Action of natural phytosanitary products on Bacillus thuringiensis subsp. kurstaki S-1905.
The objective of this study was to evaluate the effects of natural phytosanitary products (NPs) on spores and crystals of Bacillus thuringiensis subsp. kurstaki S-1905 (Btk S-1905). For the spore assay, NPs and bacteria were applied in combination and individually. For the combined application, Btk S-1905 + NP mixtures were inoculated on nutrient agar (NA), and for the separate applications, the NPs were spread on NA plates, which were later inoculated with the pathogen. The number of colony-forming units (CFU) per milliliter was quantified after 18 h of incubation. For the crystal protein degradation assay, the Btk S-1905 + NP mixtures were added to the diet of Anticarsia gemmatalis (Lepidoptera: Erebidae), and mortality was evaluated at the following time points: 12, 24, 48, and 72 h. Scanning electron microscopy and agarose gel electrophoresis were carried out. Biogermex and Ecolife® reduced the CFU ml-1 in both combined and separate applications. Biogermex, Ecolife®, and Planta Clean were antagonistic to the action of bacterial toxins, and no product affected the morphology or resulted in the degradation of the crystal proteins. The remaining products evaluated did not reduce the CFU ml-1 and had additive effect when combined with the crystal toxin.


THE EMERGING ROLE OF ADJUNCTIVE NONINSULIN ANTIHYPERGLYCEMIC THERAPY IN THE MANAGEMENT OF TYPE 1 DIABETES.
Review available data on adjunctive therapies for type 1 diabetes (T1D), with a special focus on newer antihyperglycemic agents. Published data on hypoglycemia, obesity, mortality, and goal attainment in T1D were reviewed to determine unmet therapeutic needs. PubMed databases and abstracts from recent diabetes meetings were searched using the term "type 1 diabetes" and the available and investigational sodium-glucose cotransporter (SGLT) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 inhibitors, and metformin. The majority of patients with T1D do not meet glycated hemoglobin (A1C) goals established by major diabetes organizations. Hypoglycemia risks and a rising incidence of obesity and metabolic syndrome featured in the T1D population limit optimal use of intensive insulin therapy. Noninsulin antihyperglycemic agents may enable T1D patients to achieve target A1C levels using lower insulin doses, which may reduce the risk of hypoglycemia. In pilot studies, the SGLT2 inhibitor dapagliflozin and the GLP-1 receptor agonist liraglutide reduced blood glucose, weight, and insulin dose in patients with T1D. Phase 2 studies with the SGLT2 inhibitor empagliflozin and the dual SGLT1 and SGLT2 inhibitor sotagliflozin, which acts in the gut and the kidney, have demonstrated reductions in A1C, weight, and glucose variability without an increased incidence of hypoglycemia. Newer antihyperglycemic agents, particularly GLP-1 agonists, SGLT2 inhibitors, and dual SGLT1 and SGLT2 inhibitors, show promise as adjunctive treatment for T1D that may help patients achieve better glucose control without weight gain or increased hypoglycemia.


The neuroprotective effect of ladostigil against hydrogen peroxide-mediated cytotoxicity.
The multifunctional, anti-Alzheimer drug, ladostigil (TV3326) [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate] combines the neuroprotective effects of the anti-Parkinson drug, rasagiline, a selective monoamine oxidase (MAO)-B inhibitor, with the cholinesterase (ChE) inhibitory activity of rivastigmine in a single molecule. Ladostigil has been shown to possess potent antiapoptotic and neuroprotective activities in various oxidative insults in vitro and in vivo, such as prevention of the fall in mitochondrial membrane potential and regulation of Bcl-2 family proteins. In the present study, we demonstrate that ladostigil (1 microM) increased cell viability, associated with the increase of catalase activity and decrease of intracellular reactive oxygen species (ROS) production in human SH-SY5Y neuroblastoma cells exposed to (hydrogen peroxide) H(2)O(2). Furthermore, ladostigil significantly elevated mRNA levels of the antioxidants enzymes, catalase, NAD(P)H quinone oxidoreductase 1 (NQO1) and peroxiredoxin 1 (Prx 1) in H(2)O(2)-treated SH-SY5Y cells. Chronic treatment with ladostigil (1 mg/kg gavage per day for 30 days) markedly up-regulated mRNA expression levels of various antioxidant enzymes in aged rat hippocampus (e.g. glutathione peroxidase precursor (GSHPX-P), glutathione S-transferase (GST) and glucose-6-phosphate dehydrogenase (G6PD)). These findings indicate that in addition to its multiple neuroprotective characteristics, ladostigil also possesses antioxidant properties, which might be beneficial for the treatment of oxidative stress (OS) in aging and age-associated neurodegenerative diseases.


Molecular chaperones in stroke-induced immunosuppression.
Stroke-induced immunosuppression is a process that leads to peripheral suppression of the immune system after a stroke and belongs to the central nervous system injury-induced immunosuppressive syndrome. Stroke-induced immunosuppression leads to increased susceptibility to post-stroke infections, such as urinary tract infections and stroke-associated pneumonia, worsening prognosis. Molecular chaperones are a large class of proteins that are able to maintain proteostasis by directing the folding of nascent polypeptide chains, refolding misfolded proteins, and targeting misfolded proteins for degradation. Various molecular chaperones have been shown to play roles in stroke-induced immunosuppression by modulating the activity of other molecular chaperones, cochaperones, and their associated pathways. This review summarizes the role of molecular chaperones in stroke-induced immunosuppression and discusses new approaches to restore host immune defense after stroke.


Separation and structure elucidation of a new homoflavanol derivative from Pteridium aquilinum (L.) Kuhn.
A novel homoflavanol derivative (1) with an unprecedented skeleton, as well as two known flavonoids kaempferol (2) and quercetin (3), was isolated from the plant Pteridium aquilinum (L.) Kuhn, and the structure and relative stereochemistry of the new compound (1) were elucidated on the basis of spectroscopic data.


Venous infarction of the adrenal glands.
An investigation of 78 cases of adrenal haemorrhage and necrosis disclosed that 32 were examples of adrenal venous infarction. In all these cases there was thrombosis of the main adrenal vein and in most there was also thrombosis of the capsular veins, a finding which has not been well established. In a number of cases with venous infarction there was clinical and pathological evidence that disseminated intravascular coagulation (DIC) had occurred, but it appears that it was not the direct cause of venous thrombosis. The majority of cases of venous infarction occur in patients with severe infection, frequently of the respiratory tract. Venous infarction was found in five cases with hypothermia an association which had rarely been described, and in three of these there was evidence of DIC. This is apparently the first occasion on which DIC has been demonstrated in cases of hypothermia in man. The cause of venous thrombosis in the adrenal glands is obscure in most cases of venous infarction, although in three it was due to involvement by metastatic carcinoma. It is suggested that the factors responsible for the initiation of thrombosis in the adrenal veins are catecholamines, thrombin, fibrin and endotoxin. Localisation of the thrombi to the adrenal vein is due to the unique anatomical structure of the vein which, under certain circumstances, results in the local stasis of blood.


Comparative standards of evidence in social work.
In this article the authors analyze relevant and reliable evidence on the effects of the preferable treatment customized to each social work client. In doing so, the authors look at four major standards of evidence: (1) evidence-based practice, (2) collaboration models (i.e., the Cochrane Collaboration and the Campbell Collaboration), (3) knowledge translation, and (4) the Social Work Article Club. The ultimate goal of these standards of evidence is to successfully transfer research into practice. Currently, there is a gap between research and practice as a result of a lack of collaboration. Most social workers do not possess the skills to implement change in practice based on research evidence. The authors' objective is to increase understanding by instilling, in part, positive feelings toward research.


[A case of advanced gastric cancer which disappeared histopathologically after short-time chemotherapy].
Poorly differentiated adenocarcinoma was confirmed by endoscopic biopsy. Anticancer therapy was performed preoperatively, but was discontinued after the second intravenous administration of MFC because she developed nausea, vomiting and pancytopenia. On Jan. 18, 1980, gastrectomy with extended lymph node dissection was performed. Histologically, the excised stomach showed non-specific active ulcer (ul-IV) at the side of the tumor without evidence of residual cancer cells. The cause for the disappearance of the advanced carcinoma remains unknown. Although the dosage of the anticancer chemotherapy was quite small, this treatment may have promoted the regression of the tumor in conjunction with activated antitumor immunity of the host.


[Decision making process in oncology: rationale and delineation of a composite index of relative antitumoral efficacy (In-RATE)].
Over the last decade, the development of new therapeutic options has made more patients benefit from antitumoral strategies including several lines of chemotherapy, the aim of which is a long-term control of the disease progression. In such a context of "chronic" management, the choice of tumor response as a single parameter appears restrictive to assess those new therapeutic options. For that reason, we have recently proposed a composite index of relative efficacy including response rate as well as parameters related to tumour stabilization and duration of the response. The objective of this index, published as the In-RATE is to allow the comparison of two treatments a and b as follows: In-RATE a/b = (response rate a/response rate b) x (time to progression a/time to progression b) x (progression rate b/progression rate a). Values significantly higher or less than 1 suggest the superiority, in terms of efficacy, of treatments a or b, respectively. When retrospectively applied to randomised studies, the In-RATE showed that some results and conclusions based on the response rate as a unique endpoint might be reconsidered, and that a significant difference between protocols could be detected in published reports having concluded to statistical equivalence. This paper reviews the rationale and principle of this work, and discusses the potential clinical applications of the In-RATE.


Indications of total ankle arthroplasty for rheumatoid arthritis: evaluation at 5 years or more after the operation.
Abstract The postoperative results of total ankle arthroplasty (TAA) were surveyed, and the indications of TAA for rheumatoid arthritis (RA) were examined. We have performed TAA in properly selected patients with indication of ankle joint destruction due to RA. The subjects were 18 RA patients (20 joints) who underwent TAA between April 1988 and April 1996. Type-ND or type-TNK Bioceram was used without cement for possible revision of TAA. No destruction of large joints was found in 8 patients, and TAA was used as part of multiple arthroplasty in 10 patients. After the operation, decrease in or disappearance of joint pain was obtained, and range of motion and improved ability to walk were secured. The clinical results were superior to those obtained for 17 joints of 17 patients who underwent ankle arthrodesis during the same period. However, a radiolucent zone was observed an X-ray examination in every case, after 8 years on average (range 5-12 years) after operation. Under present conditions, ankle arthrodesis should be used for younger patients. When no destruction of the hip or knee joint is found and the patient is 65 years of age or older, we believe TAA is indicated. In cases of multiple arthroplasty or with bilateral ankle joint destruction, TAA appears to be useful if patients are young, considering their better life expectancy and quality of life.


