had a smaller and transient effect on increasing urinary excretion rates of Ang-(1-7). Omapatrilat, being a single molecule inhibiting neutral endopeptidase and converting enzyme simultaneously, controlled salt-sensitive hypertension by a mechanism that was associated with sustained increases in urinary Ang-(1-7) excretion. We suggest that Ang-(1-7) may be a component of the mechanisms by which omapatrilat induces an antihypertensive response in salt sensitive hypertension.


The impact of dietary protein intake on longevity and metabolic health.
Lifespan and metabolic health are influenced by dietary nutrients. Recent studies show that a reduced protein intake or low-protein/high-carbohydrate diet plays a critical role in longevity/metabolic health. Additionally, specific amino acids (AAs), including methionine or branched-chain AAs (BCAAs), are associated with the regulation of lifespan/ageing and metabolism through multiple mechanisms. Therefore, methionine or BCAAs restriction may lead to the benefits on longevity/metabolic health. Moreover, epidemiological studies show that a high intake of animal protein, particularly red meat, which contains high levels of methionine and BCAAs, may be related to the promotion of age-related diseases. Therefore, a low animal protein diet, particularly a diet low in red meat, may provide health benefits. However, malnutrition, including sarcopenia/frailty due to inadequate protein intake, is harmful to longevity/metabolic health. Therefore, further study is necessary to elucidate the specific restriction levels of individual AAs that are most effective for longevity/metabolic health in humans.


Influence of Extraction Methods on Total Phenolic Content and Antioxidant Properties of Some of the Commonly Used Plants in Thailand.
Several plants have been commonly used in Thailand for health improvement, but the phytochemical content and its bio-activities are not yet elucidated completely. The aim of this research was to study the influence of extraction method on total phenolic content (TPC) and antioxidant activity of representative plants such as Punica granatum, Hibiscus sabdariffa, leistocalyx operculatus (Roxb.) Merr., litoria ternatea Linn., Mulberry and Oryza sativa L. indica. The samples were subjected to different extraction procedures. The TPC and phenolic compounds were determined by Folin-Ciocalteu colorimetric assay and HPLC, respectively. The antioxidant capacity of the extracts was measured by 2, 2-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid (ABTS) and ferric reducing antioxidant power (FRAP) assays and ferrous ion (Fe2+) chelating assay. The maximum TPC was observed in pomegranate peel (TTP) extract (0.1 M HCl: Ethanol extraction) and low TPC was recorded in aqueous extract of butterfly pea flower (BP) samples. The high content of protocatechuic, p-hydroxybenzoic acid were observed in pomegranate seed and seed coat (TTS). Gallic and syringic acids were found to be rich in pomegranate peel (TTP) and flower of butterfly pea (BP), respectively. Roselle flower samples (KJ) showed high content of chlorogenic, p-coumaric and caffeic acids. The maximum antioxidant activity was observed in extracts obtained by 0.1 M HCl: Ethanol extraction methods, especially pomegranate peel exhibited high free radical scavenging activity compared to that of the other samples. The results strongly revealed that the extraction method greatly influences the phytochemical content and bioactivity and strongly recommends that any plant samples, intended to study, must undergo several extraction processes to reveal the actual phytochemical content.


2D and 3D imaging of the gas phase close to an operating model catalyst by planar laser induced fluorescence.
In recent years, efforts have been made in catalysis related surface science studies to explore the possibilities to perform experiments at conditions closer to those of a technical catalyst, in particular at increased pressures. Techniques such as high pressure scanning tunneling/atomic force microscopy (HPSTM/AFM), near ambient pressure x-ray photoemission spectroscopy (NAPXPS), surface x-ray diffraction (SXRD) and polarization-modulation infrared reflection absorption spectroscopy (PM-IRAS) at semi-realistic conditions have been used to study the surface structure of model catalysts under reaction conditions, combined with simultaneous mass spectrometry (MS). These studies have provided an increased understanding of the surface dynamics and the structure of the active phase of surfaces and nano particles as a reaction occurs, providing novel information on the structure/activity relationship. However, the surface structure detected during the reaction is sensitive to the composition of the gas phase close to the catalyst surface. Therefore, the catalytic activity of the sample itself will act as a gas-source or gas-sink, and will affect the surface structure, which in turn may complicate the assignment of the active phase. For this reason, we have applied planar laser induced fluorescence (PLIF) to the gas phase in the vicinity of an active model catalysts. Our measurements demonstrate that the gas composition differs significantly close to the catalyst and at the position of the MS, which indeed should have a profound effect on the surface structure. However, PLIF applied to catalytic reactions presents several beneficial properties in addition to investigate the effect of the catalyst on the effective gas composition close to the model catalyst. The high spatial and temporal resolution of PLIF provides a unique tool to visualize the on-set of catalytic reactions and to compare different model catalysts in the same reactive environment. The technique can be applied to a large number of molecules thanks to the technical development of lasers and detectors over the last decades, and is a complementary and visual alternative to traditional MS to be used in environments difficult to asses with MS. In this article we will review general considerations when performing PLIF experiments, our experimental set-up for PLIF and discuss relevant examples of PLIF applied to catalysis.


Collagen XXV promotes myoblast fusion during myogenic differentiation and muscle formation.
Fusion of myoblasts into multinucleated myofibers is crucial for skeletal muscle development and regeneration. However, the mechanisms controlling this process remain to be determined. Here we identified the involvement of a new extracellular matrix protein in myoblast fusion. Collagen XXV is a transmembrane-type collagen highly transcribed during early myogenesis when primary myofibers form. Limb muscles of E12.5 and E14.5 Col25a1-/- embryos show a clear defect in the formation of multinucleated myofibers. In cell culture, the cleaved soluble extracellular domain of the collagen XXV is sufficient to promote the formation of highly multinucleated myofibers. Col25a1 is transiently expressed during myogenic differentiation and Col25a1 transcripts are down-regulated in multinucleated myofibers by a muscle-specific microRNA, miR-499. Altogether, these findings indicate that collagen XXV is required in vivo and in vitro for the fusion of myoblasts into myofibers and give further evidence that microRNAs participate to the regulation of this process.


Multicomponent catalytic asymmetric aziridination of aldehydes.
The first multicomponent catalytic asymmetric aziridination reaction is developed to give aziridine-2-carboxylic esters with very high diastereo- and enantioselectivity from aromatic and aliphatic aldehydes. This new method pushes the boundary of the aziridination reaction to substrates that failed with preformed imines.


Association between magnetic resonance imaging characteristics and pathological findings in entire posterior cruciate ligament with mucoid degeneration.
Magnetic resonance imaging (MRI) findings of a tram-track appearance and celery stalk appearance in mucoid degeneration of the cruciate ligament are valuable; however, their pathological basis is unclear. Because these appearances are generally seen throughout the entire ligament, the association between MRI findings and pathological findings must be verified in specimens of the whole degenerated ligament, including the ligamentous attachments to bone. We herein report two cases of mucoid degeneration of the posterior cruciate ligament with osteoarthritis of the knee requiring total knee arthroplasty. The entire degenerated ligament, including the ligamentous attachments to bone, was removed and pathologically evaluated. On pathological examination, the central portion of the lesion showed typical mucoid degeneration, whereas the marginal and adherent portions showed normal ligament tissue, consistent with a tram-track appearance on T2-weighted MRI. The fibrous normal ligament tissues in the longitudinal direction in regions of mucoid degeneration were consistent with a celery stalk appearance on T2-weighted MRI. No mucoid degeneration was found in the attachment area. The tram-track appearance and celery stalk appearance of mucoid degeneration on MRI can be explained by the pathological findings.


