Intermittent theta burst stimulation of the right dorsolateral prefrontal cortex accelerates visuomotor adaptation with delayed feedback.
Implicit adaptation to visual rotations during fast reaching is a well-recognized function of the cerebellum. However, there is still no well-established understanding of the neural underpinnings that support explicit processes during visuomotor adaptation. We tested the causative involvement of dorsolateral prefrontal cortex (DLPFC) in an adaptive reaching task by employing excitatory intermittent theta burst stimulation (iTBS) to left or right DLPFC during learning to adapt to a sudden large visual rotation with delayed terminal feedback. Spontaneous resting-state electroencephalography (EEG) signals were recorded before and immediately after the administration of iTBS. iTBS to right DLPFC, compared to left DLPFC or control, induced faster adaptation to the rotation and had a greater adjustment of aiming directions in early adaptation trials. Moreover, resting-state functional connectivity of EEG of the frontal cortex after iTBS predicted subsequent adaptation rate. These results suggest a critical role of right DLPFC in supporting explicit learning in the adaptive reaching task.


Multiple dural arteriovenous fistulas involving the cavernous sinus, transverse sinus, sigmoid sinus and spinal drainage: CT angiography findings in 14-year-old boy.
Dural arteriovenous fistulas (DAVF) are rare and constitute 10% to 15% of all intracranial arteriovenous malformations. Only few cases of DAVFs are reported in children. Here is the first case report describing CT angiographic findings in a 14 year old child having multiple DAVFs involving spinal canal, both cavernous and cerebral sinuses.


Laboratory investigations in patients with generalized psoriasis under oral retinoid treatment. A multicenter study of computerized data.
Numerous laboratory parameters were examined 235 patients with generalized psoriasis treated orally with retinoid and in 35 patients treated topically with anthralin as control. Computer evaluation of the obtained data revealed statistical trends to elevation of the total serum bilirubin level and increasing number of blood monocytes after long-term oral treatment. No other statistically significant changes of the laboratory data were found. Particularly, the liver function tests (transaminases, prothrombin and alkaline phosphatase) showed no significant alterations. Only in a few cases did the retinoid compound have an influence on the GPT and GOT levels. The reasons for this individual sensitivity to the drug remain unknown. No significant alterations were found in the control group treated topically with anthralin.


Effects of nitroprusside on myocardial blood flow in acute regional coronary ischaemia in conscious dogs with and without left ventricular distension.
To determine the effects of nitroprusside on regional myocardial ischaemia, experiments were done in 11 conscious dogs with balloon-cuff occluders implanted around the left anterior descending coronary artery (LAD). Regional myocardial blood flow by the microsphere method was determined during 5 min periods of temporary LAD occlusion with and without nitroprusside infusion. Nitroprusside decreased aortic mean and left ventricular diastolic pressures. Blood flow increased to ischaemic myocardium supplied by the occluded LAD and to non-ischaemic myocardium supplied by the patent left circumflex coronary artery. Experiments were repeated on a separate day in the presence of left ventricular distension in the same dogs. Nitroprusside again decreased aortic mean and left ventricular diastolic pressures and increased the blood flow to both ischaemic and non-ischaemic myocardial regions. These results suggest that nitroprusside can improve perfusion to acutely ischaemic myocardial tissue despite a fall in aortic pressure, presumably by decreasing resistance to flow in coronary collateral vessels or by decreasing the myocardial tissue pressure.


Sonographic assessment of the ossification of the medial clavicular epiphysis in 616 individuals.
Establishing radiation-free imaging methods for the assessment of clavicular ossification in forensic age determination is desirable as it reduces radiation exposure in living individuals. For this purpose the stage of ossification of the right medial clavicular epiphysis was determined prospectively using sonography in 309 male and 307 female healthy volunteers. The classification of stages according to Schulz et al. was used for this purpose. Stage 2 was first noticed at the age of 14.4 years in males, and at the age of 14.1 years in females. Stage 3 was first achieved by males at the age of 17.6 years and by females at the age of 17.4 years. Stage 4 first occurred in males at the age of 19.3 years and at the age of 18.9 years in females. The mean age for stage 1 was 13.6 years. The mean age of stage 2 ranged between 17.3 and 17.6 years. For stage 3 the mean age varied from 20.7 to 21.2 years, and for stage 4 from 23.3 to 23.5 years. It was concluded that sonographically determined stage 4 clavicular ossification provides evidence for the completion of the nineteenth year of life in males and the eighteenth year of life in females. In order to increase the reliability of age determination using this method it is recommended that findings be recorded by at least two experienced independent examiners who then reach a consensus.


Testing crossover studies for carryover effects.
For the study of cardiovascular disease, for instance, hypertension and angina pectoris, properly designed crossover studies are to be preferred over parallel-design studies. Many statisticians now propose that these studies should always be tested for carryover effects. In the present paper the author analyzes the crossover studies published after November, 1985, in two general and two specialist journals (New England Journal of Medicine, Lancet, Angiology, British Heart Journal). Of 73 papers only 23 (32%) consider the possibility of carryover effects. Of these latter papers 12 (16%) perform statistical tests for these effects. The results of these tests were shown in only 7 papers (10%). It is concluded that there is a discrepancy between the statistical recommendations and the data presented in the literature.


History of the surgical management of pulmonary metastases and development of the International Registry.
Pulmonary metastasectomy has been gradually recognized as a potentially curative treatment in properly selected cases, and a greater number of patients are now being offered salvage surgery. The results of the International Registry of Lung Metastases (IRLM) have defined the long-term survival after metastasectomy and provided a new classification system combining anatomical and biological features to assess prognosis in the various primary tumors.


The Diagnosis of Developmental Dysplasia of the Hip From Hip Ultrasonography Images With Deep Learning Methods.
Hip ultrasonography is very important in the early diagnosis of developmental dysplasia of the hip. The application of deep learning-based medical image analysis to computer-aided diagnosis has the potential to provide decision-making support to clinicians and improve the accuracy and efficiency of various diagnostic and treatment processes. This has encouraged new research and development efforts in computer-aided diagnosis. The aim of this study was to evaluate hip sonograms using computer-assisted deep-learning methods. The study included 376 sonograms evaluated as normal according to the Graf method, 541 images with dysplasia and 365 images with incorrect probe position. To classify the developmental hip dysplasia ultrasound images, transfer learning was applied with pretrained VGG-16, ResNet-101, MobileNetV2 and GoogLeNet networks. The performances of the networks were evaluated with the performance parameters of accuracy, sensitivity, specificity, precision, F1 score, and AUC (area under the ROC curve). The accuracy, sensitivity, specificity, precision, F1 score, and AUC results obtained by testing the VGG-16, ResNet-101, MobileNetV2, and GoogLeNet models showed performance >80%. With the pretrained VGG-19 model, 93%, 93.5%, 96.7%, 92.3%, 92.6%, and 0.99 accuracy, sensitivity, specificity, precision, F1 score, and AUC results were obtained, respectively. In this study, in addition to the ultrasonography images of dysplastic and healthy hips, images were also included of probe malpositioning, and these images were able to be successfully evaluated with deep learning methods. On the sonograms, which provided criteria appropriate for evaluation, successful differentiation could be made of healthy hips and dysplastic hips. Level-IV; diagnostic studies.


The use of flowable composites as filled adhesives.
The effect of filled adhesives on bonding resin composites to dentin has not been fully understood. Due to their filler content, filled adhesives may act as stress breakers. The aim of this in vitro study was to evaluate the use of flowable composites of different viscosities on bonding to enamel and dentin without the use of an intermediate bonding resin. Enamel and dentin bond strengths of OptiBond FL, Syntac Classic, and EBS Multi combined either with their proprietary bonding agent or a flowable resin composite (Ultraseal XT Plus or Revolution) were measured. The tests were carried out with a microtensile device at a crosshead speed of 1mm/min after 24h of storage at 37 degrees C in water. Mean bond strengths were analyzed using the Wilcoxon test and multiple comparisons according to the Mann-Whitney U-test. The micro-morphology of corresponding resin-dentin interfaces of the same teeth were analyzed using SEM and TEM. The control groups with adhesive systems used as per manufacturers' protocol showed bond strengths of 38.9-41.1 MPa to enamel and 28.8-33.4 MPa to dentin. With respect to bond strength to etched enamel, only Ultraseal XT Plus as bonding resin reached the level of the control groups. When used as bonding agents on dentin, both flowable composites produced lower microtensile bond strengths to etched and primed dentin than did the control groups. Micro-morphological analysis using SEM and TEM resulted in hybrid layer formation for both control and experimental groups. However, many areas of the resin-dentin interface showed insufficient penetration of the flowable composites at the top of the hybrid layer as well as numerous tubules obstructed by filler particles. The flowable composites tested in this study should not be used to replace bonding agents. Flowable composites of thinner viscosity, such as Ultraseal XT Plus, may bond to enamel adequately without the requirement of an intermediate bonding resin.