Unmet need in the treatment of postherpetic neuralgia.
The efficacy of first-line therapeutic agents for postherpetic neuralgia (PHN) has been established in randomized, controlled clinical trials. However, pain in PHN is often refractory to treatment. Many of the patients with PHN are elderly, with additional issues of polypharmacy and comorbidity. They experience various types of pain, suggesting that more than 1 pathophysiologic pain mechanism is involved. PHN adversely affects health-related quality of life. Up to this point, no single best treatment has been identified for PHN. Pharmacological treatments for PHN are inadequate, and many patients are undertreated. Suboptimal treatment can be related to intolerable side effects of medications, long titration periods to reach the effective dosage, inadequate dosing, poor compliance with dosing schedules, and low treatment satisfaction. Inadequate therapeutic response leads more than half the patients with PHN treated with either gabapentin or pregabalin to switch to another class of medication, and more than 30% of patients to add on another class of medication. Safety and tolerability are important considerations in therapy, especially in the elderly. Few patients with PHN and physicians are satisfied with the currently available treatments. Thus, the effective management of postherpetic neuralgia remains an ongoing challenge. New and improved treatment options are therefore needed for the effective management of PHN.


Utilizing a Spiro Core with Acridine- and Phenothiazine-Based New Hole Transporting Materials for Highly Efficient Green Phosphorescent Organic Light-Emitting Diodes.
Two new hole transporting materials, 2,7-bis(9,9-diphenylacridin-10(9H)-yl)-9,9' spirobi[fluorene] (SP1) and 2,7-di(10H-phenothiazin-10-yl)-9,9'-spirobi[fluorene] (SP2), were designed and synthesized by using the Buchwald-Hartwig coupling reaction with a high yield percentage of over 84%. Both of the materials exhibited high glass transition temperatures of over 150 °C. In order to understand the device performances, we have fabricated green phosphorescent organic light-emitting diodes (PhOLEDs) with SP1 and SP2 as hole transporting materials. Both of the materials revealed improved device properties, in particular, the SP2-based device showed excellent power (34.47 lm/W) and current (38.41 cd/A) efficiencies when compare with the 4,4'-bis(N-phenyl-1-naphthylamino)biphenyl (NPB)-based reference device (30.33 lm/W and 32.83 cd/A). The external quantum efficiency (EQE) of SP2 was 13.43%, which was higher than SP1 (13.27%) and the reference material (11.45%) with a similar device structure. The SP2 hole transporting material provides an effective charge transporting path from anode to emission layer, which is explained by the device efficiencies.


Inhibition of enzyme function by human autoantibodies to an autoantigen pyruvate dehydrogenase E2: different epitope for spontaneous human and induced rabbit autoantibodies.
Antibodies to the mitochondrial autoantigen M2, characteristic of the autoimmune liver disease primary biliary cirrhosis (PBC), react with the E2 subunit of the pyruvate dehydrogenase enzyme (PDH-E2). We examined the effect of disease sera on the enzyme activation catalysed by the PDH complex. Inhibition of enzyme activity was observed in 19 of 24 sera of patients with PBC with a level of greater than 90% inhibition in 14 at a serum dilution of 1/50. The onset of inhibition by serum was rapid, within the time of mixing, and the inhibitory activity was shown to reside in the immunoglobulin fraction of the serum. The immunoglobulin fraction of control sera from patients with other liver diseases (n = 26) and healthy persons (n = 8) failed to produce inhibitory activity. In addition sera from four rabbits, intensively immunized with a recombinant human M2 autoantigen, gave anti-M2 reactions by fluorescence, ELISA and immunoblotting, but did not inhibit the activity of PDH. The failure of experimentally induced M2 antibodies in rabbits to inhibit is interesting in view of the reactivity of the natural M2 autoantibodies of PBC with the highly conserved site on the enzyme which carries the essential lipoic acid cofactor.


Prevention of TNF-alpha-induced apoptosis in polyamine-depleted IEC-6 cells is mediated through the activation of ERK1/2.
It has been documented that polyamines play a critical role in the regulation of apoptosis in intestinal epithelial cells. We have recently reported that protection from TNF-alpha/cycloheximide (CHX)-induced apoptosis in epithelial cells depleted of polyamines is mediated through the inactivation of a proapoptotic mediator, JNK. In this study, we addressed the involvement of the MAPK pathway in the regulation of apoptosis after polyamine depletion of IEC-6 cells. Polyamine depletion by alpha-difluromethylornithine (DFMO) resulted in the sustained activation of ERK in response to TNF-alpha/CHX treatment. Pretreatment of polyamine-depleted IEC-6 cells with a cell membrane-permeable MEK1/2 inhibitor, U-0126, significantly inhibited TNF-alpha/CHX-induced ERK phosphorylation and significantly increased DNA fragmentation, JNK activity, and caspase-3 activity in response to TNF-alpha/CHX. Moreover, the dose dependency of U-0126-mediated inhibition of TNF-alpha/ CHX-induced ERK phosphorylation correlated with the reversal of the antiapoptotic effect of DFMO. IEC-6 cells expressing constitutively active MEK1 had decreased TNF-alpha/CHX-induced JNK phosphorylation and were significantly protected from apoptosis. Conversely, a dominant-negative MEK1 resulted in high basal activation of JNK, cytochrome c release, and spontaneous apoptosis. Polyamine depletion of the dominant-negative MEK1 cells did not prevent JNK activation or cytochrome c release and failed to confer protection from both TNF-alpha/CHX and camptothecin-induced apoptosis. Finally, expression of a dominant-negative mutant of JNK significantly protected IEC-6 cells from TNF-alpha/CHX-induced apoptosis. These data indicate that polyamine depletion results in the activation of ERK, which inhibits JNK activation and protects cells from apoptosis.


Impact of unhealthy childhood and unfavorable parents' characteristics on adiposity in schoolchildren.
Childhood obesity is encouraged by low physical activity (PA), time spent using screens (screen time, ST), and by sugar-sweetened beverage consumption (SSBc). It is also influenced by unfavorable parents' characteristics, such as a high body mass index (BMI) and low education level (EL). Our aim was to evaluate the overall and specific influence of these factors on childhood adiposity. Anthropometric parameters including BMI z-score, waist circumference (WC), waist to height ratio (WtHR), and fat mass were measured in a cohort of 1702 schoolchildren (6.0-14.5 years, mean 10.7 ± 1.8) and questionnaires concerning children's PA, ST, and SSBc, and parent's BMI and EL were administered to parents. Overweight/obesity prevalence was higher (P < .0001) in males (57%) than in females (43%). Less physically active children (28.9%) had a higher prevalence of overweight/obesity and higher BMI z-score, WC, WtHR, and fat mass relative to more physically active children (P < .05). PA was negatively associated with the BMI z-score (r = 0.18, P < .0001) and fat mass percentage (r = 0.18, P < .0001). Children with more ST had higher WC and WtHR than non-ST viewers (P < .05) but not BMI. Moreover, SSBc did not influence the anthropometric parameters. At multivariate analysis, male gender, less PA, and parental risk factors (parent's overweight/obesity and low/medium EL) were independently associated with overweight and obesity among childhood with a progressively increasing odds ratio (1.65, 1.40, and 1.80, respectively). Male gender, behavioral risk factors (particularly low PA), and parent's characteristics are important correlates of obesity in children.


Patient preferences and treatment adherence among women diagnosed with metastatic breast cancer.
Given the various profiles (eg, oral vs intravenous administration, risk of hot flashes vs fatigue) of treatment options (eg, endocrine therapy, chemotherapy) for metastatic breast cancer (mBC), how patients value these attributes of their medications has implications on making treatment decisions and on adherence. To understand how patients trade off medication side effects with improved effectiveness and/or quality of life, to provide estimates of nonadherence among women with mBC, and to quantify the association of medication nonadherence with health outcomes. The study was a cross-sectional, Internet-based survey of 181 women diagnosed with mBC who were recruited from cancer-specific online panels (response rate, 7%). Treatment information, demographics, nonadherent behaviors, and quality of life assessed by the Functional Assessment of Cancer Therapy-Breast (FACT-B) were collected in the survey, and each respondent completed a choice-based conjoint exercise to assess patient preferences. The patients' preferences were analyzed using hierarchical Bayesian logistic regression models, and the association between the number of nonadherent behaviors and the health outcomes was analyzed using general linear models. The mean age of the patient sample was 52.2 years (standard deviation, ±9.1), with 93.9% of participants being non-Hispanic white. Results from the conjoint model indicated that effectiveness (overall survival) was of primary importance to patients, followed by side effects-notably alopecia, fatigue, neutropenia, motor neuropathy, and nausea/vomiting-and finally, dosing regimen. In all, 34.8% of survey respondents either discontinued their treatment or were nonadherent to their treatment regimen. Among those who have ever used oral chemotherapy (N = 95; 52.5%) and those currently using oral chemotherapy (N = 44; 24.3%), the number of nonadherent behaviors was significantly associated with a decrease in functional well-being (b [unstandardized regression coefficient] = -2.01 for patients who had ever used a targeted therapy and b = -3.14 for current users of a targeted therapy), FACT-General total score (b = -4.30 and b = -7.37, respectively), FACT-B total score (b = -3.93 and b = -6.11, respectively), and FACT trial outcome index (b = -5.22 and b = -8.63, respectively; all P <.05). Patients were willing to accept substantial additional risks from side effects for gains in overall survival. Approximately 33% of women with mBC reported engaging in nonadherent behaviors. Because forgetfulness and adverse events were among the most frequent reasons for nonadherence, these results suggest that less complex treatment regimens, as well as regimens with less toxic profiles, may be associated with improvements in adherence and, subsequently, could correspond to perceptible patient benefits.


Proteomics approach to identify dehydration responsive nuclear proteins from chickpea (Cicer arietinum L.).
Dehydration or water-deficit is one of the most important environmental stress factors that greatly influences plant growth and development and limits crop productivity. Plants respond and adapt to such stress by altering their cellular metabolism and activating various defense machineries. Mechanisms that operate signal perception, transduction, and downstream regulatory events provide valuable information about the underlying pathways involved in environmental stress responses. The nuclear proteins constitute a highly organized, complex network that plays diverse roles during cellular development and other physiological processes. To gain a better understanding of dehydration response in plants, we have developed a comparative nuclear proteome in a food legume, chickpea (Cicer arietinum L.). Three-week-old chickpea seedlings were subjected to progressive dehydration by withdrawing water and the changes in the nuclear proteome were examined using two-dimensional gel electrophoresis. Approximately 205 protein spots were found to be differentially regulated under dehydration. Mass spectrometry analysis allowed the identification of 147 differentially expressed proteins, presumably involved in a variety of functions including gene transcription and replication, molecular chaperones, cell signaling, and chromatin remodeling. The dehydration responsive nuclear proteome of chickpea revealed a coordinated response, which involves both the regulatory as well as the functional proteins. This study, for the first time, provides an insight into the complex metabolic network operating in the nucleus during dehydration.