Schedules of Controlled Substances: Removal of Naldemedine From Control. Final rule.
With the issuance of this final rule, the Drug Enforcement Administration removes the substance naldemedine (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,7,9-trihydroxy-N-(2-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-yl)-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-6-carboxamide) including its salts from the schedules of the Controlled Substances Act. Prior to the effective date of this rule, naldemedine was a schedule II controlled substance because it can be derived from opium alkaloids. This action removes the regulatory controls and administrative, civil, and criminal sanctions applicable to controlled substances, including those specific to schedule II controlled substances, on persons who handle (manufacture, distribute, reverse distribute, dispense, conduct research, import, export, or conduct chemical analysis) or propose to handle naldemedine.


Oxidative imbalance in child and adolescent patients with attention-deficit/hyperactivity disorder.
Various psychological, social, genetic, and biochemical factors are thought to be involved in the aetiology of attention-deficit/hyperactivity disorder (ADHD). However, few studies have evaluated the biochemical basis of ADHD. In the present study, we evaluate whether levels of nitric oxide pool (NO+NO(2)(-)) and malondialdehyde (MDA) oxidants as well as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) antioxidant enzyme activities are associated with ADHD. The sample population consisted of thirty-five child or adolescent patients diagnosed with ADHD according to DSM-IV-TR criteria. Thirty-five healthy subjects also were included in the study as controls. Venous blood samples were collected, and NO pool and MDA levels as well as SOD, GSH-Px, and CAT activities were measured. NO and MDA levels of the patients were significantly higher than the controls. GSH-Px activities of the patients were significantly lower than the controls. CAT activities of the patients were higher than the controls; however, the difference was not statistically significant. There were no significant differences in SOD activity between the patient and control groups. Remarkably high levels of NO pool and MDA oxidants as well as low GSH-Px activities suggest an oxidative imbalance in paediatric patients with ADHD. CAT activities may be increased in response to increased oxidant levels.


In situ Thermal-Responsive Magnetic Hydrogel for Multidisciplinary Therapy of Hepatocellular Carcinoma.
Current surgical single modality treatments for hepatocellular carcinoma (HCC) were restricted by recurrence, blood loss, significant trauma, and poor prognostic. Although multidisciplinary strategies for HCC treatment have been highly recommended by the clinical guidelines, there was limited choice of materials and treatments. Herein, we reported an in situ formed magnetic hydrogel with promising bioapplicable thermal-responsiveness, strong adhesion in wet conditions, high magnetic hyperthermia, and biocompatibility, leading to efficient HCC multidisciplinary treatment including postoperative treatment and transarterial embolization therapy. In vivo results indicated that this hydrogel could reduce the postoperative recurrence rate. The hemostatic ability of the thermal-responsive hydrogel was further demonstrated in both the liver scratch model and liver tumor resection. Computed tomography imaging suggested that the hydrogel could completely embolize the arterial vessels of rabbit liver tumor by vascular intervention operation, which could serve as multidisciplinary responsive materials to external magnetic field and body temperature for HCC treatment.


Comparison of Monte Carlo methods for fluorescence molecular tomography-computational efficiency.
The Monte Carlo method is an accurate model for time-resolved quantitative fluorescence tomography. However, this method suffers from low computational efficiency due to the large number of photons required for reliable statistics. This paper presents a comparison study on the computational efficiency of three Monte Carlo-based methods for time-domain fluorescence molecular tomography. The methods investigated to generate time-gated Jacobians were the perturbation Monte Carlo (pMC) method, the adjoint Monte Carlo (aMC) method and the mid-way Monte Carlo (mMC) method. The effects of the different parameters that affect the computation time and statistics reliability were evaluated. Also, the methods were applied to a set of experimental data for tomographic application. In silico results establish that, the investigated parameters affect the computational time for the three methods differently (linearly, quadratically, or not significantly). Moreover, the noise level of the Jacobian varies when these parameters change. The experimental results in preclinical settings demonstrates the feasibility of using both aMC and pMC methods for time-resolved whole body studies in small animals within a few hours. Among the three Monte Carlo methods, the mMC method is a computationally prohibitive technique that is not well suited for time-domain fluorescence tomography applications. The pMC method is advantageous over the aMC method when the early gates are employed and large number of detectors is present. Alternatively, the aMC method is the method of choice when a small number of source-detector pairs are used.


[Operative treatment of the endobronchial tuberculosis with cicatricial bronchiarctia].
The experience of surgical treatment in 32 patients with cicatricial brochiarctia by endobronchial tuberculosis was reported. The modes of surgical treatment in the series include: sleeve resection was done in 19 cases, lobectomy in 4 cases, pneumonectomy in 7, and left principal bronchial reconstruction in 2 cases. The results were excellent and without operative death. Serious postoperative complication was bronchopleural fistula in one case. The patient was treated by surgical repair of the bronchial stump and buttressed with vascularized pedicle flaps of omentum in the second operation. 2 cases of 32 patients were affected with mild stenosis of bronchial anestomosis after a follow-up of 12 to 18 months. It was suggested that when the patient developed the endobronchial tuberculosis with cicatricial bronchiarctia, corrective operation should be performed as early as possible, and the sleeve resection should be the first choice.


Effect of pulse high-volume hemofiltration on Toll-like receptor in patients with severe sepsis.
The expression level and prognosis of Toll-like receptor 2 (TLR2) mRNA in peripheral blood mononuclear cells of patients with severe sepsis after applying pulse high-volume hemofiltration (PHVHF) were investigated. Sustained PHVHF treatment was carried out on 40 patients on the basis of conventional treatment for up to 72 h. Acute physiology and chronic health evaluation (APACHE) II scores of patients were compared before and after the treatment. CD4+, CD8+ lymphocyte counts and ratios in the peripheral blood were detected using FASort before and 24 and 48 h of PHVHF treatment. Enzyme-linked immunosorbent assay was adopted to detect tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) concentrations in plasma at different time points before and after 24, 48 and 72 h of treatment, while semi-quantitative reverse transcription-polymerase chain reaction technology was used to test TLR2 mRNA expression. After PHVHF treatment, APACHE II, Sequential Organ Failure Assessment scores were decreased (P<0.05). After 72 h of PHVHF treat-ment, TNF-α, IL-10, TLR2 mRNA expression levels in the plasma of patients were significantly decreased compared to before treatment (P<0.05), and the IL-10 / TNF-α ratio was much higher than before treatment (p<0.05). In conclusion, PHVHF can restore the pro-inflammatory/anti-inflammatory balance of the body, thereby improving the overall condition of the patients by removing inflammatory mediators and lowering TLR2 expression of mononuclear cell surface in peripheral blood.