Attitudes and Beliefs of Working and Work-Disabled People with Chronic Pain Prescribed Long-Term Opioids.
This study was designed to gain insight into the apparent contradiction between the perspectives of researchers and policy makers, who have questioned the efficacy and safety of chronic opioid therapy for non-cancer pain patients, and the patients themselves, who often indicate that the therapy has value. A convenience sample of 54 patients on chronic opioid therapy was studied. Participants completed a questionnaire specifically designed for the study, and also several standard instruments that addressed functional interference, emotional functioning, and possible misuse of opioids. Their treating physicians rated the participants on the severity of their disability and the success of their opioid therapy. Although participants reported significant ongoing pain, they gave positive global ratings to their opioid therapy, and reported little concern about addiction or side effects of opioids. They strongly endorsed the beliefs that opioids helped them control their pain and allowed them to participate in important activities such as work. They expressed the belief that their pain would be severe if they did not have access to opioids, and reported negative experiences with tapering or discontinuing opioids in the past. Work-disabled participants reported higher levels of affective distress, catastrophizing, and functional interference than working participants, and were judged by their physicians to be relatively less successful in managing their pain. The results of this study suggest several tentative hypotheses about why patients on chronic opioid therapy value opioids, and identified several areas for systematic investigation in the future.


Pertussis, diphtheria, and tetanus antibodies seroprevalence in pregnant women and neonates, as a preliminary data for introduction of preconception or prenatal DTaP vaccination among Japanese society.
An increasing number of countries have been introducing acellular pertussis vaccination during pregnancy for the prevention of neonatal pertussis. In response to the fact that infantile pertussis cases of 0-5 months age groups remained unchanged despite the universal vaccination program, prenatal pertussis vaccination has been a rising issue in Japan. Hence, we investigated the seroprevalence of pertussis, diphtheria, and tetanus antibodies in Japanese pregnant women and neonates, and evaluated the necessity of diphtheria-tetanus-acellular pertussis (DTaP) vaccination during the preconception or prenatal period. Maternal PT-IgG (EIA) and FHA-IgG (EIA) for the first trimester, within 1 week after delivery, and cord blood were collected, along with colostrum pertussis-IgA (ELISA), diphtheria-IgG (EIA), tetanus-IgG (EIA), and blood samples from the first trimester. The maternal seroprevalence of PT-IgG and FHA-IgG was 69 % and 75 %, respectively. All tested participants were positive for diphtheria-IgG and tetanus-IgG (100 %). First trimester PT-IgG/FHA-IgG antibody titers were significantly associated with cord blood PT-IgG/FHA-IgG titers (P < 0.001). We found that pertussis seroprevalence among pregnant Japanese women was approximately 70 %. The antibody seropositivity rate of pertussis was lower than that of diphtheria and tetanus. Fetal acquired passive immunity against pertussis is higher when the level of maternal antibody in the first trimester is sufficient. At least 30 % of study population did not reach to the threshold value to provide sufficient pertussis immunity for the neonates and themselves. The acellular pertussis vaccine (DTaP) approved in Japan lacks safety information for pregnancy, hence, a solution for prompt administration of prenatal acellular pertussis vaccination might be introducing DTaP in the preconception period.


Amniotic fluid prostacyclin and thromboxane in normal, preeclamptic, and some other complicated pregnancies.
To study the involvement of the antiaggregatory and vasodilator prostacyclin (PGI2) and proaggregatory and vasoconstrictor thromboxane A2 (TxA2) in complicated pregnancies, we measured by radioimmunoassay the stable metabolites of PGI2 and TxA2, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2), respectively, in samples of amniotic fluid collected at amniocentesis from 88 women between 30 and 40 weeks' normal or complicated pregnancy. The concentrations (mean +/- SE) of 6-keto-PGF1 alpha were 171.8 +/- 9.0 pg/ml in normal pregnancies (N = 27), 134.4 +/- 9.3 pg/ml in severe preeclampsia (N = 13) (0.001 less than p less than 0.005 in comparison with normal pregnancy), 175.6 +/- 13.9 pg/ml in mild preeclampsia (N = 14) (0.01 less than p less than 0.05 in comparison with severe preeclampsia), 168.5 +/- 16.9 pg/ml in diabetic pregnancies (N = 14), 158.7 +/- 5.9 pg/ml in rhesus-immunized pregnancies (N = 10), and 178.7 +/- 13.7 pg/ml in pregnancies with intrauterine fetal growth retardation (N = 10). The corresponding TxB2 concentrations were, respectively, 35.0 +/- 5.7 pg/ml, 29.1 +/- 4.6 pg/ml, 31.3 +/- 3.1 pg/ml, 35.3 +/- 4.0 pg/ml, 31.4 +/- 5.9 pg/ml, and 39.2 +/- 3.2 pg/ml, and these levels did not differ from each other. The level of 6-keto-PGF1 alpha in amniotic fluid correlated with the pregnancy week in normal and preeclamptic pregnancies, and the levels of TxB2 in amniotic fluid in normal, preeclamptic, and rhesus-immunized pregnancies. Furthermore, these two prostanoids correlated with each other in normal pregnancy and in all complications except rhesus-immunized pregnancies. Thus, it is evident that the release of PGI2 into the amniotic fluid is decreased in severe preeclampsia.


The effect of breastfeeding on spontan resolution of monosymptomatic enuresis.
The aim of this study was to examine whether the duration of breastfeeding during infancy was associated with the time of spontaneous resolution of monosymptomatic enuresis (SRME). A total of 1500 people were surveyed at four centers. One hundred and eighty-one people with a history of monosymptomatic enuresis (ME) who received no treatment and had no day time symptoms were included in the study. The relationship between the duration of breastfeeding and SRME was assessed by considering the duration of breastfeeding as both continuous and categorical (cut-off value 5 months) variable. The multivariate general linear model was used to identify independente predictors such as gender, family history, and educational status of parents. Pearson correlation analysis of the age of SRME and duration of breastfeeding found no statistically significant relationship. However, there was a significant difference in the age of SRME of those who were breastfed for 5 months or less compared to those who were breastfed for more than 5 months. According to the multivariate analysis, gender and educational status of parents were not effective on the age of SRME. Stepwise linear regression model showed that breastfeeding for five months or less and family history could affect the age of SRME. The regression formula was: age of SRME=9.599 + (3.807×five months or less of breastfeeding) + (1.258×positive family history). It was found that when breastfeeding lasted for more than 5 months, there was a positive contribution to SRME.


Lin28a is a putative factor in regulating cancer stem cell-like properties in side population cells of oral squamous cell carcinoma.
Cancer stem cells (CSCs) are among the target cells of cancer therapy because they are uniquely involved in both cancer progression and sensitivity to chemotherapeutic agents. We identified side population (SP) cells, which are known to be an enriched population of CSC, in five oral squamous cell carcinoma (OSCC) cells (SCC9, SCC25, TOSCC7, TOSCC17, and TOSCC23). The percentages of SP cells ranged from 0% to 3.3%, with TOSCC23 cells showing the highest percentages of SP cells (3.3% of the total cell population). The SP cells isolated from TOSCC23 cells also showed greater cell proliferation and invasion compared to non-SP (MP) cells. Therefore, our initial findings suggested that SP cells were enriched for CSC-like cells. Furthermore, DNA microarray analysis revealed that the expression of cell proliferation-related and anti-apoptotic genes was greater in SP cells compared to MP cells. We focused on Lin28a, which showed the highest expression (approximately 22-fold) among the upregulated genes. The overexpression of Lin28a in TOSCC23 cells increased their proliferation, colony formation, and invasion. These findings suggest that Lin28a is an appropriate CSC target molecule for OSCC treatment.