Eco-friendly synthesized nanoparticles as antimicrobial agents: an updated review.
Green synthesis of NPs has gained extensive acceptance as they are reliable, eco-friendly, sustainable, and stable. Chemically synthesized NPs cause lung inflammation, heart problems, liver dysfunction, immune suppression, organ accumulation, and altered metabolism, leading to organ-specific toxicity. NPs synthesized from plants and microbes are biologically safe and cost-effective. These microbes and plant sources can consume and accumulate inorganic metal ions from their adjacent niches, thus synthesizing extracellular and intracellular NPs. These inherent characteristics of biological cells to process and modify inorganic metal ions into NPs have helped explore an area of biochemical analysis. Biological entities or their extracts used in NPs include algae, bacteria, fungi, actinomycetes, viruses, yeasts, and plants, with varying capabilities through the bioreduction of metallic NPs. These biosynthesized NPs have a wide range of pharmaceutical applications, such as tissue engineering, detection of pathogens or proteins, antimicrobial agents, anticancer mediators, vehicles for drug delivery, formulations for functional foods, and identification of pathogens, which can contribute to translational research in medical applications. NPs have various applications in the food and drug packaging industry, agriculture, and environmental remediation.


Effect of Previous Lower Abdominal Surgery on Outcomes Following Totally Extraperitoneal (TEP) Inguinal Hernia Repair.
Previous lower abdominal surgery is generally considered as a relative contraindication for laparoscopic totally extraperitoneal (TEP) inguinal hernia repair. Our objective was to investigate the feasibility and safety of TEP repair in patients with a history of lower abdominal surgery. A retrospective analysis of 301 patients with inguinal hernia who underwent elective laparoscopic TEP repair between August 2010 and August 2014 was conducted. One-hundred five patients (34.9%) had previously undergone lower abdominal surgery. The main outcome measures included intraoperative and postoperative morbidity and mortality. Secondary outcomes were immediate postoperative pain, presence of chronic pain at follow-up, and hernia recurrence. Patient demographics and clinical variables were balanced between the 2 groups, with the exception of age. Intraoperative morbidity was similar between cases without previous lower abdominal surgery (nPS) and cases with history of lower abdominal surgery (PS) [nPS vs. PS: 0.5% (n=1) vs. 2.8% (n=3), P=0.09]. Overall 30-day morbidity was found to be significantly higher in the PS patient group [nPS vs. PS: 1.5% (n=3) vs. 6.6% (n=7), P=0.018]. Mortality was nil. There were no differences noted between the 2 groups with respect to early postoperative pain and chronic inguinal pain. Complete follow-up information was available for 149 of 301 patients (follow-up rate of 49.5%, range: 3 to 48 mo) with a mean follow-up time of 20.38 months (SD=7.7). There was no statistically significant difference noted in the recurrence rate between the 2 patient groups at follow-up [nPS vs. PS: 3.2% (n=3) vs. 1.8% (n=1), P=0.6]. The present work demonstrates higher incidence of postoperative scrotal hematoma after TEP repair in patients with history of previous lower abdominal surgery. All remaining outcomes of interest were found to be similar between the 2 patient groups. Further trials will be needed to verify our findings.


A method for construction of long randomized open reading frames and polypeptides.
A method is presented for construction of randomized open reading frame sequences (ORFs) and gene libraries containing them. The building blocks for the ORFs were 75 bp long DNA fragments generated by cloning sequences from a single synthetic oligonucleotide preparation by bridge mutagenesis. The fragments had the property that, regardless of their orientation in the ligated product, the ORF of the construct was maintained. The heterogeneity of the ORFs resulted from the random ligation of 2000 different DNA fragments. The randomized ORFs were cloned downstream from the lac promoter in a multicopy plasmid in Escherichia coli. To test the method, a library of 10(6) clones was constructed.


Intellectual decline after stroke: the Framingham Study.
The causes and characteristics of cognitive decline after stroke are poorly defined, because most studies have relied on the diagnosis of dementia after stroke, without measurement of prestroke cognitive function. The Mini-Mental State Examination (MMSE) was used to assess the cognitive performance of 74 subjects from the Framingham Study cohort who had suffered a stroke during a 13-year period. We compared their poststroke cognitive performance with the prestroke MMSE scores collected during their biennial examinations, and their prestroke/poststroke changes in MMSE score were then compared with those of 74 control subjects matched for age and sex. Cases and controls underwent testing for symptoms of depression using the Center for Epidemiologic Studies of Depression (CES-D) scale, and these findings were correlated with their cognitive performance. Changes in cognitive performance in the cases were correlated with the CT-documented characteristics of the stroke. The cases had a significantly lower mean+/-SE MMSE score at prestroke baseline (27.28+/-0.34) than did the control subjects (28.08+/-0.21), a difference that became more pronounced (23.57+/-0.92 versus 28.31+/-0.25; P<.001) after stroke. The poststroke decline in cognitive function in the cases was correlated only with a large, left-sided stroke on CT. The CES-D scores were significantly higher in the cases, but nondepressed cases had significantly lower MMSE scores than nondepressed controls. Stroke is followed by a significant decline in cognitive performance when prestroke and poststroke measurements are compared. Although depression is more frequent in the stroke patients, their intellectual decline appears to be independent from the presence of depression.


Live-pig-airway surface imaging and whole-pig CT at the Australian Synchrotron Imaging and Medical Beamline.
The Australian Synchrotron Imaging and Medical Beamline (IMBL) was designed to be the world's widest synchrotron X-ray beam, partly to enable clinical imaging and therapeutic applications for humans, as well as for imaging large-animal models. Our group is currently interested in imaging the airways of newly developed cystic fibrosis (CF) animal models that display human-like lung disease, such as the CF pig. One key outcome measure for assessing the effectiveness of CF airway therapies is the ability of the lung to clear inhaled particulates by mucociliary transit (MCT). This study extends the ex vivo sheep and pig tracheal-tissue studies previously performed by the authors at the IMBL. In the present study, attempts were made to determine whether the design of the IMBL is suitable for imaging tracheal MCT in live pigs. The movement of 200 µm-diameter high-refractive-index (HRI) glass-bead marker particles deposited onto the tracheal airway surface of eight live piglets was tracked and quantified and the MCT response to aerosol delivery was examined. A high-resolution computed tomographic (CT) whole-animal post-mortem scan of one pig was also performed to verify the large sample CT capabilities of the IMBL. MCT tracking particles were visible in all animals, and the automated MCT tracking algorithms used were able to identify and track many particles, but accuracy was reduced when particles moved faster than ∼6 mm min-1 (50 pixels between exposures), or when the particles touched or overlapped. Renderings were successfully made from the CT data set. Technical issues prevented use of reliable shuttering and hence radiation doses were variable. Since dose must be carefully controlled in future studies, estimates of the minimum achievable radiation doses using this experiment design are shown. In summary, this study demonstrated the suitability of the IMBL for large-animal tracheal MCT imaging, and for whole-animal CT.


LncRNA GAS5 and miR-137 Polymorphisms and Expression are Associated with Multiple Sclerosis Risk: Mechanistic Insights and Potential Clinical Impact.
The pathogenesis of multiple sclerosis (MS) is influenced by the interaction of genetic and epigenetic mechanisms. The long noncoding RNA GAS5 acts as a competing endogenous RNA for microRNA-137 and is involved in demyelination. We investigated the association of GAS5 and miR-137 expression and their polymorphisms with MS susceptibility. One hundred and eight MS patients and 104 healthy controls were included. Expression analysis and genotyping of GAS5-rs2067079 and miR-137-rs1625579 single nucleotide polymorphisms were performed by qPCR. Serum GAS5 was upregulated, while serum miR-137 was downregulated in MS compared with the controls. Serum miR-137 was an excellent discriminator of MS patients from the controls (AUC = 0.97) and a negative independent predictor of MS in multivariate logistic analysis. Serum GAS5 expression was positively correlated with the expanded disability status scale scores in the relapsing-remitting MS patients. The rs2067079TT minor homozygote genotype was associated with an increased MS risk, while the rs1625579G minor allele was protective. rs1625579 showed an age-specific effect, while the rs2067079 affected the MS risk in gender- and age-specific manners. In MS patients, rs2067079TT was associated with a higher serum GAS5 than other genotypes, while serum miR-137 did not differ between rs1625579 genotypes. Our results suggest serum GAS5 and miR-137 as MS biomarkers, with miR-137 as a negative predictor of MS risk and GAS5 as a marker of MS severity. We propose rs2067079 and rs1625579 as novel genetic markers of MS susceptibility, and at least, rs2067079 possibly impacts the crosstalk between GAS5 and miR-137.


Effects of an attachment-based intervention on the cortisol production of infants and toddlers in foster care.
Studies with nonhuman primates and rodents, as well as with human children, have suggested that early separations from caregivers are often associated with changes in the functioning of the hypothalamus-pituitary-adrenal (HPA) axis. On the basis of these findings, we designed a relational intervention that was intended to normalize HPA functioning among children in foster care. This paper presents findings from a randomized clinical trial that assessed the effectiveness of a relational intervention (Attachment and Biobehavioral Catch-up [ABC]) with regard to HPA functioning. The ABC intervention was intended to enhance children's ability to regulate physiology and behavior. The control intervention (Developmental Education for Families) was intended to enhance children's cognitive skills. A comparison group of children who had never been in foster care was also included. Children's cortisol production was assessed upon arrival at the lab, and 15 and 30 min following the Strange Situation. Random effects analyses of variance were performed to assess differences in initial values and change between children in the two intervention groups. Children in the ABC intervention and comparison group children showed lower initial values of cortisol than children in the treatment control group, considering arrival at lab as initial values (p < .05). Groups did not differ significantly in change over time. These results suggest that the ABC intervention is effective in helping children regulate biology in ways more characteristic of children who have not experienced early adversity.