Transcatheter embolization with sodium tetradecyl sulfate. Experimental and clinical results.
Sodium tetradecyl sulfate (Sotradecol), which has been employed for sclerotherapy of varicose veins, was evaluated in dogs and humans as an agent for selective arterial embolization. In dogs, intraarterial injection of Sotradecol 3% into the proximally occluded renal, hepatic, splenic, and deep femoral arteries produced arterial occlusion and tissue destruction. Transcatheter embolization with Sotradecol was performed in 11 patients and was successful in 10; in the remaining patient, failure was attributed to rapid dilution by unobstructed blood flow in arteriovenous malformations of the neck. The authors conclude that Sotradecol is a safe and efficient agent for selective arterial embolization.


The potential use of tideglusib as an adjuvant radio-therapeutic treatment for glioblastoma multiforme cancer stem-like cells.
Glioblastoma multiforme (GBM), a stage IV astrocytoma, is the most common brain malignancy among adults. Conventional treatments of surgical resection followed by radio and/or chemotherapy fail to completely eradicate the tumor. Resistance to the currently available therapies is mainly attributed to a subpopulation of cancer stem cells (CSCs) present within the tumor bulk that self-renew leading to tumor relapse with time. Therefore, identification of characteristic markers specific to these cells is crucial for the development of targeted therapies. Glycogen synthase kinase 3 (GSK-3), a serine-threonine kinase, is deregulated in a wide range of diseases, including cancer. In GBM, GSK-3β is overexpressed and its suppression in vitro has been shown to induce apoptosis of cancer cells. In our study, we assessed the effect of GSK-3β inhibition with Tideglusib (TDG), an irreversible non-ATP competitive inhibitor, using two human GBM cell lines, U-251 MG and U-118 MG. In addition, we combined TDG with radiotherapy to assess whether this inhibition enhances the effect of standard treatment. Our results showed that TDG significantly reduced cell proliferation, cell viability, and migration of both GBM cell lines in a dose- and time-dependent manner in vitro. Treatment with TDG alone and in combination with radiation significantly decreased the colony formation of U-251 MG cells and the sphere formation of both cell lines, by targeting and reducing their glioblastoma cancer stem-like cells (GSCs) population. Finally, cells treated with TDG showed an increased level of unrepaired radio-induced DNA damage and, thus, became sensitized toward radiation. In conclusion, TDG has proven its effectiveness in targeting the cancerous properties of GBM in vitro and may, hence, serve as a potential adjuvant radio-therapeutic agent to better target this deadly tumor.


Antioxidant activity of isolated ellagitannins from red raspberries and cloudberries.
Ellagitannins from red raspberries (Rubus idaeus) and cloudberries (Rubus chamaemorus) were isolated by using column chromatography and preparative HPLC. The berry phenolic isolates consisted of 80% (cloudberry) and of 60% (raspberry) of ellagitannins, with raspberries also containing anthocyanins. The main ellagitannins of both raspberries and cloudberries were identified by ESI-MS to consist of the dimeric sanguiin H-6 and the trimeric lambertianin C. Monomeric ellagitannins such as casuarictin in raspberries and pedunculagin in cloudberries were also found. The antioxidant activity of the berry phenolic isolate, ellagitannin isolate (mixture), ellagitannin main fraction (dimer and trimer), and ellagic acid was studied in bulk and emulsified methyl linoleate, in human low-density lipoprotein in vitro, and the radical scavenging activity was studied in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) test. Cloudberry and red raspberry ellagitannins were highly effective as radical scavengers. Berry ellagitannins also showed significant antioxidant activity toward oxidation of both human LDL and methyl linoleate emulsions. However, only weak or moderate antioxidant activity was exhibited by ellagitannins toward oxidation of bulk oil. Thus, ellagitannins contribute significantly to the antioxidant capacity of cloudberries and red raspberries in lipoprotein and lipid emulsion environments, the latter being more relevant for food applications.


Identifying biomarkers to select patients with early breast cancer suitable for extended adjuvant endocrine therapy.
In this review, we summarize recent and current biomarkers and assays that are being considered in the selection of suitable patients with estrogen receptor-positive early breast cancer for extended (years 5-10) adjuvant endocrine therapy (AET). Women with estrogen receptor-positive early-stage breast cancer (65% of cases) continue to have late risk for distant recurrence extending beyond 5 years from surgery. Recent large trials have consistently demonstrated improvement for prolonging endocrine therapy. However, endocrine therapy can cause women bothersome side effects and can negatively impact quality of life. Determining which patients remain at risk for disease recurrence and predicting which of these patients would derive the most benefit from the addition of extended AET are key issues faced by patients and oncologists today. A number of predictive molecular assays have been developed and are being considered as tools to be used in guiding the implementation of adjuvant systemic therapy. The future holds much promise and as more information and understanding is acquired, treatment regimens will increasingly incorporate clinically validated biomarker assays in the decision-making process that will be of great benefit to these patients. Proving clinical utility, though, will ultimately decide their implementation.


Mating alters the cuticular hydrocarbons of female Anopheles gambiae sensu stricto and aedes Aegypti (Diptera: Culicidae).
The cuticular hydrocarbons of female Anopheles gambiae Giles sensu stricto and Aedes aegypti (L.) mosquitoes were analyzed before and after they mated. In An. gambiae, the proportions of the two cuticular hydrocarbon components, n-heneicosane and n-tricosane, were significantly reduced as the female aged and after it mated. There were no changes in the hydrocarbon composition of males after they mated. Hydrocarbon extracts from mated and unmated An. gambiae females as well as those from males caused a reduction in the rates of female insemination when they were applied to unmated females. Female Ae. aegypti showed significant changes in the proportions of n-heptadecane, n-pentacosane and n-hexacosane in their cuticles after mating. These data suggest that cuticular hydrocarbons may play some role in chemical communication during mosquito courtship.