Severe loss of appetite in amyotrophic lateral sclerosis patients: online self-assessment study.
Undesirable loss of weight is a major challenge in amyotrophic lateral sclerosis (ALS). However, little is known about loss of appetite in ALS patients. We investigated loss of appetite in ALS patients by means of an online self-assessment and whether ALS-related symptoms were associated with it. Loss of appetite in 51 ALS patients was assessed using the Council on Nutrition Appetite Questionnaire (CNAQ). Loss of appetite is defined as a CNAQ-score of 28 or less with a predicted weight loss of at least 5% within 6 months. We developed an Internet portal to facilitate self-assessment. Approximately half of the ALS patients (47%, 24/51) suffered from severe loss of appetite; after 6 months this increased to nearly two-thirds (65%, 22/34). An average weight loss of 5% was found in the group with severe loss of appetite as compared to only 2% of patients with normal appetite. Interestingly, loss of appetite was associated with respiratory dysfunction (P=.001, R(2)=.223). Loss of appetite was more common and more severe than expected. It was found to be an independent risk factor for unintended weight loss and may be related to dyspnea. The impact of severe loss of appetite on survival and quality of life should be established in further studies.


Synthesis of 3'-(4-nitroimidazol-1-yl)-2',3'-dideoxynucleosides of pyrimidine analogues and their biological evaluation against HIV.
Reaction of 1,5-di-O-acetyl-2,3-dideoxy-3-phthalimido-beta-D-erythro-pento-fur anose (1) with silylated pyrimidinediones 2a-c using the Lewis acid trimethylsilyl triflate as catalyst afforded nucleosides 3a-c and 4a,c which were deprotected with 33% methylamine/ethanol to give the corresponding 3-aminonucleosides 5a-c and 6. These were reacted with 1,4-dinitroimidazoles 7a,b to give the 3-imidazolyldideoxynucleosides 8a,b and 9a-f. At sub-toxic concentrations these compounds were ineffective against HIV-1.


Vertical banded gastroplasty as an antireflux procedure.
Vertical banded gastroplasty creates a channel by two applications of the TA-90 stapler from an end-to-end anastomosis window above the crow's foot to the angle of His, against a 32 F. tube along the lesser curvature. The caudad end of the channel is restricted by a 5 cm collar. Thirty-one obese patients more than 45 kg overweight were studied by interview, barium swallow, endoscopy, and manometry. These procedures were repeated 13 +/- 5.5 weeks postoperatively, after resolution of operative edema and before extensive weight loss. Preoperative symptoms included heartburn in 24 patients, regurgitation in 17 patients, and aspiration in 2 patients, and barium swallow demonstrated hiatal hernia in 7 patients and reflux in 7 patients (5 with hiatal hernia). In addition, endoscopy detected mild esophagitis in 3 patients, and hiatal hernia in 11 patients. Postoperatively, the incidence of heartburn decreased in all patients, barium swallow showed slow channel emptying but no hiatal hernia or reflux, and endoscopy did not identify any esophagitis. Preoperative lower esophageal sphincter pressure was 14.5 +/- 7.2 mm Hg. Postoperatively, the vertical banded gastroplasty channel had an initial peak (collar) pressure of 19.2 +/- 7.8 mm Hg (p less than 0.01 compared with preoperative lower esophageal sphincter pressure), a channel pressure of 9.5 +/- 6 mm Hg, a lower esophageal sphincter pressure of 20.1 +/- 7.7 mm Hg (p less than 0.005), and a channel length of 6.8 +/- 1.4 cm. Vertical banded gastroplasty creates a high pressure channel, inhibiting reflux of gastric juice without the need for any additional procedure.


Moving forward with strengthening routine immunization delivery as part of measles and rubella elimination activities.
The Global Vaccine Action Plan includes a goal of meeting global and regional measles and rubella elimination targets, noting that such efforts should not operate in silos but be coordinated with other immunization efforts. Similarly, the Global Measles and Rubella Strategic Plan for 2012-2020 emphasizes the need for integrated approaches to achieve and maintain very high levels of population immunity using both routine immunization and supplemental immunization activities (SIAs). The strategic plan also includes routine vaccination coverage targets, highlighting the critical role of strong routine immunization systems as a cornerstone for sustainable measles control/elimination efforts. It encourages exploiting the resources and visibility of SIAs to strengthen routine immunization, thereby reducing the frequency with which SIAs are needed. Documented examples of doing so include training health workers, procuring cold chain equipment, and improving injection safety and adverse events management. However, the concept has been put into practice only to a limited extent and missed opportunities persist regarding this aspect of SIA planning and execution. This paper draws on recent studies of the interaction between measles activities and health systems as well as country experiences in using SIAs to strengthen routine immunization. It identifies obstacles and enabling factors to doing so and proposes options for systematically strengthening routine immunization as part of a best practice SIA.


A model for oxygen storage by hemoglobin.
An oxygen store based on the reversible combination of oxygen with hemoglobin or related hemoproteins could be of considerable value to organisms or tissues faced with intermittent hypoxia or anoxia. It would be of interest, therefore, to know the physical and chemical requirements and limitations of useful storage. A model is presented which predicts storage time from physical, chemical, and geometric properties of the store. Storage time is arbitrarily defined as the time for 50% of the stored O2 to diffuse from a fully-loaded store when the store is exposed to a zero O2 environment. Results are presented in the form of simple approximate equations and in graphical form and indicate that: (1) a wide range of storage times can be obtained with reasonable biological parameters; (2) storage times approaching 1,000 s can be achieved even with stores of microscopic dimension; (3) biological O2 storage is predominantly diffusion-limited, although reaction-limited behavior is not impossible; and (4) the major effect of co-operativity appears to be on the form of O2 release: hemoglobins without co-operativity release O2 at a constantly declining rate, whereas those with high co-operativity release O2 at a constant rate. The model is applicable not only to hemoglobin-based O2 storage, but also to any reaction-diffusion system in which one substance can be "stored" by reversible combination with some other substance which acts as the store.


Epigenetic regulation of EBV and KSHV latency.
The gammaherpesviruses are unique for their capacity to establish a variety of gene expression programs during latent and lytic infection. This capacity enables the virus to control host-cell proliferation, prevent programmed cell death, elude immune cell detection, and ultimately adapt to a wide range of environmental and developmental changes in the host cell. This remarkable plasticity of gene expression results from the combined functionalities of viral and host factors that biochemically remodel and epigenetically modify the viral chromosome. These epigenetic modifications range from primary DNA methylations, to chromatin protein post-translational modifications, to higher-order chromosome conformations. In addition, gammaherpesviruses have acquired specialized tools to modulate the epigenetic processes that promote viral genome propagation and host-cell survival.


Determinative Structural Features Identified With Probe-based Confocal Endomicroscopy for the Accurate Diagnosis of Gallbladder Malignancy.
Probe-based confocal laser endomicroscopy (pCLE) can visualize microscopic structures at high resolution but has not yet yielded definitive diagnostic features of gallbladder malignancy, as opposed to benign changes. A total of 73 patients had their gallbladder evaluated with pCLE performed on resected benign and malignant gallbladder surgical specimens, which were sprayed with fluorescein. Malignant and benign features of pCLE findings were identified on the basis of Miami and Paris Classifications. Standard histopathological diagnoses and individual patient pCLE findings of gallbladder lesions were correlated. Of the 73 consecutive patients that had their gallbladder evaluated ex vivo with pCLE, 11 were identified with gallbladder malignancy. pCLE identified features of gallbladders examined ex vivo, including the presence of thick dark bands and dark clumps, which together correlated with histopathologically-determined biliary malignancy at 100% sensitivity. Thick white bands and visualized epithelium, also identified with pCLE, together correlated with histopathologically-determined malignancy at 100% specificity. pCLE can be used for real-time differentiation of cancerous/non-cancerous regions in the gallbladder using the diagnostic criteria identified in the present study.