The role of complement in glucan-induced protection against septic shock.
Previous studies from our laboratory have shown that glucan will significantly enhance survival, decrease bacteremia, maintain reticuloendothelial function, and reduce histopathology in a murine model of gram-negative septic shock [1]. The present study was undertaken to evaluate the role of complement in glucan-enhanced protection against septic shock. AKR/J mice, which are congenitally C5-deficient, and ICR/HSD mice that were complement-depleted by treatment with purified cobra venom factor (CVF), were injected IP with glucan (50 mg/kg) on days 5 and 3 prior to IP challenge with 1 X 10(8) E. coli. Survival data indicated that glucan (p less than 0.05) increased survival in both C5-deficient and complement-depleted mice. Glucan prophylaxis resulted in a neutrophilic leukocytosis 8 h following E. coli challenge. However, glucan did not alter bone marrow proliferation. We conclude that, 1) glucan's protective effect on survival is not dependent on complement, 2) complement is not required for glucan-induced neutrophilic leukocytosis in this model, and 3) glucan does not enhance bone marrow proliferation in complement-deficient mice.


[The effect of adjuvant radiotherapy on postoperative complications of immediate deep inferior epigastric artery perforator flap breast reconstruction].
Objective: To examine the effect of adjuvant radiotherapy on postoperative complications of immediate deep inferior epigastric artery perforator (DIEP) flap breast reconstruction. Methods: Data was collected from 185 patients underwent immediate DIEP reconstruction during November 2006 to March 2020 Department of Breast surgery, Fudan University shanghai Cancer Center. All the patients were female, aging (43.0±7.8) years (range: 29 to 61 years). The series included with a total of 187 flaps (2 bilateral, 183 unilateral). Included patients were divided into 2 groups: immediate DIEP reconstruction requring or not requring post-mastectomy radiation therapy (71 cases (71 flaps) in PMRT group, 114 cases (116 flaps) in control group). The aesthetic outcome were measured by Kroll score system and compared between the groups by t test. The complications included partial flap loss, minor necrosis were analyzed between the groups by χ2 test, while the influence of the other correlation factors on complication occurrence was analyzed by Logistic analysis. Results: The controll groups showed higher aesthetic results (2.21±0.55 vs. 2.47±0.82, t=-2.593, P=0.010). Complication rate in PMRT group was higher than that in control group (19.7% (15/71) vs. 4.2% (4/116), χ²=15.079,P<0.01). The complication rate was not correlated with age, body mass index, perforator number, neoadjuvant chemotherapy and adjuvant chemotherapy. Conclusions: Correlation was observed between adiuvant radiotherapy and post-operative complication of the DIEP flap. However, the complication occurrence and aesthetic results remain in the acceptable range. The other factors such as age, body mass index, perforator number, neoadjuvant chemotherapy and adjuvant chemotherapy should not be considered as prognosis factor of post-operative complication of the DIEP flap.


Inter-relationship between radiocarpal and metacarpophalangeal joint deformities in rheumatoid arthritis.
The roentgen evaluation of 96 rheumatoid hands and wrists, supplemented with anatomic and pathologic material from cadavers and patients with rheumatoid arthritis, allowed evaluation of deformities at the radiocarpal and metacarpophalangeal articulations. Measurements of specific coordinates in these patients were compared to those in "controls" and, despite significant error introduced by variability in patient positioning during radiography, definite inter-relationships between radiocarpal and metacarpophalangeal malalignments became evident. Radial deviation at the wrist was associated with ulnar deviation of the digits producing the "zig-zig" deformity of the rheumatoid hand. The pathogenetic and therapeutic aspects of the roentgen findings are discussed.


Three new species of Oppioidea (Acari: Oribatida) from India.
Three new oribatid mite species of the superfamily Oppioidea--Cycloppia asetosa sp. nov., C. spindleformis sp. nov. and Hammerella (Hammerella) excisa sp. nov.--are described from India. The genus Cycloppia and subgenus Hammerella (Hammerella) are for the first time recorded in India. Cycloppia asetosa sp. nov. differs from all species of Cycloppia by the rostrum with indentation and the absence of interlamellar setae and their alveoli. Cycloppia spindleformis sp. nov. dif- fers from all species of Cycloppia by the presence of interlamellar alveoli only. Hammerella (H.) excisa sp. nov. differs from all species of Hammerella (Hammerella) by the rostrum with indentation and the presence of notogastral setae c. The identification keys to all known species of Cycloppia and Hammerella (Hammerella) are provided.


DNA adducts of cisplatin and carboplatin in tissues of cancer patients.
An enzyme-linked immunosorbent assay (ELISA) has been developed with an antiserum elicited against cisplatin-modified DNA and used to quantify the intrastrand bidentate d(GpG)- and d(ApG)-diammineplatinum adducts in DNA samples prepared from nucleated blood cells and tissues of cancer patients receiving cisplatin or carboplatin chemotherapy. In nucleated blood cell DNA, adducts accumulated with increasing dose administered over a period of months, and a correlation was observed between the ability of a patient to form high levels of adduct and the frequency of tumour remission. Thus, many patients who did not form adducts also did not respond to therapy. Adduct distribution was shown to be widespread in many human tissues, and similar quantities of adducts were formed in peripheral blood cell DNA and tumour tissue. In addition, evidence suggests that residues of persistent adducts remain in many tissues weeks and even months after treatment. All of the above observations were obtained with the cisplatin-DNA ELISA; however, in comparison with other published data, the adduct levels reported are low. It now appears certain that the cisplatin-DNA ELISA results in an underestimation of adduct values in biological samples, since some human samples have been assayed by both this and two other procedures--the G-Pt-GMP ELISA and atomic absorbance spectroscopy. Values obtained with the two other procedures compare well with each other, but those obtained with the cisplatin-DNA ELISA for three human samples are 10-300-fold lower. The factors that result in this discrepancy are still under investigation.


Interleukin-2 treatment potentiates induction of oral tolerance in a murine model of autoimmunity.
The present study addresses the feasibility of potentiating oral tolerance by immunomanipulation, using the murine model of experimental autoimmune uveoretinitis (EAU) induced by immunization with the retinal antigen interphotoreceptor retinoid binding protein (IRBP). Three feedings of 0.2 mg IRBP every other day before immunization did not protect against EAU, whereas a similar regimen of five doses was protective. However, supplementing the nonprotective 3x regimen with as little as one injection of 1,000 U of human recombinant interleukin-2 (IL-2) resulted in disease suppression that was equal to that of the protective 5x regimen. The protective effect was maintained across a range of IL-2 doses and times of administration; none of the IL-2 regimens tested resulted in disease enhancement. Peyer's Patch cells of 3x-fed and IL-2-treated mice showed greatly increased production of TGF-beta, IL-4, and IL-10 compared with animals given the nonprotective 3x regimen and to animals given the protective 5x regimen. We propose that IL-2 treatment enhances protection from EAU at least in part by stimulating production of antiinflammatory cytokines by regulatory cells in Payer's Patches. Moreover, the observed lymphokine production patterns suggest that whereas protection induced by the 3x + IL-2 regimen is likely to involve antiinflammatory cytokines, protection induced by the 5x regimen might involve anergy or deletion of the uveitogenic T cells. These results could have practical implications for use of IL-2 as a safe and effective way of potentiating oral tolerance.


Localization of VZV in saliva of zoster patients.
Varicella zoster virus (VZV) in saliva from six herpes zoster patients and one chickenpox patient was found to be exclusively associated with epithelial cells by confocal microscopy. VZV localization with antibody specific to the VZV glycoprotein E was detected primarily on the membrane but was also inside the cell. Epithelial cells with VZV were still present in saliva in one out of two tested zoster patients after 10 months of recovery. Saliva from healthy controls (non-shingles patients, n = 5) did not show any sign of VZV by polymerase chain reaction or by confocal microscopy. No VZV was found in the liquid fraction of saliva. Further work is required to understand the movement of VZV in the saliva cells of infected patients.


Cancer risk among Holocaust survivors in Israel-A nationwide study.
Holocaust survivors during World War II were exposed to various factors that are associated with cancer risk. The objective of this study was to determine whether Holocaust survivors had an increased risk for developing cancer. The study population included 152,622 survivors. The main analysis was based on a comparison between individuals who were entitled to compensation for suffering persecution during the war and individuals who were denied such compensation. A complementary analysis compared survivors who were born in countries governed by Nazi Germany with survivors born in nonoccupied countries. A Cox proportional hazards model was used, with the time at risk of cancer development starting on either January 1, 1960, or the date of immigration to the date of cancer diagnosis or death or the date of last follow-up (December 31, 2006). Cancer was diagnosed in 22.2% of those who were granted compensation versus 16% of those who were denied compensation (P < .0001). Adjusting for birth cohort, sex, country of origin, and period of immigration, both analyses revealed significant increased risks of developing cancer in those who were exposed. For those who were granted versus denied compensation, the hazard ratios were 1.06 (P < .001) for all sites, 1.12 (P = .07) for colorectal cancer, and 1.37 (P = .008) for lung cancer. For those born in occupied countries versus nonoccupied countries, the hazard ratios were 1.08 (P < .001), 1.08 (P = .003), and 1.12 (P = .02), respectively. The current results, based on a large cohort of Holocaust survivors who were exposed to a variety of severe deprivations, add to the conflicting and sparse knowledge on this issue and support the notion that this group has a small but consistent increase in cancer development. Cancer 2017;123:3335-45. © 2017 American Cancer Society.


Transcranial Direct Current Stimulation Improves Semantic Speech-Gesture Matching in Patients With Schizophrenia Spectrum Disorder.
Patients with schizophrenia spectrum disorders (SSD) have severe deficits in speech and gesture processing that contribute considerably to the burden of this disorder. Brain imaging shows left inferior frontal gyrus involvement for impaired processing of co-verbal gestures in patients with schizophrenia. Recently, transcranial direct current stimulation (tDCS) of the left frontal lobe has been shown to modulate processing of co-verbal gestures in healthy subjects. Although tDCS has been used to reduce symptoms of patients with SSD, the effects of tDCS on gesture processing deficits remain hitherto unexplored. Here we tested the hypothesis that inhibitory cathodal tDCS of the left frontal lobe decreases pathological dysfunction and improves semantic processing of co-verbal gestures in patients with SSD. We measured ratings and reaction times in a speech-gesture semantic relatedness assessment task during application of frontal, frontoparietal, parietal, and sham tDCS to 20 patients with SSD and 29 healthy controls. We found a specific effect of tDCS on speech-gesture relatedness ratings of patients. Frontal compared to parietal and sham stimulation significantly improved the differentiation between related and unrelated gestures. Placement of the second electrode (right frontal vs parietal) did not affect the effect of left frontal stimulation, which reduced the preexisting difference between patients and healthy controls. Here we show that left frontal tDCS can improve semantic co-verbal gesture processing in patients with SSD. tDCS could be a viable tool to normalize processing in the left frontal lobe and facilitate direct social communicative functioning in patients with SSD.