Craniocervical arterial dissection in children: diagnosis and treatment.
Diagnosis of craniocervical arterial dissection (CCAD) in children begins with a careful history and physical in a child with a transient ischemic attack (TIA) or arterial ischemic stroke (AIS). The extent of radiologic evaluation for suspected CCAD is based upon careful consideration of the risks associated with the best imaging techniques, weighed against the benefits of enhanced vascular imaging with better diagnostic sensitivity. Although conventional angiography (CA) and CT angiography (CTA) have a higher sensitivity than magnetic resonance angiography (MRA), they are accompanied by risks: for CA, femoral hematoma, femoral arterial pseudoaneurysm, recurrent AIS, and radiation exposure; for CTA, radiation. For children (non-neonates) with suspected CCAD, MRI with MRA is recommended as the first-line imaging study. MRI usually includes diffusion-weighted, FLAIR, and T1 images of the brain, and T1 or T2 fat-saturation axial imaging through the neck. MRA should include 3D time-of-flight MRA of the head and neck (from the aortic arch through the circle of Willis). Contrast-enhanced MRA should be highly considered in neck imaging. If MRI/MRA is equivocal, CCAD is strongly suspected but not detected on MRI/MRA (especially in the posterior circulation), or the child has recurrent events, additional imaging of the craniocervical vasculature is likely warranted. Individual clinical circumstances warrant careful, case-by-case consideration. Treatment of CCAD in children is challenging and differs for intracranial and extracranial dissections. In extracranial CCAD, we most commonly use anticoagulation for 6 weeks to 6 months in patients with TIA or AIS. Typically, unfractionated heparin is used in the acutely ill patient at heightened risk for bleeding (because of its short half-life), whereas low-molecular-weight heparin (LMWH) or warfarin are reserved for the stable patient. If the history is suspicious for dissection (head and neck trauma, recent cervical chiropractic manipulation, recent car accident, or neck pain), we consider treatment for dissection even with normal MRI/MRA. For patients with CCAD with a stroke size greater than one third to one half of the middle cerebral artery territory (or other bleeding risk factors) and extracranial CCAD, in whom there is concern about heightened risk for hemorrhagic conversion, we commonly use aspirin therapy during the acute phase. Regardless of their treatment in the initial weeks to months, we subsequently treat all patients with aspirin for 1 year after their event, and sometimes longer if they have other risk factors. Interventional techniques, such as extracranial cerebral arterial stent placement or selective occlusion, are understudied in children. Interventional techniques are typically reserved for patients who fail aggressive medical management and have recurrent TIA or AIS. The diagnosis and treatment of intracranial dissection is extraordinarily challenging in children, in whom inflammatory intracranial arteriopathies are common. When intracranial arteriopathy is clearly associated with dissection, the clinician should look for the presence of subarachnoid hemorrhage and/or dissecting aneurysm. Treatment decisions should be made by a multidisciplinary pediatric stroke team, given the lack of data in this area. Intracranial cerebral artery stent placement carries high risk and is not recommended for intracranial CCAD in children. Most importantly, we educate all children with CCAD and their parents about the paucity of evidence in the treatment of this disease, the risks of enhanced imaging techniques such as CTA or CA, and the challenges involved in weighing the risks of aggressive therapies and interventions against the costs of unclear diagnosis and potentially ineffective treatments. We also educate our patients with CCAD about the signs and symptoms of recurrence and the importance of emergent evaluation.


Chimeric Antigen Receptor, Teamwork, Education, Assessment, and Management (CAR-TEAM): A Simulation-Based Inter-professional Education (IPE) Intervention for Management of CAR Toxicities.
Chimeric antigen receptor (CAR) therapies such as tisagenlecleucel, indicated for children and young adults with relapsed and/or refractory CD19+ acute lymphoblastic leukemia (ALL), have been associated with striking treatment outcomes and overall survival. Yet, they are also associated with unique and potentially life-threatening complications. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are generally reversible complications of CAR therapies, but many patients may require critical care support especially if they are not promptly recognized and appropriately managed by frontline healthcare staff. As CAR therapies become more widely available, it is important that inter-professional staff members be aware of general principles regarding diagnosis and management. We hypothesized that an inter-professional education (IPE) simulation-based education intervention (CAR-TEAM) would improve knowledge base and confidence regarding complications of CAR therapies among inter-professional staff. Here, we demonstrate that following CAR-TEAM training, >90% of participants demonstrated knowledge proficiency and confidence in the IPE content area. CAR-TEAM training may serve as an important tool to establish initial and continued competency among sites introducing CAR therapies.


RNA-seq based detection of differentially expressed genes in the skeletal muscle of Duroc pigs with distinct lipid profiles.
We have used a RNA-seq approach to investigate differential expression in the skeletal muscle of swine (N = 52) with divergent lipid profiles i.e. HIGH (increased intramuscular fat and muscle saturated and monounsaturated fatty acid contents, higher serum lipid concentrations and fatness) and LOW pigs (leaner and with an increased muscle polyunsaturated fatty acid content). The number of mRNAs and non-coding RNAs (ncRNAs) expressed in the porcine gluteus medius muscle were 18,104 and 1,558, respectively. At the nominal level of significance (P-value ≤ 0.05), we detected 1,430 mRNA and 12 non-coding RNA (ncRNA) transcripts as differentially expressed (DE) in the gluteus medius muscle of HIGH vs LOW pigs. This smaller contribution of ncRNAs to differential expression may have biological and technical reasons. We performed a second analysis, that was more stringent (P-value ≤ 0.01 and fold-change ≥ 1.5), and only 96 and 0 mRNA-and ncRNA-encoding genes happened to be DE, respectively. The subset of DE mRNA genes was enriched in pathways related with lipid (lipogenesis and triacylglycerol degradation) and glucose metabolism. Moreover, HIGH pigs showed a more lipogenic profile than their LOW counterparts.


Evaluation of differential toxicity of varying doses of bevacizumab on retinal ganglion cells, retinal pigment epithelial cells, and vascular endothelial growth factor-enriched choroidal endothelial cells.
To evaluate in vitro the effects of bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, on retinal pigment epithelial cells (RPE) and retinal ganglion cells (RGC), at doses that were inhibitory to VEGF-enriched choroidal endothelial cells (CEC). Monkey CEC (RF6A), human RPE cells (ARPE-19), and rat RGC (RGC-5) were exposed for 24 h to increasing doses of bevacizumab. Cell numbers were quantified with WST-1 assay. Cell death was assessed using propidium iodide (PI) staining via flow cytometry and fluorescent microscopy. Bevacizumab was inhibitory to RF6A at 2.0 mg/mL (P < 0.005). No effect on cell viability was noted on ARPE-19 and RGC-5 cell lines at this particular dose of bevacizumab. These results were supported by fluorescent microscopy of PI-stained cells. VEGF-stimulated proliferation of CEC was inhibited by bevacizumab. Bevacizumab was not cytotoxic to human RPE and rat RGC in vitro at a dose that is inhibitory to monkey CEC.


Nutritional intervention in uremia--myth or reality?
Nutritional intervention in uremia, specifically the restricted protein diet, has been under debate for decades. The results of various clinical trials have not been concordant, as some studies have reported positive effects of the low-protein diets, whereas others have shown no benefit. Recently published data show that the restricted protein diets seem to be effective and safe in ameliorating nitrogen waste products retention and the disturbances in acid-base and calcium-phosphorus metabolism, and in delaying the initiation of renal replacement therapy (RRT), without any deleterious effect on the nutritional status of patients with chronic kidney disease. The nutritional support and particularly the supplemented very low protein diet could be a new link to the RRT-integrated care model. A possible delay in RRT initiation through nutrition could have a major economic effect, particularly in developing countries, where the dialysis facilities still do not meet the requirements. However, a careful selection of motivated patients who could benefit from such a diet, closer nutritional monitoring, and dietary counseling are required.


Management of osteoporosis: a national survey of Israeli dietitians' knowledge and perceptions.
The aim of this study was to assess Israeli dietitians' knowledge and attitudes regarding osteoporosis. Participants were 320 dietitians responding to a mail survey. Israeli dietitians scored highly on the Facts on Osteoporosis Quiz-FOOQ. Israeli dietitians' dietary knowledge regarding calcium (recommended dietary allowance, content in food and in supplements) was fairly high; unlike knowledge regarding vitamin D. Israeli dietitians had a firm positive opinion of their role in the prevention and treatment of osteoporosis.