Attenuation of myocardial ischemia-reperfusion injury with nitric oxide replacement therapy.
The coronary vascular endothelium produces nitric oxide (NO) during the conversion of L-arginine to L-citrulline. Although NO is a potent vasodilator, at lower concentrations, it also has antineutrophil actions that reduce the inflammatorylike components of ischemia-reperfusion injury. The endothelium is damaged in the early minutes after reperfusion, ie, before neutrophils accumulate and before myocardial necrosis fully develops, and this suggests that endothelial injury is a springboard event in the postischemic inflammatory cascade. Studies of coronary artery occlusion and reperfusion suggest that early damage to the coronary endothelium impairs NO production, which, in turn, abrogates the endogenous antineutrophil effects of NO. However, this impaired endogenous NO-related cardioprotection can be restored either by providing specifically at the onset of reperfusion the precursor to NO (L-arginine) or by providing agents that donate NO. In studies, L-arginine or NO donors reduce infarct size in models of coronary occlusion and reperfusion. The mechanism or mechanisms of this cardioprotection involve preservation of endothelial function and inhibition of neutrophil accumulation in ischemic-reperfused tissue. The cardioprotective potential of NO offers a new therapeutic approach to the reduction of ischemia-reperfusion injury after coronary artery occlusion.


Bis(triazacyclohexane) sandwich complexes of (Cu(I))(2), Cu(II) and Zn(II): complexes with cuprophilic attraction between two cationic copper(I) leading to unusual reactivity with dioxygen.
As the first 1st-row transition metal complexes having six tertiary amine donor groups, bis(triazacyclohexane) sandwich complexes [L2M](BF4)2 (L = benzyl- or p-fluorobenzyl-triazacyclohexane, M = Cu or Zn) have been obtained by the protonolysis of Et2Zn in the presence of L or by reaction of [Cu(MeCN)4](BF4) with L in CH2Cl2 and subsequent air oxidation via an unprecedented Cu(I)(2) sandwich complex containing a short Cu-Cu contact.


Socioeconomic deprivation and long-term outcomes after elective surgery: analysis of prospective data from two observational studies.
Socioeconomic deprivation is associated with health inequalities. We explored relationships between socioeconomic group and outcomes after elective surgery in the UK National Health Service (NHS). We combined data from two observational studies in 115 NHS hospitals and determined socioeconomic group using the Index of Multiple Deprivation (IMD) quintiles based on place of residence. Postoperative complications and 3-yr survival were assessed using logistic and Cox regression. Univariate analyses were adjusted for age differences between IMD quintiles. Multivariable analyses were used to account for other baseline risk factors including sex and comorbid disease. Results are reported as n (%), hazard ratios (HR) or odds ratios (OR) with 95% confidence intervals. Postoperative complications developed in 971/9051 patients (10.7%) and 1597/9043 patients (17.7%) died within 3 yr. Complication rates increased with deprivation (reference group least-deprived IMD5): IMD1 (OR=1.44 [1.17-1.78]; P<0.001), IMD2 (OR=1.38 [1.12-1.70]; P<0.01), IMD3 (OR=1.09 [0.88-1.35]: P=0.44), IMD4 (OR=0.89 [0.71-1.11]; P=0.30). More patients from the most deprived quintile died (IMD1) (n=349, 18.8%) compared with the least deprived (IMD5) (n=297, 15.9%) with a trend across the socioeconomic spectrum (P=0.01). After age adjustment, patients in the most deprived areas experienced reduced 3-yr survival: IMD1 (HR=1.43 [1.23-1.67]; P<0.0001), IMD2 (HR=1.35 [1.15-1.57]; P<0.001), IMD3 (HR=1.04 [0.89-1.23]; P=0.60), and IMD4 (HR=1.11 [0.95-1.30]; P=0.19). This finding persisted in risk-adjusted analyses. Increased complication rates only partially explained this reduced survival. Socioeconomic deprivation is associated with worse long-term outcomes after elective surgery. This risk factor should be considered when planning perioperative care for patients from deprived areas.


Factors associated with antimicrobial use in pig and veal calf farms in the Netherlands: A multi-method longitudinal data analysis.
Minimizing antimicrobial use (AMU) in livestock is needed to control antimicrobial resistance (AMR). In the Netherlands, the livestock sector reduced AMU by almost 70 % since 2009, but this reduction stagnated in recent years. With only therapeutic AMU allowed, it is clear that besides socio-economic and behavioral factors, also the farm technical characteristics influence the conditions under which farmers need AMU. These characteristics pertain to farm management, including biosecurity, vaccination schemes, nutrition, micro-climate and husbandry practices. Identifying farm-related risk factors for AMU is needed to control AMR in a sustainable and pragmatic way. This need, often concerns the overall contribution of seemingly related (rather than individualized) factors. Here, risk factors for AMU in pig and calf farms were determined using two approaches: a typical risk factor analysis based on generalized estimating equations (GEEs) or hierarchical mixed-effects models and a multiblock partial least-squares regression analysis. These methods were applied to longitudinal data from two previous studies, i.e. a panel study and an intervention study involving 36 multiplier pig farms and 51 veal calf farms in the Netherlands, respectively. The multiblock analysis allowed us to quantify the importance of each factor and their respective block (i.e. farm management domain). For pigs, factors related to internal biosecurity had the highest impact on AMU, while for calves, these were mainly related to micro-climate. Structural characteristics, such as farm size and production type, followed in importance for both sectors. While both methods provided similar outcomes, the multiblock approach provided further insights by grouping and comparing factors believed to be inter-related.


Sanpodo controls sensory organ precursor fate by directing Notch trafficking and binding γ-secretase.
In Drosophila peripheral neurogenesis, Notch controls cell fates in sensory organ precursor (SOP) cells. SOPs undergo asymmetric cell division by segregating Numb, which inhibits Notch signaling, into the pIIb daughter cell after cytokinesis. In contrast, in the pIIa daughter cell, Notch is activated and requires Sanpodo, but its mechanism of action has not been elucidated. As Sanpodo is present in both pIIa and pIIb cells, a second role for Sanpodo in regulating Notch signaling in the low-Notch pIIb cell has been proposed. Here we demonstrate that Sanpodo regulates Notch signaling levels in both pIIa and pIIb cells via distinct mechanisms. The interaction of Sanpodo with Presenilin, a component of the γ-secretase complex, was required for Notch activation and pIIa cell fate. In contrast, Sanpodo suppresses Notch signaling in the pIIb cell by driving Notch receptor internalization. Together, these results demonstrate that a single protein can regulate Notch signaling through distinct mechanisms to either promote or suppress signaling depending on the local cellular context.


Experience with thoracoscopic surgery for primary bronchial stump fistula after pneumonectomy.
After a left pneumonectomy, thoracoscopic closure with fibrin glue was performed for a fistula on the bronchial stump and the postoperative state progressed favorably thereafter. In this paper, we report on this successful case. A 61 year-old male, who underwent a left pneumonectomy on January 17, 1996 for pulmonary carcinoma (T 3 N 1M 0 stage III A). The bronchial stump was covered with anterior serratus muscle flap. On April 1 (the 76th postoperative day), after two courses of Carboplatin and Vindesine treatment, the patient suddenly developed a fistula on the bronchial stump. Bronchofiberscopic closure with fibrin glue was attempted, but failed to close the fistula. Thoracoscopic surgery was then performed on May 15 (the 45th day after the onset of the fistula). After the intrathoracic opening of the fistula was found with a contrast medium, fibrin glue was injected to fill up to the bronchial stump, and communication with the thoracic cavity was blocked. Owing to coverage with a myocutaneous flap, the patient's general postoperative state remained relatively stable. Thoracoscopic surgery is useful as a treatment for some cases of bronchial stump fistula after pneumonectomy.