Dopamine transporters are phosphorylated on N-terminal serines in rat striatum.
Dopamine transporters (DATs) are neuronal phosphoproteins that clear dopamine from the synaptic cleft. Activation of protein kinase C (PKC) and inhibition of protein phosphatases by okadaic acid (OA) increase phosphorylation of DAT and lead to concomitant reduction in DAT activity and cell surface expression. Numerous potential sites for phosphorylation are present on DAT, but the sites utilized and their relationship to transport regulation are currently unknown. We used peptide mapping and epitope-specific immunoprecipitation to identify the region of DAT that undergoes phosphorylation in rat striatal tissue. Phosphoamino acid analysis revealed that basal and stimulated samples were phosphorylated primarily on serine. Digestion of (32)PO(4)-labeled DAT with trypsin and immunoprecipitation with N- or C-terminal specific antisera failed to isolate phosphopeptide fragments corresponding to photoaffinity-labeled fragments that contain all internal interhelical loops. However, digestion of (32)PO(4)-labeled DAT with endoproteinase asp-N and immunoprecipitation with an N-terminal antiserum extracted two phosphopeptide fragments from both basal and PKC/OA-stimulated samples, demonstrating that the N-terminal cytoplasmic tail is a major site of phosphorylation. Aminopeptidase treatment of PKC- and/or OA-stimulated DAT cleaved essentially all (32)PO(4) label without proteolysis extending past transmembrane domains 1 and 2, providing further evidence that most phosphorylation sites are near the N terminus and not in intracellular loops or C-terminal domains. In situ proteolysis of the N-terminal tail indicates that the majority of stimulated phosphorylation sites are N-terminal to an antibody epitope at residues 42-59. Two-dimensional analysis of purified protein produced three tryptic phosphopeptides that may result from phosphorylation of multiple sites, but the fragments did not co-migrate with synthetic tryptic peptides phosphorylated at serines 2 and 4. These results indicate that most or all of the basal and stimulated phosphorylation of DAT in striatal tissue occurs on one or more residues in a group of six serines clustered near the distal end of the cytoplasmic N terminus.


[CT & MRI findings of refractory vasculitis].
We described CT and MRI findings of various refractory vasculitis. Refractory vasculitis must be divided into two categories including one group with major vascular involvement and another one with small or microvascular involvement. In cases with major vessel involvement such as Takayasu's arteritis, Kawasaki disease or vasculo-Behçet disease, CT and MRI depicted direct findings of vessels itself including stenosis, obstruction, aneurysm, and wall thickening. On the other hand, CT and MRI showed various extravascular findings in cases with small or microvascular involvement, such as CNS involvement in collagen vascular disease, pulmonary lesions in Wegener's granulomatosis and Churg-Strauss syndrome, and peritoneal lesion in SLE. Our results suggest that CT and MRI findings reflect various vascular condition of refractory vasculitis and correspond to various pathology.


Accurate Detection of Methicillin-Resistant Staphylococcus aureus in Mixtures by Use of Single-Bacterium Duplex Droplet Digital PCR.
Accurate and rapid identification of methicillin-resistant Staphylococcus aureus (MRSA) is needed to screen MRSA carriers and improve treatment. The current widely used duplex PCR methods are not able to differentiate MRSA from coexisting methicillin-susceptible S. aureus (MSSA) or other methicillin-resistant staphylococci. In this study, we aimed to develop a direct method for accurate and rapid detection of MRSA in clinical samples from open environments, such as nasal swabs. The new molecular assay is based on detecting the cooccurrence of nuc and mecA markers in a single bacterial cell by utilizing droplet digital PCR (ddPCR) with the chimeric lysin ClyH for cell lysis. The method consists of (i) dispersion of an intact single bacterium into nanoliter droplets, (ii) temperature-controlled release of genomic DNA (gDNA) by ClyH at 37°C, and (iii) amplification and detection of the markers (nuc and mecA) using standard TaqMan chemistries with ddPCR. Results were analyzed based on MRSA index ratios used for indicating the presence of the duplex-positive markers in droplets. The method was able to achieve an absolute limit of detection (LOD) of 2,900 CFU/ml for MRSA in nasal swabs spiked with excess amounts of Escherichia coli, MSSA, and other mecA-positive bacteria within 4 h. Initial testing of 104 nasal swabs showed that the method had 100% agreement with the standard culture method, while the normal duplex qPCR method had only about 87.5% agreement. The single-bacterium duplex ddPCR assay is rapid and powerful for more accurate detection of MRSA directly from clinical specimens.


Haplotype-assisted accurate non-invasive fetal whole genome recovery through maternal plasma sequencing.
The applications of massively parallel sequencing technology to fetal cell-free DNA (cff-DNA) have brought new insight to non-invasive prenatal diagnosis. However, most previous research based on maternal plasma sequencing has been restricted to fetal aneuploidies. To detect specific parentally inherited mutations, invasive approaches to obtain fetal DNA are the current standard in the clinic because of the experimental complexity and resource consumption of previously reported non-invasive approaches. Here, we present a simple and effective non-invasive method for accurate fetal genome recovery-assisted with parental haplotypes. The parental haplotype were firstly inferred using a combination strategy of trio and unrelated individuals. Assisted with the parental haplotype, we then employed a hidden Markov model to non-invasively recover the fetal genome through maternal plasma sequencing. Using a sequence depth of approximately 44X against a an approximate 5.69% cff-DNA concentration, we non-invasively inferred fetal genotype and haplotype under different situations of parental heterozygosity. Our data show that 98.57%, 95.37%, and 98.45% of paternal autosome alleles, maternal autosome alleles, and maternal chromosome X in the fetal haplotypes, respectively, were recovered accurately. Additionally, we obtained efficient coverage or strong linkage of 96.65% of reported Mendelian-disorder genes and 98.90% of complex disease-associated markers. Our method provides a useful strategy for non-invasive whole fetal genome recovery.


Evaluation of the potency of telaprevir and its metabolites as inhibitors of renal organic cation transporters, a potential mechanism for the elevation of serum creatinine.
Telaprevir-based triple therapy is a highly effective treatment for chronic hepatitis C. However, adverse reactions include reversible and dose-dependent elevation of serum creatinine levels. We speculated that this effect reflects inhibition of the renal organic cation transporters hOCT2, hMATE1, and hMATE2-K by telaprevir or its metabolites (VRT-127394 and VRT-0922061). Telaprevir, VRT-127394, and VRT-0922061 showed negligible or weak effects on hOCT2 at concentrations of ≥20 µM, but inhibited hMATE1 by 35, 38, and 53% and hMATE2-K by 47, 45, and 61% at 100 µM, respectively. Telaprevir or its metabolites (10 µM) did not affect basal-to-apical transport of MPP(+) across monolayers of hOCT2-hMATE1 double-transfected MDCKII cells, whereas pyrimethamine, a potent inhibitor of hMATE1, markedly inhibited MPP(+) transport. Taken together, inhibition of hOCT2, hMATE1, and hMATE2-K is unlikely to be clinically relevant because unbound plasma concentrations of telaprevir and its metabolites reach only 2 µM following oral administration of a dose of 750 mg telaprevir. Hence, elevated serum creatinine during telaprevir therapy may not be related to direct inhibition of renal organic cation transporters.


An improved population migration algorithm introducing the local search mechanism of the leap-frog algorithm and crossover operator.
The population migration algorithm (PMA) is a simulation of a population of the intelligent algorithm. Given the prematurity and low precision of PMA, this paper introduces a local search mechanism of the leap-frog algorithm and crossover operator to improve the PMA search speed and global convergence properties. The typical test function verifies the improved algorithm through its performance. Compared with the improved population migration and other intelligential algorithms, the result shows that the convergence rate of the improved PMA is very high and its convergence is proved.


NAC transcription factor family genes are differentially expressed in rice during infections with Rice dwarf virus, Rice black-streaked dwarf virus, Rice grassy stunt virus, Rice ragged stunt virus, and Rice transitory yellowing virus.
Expression levels of the NAC gene family were studied in rice infected with Rice dwarf virus (RDV), Rice black-streaked dwarf virus (RBSDV), Rice grassy stunt virus (RGSV), Rice ragged stunt virus (RRSV), and Rice transitory yellowing virus (RTYV). Microarray analysis showed that 75 (68%) OsNAC genes were differentially regulated during infection with RDV, RBSDV, RGSV, and RRSV compared with the control. The number of OsNAC genes up-regulated was highest during RGSV infection, while the lowest number was found during RTYV infection. These phenomena correlate with the severity of the syndromes induced by the virus infections. Most of the genes in the NAC subgroups NAC22, SND, ONAC2, ANAC34, and ONAC3 were down-regulated for all virus infections. These OsNAC genes might be related to the health stage maintenance of the host plants. Interestingly, most of the genes in the subgroups TIP and SNAC were more highly expressed during RBSDV and RGSV infections. These results suggested that OsNAC genes might be related to the responses induced by the virus infection. All of the genes assigned to the TIP subgroups were highly expressed during RGSV infection when compared with the control. For RDV infection, the number of activated genes was greatest during infection with the S-strain, followed by the D84-strain and the O-strain, with seven OsNAC genes up-regulated during infection by all three strains. The Os12g03050 and Os11g05614 genes showed higher expression during infection with four of the five viruses, and Os11g03310, Os11g03370, and Os07g37920 genes showed high expression during at least three viral infections. We identified some duplicate genes that are classified as neofunctional and subfunctional according to their expression levels in different viral infections. A number of putative cis-elements were identified, which may help to clarify the function of these key genes in network pathways.


Identifying Risk Factors Associated with Repeated Referrals Within a Pediatric Navigation Program.
Approximately 1-in-5 children have a diagnosed mental, behavioral, and/or developmental disorder or delay by age 8 in the United States. Children with such conditions often require complex, complicated diagnostic and specialty care, making them susceptible to repeated referrals and ongoing unmet healthcare needs. Patient navigation programs (PNPs) are designed to integrate care from primary care providers to community-based services, using trained navigators to help patients and their families manage referrals and connect with referred services. This study examines factors associated with repeated referrals to an active PNP to inform ongoing referral patterns and adaptations to standard navigation support within a large healthcare system in South Carolina (SC). Data is sourced from the inception of the PNP in 2017 through 2022, including 15,702 referrals. Overall, 71.07% had no repeated referrals. Children who are older, diagnosed with attention deficit disorder(s), behavioral concerns, depression, multiple referral needs, and insured by Medicaid were found to be most susceptible to repeated referrals. Conversely, children who are non-Hispanic Black, were referred at a well-child visit, and are primarily insured by private insurance or Tricare were least likely to have repeated referrals. Children who are insured by Medicaid are more likely to be younger, identify as non-Hispanic Black, Hispanic, or another race/ethnicity, and have multiple needs at time of initial referral, identifying a potentially compounded risk for those who hold multiple risk factors to experiencing repeated referrals. Findings may inform adaptations to this PNP model to adjust navigator protocol for at-risk populations and equitably optimize referral-to-service connection.