C-type lectins DC-SIGN and L-SIGN mediate cellular entry by Ebola virus in cis and in trans.
Ebola virus is a highly lethal pathogen responsible for several outbreaks of hemorrhagic fever. Here we show that the primate lentiviral binding C-type lectins DC-SIGN and L-SIGN act as cofactors for cellular entry by Ebola virus. Furthermore, DC-SIGN on the surface of dendritic cells is able to function as a trans receptor, binding Ebola virus-pseudotyped lentiviral particles and transmitting infection to susceptible cells. Our data underscore a role for DC-SIGN and L-SIGN in the infective process and pathogenicity of Ebola virus infection.


High Rates of Pre-exposure Prophylaxis Eligibility and Associated HIV Incidence in a Population With a Generalized HIV Epidemic in Rakai, Uganda.
The utility of using pre-exposure prophylaxis (PrEP) eligibility assessments to identify eligibility in general populations has not been well studied in sub-Saharan Africa. We used the Rakai Community Cohort Study to conduct a cross-sectional analysis to estimate PrEP eligibility and a cohort analysis to estimate HIV incidence associated with PrEP eligibility. Based on Uganda's national PrEP eligibility tool, we defined eligibility as reporting at least one of the following HIV risks in the past 12 months: sexual intercourse with more than one partner of unknown HIV status; nonmarital sex act without a condom; sex engagement in exchange for money, goods, or services; or experiencing genital ulcers. We used log-binomial and modified Poisson models to estimate prevalence ratios for PrEP eligibility and HIV incidence, respectively. We identified 12,764 participants among whom to estimate PrEP eligibility prevalence and 11,363 participants with 17,381 follow-up visits and 30,721 person-years (pys) of observation to estimate HIV incidence. Overall, 29% met at least one of the eligibility criteria. HIV incidence was significantly higher in PrEP-eligible versus non-PrEP-eligible participants (0.91/100 pys versus 0.41/100 pys; P < 0.001) and independently higher in PrEP-eligible versus non-PrEP-eligible female participants (1.18/100 pys versus 0.50/100 pys; P < 0.001). Among uncircumcised male participants, HIV incidence was significantly higher in PrEP-eligible versus non-PrEP-eligible participants (1.07/100 pys versus 0.27/100 pys; P = 0.001), but there was no significant difference for circumcised male participants. Implementing PrEP as a standard HIV prevention tool in generalized HIV epidemics beyond currently recognized high-risk key populations could further reduce HIV acquisition and aid epidemic control efforts.


One- and two-dimensional solitons in second-harmonic-generating lattices.
In a model of a dynamical lattice with the on-site second-harmonic-generating nonlinearity and harmonic intersite couplings (that may be equal or different for the fundamental and second harmonics), various solitary-wave solutions are considered in one and two dimensions (1D and 2D). Fundamental (single-hump) solitons are identified in either dimension and their stability is examined and compared to previous results as well as to what is known for the model's continuum counterpart. Stability limits in terms of the coupling constants, which depend on the value of the phase-mismatch parameter, are found for solitons of the twisted-mode type in the 1D lattice, and for their counterparts of two different types (one being a discrete vortex) in the 2D lattice. When the twisted-mode soliton is unstable, the instability, which may be either oscillatory or due to imaginary eigenfrequency pairs, transforms the unstable soliton into a stable fundamental one, in both 1D and 2D cases.


Environmental and Seasonal Factors Affecting the Frost-induced Stage of Cold Acclimation in Cornus stolonifera Michx.
Stem tissues of red-osier dogwood (Cornus stolonifera Michx.) acclimated from -3 C to -40 or -50 C in 8 to 10 weeks under a short photoperiod (9 hours) and controlled temperature conditions. During the summer months plants did not acclimate as well as at other times. The sequence of day/night temperature regimes which induced maximum acclimation was 20/15 C for 5 to 6 weeks; 15/5 C for 2 to 3 weeks; 15/5 C plus 1 hour of frost per day for 1 week. The duration of exposure to each temperature regime influenced the rate and intensity of frost-induced acclimation. Less than 5 weeks of warm temperature preconditioning at 20/15 C reduced subsequent frost-induced acclimation. The inductive influence of frost on cold acclimation was additive over 5 days of repeated exposure, but its effects after the first exposure(s) were not immediate-requiring 1 to 4 days of 15/5 C following the frost treatments for the expression of the frost-induced acclimation to be manifest. There was a 75% increase in rRNA following 3 days of frost exposure and plants in an O(2)-free atmosphere during frost exposure failed to acclimate. The results suggest that seasonal acclimation behavior was due to endogenous rhythms rather than developmental stage, and that the frost-induced phase of acclimation involves aerobic metabolic processes.


Revealing the significance of chlorophyll b in the moss Physcomitrium patens by knocking out two functional chlorophyllide a oxygenase.
The chlorophyllide a oxygenase (CAO) plays a crucial role in the biosynthesis of chlorophyll b (Chl b). In the moss Physcomitrium patens (P. patens), two distinct gene copies, PpCAO1 and PpCAO2, are present. In this study, we investigate the differential expression of these CAOs following light exposure after a period of darkness (24 h) and demonstrate that the accumulation of Chl b is only abolished when both genes are knocked out. In the ppcao1cao2 mutant, most of the antenna proteins associated with both photosystems (PS) I and II are absent. Despite of the existence of LHCSR proteins and zeaxanthin, the mutant exhibits minimal non-photochemical quenching (NPQ) capacity. Nevertheless, the ppcao1cao2 mutant retains a certain level of pseudo-cyclic electron transport to provide photoprotection for PSI. These findings shed light on the dual dependency of Chl b synthesis on two CAOs and highlight the distinct effects of Chl b deprival on PSI and PSII core complexes in P. patens, a model species for bryophytes.


Continuous quantitative measurement of the proximal airway dimensions and lung density on four-dimensional dynamic-ventilation CT in smokers.
Four-dimensional dynamic-ventilation computed tomography (CT) imaging demonstrates continuous movement of the airways and lungs, which cannot be depicted with conventional CT. We aimed to investigate continuous changes in lung density and airway dimensions and to assess the correlation with spirometric values in smokers. This retrospective study was approved by the Institutional Review Board, and informed consent was waived. Twenty-one smokers including six patients with COPD underwent four-dimensional dynamic-ventilation CT during free breathing (160 mm in length). The mean lung density (MLD) of the scanned lung and luminal areas (Ai) of fixed points in the trachea and the right proximal bronchi (main bronchus, upper bronchus, bronchus intermedius, and lower bronchus) were continuously measured. Concordance between the time curve of the MLD and that of the airway Ai values was expressed by cross-correlation coefficients. The associations between these quantitative measurements and the forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) values were assessed by Spearman's rank correlation analysis. On the time curve for the MLD, the Δ-MLD1.05 values between the peak inspiratory frame to the later third frame (1.05 seconds later) were strongly correlated with the FEV1/FVC (ρ=0.76, P<0.0001). The cross-correlation coefficients between the airway Ai and MLD values were significantly correlated with the FEV1/FVC (ρ=-0.56 to -0.66, P<0.01), except for the right upper bronchus. This suggested that the synchrony between the airway and lung movement was lost in patients with severe airflow limitation. Respiratory changes in the MLD and synchrony between the airway Ai and the MLD measured with dynamic-ventilation CT were correlated with patient's spirometric values.