Synthesis of 1-/2-substituted-[1,2,3]triazolo[4,5-g]phthalazine-4,9-diones and evaluation of their cytotoxicity and topoisomerase II inhibition.
Studies on antitumor heterocyclic quinones containing nitrogens revealed that the number and position of nitrogens on the heterocyclic ring have significance on cytotoxicity of quinones. In our continuous effort to find more cytotoxic quinone compounds, we designed triazolophthalazine analogues in order to introduce more nitrogens on the heterocyclic quinones. 1-/2-Substituted-[1,2,3]triazolo[4,5-g]phthalazine-4,9-diones were synthesized by 1,3-dipolar addition of phthalazine-5,8-dione and 4-methoxybenzyl azide by modification of previously reported method. The cytotoxicity of the synthesized compounds was evaluated by a SRB (sulforhodamine B) assay against nine types of human cancer cell lines and inhibition against topoisomerase II (Topo II) of them was assessed by a decatenation assay. Most of the synthesized compounds showed considerably higher cytotoxicity than that of doxorubicin. Also, topoisomerase II inhibitory activity of the tested compounds was higher than that of etoposide and IC(50) values of the compounds were 19.4-64.5 microM.


A comparison of plants and animals in their responses to risk of consumption.
Both plants and animals reduce their risk of being eaten by detecting and responding to herbivore and predator cues. Plants tend to be less mobile and rely on more local information perceived with widely dispersed and redundant tissues. As such, plants can more easily multi-task. Plants are more tolerant of damage and use damage to their own tissues as reliable cues of risk; plants have a higher threshold before responding to the threat of herbivory. Plants also use diverse cues that include fragments of plant tissue and molecular patterns from herbivores, herbivore feeding, or microbial associates of herbivores. Instead of fleeing from attackers, plants reallocate valuable resources to organs at less risk. They minimize unnecessary defenses against unrealized risks and costs of failing to defend against actual risk. Plants can remember and learn, although these abilities are poorly understood.


Revision of ureteral reimplantation by the transverse advancement technique.
Antireflux ureteral reimplantation may be performed by a variety of techniques with consistently satisfactory results. Complications, such as persistent reflux and postoperative ureterovesical obstruction, may be encountered occasionally and, when significant, they will necessitate a revision operation. Herein 6 cases are described of failed ureteral reimplantation, which were revised successfully by performing a transverse advancement ureteral reimplantation.


Zinc oxide nanoparticles coated urea enhances nitrogen efficiency and zinc bioavailability in wheat in alkaline calcareous soils.
Nitrogenous fertilizers have low efficiency in alkaline calcareous soils due to volatilization and denitrification. These losses cause economic environmental constraints. Coating of urea with nanoparticles (NPs) is an innovative strategy to improve crop yields by sustaining N availability. In the current study, zinc oxide nanoparticles (ZnO NPs) were synthesized by precipitation method and characterized for morphology and configuration, bond formation, and crystal assemblage using the X-ray diffraction and scanning electron microscope (SEM). The SEM results confirmed the size of ZnO NPs in the size range of 25 nm with cuboid shape. Urea fertilizer, coated with ZnO NPs, was applied to wheat crop in a pot trial. Two rates of ZnO NPs at 2.8 and 5.7 mg kg-1 were selected to coat the commercial urea. A batch experiment was conducted to ensure the ammonium (NH4+) and nitrate (NO3-) ions release by amending the soil with ZnO NPs coated urea and comparing with non-amended soil. The gradual release of NH4+ was observed for 21 days from the ZnO NP-coated urea. In the second part of trial, seven different treatments of coated and uncoated urea were tested on wheat crop. Urea coated with ZnO nanoparticles at 5.7 mg kg-1 improved all growth attributes and yields. The ZnO NP coated urea increased the N content shoot (1.90 g 100g-1 DW) and potentially biofortified Zn content (47.86 mg kg-1) in wheat grain. The results are indicative of viability of a novel coating for commercial urea that will not only reduce N losses but also supplement Zn without additional cost of labor.


Motion sickness: effect of the magnitude of roll and pitch oscillation.
Rotational oscillation in roll and pitch can cause motion sickness, but it is not known how sickness depends on the magnitude of rotational oscillation or whether there is a difference between the two axes of motion. It was hypothesized that motion sickness would increase similarly with increasing magnitudes of roll and pitch oscillation. There were 120 subjects (6 groups of 20 subjects) who were exposed to 30 min of 0.2-Hz sinusoidal roll or pitch oscillation at 1 of 3 magnitudes: 1) +/- 1.830; 2) +/- 3.66 degrees; or 3) +/- 7.32 degrees. Subjects sitting in a closed cabin with their eyes open gave ratings of their illness on a 7-point illness rating scale at 1-min intervals. Over the six conditions, mild nausea was reported by 17.5% of subjects. With both roll oscillation and pitch oscillation, mean illness ratings were least with +/- 1.83 degrees of rotational oscillation and greater with +/- 3.66 degrees and +/- 7.32 degrees of oscillation. At none of the three magnitudes of oscillation was there a significant difference in motion sickness caused by roll and pitch oscillation. With rotational oscillation about an Earth-horizontal axis, there is a trend for motion sickness to increase with increasing motion magnitude. For the conditions investigated, similar motion sickness was caused by roll and pitch oscillation.


Indole pyruvate decarboxylase gene regulates the auxin synthesis pathway in rice by interacting with the indole-3-acetic acid-amido synthetase gene, promoting root hair development under cadmium stress.
This research focused on cadmium (Cd), which negatively affects plant growth and auxin hemostasis. In plants, many processes are indirectly controlled through the expression of certain genes due to the secretion of bacterial auxin, as indole-3-acetic acid (IAA) acts as a reciprocal signaling molecule in plant-microbe interaction. The aim of current studies was to investigate responsible genes in rice for plant-microbe interaction and lateral root development due to the involvement of several metabolic pathways. Studies revealed that GH3-2 interacts with endogenous IAA in a homeostasis manner without directly providing IAA. In rice, indole-3-pyruvate decarboxylase (IPDC) transgenic lines showed a 40% increase in lateral roots. Auxin levels and YUCCA (auxin biosynthesis gene) expression were monitored in osaux1 mutant lines inoculated with Bacillus cereus exposed to Cd. The results showed an increase in root hairs (RHs) and lateral root density, changes in auxin levels, and expression of the YUCCA gene. B. cereus normalizes the oxidative stress caused by Cd due to the accumulation of O 2 - and H2O2 in osaux1 mutant lines. Furthermore, the inoculation of B. cereus increases DR5:GUS expression, indicating that bacterial species have a positive role in auxin regulation. Thus, the current study suggests that B. cereus and IPDC transgenic lines increase the RH development in rice by interacting with IAA synthetase genes in the host plant, alleviating Cd toxicity and enhancing plant defense mechanisms.


Slitrk2 controls excitatory synapse development via PDZ-mediated protein interactions.
Members of the Slitrk (Slit- and Trk-like protein) family of synaptic cell-adhesion molecules control excitatory and inhibitory synapse development through isoform-dependent extracellular interactions with leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs). However, how Slitrks participate in activation of intracellular signaling pathways in postsynaptic neurons remains largely unknown. Here we report that, among the six members of the Slitrk family, only Slitrk2 directly interacts with the PDZ domain-containing excitatory scaffolds, PSD-95 and Shank3. The interaction of Slitrk2 with PDZ proteins is mediated by the cytoplasmic COOH-terminal PDZ domain-binding motif (Ile-Ser-Glu-Leu), which is not found in other Slitrks. Mapping analyses further revealed that a single PDZ domain of Shank3 is responsible for binding to Slitrk2. Slitrk2 forms in vivo complexes with membrane-associated guanylate kinase (MAGUK) family proteins in addition to PSD-95 and Shank3. Intriguingly, in addition to its role in synaptic targeting in cultured hippocampal neurons, the PDZ domain-binding motif of Slitrk2 is required for Slitrk2 promotion of excitatory synapse formation, transmission, and spine development in the CA1 hippocampal region. Collectively, our data suggest a new molecular mechanism for conferring isoform-specific regulatory actions of the Slitrk family in orchestrating intracellular signal transduction pathways in postsynaptic neurons.