Targeting Oct1 genomic function inhibits androgen receptor signaling and castration-resistant prostate cancer growth.
Androgen receptor (AR) functions as a ligand-dependent transcription factor to regulate its downstream signaling for prostate cancer progression. AR complex formation by multiple transcription factors is important for enhancer activity and transcriptional regulation. However, the significance of such collaborative transcription factors has not been fully understood. In this study, we show that Oct1, an AR collaborative factor, coordinates genome-wide AR signaling for prostate cancer growth. Using global analysis by chromatin immunoprecipitation sequencing (ChIP-seq), we found that Oct1 is recruited to AR-binding enhancer/promoter regions and facilitates androgen signaling. Moreover, a major target of AR/Oct1 complex, acyl-CoA synthetase 3 (ACSL3), contributes to tumor growth in nude mice, and its high expression is associated with poor prognosis in prostate cancer patients. Next, we examined the therapeutic effects of pyrrole-imidazole polyamides that target the Oct1-binding sequence identified in the center of the ACSL3 AR-binding site. We observed that treatment with Oct1 polyamide severely blocked the Oct1 binding at the ACSL3 enhancer responsible for its transcriptional activity and ACSL3 induction. In addition, Oct1 polyamides suppressed castration-resistant tumor growth and specifically repressed global Oct1 chromatin association and androgen signaling in prostate cancer cells, with few nonspecific effects on basal promoter activity. Thus, targeting Oct1 binding could be a novel therapeutic strategy for AR-activated castration-resistant prostate cancer.


Psychotic Symptoms in a Child with Long Standing SLE Nephritis: Neuropsychiatric Manifestation or Sequelae to Lupus?
Systemic Lupus Erythematosus (SLE) is a prototypic autoimmune disease of unknown etiology, which affects multiple organ systems including the central nervous system (CNS). Though not common, childhood onset SLE is a known and established entity. Neuropsychiatric symptoms are common in childhood onset SLE. Of these, psychosis and behavioural symptoms are relatively rare, and there is no consensus on the proper treatment of such cases. We report a case of 13-year-old boy, diagnosed with lupus nephritis, and presented with psychosis and behavioural symptoms. The highlight of this case is that the psychiatric symptoms were present despite the primary illness being quiescent. Thus, the patient was treated with Olanzapine and lorazepam, while continuing immunosuppressive therapy as previously. Also, MRI brain revealed vasculitic changes in the right hemisphere, which might be one of the etiological factors playing role in the development of these neuropsychiatric symptoms.


Acute hemorrhagic leukoencephalitis: neuroimaging features and neuropathologic diagnosis.
A case of biopsy-proven acute hemorrhagic leukoencephalitis is reported. The early computed tomography scans showed extensive bilateral hypodensities with mass effects and foci of microhemorrhages. Bilateral asymmetric hyperintensities in the mesiotemporal and frontal lobes and massive edema were found on T2-weighted and fluid-attenuated inversion recovery magnetic resonance images in a pattern classic for herpes simplex encephalitis. This fulminant demyelinating disease progresses to coma and death within days. Early diagnosis with neuroimaging studies and rapid correlation with the clinical findings of this disease are vital for the institution of potentially lifesaving treatments.


Altered Expression of Brain-specific Autism-Associated miRNAs in the Han Chinese Population.
Autism is a complex neurodevelopmental disorder. However, its etiology is still unknown. MicroRNAs (miRNAs) are key post-transcriptional regulators. They play an important role in neurodevelopment and brain functions and may be involved in the pathogenesis of autism. Previous studies indicated altered expression of miRNAs in patients with autism. However, the findings were not consistent, and further explorations were needed. This study aimed to investigate whether miRNAs were dysregulated in autism. We examined the expression of 30 brain-specific autism-associated miRNAs in 110 patients with autism and 113 controls in the Han Chinese population using quantitative reverse transcription-polymerase chain reaction. The results demonstrated that 10 miRNAs (hsa-miR-191-5p, hsa-miR-151a-3p, hsa-miR-139-5p, hsa-miR-181a-5p, hsa-miR-432-5p, hsa-miR-181b-5p, hsa-miR-195-5p, hsa-miR-328-3p, hsa-miR-106a-5p, and hsa-miR-484) were significantly differentially expressed (false discovery rate <0.05). All of them were up-regulated in patients with autism compared with controls. The targets of these miRNAs were enriched for genes and pathways related to neurodevelopment, brain functions and autism. These findings suggested the participation of these 10 miRNAs in the pathogenesis of autism in the Han Chinese population.


MCL1 enhances the survival of CD8+ memory T Cells after viral infection.
Viral infection results in the generation of massive numbers of activated effector CD8(+) T cells that recognize viral components. Most of these are short-lived effector T cells (SLECs) that die after clearance of the virus. However, a small proportion of this population survives and forms antigen-specific memory precursor effector cells (MPECs), which ultimately develop into memory cells. These can participate in a recall response upon reexposure to antigen even at protracted times postinfection. Here, antiapoptotic myeloid cell leukemia 1 (MCL1) was found to prolong survival upon T cell stimulation, and mice expressing human MCL1 as a transgene exhibited a skewing in the proportion of CD8(+) T cells, away from SLECs toward MPECs, during the acute phase of vaccinia virus infection. A higher frequency and total number of antigen-specific CD8(+) T cells were observed in MCL1 transgenic mice. These findings show that MCL1 can shape the makeup of the CD8(+) T cell response, promoting the formation of long-term memory. During an immune response to a virus, CD8(+) T cells kill cells infected by the virus, and most die when the infection resolves. However, a small proportion of cells survives and differentiates into long-lived memory cells that confer protection from reinfection by the same virus. This report shows that transgenic expression of an MCL1 protein enhances survival of memory CD8(+) T cells following infection with vaccinia virus. This is important because it shows that MCL1 expression may be an important determinant of the formation of long-term CD8(+) T cell memory.


Effects of Mechanical Drying on the Removal of Pollen Allergens.
Pollen may spread indoors through clothes contaminated during outdoor activities. This study aimed to evaluate the pollen removal efficacy of a mechanical dryer. Cotton clothes served as laundry, and fabrics measuring 2 × 5 cm served as test samples. Pollen was spread evenly on the test fabrics. The fabrics were then fixed on the cloth and left for 8 h to imitate real-life conditions. This experiment was conducted under 2 conditions, wet (after washing clothes) and dry (without washing). After drying, we counted pollen on the test fabrics to evaluate the pollen removal rate. We measured the remaining allergens in extracts from the contaminated fabrics after mechanical drying. The concentrations of allergens (Amb a 1, Bet v 1, Crp j 1, and Phl p 1) in each extracted solution were measured using 2-site ELISA. For ragweed, Japanese cedar, birch, and timothy grass, the mean pollen removal ratios for the dry samples were 99.88 ± 0.09%, 99.96 ± 0.03%, 99.89 ± 0.02%, and 99.82 ± 0.11%, respectively, and those for the wet samples were 98.83 ± 0.87%, 97.91 ± 1.81%, 97.29 ± 1.19%, and 96.3 ± 0.92%, respectively. Further, for the pollen allergens Amb a 1 [ragweed], Crp j 1 [Japanese cedar], Bet v 1 [birch], and Phl p 1 [timothy grass], the mean pollen allergen removal ratios for the dry samples were 99.81 ± 0.06%, 99.94 ± 0.23%, 99.90 ± 0.11%, and 99.84 ± 0.17%, respectively, and those for the wet samples were 98.11 ± 0.14%, 96.04 ± 1.52%, 97.21 ± 0.83%, and 95.23 ± 0.92%, respectively. There was no statistically significant difference for each species. Mechanical drying effectively removed pollen and allergens from dry and wet fabrics. We expect that further studies on the removal of other indoor allergens would contribute to improved environmental control for allergy patients.


Global burden of road traffic accidents in older adults: A systematic review and meta-regression analysis.
This study aims to estimate the burden of road traffic accidents and death among older adults. A systematic literature review was conducted on 10 electronic databases for articles describing Road Traffic Accident(RTA) mortality in older adults until September 2016. A random-effects meta-regression analyses was conducted to estimate the pooled rates of road traffic accidents and death. A total 5018 studies were identified and 23 studies were included. Most of the reported older adults were aged between 60 and 74 years, with majority being male gender and sustained minor trauma due to Motor-Vehicle Collision (MVC). The overall pooled mortality rate was 14% (95% Confidence Interval, CI: 11%, 16%), with higher mortality rates in studies conducted in North America (15%, 95% CI: 12%, 18%) and older adults admitted to trauma centers (17%, 95% CI: 14%, 21%). Secondary analysis showed that the very elderly adults (aged >75years) and pedestrians had higher odds of mortality death (Odds Ratio, OR: 2.05, 95% CI: 1.25, 3.38; OR: 2.08, 95% CI: 1.63, 2.66, respectively). A new comprehensive trauma management guidelines tailored to older adults should be established in low and middle-income countries where such guidelines are still lacking.