Current status of autologous breast tumor cell-based vaccines.
Approximately nine out of ten breast cancer-related deaths are attributable to metastasis. Yet, less than 4% of breast cancer patients are initially diagnosed with metastatic cancer. Therefore, the majority of breast cancer-related deaths are due to recurrence and progression of non-metastatic disease. There is tremendous clinical opportunity for novel adjuvant strategies, such as immunotherapies, that have the potential to prevent progressive recurrences. In particular, autologous tumor cell-based vaccines (ATCVs) can train a patient's immune system to recognize and eliminate occult disease. ATCVs have several advantages including safety, multivalency and patient specificity. Furthermore, because lumpectomy or mastectomy is indicated for the vast majority of breast cancer patients, resected tumors offer a readily available, patient-specific source of tumor antigen. Disadvantages of ATCVs include poor immunogenicity and production inconsistencies. This review summarizes recent progress in the development of autologous breast tumor vaccines and offers insight for overcoming existing limitations.


Suppression of cholangiocarcinoma cell growth by human umbilical cord mesenchymal stem cells: a possible role of Wnt and Akt signaling.
Emerging evidence indicates that human mesenchymal stem cells (hMSCs) can be recruited to tumor sites, and affect the growth of human malignancies. However, little is known about the underlying molecular mechanisms. Here, we observed the effects of hMSCs on the human cholangiocarcinoma cell line, HCCC-9810, using an animal transplantation model, and conditioned media from human umbilical cord-derived mesenchymal stem cells (hUC-MSCs). Animal studies showed that hUC-MSCs can inhibit the growth of cholangiocarcinoma xenograft tumors. In cell culture, conditioned media from hUC-MSCs inhibited proliferation and induced apoptosis of tumor cells in a dose- and time-dependent manner. The proliferation inhibition rate increased from 6.21% to 49.86%, whereas the apoptosis rate increased from 9.3% to 48.1% when HCCC-9810 cells were cultured with 50% hUC-MSC conditioned media for 24 h. Immunoblot analysis showed that the expression of phosphor-PDK1 (Ser241), phosphor-Akt (Ser 437 and Thr308), phosphorylated glycogen synthase kinase 3β (phospho-GSK-3β(Ser9)), β-catenin, cyclin-D1, and c-myc were down-regulated. We further demonstrated that CHIR99021, a GSK-3β inhibitor reversed the suppressive effects of hUC-MSCs on HCCC-9810 cells and increased the expression of β-catenin. The GSK-3β activator, sodium nitroprusside dehydrate (SNP), augmented the anti-tumor effects of hUC-MSCs and decreased the expression of β-catenin. IGF-1 acted as an Akt activator, and also reversed the suppressive effects of hUC-MSCs on HCCC-9810 cells. All these results suggest that hUC-MSCs could inhibit the malignant phenotype of HCCC-9810 human cholangiocarcinoma cell line. The cross-talk role of Wnt/β-catenin and PI3K/Akt signaling pathway, with GSK-3β as the key enzyme bridging these pathways, may contribute to the inhibition of cholangiocarcinoma cells by hUC-MSCs.


Exploring the association between overweight and dental caries among US children.
The purpose of this study was to examine the relationship between age-specific body mass index (BMI-for-age) and dental caries among US children. Body measures data and oral health data came from the 1999-2002 National Health and Nutrition Examination Survey. Outcome measures for primary and permanent dentitions were: (1) dental caries prevalence; and (2) severity (geometric mean dft and DMFT). Covariates included: (1) age; (2) gender; (3) race/ethnicity; and (4) poverty status. Analysis was limited to children 2 to 17 years old. Approximately 36% of overweight children 2 to 6 years old and 39% of overweight children 6 to 17 years old had dental caries. Geometric mean dental caries scores for overweight children were dft=3.3 and DMFT=2.5 for primary and permanent dentitions, respectively. Controlling for covariates, there was no significant association between BMI-for-age and dental caries prevalence in either dentition. In addition, among children with a positive history of dental caries, BMI-for-age was significantly associated with dental caries severity in the permanent dentition - overweight children had a lower geometric mean DMFT than did normal weight children. Although it was hypothesized that age-specific body mass index would be associated with increased dental caries prevalence and severity, these associations were not found. Rather, overweight was found to be associated with lower geometric mean DMFT. Future studies should address which factors specific to overweight in children might be protective against dental caries in the permanent dentition. Given the importance of overweight as a public health problem, however, clinicians are encouraged to continue providing health education and dietary counseling to their overweight child patients.


Percolation of binary disk systems: Modeling and theory.
The dispersion and connectivity of particles with a high degree of polydispersity is relevant to problems involving composite material properties and reaction decomposition prediction and has been the subject of much study in the literature. This work utilizes Monte Carlo models to predict percolation thresholds for a two-dimensional systems containing disks of two different radii. Monte Carlo simulations and spanning probability are used to extend prior models into regions of higher polydispersity than those previously considered. A correlation to predict the percolation threshold for binary disk systems is proposed based on the extended dataset presented in this work and compared to previously published correlations. A set of boundary conditions necessary for a good fit is presented, and a condition for maximizing percolation threshold for binary disk systems is suggested.


Relationship between post-systolic motion during dobutamine stress echocardiography and functional recovery of myocardium after successful percutaneous coronary intervention.
Doppler myocardial imaging (DMI) has been suggested as a method of quantifying inducible ischemia during dobutamine stress echocardiography (DSE). Post-systolic motion (PSM) detected by DMI is related to peri-infarct ischemia during DSE. We hypothesized that PSM during DSE would predict recovery of dysfunctional myocardium after successful percutaneous coronary intervention (PCI). Thirty patients with dysfunctional myocardium in the left anterior descending coronary artery (LAD) territory were divided into two groups according to improvement of wall motion score index (WMSI) in the LAD territory at 6 months after successful PCI of the LAD. DMI was evaluated in the LAD territory during DSE. Fifteen patients showed improved WMSI (1.42+/-0.39) while the other 15 had unchanged WMSI (1.75+/-0.46) 1 month after PCI. Myocardial velocity was measured in the mid-septal, apico-septal, and basal anterior segments of the LAD artery territory. PSM was defined as a positive wave appearing after the curve of systolic ejection had reached the zero line. Although there was no difference between resting PSMs in both groups, PSM during DSE was significantly higher in the improved WMSI group than in the WMSI group where it was unchanged. PSM during DSE predicts recovery of dysfunctional myocardium after successful PCI.