Metastatic carcinoma of the prostate presenting radiographically as lymphoma.
Anterior mediastinal and retroperitoneal lymphadenopathy is rarely clinically evident in patients with metastatic carcinoma of the prostate. We report a case in which the nodal disease was suggestive of the diagnosis of malignant lymphoma. Immunohistochemical stain for prostate specific antigen was useful in assuring the diagnosis.


Regular nicotine intake increased tooth movement velocity, osteoclastogenesis and orthodontically induced dental root resorptions in a rat model.
Orthodontic forces have been reported to significantly increase nicotine-induced periodontal bone loss. At present, however, it is unknown, which further (side) effects can be expected during orthodontic treatment at a nicotine exposure corresponding to that of an average European smoker. 63 male Fischer344 rats were randomized in three consecutive experiments of 21 animals each (A/B/C) to 3 experimental groups (7 rats, 1/2/3): (A) cone-beam-computed tomography (CBCT); (B) histology/serology; (C) reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR)/cotinine serology-(1) control; (2) orthodontic tooth movement (OTM) of the first and second upper left molar (NiTi closed coil spring, 0.25 N); (3) OTM with 1.89 mg·kg-1 per day s.c. of L(-)-nicotine. After 14 days of OTM, serum cotinine and IL-6 concentration as well as orthodontically induced inflammatory root resorption (OIIRR), osteoclast activity (histology), orthodontic tooth movement velocity (CBCT, within 14 and 28 days of OTM) and relative gene expression of known inflammatory and osteoclast markers were quantified in the dental-periodontal tissue (RT-qPCR). Animals exposed to nicotine showed significantly heightened serum cotinine and IL-6 levels corresponding to those of regular European smokers. Both the extent of root resorption, osteoclast activity, orthodontic tooth movement and gene expression of inflammatory and osteoclast markers were significantly increased compared to controls with and without OTM under the influence of nicotine. We conclude that apart from increased periodontal bone loss, a progression of dental root resorption and accelerated orthodontic tooth movement are to be anticipated during orthodontic therapy, if nicotine consumption is present. Thus patients should be informed about these risks and the necessity of nicotine abstinence during treatment.


[Crohn's disease (acute regional colitis) (author's transl)].
This article reports the observation of acute form of Crohn's disease, limited to colonic involvement, in a 40-year old female. Diagnosis was based upon pathologic examination of biopsy. The patient died after four months of acute disease. Clinical and paraclinical justification of the diagnosis of Crohn's disease (colonic), as well as description of treatment are given.


Primary squamous cell carcinoma of the endometrium: two cases and a review of the literature.
Primary squamous cell carcinoma of the endometrium (PSCCE) is a rare entity, with fewer than 100 cases reported in the literature. We report two cases of PSCCE and review the literature regarding associated markers and treatment outcomes. Many different markers have been tested for association with PSCCE, with mixed results. Thus, it is likely that several etiologic factors are responsible for the development of PSCCE. Further, due to the rarity of the condition, the optimal postoperative management of patients with PSCCE remains to be defined.


A review on determination of steroids in biological samples exploiting nanobio-electroanalytical methods.
The applications of nanomaterial modified sensors, molecularly imprinting polymer based, aptamer based, and immunosensors have been described in the determination of steroids using electroanalytical techniques. After a brief description of the steroids and assays in biological fluids, the principles of electrochemical detection with the advantages and the limitations of the various sensors are presented. The nanomaterial modified sensors catalyze the oxidation/reduction of steroids and are suitable for sensing them in environmental samples and biological fluids. The determination of steroids based on their reduction has been found more useful in comparison to oxidation as the common metabolites present in the biological fluids do not undergo reduction in the usual potential window and hence, do not interfere in the determination. The sensors based on immunosensors and aptamers were found more sensitive and selective for steroid determination. Conducting polymer modified bio-sensors and microchip devices are suggested as possible future prospects for the ultra sensitive and simultaneous determination of steroids and their metabolites in various samples.


Energetics of activation in frog skeletal muscle at sarcomere lengths beyond myofilament overlap.
Experiments were designed to gain information about the effects of extremely long sarcomere lengths (greater than 3.8 microns) on muscle activation. The amount of energy liberated in an isometric twitch by muscles stretched to sarcomere lengths where myofilament overlap is vanishingly small (greater than 3.6 microns) is thought to be an indirect measure of the Ca2+ cycled during contraction. The effects of altering sarcomere length from 3.8 to 4.3 microns on the amount of Ca2+ cycled was measured using twitch energy liberation as an indicator of the Ca2+ cycled. Twitch energy liberation decreased by approximately 20% over this sarcomere length region, suggesting that the amount of Ca2+ released by a single action potential is not altered dramatically when a muscle is stretched to extreme lengths.


DNA and prognosis of meningiomas: a comparative cytological and fluorescence-cytophotometrical study of 71 tumours.
DNA analysis in meningiomas was performed using flow-fluorescence cytometry in 71 tumours. Three subcategories of rather small, medium-sized or clearly abnormal growth activities were evident in each of the fibroblastic, transitional and syncytial tumour types. These categories reflected grades 1, 2 or 3 of malignancy on a four-grade scale in which the primary fibroscarcomas of the meninges are grade 4. Richly vascularized (haemangioblastic) meningiomas of our series comprised only two subcategories: these included 7 tumours with slight signs of proliferation and 1 with increased growth, probably indicating a propensity to recur. Tumours of grades 2 and 3 have a tendency to recur, which is probably due more to their biological behaviour than to the efficiency of the surgical treatment. The most variable patterns of DNA distribution are detected in the so-called "anaplastic" meningiomas: some of them are microscopically polymorphous blastomas but show unimodal diploid karyograms, whereas the proliferative indizes, ranging between 1 to 15, were obviously indicative for slow-growing benign tumours. The majority of polymorphous and anaplastic meningiomas, however, are characterized by a rather abnormal tetraploidy or aneu/polyploidy not uncommon in a relapse. The corresponding DNA distribution was demonstrated in a recurrent papillomatous meningioma in agreement with its dubious histological prognosis.


Myocardial infarction following COVID-19 vaccine administration; a systematic review.
Covid-19 vaccines have been assessed in randomized trials, which are designed to establish efficacy and safety, but are insufficient in power to detect rare adverse outcomes. Among the adverse cardiac events associated with mRNA COVID-19 vaccines are inflammations (e.g., pericarditis or myocarditis), thrombosis, and ischemia. This systematic review aims to evaluate the reported cases of myocardial infarction (MI) after COVID-19 vaccinations. Web of Science, MEDLINE on OVID, PubMed, and Google Scholar were searched for English-language papers published until March 25, 2022. This study included 15 papers (10 case reports and 5 case series). In total, 20 individuals were included who had received COVID-19 vaccines and experienced MI. Males (55%) reported more adverse occurrences than females (45%) across the majority of event categories. The mean time from the administration of the vaccine to the onset of symptoms was 2 days (0-10 days). The AstraZeneca vaccine was responsible for more than half of the reported events. In the majority of cases, the event developed after receiving the first dose of vaccination. MI related to COVID19 vaccination is a rare, but serious and life-threatening condition. Chest discomfort should be regarded as a warning sign, particularly in people who have been administered a dose of the vaccine within the previous two days.


2-(Anthracen-9-yl)benzothiazole-modified graphene oxide-nickel ferrite nanocomposite for anodic stripping voltammetric detection of heavy metal ions.
A novel electrochemical sensor, 2-(anthracen-9-yl)benzothiazole (ABT)-modified nickel ferrite reduced graphene oxide (NF@rGO) has been designed for the individual and simultaneous detection of Cd2+, Cu2+, and Hg2+ ions. Herein, NF@rGO nanocomposite, synthesized by a simple hydrothermal methodology, was hooked to ABT under easy and simple stirring conditions. Chelation of active functional groups of ABT with metal ions was augmented with higher adsorption and conductivity provided by NF@rGO. The created synergy resulted in analytical signals via selective oxidation of the ions within a potential ranging from - 1.2 to + 1.2 V vs sat. KCl. The proposed protocol exhibited a wide linear range from 0.05 to 1250 nM with excellent detection limit of 123, 54.1, and 86.6 pM via anodic stripping voltammetry for the simultaneous determination of Cd2+, Cu2+, and Hg2+ ions, respectively. Simple cost-effective synthetic approach, improved sensitivity with high selectivity, noteworthy repeatability (RSD less than 3%), and reproducibility (RSD less than 7%) equipped with successful real time monitoring (apparent recovery more than 90%) bring about a spiffing sensing platform for the detection of hazardous metal ions.