A randomized, double-blind, crossover study of once-daily dexmethylphenidate in children with attention-deficit hyperactivity disorder: rapid onset of effect.
Long-acting methylphenidate formulations provide control of attention-deficit hyperactivity disorder (ADHD) symptoms for up to 12 hours; however, not all formulations have rapid onset of therapeutic effect, which is essential for providing symptom control during morning hours. The primary objective of this randomized, double-blind, crossover study was to assess the efficacy of dexmethylphenidate extended release (ER) versus placebo by measuring the change from pre-dose to 0.5 hours post-dose on the Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) rating scale. Eighty-six children (6-12 years) with ADHD diagnosed using the DSM-IV criteria were randomized to receive dexmethylphenidate ER 20 mg/day or placebo, sequentially, for 7 days, with the final dose administered in a laboratory classroom setting on day 7 of each treatment period. The primary efficacy comparison was change in the SKAMP-Combined score from pre-dose to 0.5 hours post-dose, with additional secondary assessments at 1, 2, 4, 6 and 8 hours post-dose. Secondary efficacy measures included change from pre-dose at all timepoints in the SKAMP-Attention and SKAMP-Deportment, Math Test-Attempted and Math Test-Correct scores, and change from baseline on the Conners' ADHD/DSM-IV Scale for Parents (CADS-P). In an exploratory analysis, a daily diary card was completed by parents on the children's in-home behaviour before school. Safety was assessed by occurrence of adverse events, monitoring of vital signs and interpretation of ECGs. Significant improvements were noted at 0.5 hours and at all timepoints post-dose throughout the 8-hour laboratory classroom day for dexmethylphenidate ER vs placebo in the primary outcome measure of the SKAMP-Combined scores (p < 0.001), as well as SKAMP-Attention, SKAMP-Deportment, Math Test-Attempted and Math Test-Correct scores (p < 0.05). The changes from baseline in CADS-P scores were significantly greater with dexmethylphenidate ER than placebo (-16.382 vs -4.622; p < 0.001). Responses to all diary questions indicated significant improvement with dexmethylphenidate ER treatment versus placebo (all p < 0.001). The most common adverse events were abdominal pain (dexmethylphenidate ER 3.5%; placebo 4.7%), headache (dexmethylphenidate ER 3.5%; placebo 2.3%) and increased appetite (dexmethylphenidate ER 0%; placebo 3.5%). Compared with placebo, once-daily dexmethylphenidate ER 20 mg provided rapid and significant improvement at 0.5 hours post-dose in attention, deportment and academic performance, which was sustained for 8 hours post-dose. Overall, once-daily dexmethylphenidate ER 20 mg was well tolerated. In an analysis of parental assessment of diary responses, children appeared more organized, and morning preparation for school was smoother and less frustrating with once-daily dexmethylphenidate ER compared with placebo.


Scalable Ti3C2Tx MXene Interlayered Forward Osmosis Membranes for Enhanced Water Purification and Organic Solvent Recovery.
The design of nanosheets interlayer between the substrate and polyamide layer has attracted growing attention to improve the performance of thin-film composite membranes. However, the membrane size is limited by current fabrication methods such as vacuum filtration. Herein, a high-performance MXene (Ti3C2Tx) interlayered polyamide forward osmosis (FO) membrane is fabricated based on a combination of a facile and scalable brush-coating of MXene on nylon substrates and the interfacial polymerization process. The as-prepared FO membrane shows high water permeability of 31.8 L m-2 h-1 and low specific salt flux of 0.27 g L-1 using 2.0 mol L-1 sodium chloride as the draw solution. This is attributed to the adjustment of substrate properties and the polyamide layer by coating of MXene as well as the facilitation of water transportation by the interlayer distances between Ti3C2Tx. The membrane also exhibits a good organic solvent forward osmosis performance with high ethanol flux as 9.5 L m-2 h-1 and low specific salt flux of 0.4 g L-1 using 2.0 mol L-1 lithium chloride as the draw solution. Moreover, the MXene interlayered FO membrane demonstrates a feasible application in real seawater desalination and industrial textile wastewater treatment. This work presents an effective approach to fabricating nanomaterials interlayered FO membranes with superior performance for both desalination and organic solvent recovery.


Thiazole-5-carbaldehyde Synthesis by Cascade Annulation of Enaminones and KSCN with Dess-Martin Periodinane Reagent.
The Dess-Martin periodinane (DMP) reagent-mediated reactions of tertiary enaminones with potassium thiocyanate for the synthesis of thiazole-5-carbaldehydes are developed. The product formation involves cascade hydroxyl thiocyanation of the C═C double bond, intramolecular hydroamination of the C≡N bond, and thiazole annulation by condensation on the ketone carbonyl site, representing novel reaction pathways in the reactions between enaminones and thiocyanate salt. DMP plays dual roles in mediating the free radical thiocyanation and inducing the unconventional selective thiazole-5-carbaldehyde formation by masking the in situ generated formyl group during the reaction process.


Organ Preservation into the 2020s: The Era of Dynamic Intervention.
Organ preservation has been of major importance ever since transplantation developed into a global clinical activity. The relatively simple procedures were developed on a basic comprehension of low-temperature biology as related to organs outside the body. In the past decade, there has been a significant increase in knowledge of the sequelae of effects in preserved organs, and how dynamic intervention by perfusion can be used to mitigate injury and improve the quality of the donated organs. The present review focuses on (1) new information about the cell and molecular events impacting on ischemia/reperfusion injury during organ preservation, (2) strategies which use varied compositions and additives in organ preservation solutions to deal with these, (3) clear definitions of the developing protocols for dynamic organ perfusion preservation, (4) information on how the choice of perfusion solutions can impact on desired attributes of dynamic organ perfusion, and (5) summary and future horizons.


Hemopoietic effects of short-term in vivo treatment of mice with various doses of rhG-CSF.
Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was injected s.c., twice daily, into normal adult male BDF1 mice for a period of 4-5 days in doses ranging from 10 to 2500 micrograms/kg/day. The number of peripheral blood cells and their morphology was examined daily from the beginning of the experiment for 6 days. On the 5th day of treatment parameters such as spleen weight and cellularity, bone marrow morphology and cellularity, content of granulocyte-macrophage colony-forming cells (GM-CFC) or multipotential stem cells (CFU-S) in spleen and marrow, and also histology of lung and liver were examined. We observed a dose-dependent increase in the number of blood neutrophils, and an increase in weight, cellularity, and numbers of GM-CFC and CFU-S in the spleen. In the bone marrow, cellularity decreased to 40% of normal. Numbers of GM-CFC and CFU-S in marrow were also decreased, and examination of marrow morphology revealed an inhibition of erythropoiesis.


Improved bayesian network inference using relaxed gene ordering.
Bayesian Networks (BNs) have become one of the most powerful means of reconstructing signalling pathways in silico. Excessive computational loads limit the applications of BNs to learn larger sized network structures. Recent bioinformatics research found that signalling pathways are likely hierarchically organised. Genes resident in hierarchical layers constitute biological constraint, which can be readily used by BN structural learning algorithms to substantially reduce the computational load. We propose a constrained BN structural learning algorithm that solves the NP-complete computational problem in a heuristic manner. We demonstrate the utility of our algorithm in constructing two important signalling pathways in S. cerevisiae.


Pan-HSP90 ligand binding reveals isoform-specific differences in plasticity and water networks.
Isoforms of heat shock protein 90 (HSP90) fold oncoproteins that facilitate all 10 hallmarks of cancer. However, its promise as a therapeutic target remains unfulfilled as there is still no FDA-approved drug targeting HSP90 in disease. Among the reasons hindering progress are side effects caused by pan-HSP90 inhibition. Selective targeting of the four isoforms is challenging due to high sequence and structural similarity. Surprisingly, while decades of drug discovery efforts have produced almost 400 human HSP90 structures, no single ligand has been structurally characterized across all four human isoforms to date, which could reveal structural differences to achieve selectivity. To better understand the HSP90 landscape relevant for ligand binding and design we take a three-pronged approach. First, we solved the first complete set of structures of a single ligand bound to all four human isoforms. This enabled a systematic comparison of how side-chains and water networks respond to ligand binding across isoforms. Second, we expanded our analysis to publicly available, incomplete isoform-ligand series with distinct ligand chemistry. This highlighted general trends of protein and water mobility that differ among isoforms and impact ligand binding. Third, we further probed the Hsp90α conformational landscape for accommodating a congeneric series containing the purine scaffold common to HSP90 inhibitors. This revealed how minor ligand modifications flip ligand poses and perturb water and protein conformations. Taken together, this work illustrates how a systematic approach can shed new light on an "old" target and reveal hidden isoform-specific accommodations of congeneric ligands that may be exploited in ligand discovery and design.


N-acetylcysteine neither lowers plasma homocysteine concentrations nor improves brachial artery endothelial function in cardiac transplant recipients.
N-acetylcysteine is a novel antioxidant that has been reported to reduce plasma homocysteine concentrations and improve endothelial function. Cardiac transplant recipients have a high incidence of coronary endothelial dysfunction and hyperhomocysteinemia, both of which may lead to the development of transplantation coronary artery disease. It was hypothesized that N-acetylcysteine would reduce plasma homocysteine concentrations and improve brachial endothelial function in cardiac transplant recipients. A cohort of stable cardiac transplant recipients was recruited from the outpatient clinic at the Toronto General Hospital, Toronto, Ontario. Brachial artery endothelial functions were studied according to standard techniques to determine flow-mediated dilation of the brachial artery. Plasma homocysteine concentrations were assayed using high performance liquid chromatography with electrochemical detection and pulsed integrated amperometry. After baseline testing, patients were treated in an unblinded fashion with N-acetylcysteine 500 mg/day. After 10 weeks of therapy, patients returned for follow-up endothelial function and homocysteine testing. Thirty-one patients were initially enrolled. Two patients withdrew due to excessive gastrointestinal upset. Two patients did not return for follow-up testing. The remaining 27 patients tolerated the treatment well. At baseline, 85% of the patients had hyperhomocysteinemia (greater than 15 mol/L) with a mean plasma concentration of 18.6 4.7 mol/L. No changes in homocysteine concentrations were seen at follow-up. At baseline, the average flow-mediated dilation was only 4.7 6.3%. No changes were seen at follow-up. Hyperhomocysteinemia and brachial endothelial dysfunction are common in stable cardiac transplant recipients and are unaffected by supplementation with N-acetylcysteine.


HIP1 propagates in cyanobacterial DNA via nucleotide substitutions but promotes excision at similar frequencies in Escherichia coli and Synechococcus PCC 7942.
The sequence 5'-GCGATCGC-3', designated HIP1, for highly iterated palindrome, was first identified at the borders of a gene-deletion event and subsequently shown to constitute up to 2.5% of the DNA in some cyanobacteria. It is now reported that HIP1 is polyphyletic, occurring in several distinct cyanobacterial lineages and not defining a clade. HIP1 does not introduce gaps into sequence alignments. It aligns with partial HIP1 sites in related sequences showing that it propagates by nucleotide substitutions rather than insertion. Constructs have been created to determine the frequencies at which deletion events occur between palindromes located within the selectable marker neo. Deletion between HIP1 sites was more frequent in Synechococcus PCC 7942 than deletion between control palindromes, 5'-CCGATCGG-3', designated PAL0. However, this is not due to a recombinase that recognises HIP1 and is peculiar to cyanobacteria because similar deletion frequencies were detected in Escherichia coli. Furthermore, the frequency of deletion of DNA flanked asymmetrically by one HIP1 site and one PAL0 site was less than the frequency of deletion of DNA flanked asymmetrically by identical copies of either palindrome. This is consistent with deletion by copy-choice.