Delayed access to health care: risk factors, reasons, and consequences.
To determine characteristics of patients reporting delays in care before hospitalization and the reasons for those delays. Survey; personal interviews. Five hospitals in Massachusetts. Subjects were drawn from a consecutive sample of all adult patients (excluding obstetrics or psychiatry patients) hospitalized during the first 6 months of 1987 as part of a larger study of hospital costs. For the current study, if patients were re-admitted, we included in our analysis only data on the first admission during the study period. We obtained usable survey data from 12,068 of 17,231 eligible patients. Delays in care were reported by 16% of patients. The odds of reporting delays in care among patients who were black, poor, uninsured, or without a regular physician were 40% to 80% greater than those for other patients (P less than 0.01). Most patients who reported delays thought that their problem was not serious (64%). Cost was an important factor in delaying care for patients in lower socioeconomic positions; the odds of delaying care because of cost for patients who were both poor and uninsured were 12 times greater than the odds for other patients (P less than 0.001). After controlling for diagnosis-related groups (DRGs) and severity, patients who reported delays had 9% longer hospital stays compared with others (P less than 0.001). Patients generally thought to be disadvantaged are at especially high risk for delaying care for conditions that eventually lead to hospitalization. Because these delays are associated with longer hospital stays and potentially poorer health outcomes, interventions that reduce delays seem especially important.


Heme A synthase enzyme functions dissected by mutagenesis of Bacillus subtilis CtaA.
Heme A, as a prosthetic group, is found exclusively in respiratory oxidases of mitochondria and aerobic bacteria. Bacillus subtilis CtaA and other heme A synthases catalyze the conversion of a methyl side group on heme O into a formyl group. The catalytic mechanism of heme A synthase is not understood, and little is known about the composition and structure of the enzyme. In this work, we have: (i) constructed a ctaA deletion mutant and a system for overproduction of mutant variants of the CtaA protein in B. subtilis, (ii) developed anaffinity purification procedure for isolation of preparative amounts of CtaA, and (iii) investigated the functional roles of four invariant histidine residues in heme A synthase by in vivo and in vitro analyses of the properties of mutant variants of CtaA. Our results show an important function of three histidine residues for heme A synthase activity. Several of the purified mutant enzyme proteins contained tightly bound heme O. One variant also contained trapped hydroxylated heme O, which is a postulated enzyme reaction intermediate. The findings indicate functional roles for the invariant histidine residues and provide strong evidence that the heme A synthase enzyme reaction includes two consecutive monooxygenations.


Plasticity within Aldehyde Dehydrogenase-Positive Cells Determines Prostate Cancer Radiosensitivity.
Tumor heterogeneity and cellular plasticity are key determinants of tumor progression, metastatic spread, and therapy response driven by the cancer stem cell (CSC) population. Within the current study, we analyzed irradiation-induced plasticity within the aldehyde dehydrogenase (ALDH)-positive (ALDH+) population in prostate cancer. The radiosensitivity of xenograft tumors derived from ALDH+ and ALDH-negative (ALDH-) cells was determined with local tumor control analyses and demonstrated different dose-response profiles, time to relapse, and focal adhesion signaling. The transcriptional heterogeneity was analyzed in pools of 10 DU145 and PC3 cells with multiplex gene expression analyses and illustrated a higher degree of heterogeneity within the ALDH+ population that even increases upon irradiation in comparison with ALDH- cells. Phenotypic conversion and clonal competition were analyzed with fluorescence protein-labeled cells to distinguish cellular origins in competitive three-dimensional cultures and xenograft tumors. We found that the ALDH+ population outcompetes ALDH- cells and drives tumor growth, in particular upon irradiation. The observed dynamics of the cellular state compositions between ALDH+ and ALDH- cells in vivo before and after tumor irradiation was reproduced by a probabilistic Markov compartment model that incorporates cellular plasticity, clonal competition, and phenotype-specific radiosensitivities. Transcriptional analyses indicate that the cellular conversion from ALDH- into ALDH+ cells within xenograft tumors under therapeutic pressure was partially mediated through induction of the transcriptional repressor SNAI2. In summary, irradiation-induced cellular conversion events are present in xenograft tumors derived from prostate cancer cells and may be responsible for radiotherapy failure. The increase of ALDH+ cells with stem-like features in prostate xenograft tumors after local irradiation represents a putative cellular escape mechanism inducing tumor radioresistance.


Patients' satisfaction with primary heath care in kuwait after electronic medical record implementation.
This study aimed at assessing the level of patients' satisfaction with primary heath care services after implementation of the electronic medical record system (EMR). Also, to explore the relationship of some participants' characteristics with satisfaction which are of importance in planning, managing and evaluation. A descriptive cross-sectional approach was adopted. Ten primary health care centers (out of total 78) related to the five health regions in Kuwait were randomly selected. A random sample of 200 people (at age of 18 years and above) attending the two-shift periods of the chosen centers were included. Through an exit interview, a well trained investigator interviewed them about their satisfaction with the primary heath care services provided after implementation of electronic medical record system. A structured questionnaire for measuring satisfaction was used. The response rate was 93.02% of whom 47.5% were males and 52.5% were females. The mean overall satisfaction percent score as reported by subjects was 85.6% (SD 4.9). There were statistically significant associations between mean percent satisfaction score of the participants and their age, level of education visiting the center at morning shift, and waiting less than 10 minutes before the examination. The vast majority of participants indicated that overall service at the center had greatly improved after EMR implementation. The system also helped in improvement of the physician performance, arrangement of patient's turn, dispense medication from pharmacy, written guidance of medication, accuracy and easiness of follow up for health status, time spent to retrieve medical record and that for receiving medication. However, it didn't achieve much improvement in physician selection or waiting time. The majority of interviewees (96.5%) were totally satisfied with the overall quality of service at the center, location of the center (96.5%), hours when the center is open (96.5%), thoroughness of examination and accuracy of diagnosis (97.0%), advices to avoid illness (96.0%) and outcome of medical care (97.0%). However, the lowest items of satisfaction were those related to explanation of medical procedures and tests (46.5%) and ease of seeing physician of choice (61.0%). Almost 62.0% of the interviewed persons expressed their satisfaction with overall PHC service provided after EMR implementation. The leading two items of dissatisfaction that showed by the majority of dissatisfied participants were non-compliance of physician with good practice in prescription writing (75.0%) and inability to see the same physician in every visit (72.4%). The results showed that although the overall satisfaction was relatively high, certain aspects of the service showed some degree of dissatisfaction. This study demonstrated patient acceptance and support for the electronic medical record system at the primary care setting. These findings should encourage physicians to promote the use of electronic medical record system.


Self-Assembled Donor-Acceptor Dyad Molecules Stabilize the Heterojunction of Inverted Perovskite Solar Cells and Modules.
The heterointerface between a semiconducting metal oxide and a perovskite critically impacts on the overall performance of perovskite solar cells (PVSCs). Herein, we report a feasible yet effective strategy to suppress the interfacial reaction between nickel oxide and the perovskite via chemical passivation with self-assembled dyad molecules, which leads to the simultaneous improvement of the power conversion efficiencies (PCEs) and operational lifetimes of inverted PVSCs. As a result, inverted PVSCs consisting of simple methylammonium iodide perovskites have achieved an excellent PCE of 20.94% and decent photostability with 93% of the initial value after 600 h of 1 sun equivalent illumination. Moreover, this strategy can be readily translated into slot-die fabrication of perovskite modules, achieving a high PCE of 14.90% with an area of 19.16 cm2 (no shade in the interconnecting area) and a geometrical fill factor of 93%. Overall, this work provides an effective strategy to stabilize the vulnerable heterointerface in PVSCs.