The heat-sensitive Escherichia coli grpE280 phenotype: impaired interaction of GrpE(G122D) with DnaK.
GrpE is the nucleotide-exchange factor of the DnaK chaperone system. Escherichia coli cells with the classical temperature-sensitive grpE280 phenotype do not grow under heat-shock conditions and have been found to carry the G122D point mutation in GrpE. To date, the molecular mechanism of this defect has not been investigated in detail. Here, we examined the structural and functional properties of isolated GrpE(G122D) in vitro. Similar to wild-type GrpE, GrpE(G122D) is an elongated dimer in solution. Compared to wild-type GrpE, GrpE(G122D) catalyzed the ADP/ATP exchange in DnaK only marginally and did not compete with wild-type GrpE in interacting with DnaK. In the presence of ADP, GrpE(G122D) in contrast to wild-type GrpE, did not form a complex with DnaK detectable by size-exclusion chromatography with on-line static light-scattering and differential refractometry. Apparently, GrpE(G122D) in the presence of ADP binds to DnaK only with much lower affinity than wild-type GrpE. GrpE(G122D) could not substitute for wild-type GrpE in the refolding of denatured proteins by the DnaK/DnaJ/GrpE chaperone system. In the crystal structure of a (Delta1-33)GrpE(G122D).DnaK-ATPase complex, which as yet is the only available structure of a GrpE variant, Asp122 does not interact directly with neighboring residues of GrpE or DnaK. The far-UV circular dichroism spectra of mutant and wild-type GrpE proved slightly different. Possibly, a discrete change in conformation impairs the formation of the complex with DnaK and renders GrpE(G122D) virtually inactive as a nucleotide exchange factor. In view of the drastically reduced ADP/ATP-exchange activity of GrpE(G122D), the heat sensitivity of grpE280 cells might be explained by the ensuing slowing of the chaperone cycle and the increased sequestering of target proteins by high-affinity, ADP-liganded DnaK, both effects being incompatible with efficient chaperone action required for cell growth.


[Accidental immobilization of the proximal joint of the index finger].
In connexion with one case a rare clinical picture is described by the authors. The stoppage of movement observed in young individuals in the MP articulation of the forefinger occurs under the effect of trauma, - under normal articular conditions, - on strongly flexed finger, under the effect of powerful ulnar duction.


Relation of BsmI vitamin D receptor gene polymorphism to bone mineral density and occurrence of osteoporosis in postmenopausal Chinese women in Taiwan.
Osteoporosis is a common disorder with a strong genetic component. Our aim was to evaluate the correlation of the vitamin D receptor gene intron 8 BsmI polymorphism with bone mineral density (BMD) and their relationship to osteoporosis. We determined the vitamin D receptor gene intron 8 BsmI polymorphfsm using polymerase chain reaction-based restriction analysis in 171 postmenopausal Chinese women in Taiwan. The polymorphism was detected using the restriction enzyme BsmI, where the B allele indicated absence of the cuttable site and the b allele its presence. BMD of the lumbar spine and proximal femur were measured using dual-energy X-ray absorptiometry. The allelic frequencies for postmenopausal Chinese women in Taiwan were 12.3% for B and 87.7% for b in BsmI restriction fragment length polymorphisms. The prevalence of each genotype in the study population was: 6.4% BB, 11.7% Bb and 81.9% bb. The three genotypic groups differed significantly in BMD at the lumbar spine and the femoral neck. These differences corresponded to significant gene-dose effects at the lumbar spine and femoral neck (p<0.001 for both sites). The relative risk for the development of osteoporosis was about 2-3 times as great as that predicted by the differences between genotypes in BMD, and remained significant even after adjustment for age, height and weight. The vitamin D receptor gene intron 8 BsmI polymorphism is associated with reduced BMD and predisposes women to osteoporosis.


Spontaneous epidural hematoma induced by rivaroxaban: A case report and review of the literature.
Trauma is the most frequent reason for epidural bleeding. However, numerous investigation had discovered that anticoagulants such as rivaroxaban could cause epidural hematoma. Here, we present a case of epidural hematoma in young man who got rivaroxaban as treatment of deep vein thrombosis. A 27-year-old male with a history of deep vein thrombosis and one month of rivaroxaban medication presented with seizure and loss of consciousness following a severe headache. A CT scan of the head revealed epidural bleeding, and emergency blood clot removal was performed. As a reversal, prothrombin complex was utilized. Rivaroxaban has the potential to cause an epidural hemorrhage. Reversal anticoagulant should be administered before doing emergency surgery.


Determinants of repressor/operator recognition from the structure of the trp operator binding site.
On the basis of the crystal structure of the trp repressor/operator complex, it has been proposed that the specificity of the interaction can be explained not only by direct hydrogen bonding and non-polar contacts between the protein and the bases of its target DNA, but also by indirect structural effects and water-mediated interactions. To understand the contribution of DNA structure and hydration in this context, the structure of the free DNA must be compared with its structure when complexed with the protein. Here we present the high-resolution crystal structure of the trp operator region that is most important in the recognition process. By comparing the free and bound states of the DNA regulatory sequence, we show that the structure and hydration of the DNA target are important elements in its recognition by the repressor protein.


Prostaglandin- and isoproterenol-stimulated cyclic AMP accumulation in rat perinatal lung fibroblasts: effects of developmental age.
The fibroblast of the fetal and neonatal lung is intimately involved with lung development and function. Additionally, the perinatal rat lung fibroblast is a significant source of prostaglandins (PG) I2 and E2, which in turn affect lung development and function. Their effects may be mediated by cAMP. We, therefore, tested both the relative effectiveness of PG and the beta-adrenergic agonist, isoproterenol, and the developmental age sensitivity to these agonists on rat perinatal lung fibroblast cAMP accumulation. Confluent monolayer cultures of 3rd-passage fibroblasts (greater than 95% purity) from d-3 newborn rats responded in a concentration-dependent fashion to several PG (10(-8)-10(-4) M) and isoproterenol (10(-7)-2 x 10(-6) M) by increasing cAMP accumulation. The rank order of responsiveness, in terms of maximum accumulated cAMP, were carba PGI2 greater than PGE1 = PGI2 Na salt = PGI2 methyl ester much greater than PGE2 greater than isoproterenol. At the 3 developmental d tested [d 20 fetus, d 1 newborn, and d 3 newborn (term = d 22)], PGE2, carba PGI2, and isoproterenol each elicited concentration-dependent increases in cAMP accumulation. Unstimulated cAMP levels were 2-5 fmol/micrograms protein/15 min at all three ages. On d 20 of gestation, the highest accumulation achieved at the highest concentration tested was 30-70 fmol/micrograms protein/15 min for each agonist. There was no age-dependent change in responsiveness to PGE2. Carba PGI2-stimulated cAMP accumulation increased from d 20 of gestation with each advancing age tested to approximately 15-fold by d 3 newborn.(ABSTRACT TRUNCATED AT 250 WORDS)


A comparison of some pharmacological actions of prostaglandin E1, 6-oxo-PGE1 and PGI2.
Some pharmacological actions of prostaglandin E1 (PGE1), 6-oxo-PGE1 and PGI2 have been studied. 6-oxo-PGE1 and PGE1 relaxed guinea-pig tracheal muscle in vitro and increased nasal patency in normal volunteers and in subjects with vasomotor rhinitis whereas PGI2 produced opposite effects. All three compounds produced bronchodilatation in the anaesthetised guinea-pig and relaxed human respiratory tract muscle in vitro. PGI2 was several times more potent than either 6-oxo-PGE1 or PGE1 against ADP-induced aggregation of human and baboon platelets in vitro. Intravenous 6-oxo-PGE1 in the baboon caused an ex vivo inhibition of platelet aggregation, but the EC50 was 7.7 times that of PGI2. As a vasodepressor in the baboon 6-oxo-PGE1 and PGI2 were equipotent. Thus with the exception of the vasodepressor effect, the actions of 6-oxo-PGE1 qualitatively and quantitatively resembled those of the structurally related PGE1 rather than those of PGI2.