General Design Concept for Single-Atom Catalysts toward Heterogeneous Catalysis.
As a new and popular material, single-atom catalysts (SACs) exhibit excellent activity, selectivity, and stability for numerous important reactions, and show great potential in heterogeneous catalysis due to their high atom utilization efficiency and the controllable characteristics of the active sites. The composition and coordination would determine the geometric and electronic structures of SACs, and thus greatly influence the catalytic performance. Based on atom economy, rational design and controllable synthesis of SACs have become central tasks in the fields of low-cost and green catalysis. Herein, an introduction to the recent progress in the precise synthesis of SACs including the regulation of the coordination structure and the choice of different systems is presented. Thereafter, the potentials of SACs in different applications are comprehensively summarized and discussed. Furthermore, a detailed discussion of the recent developments regarding the large-scale preparation of SACs is provided, including the major issues and prospects for industrialization. Finally, the main challenges and opportunities of rapid large-scale industrialization of SACs are briefly discussed.


[Effects of nitric oxide synthase inhibitor on dentate gyrus neurogenesis after diffuse brain injury in adult rats].
To investigate the effects of selective nitric oxide synthase (NOS) inhibitors on dentate gyrus (DG) neurogenesis after diffuse brain injury (DBI) in adult rats. DBI models were established in adult male SD rats, followed by systemic bromodeoxyuridine (BrdU) labeling of the dividing cells and immunohistochemical assay of the proliferation rates of neural precursor cells in the DG for comparison between NOS inhibitor (7-nitroindazole and Aminoguanidine) groups and the corresponding control groups at various time points after DBI. Intraperitoneal administration of 7-nitroindazole significantly reduced the number of BrdU-labeled cells in the DG of adult rats 2, 4 and 6 d after DBI (P<0.05). Aminoguanidine also significantly inhibited the proliferation of neural precursor cells in the DG induced by DBI at various time points (P<0.01). The activation of NOS after DBI may be an important regulatory factor for DG neurogenesis in adult rats, and NO generated by nNOS is probably involved mainly in the early stage of enhanced neurogenesis after DBI, while the NO from iNOS might participated primarily in the later stages.


Factoring Origin of Life Hypotheses into the Search for Life in the Solar System and Beyond.
Two widely-cited alternative hypotheses propose geological localities and biochemical mechanisms for life's origins. The first states that chemical energy available in submarine hydrothermal vents supported the formation of organic compounds and initiated primitive metabolic pathways which became incorporated in the earliest cells; the second proposes that protocells self-assembled from exogenous and geothermally-delivered monomers in freshwater hot springs. These alternative hypotheses are relevant to the fossil record of early life on Earth, and can be factored into the search for life elsewhere in the Solar System. This review summarizes the evidence supporting and challenging these hypotheses, and considers their implications for the search for life on various habitable worlds. It will discuss the relative probability that life could have emerged in environments on early Mars, on the icy moons of Jupiter and Saturn, and also the degree to which prebiotic chemistry could have advanced on Titan. These environments will be compared to ancient and modern terrestrial analogs to assess their habitability and biopreservation potential. Origins of life approaches can guide the biosignature detection strategies of the next generation of planetary science missions, which could in turn advance one or both of the leading alternative abiogenesis hypotheses.


Socio-cultural issues and patient safety: a case study into the development of an electronic support tool for clinical handover.
This paper describes a case study into the development of an electronic support tool for clinical handover conducted in the Royal Hobart Hospital's Department of General Internal Medicine. By directly involving clinicians as co-participants in the development, and by conceptualising the system to be built as a support tool rather than as a 'total solution' this case study outlines the practical experience of dealing with a diversity of user requirements. The approach involved in-depth fieldwork to understand the factors and their inter-relationships in clinical handover processes. From an analysis of the data generated key issues relating to work processes and potential impacts on patient safety were identified and discussed with clinicians. A support tool incorporating a series of design features aimed at improving patient safety and supporting existing work processes identified as important by the clinicians was developed. Through early and continual involvement of clinicians in the project, this case study highlights how socio-cultural analysis can be translated meaningfully (in terms of the end-users) into systems design. The paper aims to contribute to a stronger recognition within the domain of eHealth of user-centred approach to systems development for patient safety.


Reliability and Validity of the Footprint Assessment Method Using Photoshop CS5 Software in Young People with Down Syndrome.
People with Down syndrome present skeletal abnormalities in their feet that can be analyzed by commonly used gold standard indices (the Hernández-Corvo index, the Chippaux-Smirak index, the Staheli arch index, and the Clarke angle) based on footprint measurements. The use of Photoshop CS5 software (Adobe Systems Software Ireland Ltd, Dublin, Ireland) to measure footprints has been validated in the general population. The present study aimed to assess the reliability and validity of this footprint assessment technique in the population with Down syndrome. Using optical podography and photography, 44 footprints from 22 patients with Down syndrome (11 men [mean ± SD age, 23.82 ± 3.12 years] and 11 women [mean ± SD age, 24.82 ± 6.81 years]) were recorded in a static bipedal standing position. A blinded observer performed the measurements using a validated manual method three times during the 4-month study, with 2 months between measurements. Test-retest was used to check the reliability of the Photoshop CS5 software measurements. Validity and reliability were obtained by intraclass correlation coefficient (ICC). The reliability test for all of the indices showed very good values for the Photoshop CS5 method (ICC, 0.982-0.995). Validity testing also found no differences between the techniques (ICC, 0.988-0.999). The Photoshop CS5 software method is reliable and valid for the study of footprints in young people with Down syndrome.


Current and future drugs targeting one class of innate immunity receptors: the Toll-like receptors.
Innate immunity receptors are germline-encoded receptors that can sense molecular signatures of pathogens and cancer cells. Recent advances in immunology demonstrate the key role of these receptors in inflammation and initiation of subsequent immune responses, including adaptive immunity. Pharmaceutical interest in this field has grown with the retrospective demonstration that some marketed drugs targeting cancer or infectious diseases act via those receptors. In this review, I present an update on the scientific rationale for targeting one class of innate immunity receptor, the Toll-like receptors, and an update on the development status of corresponding drug candidates in infectious diseases, cancer, allergy and vaccines.


Diagnostic value of cerebral vasospasm by transcranial doppler ultrasound in Vietnamese patients with subarachnoid hemorrhage.
Although the application of transcranial Doppler (TCD) ultrasonography in clinical diagnosis of cerebral vasospasm is popular in clinical practice in Vietnam, available evidence of the predictive value of vasospasm on TCD in the literature was mostly reported from large institutions in developed countries. Hence, this study was conducted to evaluate the value of TCD ultrasonography in the diagnosis of vasospasm in patients with subarachnoid hemorrhage (SAH) in Vietnam. This is a prospective observational study of all aneurysmal SAH patients consecutively admitted to a single center between 2008 and December 2011. TCD and 64-slice computed tomographic angiography (CTA) were used to cerebral vasospasm in SAH patients. 316 patients were analyzed (mean age = 52.97±12.27 years, 52.2% males). There were statistically significant difference rates of the cerebral vasospasm by Hunt and Hess Classification and Fisher classification (p <0.01). The proportion of the patients with cerebral vasospasm who were diagnosed exactly by TCD was 95.2%, while the proportion of the patients without cerebral vasospasm diagnosed exactly was 91.5%. TCD predictive diagnostic value was the highest, with the sensitivity of 0.95 (95% CI: 0.91-0.98), specificity of 0.91 (95% CI: 0.85-0.96), positive predictive value of 0.94 (5% CI: 0.90-0.97) and negative predictive value of 0.93 (95 CI: 0.87-0.97). Hemiplegia was the clinical symptom with the highest diagnostic value with the sensitivity of 0.34 (95% CI: 0.27-0.41), specificity of 0.92 (95% CI: 0.86-0.96), positive predictive value of 0.86 (95% CI: 0.76-0.93) and negative predictive value of 0.49 (95% CI: 0.41-0.54). Evidence of vasospasm diagnosis on TCD ultrasonography was found with high accuracy. Current study enables to suggest the wide application of TCD in Vietnam health facilities from central to grassroots levels instead of the CTA use.


Rethinking the benefits and costs of childhood vaccination: the example of the Haemophilus influenzae type b vaccine.
Economic evaluations of health interventions, such as vaccinations, are important tools for informing health policy. Approaching the analysis from the appropriate perspective is critical to ensuring the validity of evaluation results for particular policy decisions. Using the example of cost-benefit analysis (CBA) of Haemophilus influenzae type b (Hib) vaccination, we demonstrate that past economic evaluations have mostly adopted narrow evaluation perspectives, focusing primarily on health gains, health-care cost savings, and reductions in the time costs of caring, while usually ignoring other important benefits including outcome-related productivity gains (improved economic productivity due to prevention of mental and physical disabilities), behavior-related productivity gains (economic growth due to fertility reductions as vaccination improves child survival), and community externalities (herd immunity and prevention of antibiotic resistance). We further show that potential cost reductions that could be attained through changes in the delivery of the Hib vaccine have also generally been ignored in economic evaluations. Future economic evaluations of childhood vaccinations should take full account of benefits and costs, so that policymakers have sufficient information to make well-informed decisions on vaccination implementation.


The activity of superoxide dismutases (SODs) at the early stages of wheat deetiolation.
Unbound tetrapyrroles, i.e. protochlorophyllide (Pchlide), chlorophyllide and chlorophylls, bring the risk of reactive oxygen species (ROS) being generated in the initial stages of angiosperm deetiolation due to inefficient usage of the excitation energy for photosynthetic photochemistry. We analyzed the activity of superoxide dismutases (SODs) in etiolated wheat (Triticum aestivum) leaves and at the beginning of their deetiolation. Mn-SOD and three isoforms of Cu/Zn-SODs were identified both in etiolated and greening leaves of T. aestivum. Two Cu/Zn-SODs, denoted as II and III, were found in plastids. The activity of plastidic Cu/Zn-SOD isoforms as well as that of Mn-SOD correlated with cell aging along a monocot leaf, being the highest at leaf tips. Moreover, a high Pchlide content at leaf tips was observed. No correlation between SOD activity and the accumulation of photoactive Pchlide, i.e. Pchlide bound into ternary Pchlide:Pchlide oxidoreductase:NADPH complexes was found. Cu/Zn-SOD I showed the highest activity at the leaf base. A flash of light induced photoreduction of the photoactive Pchlide to chlorophyllide as well as an increase in all the SODs activity which occurred in a minute time-scale. In the case of seedlings that were deetiolated under continuous light of moderate intensity (100 μmol photons m-2 s-1), only some fluctuations in plastidic Cu/Zn-SODs and Mn-SOD within the first four hours of greening were noticed. The activity of SODs is discussed with respect to the assembly of tetrapyrroles within pigment-protein complexes, monitored by fluorescence spectroscopy at 77 K.