[Twice-daily and weekly exenatide: Clinical profile of two pioneer formulations in incretin therapy].
GLP-1 receptors agonists have been a substantial change in treatment of type 2 diabetes mellitus, and its weekly administration has broken pre-established schemes. Daily exenatide is administered every 12 hours (BID) subcutaneously, while weekly exenatide is administered once a week. Both molecules share a common mechanism of action but have differential effects on basal and postprandial glucose. We review the major clinical trials with both exenatide BID and weekly exenatide. It can be concluded that exenatide BID shows a hypoglycemic effect similar to other treatments for type 2 DM but adding significant weight loss with low incidence of hypoglycemia. Weekly exenatide decreases HbA1c similar to liraglutide but larger than exenatide BID, both glargine and biphasic insulin, sitagliptin, and pioglitazone, maintaining weight loss and adding to gastrointestinal intolerance the induration at the injection site as a side effect.


Combined numerical and experimental approach to determine numerical model of abdominal scaffold.
A proper junction of the prosthesis and the abdominal wall is important in successful hernia repair. The number of tacks should be balanced to assure appropriate mesh fixation and not to induce post-operative pain. Numerical simulations help to find this balance. The study is aimed at creating a proper numerical model of a knitted surgical mesh subjected to boundary conditions and load occurring in the abdominal cavity. Continuous, anisotropic constitutive relation is considered to reflect the mesh behaviour. Different sets of material law parameters are determined on the basis of different bi-axial tests setups. Force- and displacement-controlled tests with different ratios are considered. Consequently, some numerical model variants are obtained featuring various reaction distributions in the scaffold fixation points. The proper variant is selected based on comparison of the position of maximal reaction force in the numerical model and in the reference physical model of operated hernia. Force-driven tests have shown anisotropic mesh behaviour, while equibiaxial displacement-driven test has demonstrated reduced anisotropic response. Within seven scenarios of constitutive parameters identification (based on single or combined experimental data), the equibiaxial force-controlled test appeared to produce the most relevant model to follow the prosthesis behaviour under pressure. The position of maximal reaction force in such model is similar to obtained in the physical hernia model. The equibiaxial force-driven test provides most suitable data for Gasser-Ogden-Holzapfel constitutive model identification of a considered surgical mesh to be used to model the mesh under pressure.


Neurobiological structure of the revised limit cycle reciprocal interaction model of REM cycle control.
New data bearing on the neurobiological basis of REM sleep and on mechanisms of EEG synchronization/desynchronization are presented. The revision of the limit cycle reciprocal interaction model (LCRIM) of REM cycle control incorporates new information on monoamine inhibition of mesopontine cholinergic neurons and of cholinergic mechanisms promoting REM sleep. New data also show cortical slow-wave activity is controlled by thalamocortical neurons' membrane potential level, which, in turn, is strongly controlled during sleep by brainstem cholinergic input arising from REM-on neurons. This new knowledge leads to a neurobiologically justified integration of the LCRIM and of the two-process model of sleep control.


Fine-needle aspiration cytology of metastatic ovarian carcinoma to the breast.
Metastatic ovarian carcinoma to the breast is rare. It represents a diagnostic challenge to the cytologist. It usually signifies a progressive widespread metastatic ovarian tumor with a poor prognosis. This report evaluates the breast fine-needle aspiration (FNA) cytomorphologic features of six cases of metastatic ovarian carcinoma and compares them to those reported in the literature. The cytologic features included hypercellularity, abundant papillary fragments, and necrotic background. The tumor cells showed high nuclear/cytoplasmic ratio, anisonucleosis, prominent nucleoli, and psammoma bodies in cases of serous papillary carcinoma. In addition, the clear-cell carcinoma had prominent finely vacuolated and clear cytoplasm, multinucleated giant cells, and papillary fragments with hobnail nuclei. Recognition of these unusual patterns in a breast FNA cytology should raise the suspicion of a metastatic ovarian tumor. Direct comparison between the breast FNA cytology and the original primary ovarian tumor should confirm the diagnosis. The proper diagnosis of metastatic ovarian cancer to the breast will prevent unnecessary surgical treatment and ensure the appropriate therapy.


[Change of cardiac mitochondrial STAT3 activity in rats with selenium deficiency and its relation with myocardial injury].
To study the phosphorylation activity of mitochondrial signal transducer and activator of transcription 3 (STAT3) in the myocardium of rats with selenium deficiency and its association with myocardial injury. Thirty-six rats were randomized into normal control group (n=18) and selenium deficiency model group (n=18) for feeding with normal and low-selenium chow, respectively, for 20, 30 and 40 weeks. The cardiac function of the rats was evaluated by carotid artery intubation, and the damage of cardiac mitochondria was observed under electron microscopy. The cardiac mitochondria were extracted for assessing succinate dehydrogenase and cytochrome C oxidase activities, and the protein expressions of phosphorylated and total STAT3 were detected. Compared with the corresponding control groups, the rats in the model group showed significantly decreased cardiac function with obvious structural and functional damage of the cardiac mitochondria (P<0.05), which aggravated as the low-selenium feeding time extended (P<0.05). The rats in the model group also showed significantly decreased mitochondrial STAT3 activity (p-STAT3/STAT3) in the myocardium as the low-selenium feeding time prolonged (P<0.05). Pearson linear correlation analysis showed that the activity of cardiac mitochondrial STAT3 had positive correlations with the left ventricular systolic pressure, maximal increased rate of the left ventricular pressure, and the activities of succinate dehydrogenase and cytochrome C oxidase (P<0.01). Selenium deficiency down-regulates the activity of mitochondrial STAT3 in rat heart to contribute to cardiac mitochondrial injury and the progression of heart failure.


Caldesmon: a bifunctional (calmodulin and actin) binding protein which regulates stimulated gonadotropin release.
Calmodulin (CaM) serves as an intracellular Ca2+ receptor in the gonadotrope and appears to mediate GnRH-stimulated gonadotropin release. Recently we have specifically identified three CaM binding proteins of the gonadotrope as calcineurin, caldesmon, and spectrin. Caldesmon (identified by seven polyclonal and a monoclonal antibody, as well as by functional characteristics) appears to be a CaM-regulated, F-actin binding, protein. This 84,000 mol wt component (CaD84) is heat stable and cosediments with F-actin in the absence of Ca2+. In the presence of Ca2+ (greater than 1 microM) this protein disassociates from F-actin and reassociates with calmodulin. We have prepared an antibody which blocks the caldesmon-actin interaction. In the present study, we have loaded this antibody into cells to prevent the (re-)association of caldesmon with F-actin. This treatment synergistically augments the ability of GnRH and other secretogogues (maitotoxin, phorbol myristyl acetate) to stimulate gonadotropin release from the pituitary. This finding, along with the previous observations that GnRH provokes a sufficient rise in intracellular Ca2+ to allow CaM to redistribute and bind proteins which it regulates, suggests a role for caldesmon in GnRH-stimulated gonadotropin release from the pituitary.