The 64 kDa polypeptide of spinach may not be the LHCII kinase, but a lumen-located polyphenol oxidase.
Phosphorylation of chlorophyll alb-binding proteins of the of photosystem II light-harvesting assembly controls the energy distribution between the two photosystems as well as the turnover of thylakoid membrane proteins. The LHCII kinase, suggested to be a 64 kDa protein, is light-regulated by a mechanism involving reduction of plastoquinone and the participation of the cytochrome b6lf complex. A cDNA encoding that protein has been isolated from a lambda gt11-based library made from spinach polyadenylated RNA using a two-step strategy involving screening by polyclonal monospecific antisera and plaque hybridization. The protein of 73.1 kDa molecular mass represents a precursor which contains a bipartite transit peptide of 101 amino acid residues (11.0 kDa) that directs the protein into the thylakoid lumen. It can be phosphorylated in vitro, and exhibits significant homology to plant polyphenol oxidases not to kinases. The gene was therefore designated PpoA. Reinvestigation of components in the molecular mass range of 50-70 kDa disclosed five additional proteins which can accompany kinase-active cytochrome b6lf, photosystem II and AMS [1] preparations. Four of them can be phosphorylated in vitro; two with apparent molecular masses of 53 and 66 kDa are capable of phosphorylation and represent new, yet unidentified proteins.


Weight Gain in Early Infancy Impacts Appetite Regulation in the First Year of Life. A Prospective Study of Infants Living in Cyprus.
Eating behavior is associated with weight gain in infancy and childhood. Few studies found a bidirectional association between weight gain and eating behavior development in childhood, but there is little data on the association in early infancy, a period critical for the programming of obesity risk. We investigated the bidirectional association between appetite traits and weight gain during the first year of life. Participants were part of a cohort of 432 infants born in Cyprus. Appetite traits were measured using the Baby Eating Behavior Questionnaire or the Child Eating Behavior Questionnaire at age 2 to 4 wk, 6 mo, and 12 mo. Weight and length were collected at birth, 4 wk, 6 mo, and 12 mo. Multivariable linear regression was used to analyze associations between appetite traits at 2 to 4 wk and 6 mo and weight for age z-score change (WFAZC) between 4 wk and 6 mo and 6 and 12 mo. Associations were also analyzed in the opposite direction, between WFAZC from birth to 4 wk, 4 wk to 6 mo, and 6 mo to 12 mo and appetite traits at 4 wk, 6 mo, and 12 mo. Satiety responsiveness (SR) at 2 to 4 wk was associated with lower WFAZC from 4 wk to 6 mo (β: -0.17; 95% CI: -0.30, -0.04) and SR at age 6 mo was associated with lower WFAZC from 6 to 12 mo (β: -0.09; 95% CI: -0.17, -0.02). WFAZC from 4 wk to 6 mo was associated with higher enjoyment of food at 12 mo (β: 0.11; 95% CI: 0.01, 0.20), higher food responsiveness at 12 mo (β: 0.17; 95% CI: 0.04, 0.30), and lower SR at both 6 mo (β: -0.11; 95% CI: -0.21, -0.01) and 12 mo (β: -0.14; 95% CI: -0.24, -0.03). We found a bidirectional association between weight gain and appetite traits in infancy, suggesting that the effect of postnatal weight gain on obesity development is partly mediated by programming of appetite traits.


"Basal durotomy" to prevent massive intra-operative traumatic brain swelling.
Massive intraoperative swelling (IOS) is a potential complication of intracranial surgery for traumatic hematomas. We present a novel design of dural opening to minimize the risks of IOS. Over the last eight years, we have used and evaluated a "reversed U-shaped" durotomy incision, which leaves the dura intact in the parasagittal region. Accordingly, the dura should be opened initially over the fronto-basal eminence of the frontal lobe anterior to the middle meningeal artery and sylvian region. The incision is then carried across the middle meningeal into the temporal region. Additional slit incisions may be made, as needed, around the circumference of the craniotomy in order to obtain sufficient access to remove a subdural hematoma. We have employed this technique in 220 trauma craniotomies without any case of uncontrolled IOS. In all patients a complete dural closure was obtained. When IOS is suspected, basal durotomy proved to be an excellent technique to prevent it, without compromising the total evacuation of the traumatic intracranial hematoma.


A novel avian isolate of hepatitis E virus from Pakistan.
Avian hepatitis E virus (aHEV) has been associated with hepatitis-splenomegaly syndrome (HSS) in chickens along with asymptomatic subclinical infection in many cases. So far, four genotypes have been described, which cause infection in chickens, specifically in broiler breeders and layer chickens. In the present study, we isolated and identified two novel aHEV strains from the bile of layer chickens in Pakistan evincing clinical symptoms related to HSS. Histology of liver and spleen tissues was carried out to observe histopathological changes in these tissues. Bile fluid and fecal suspensions were used for viral RNA isolation through MegNA pure and Trizol method which was further used for viral genome detection and characterization by cDNA synthesis and amplification of partial open reading frame (ORF) 1, ORF2 and complete ORF3. The bioinformatics tools; Molecular Evolutionary Genetics Analysis version 6.0 (MEGA 6), Mfold and ProtScale were used for phylogenic analysis, RNA secondary structure prediction and protein hydropathy analysis, respectively. Sequencing and phylogenetic analysis on the basis of partial methyltranferase (MeT), helicase (Hel) domain, ORF2 and complete ORF3 sequence suggests these Pakistani aHEV (Pak aHEV) isolates may belong to a Pakistani specific clade. The overall sequence similarity between the Pak aHEV sequences was 98-100%. The ORF1/ORF3 intergenic region contains a conserved cis-reactive element (CRE) and stem-loop structure (SLS). Analysis of the amino acid sequence of ORF3 indicated two hydrophobic domains (HD) and single conserved proline-rich domain (PRD) PREPSAPP (PXXPXXPP) with a single PSAP motif found in C-terminal. Amino acid changes S15 T, A31T, Q35H and G46D unique to the Pak aHEV sequences were found in the N-terminal region of ORF3. Our data suggests that Pak aHEV isolates may represent a novel Pakistani clade and high sequence homology to each other support the supposition they may belong to a monophyletic clade circulating in the region around Pakistan. The data presented in this study provide further information for aHEV genetic diversity, genotype mapping, global distribution and epidemiology.


Role of international network on surveillance and response system leading to malaria elimination: China's engagement in global health.
China has accumulated multiple practices and experiences in building and enhancing malaria surveillance and response system. As China's engagement into global health has gathered stronger momentum than ever, China together with the Swiss Tropical and Public Health Institute and WHO has organised five sessions of the International Forum on Surveillance-Response System Leading to Tropical Diseases Elimination during 2012-2020, in which malaria elimination has always been one of the hottest topics. In this study, the roles of international network on the surveillance and response system were explored to achieve a global malaria-free goal. China's approach to malaria elimination has demonstrated significance of global collaboration on taking joint prevention and control, and building a worldwide institutional-based network.


Views of People With High and Low Levels of Health Literacy About a Digital Intervention to Promote Physical Activity for Diabetes: A Qualitative Study in Five Countries.
Low health literacy is associated with poor health-related knowledge, illness self-management, health service use, health, and survival, and thus addressing issues related to low health literacy has been highlighted as a pressing international priority. To explore views of a digital health promotion intervention designed to be accessible to people with lower levels of health literacy, in particular examining reactions to the interactive and audiovisual elements of the intervention. Qualitative think-aloud interviews were carried out with 65 adults with type 2 diabetes in the UK, Ireland, USA, Germany, and Austria, with purposive sampling to ensure representation of people with lower levels of health literacy. Inductive thematic analysis was used to identify common themes. We then systematically compared views in subgroups based on country, health literacy level, age, gender, and time since diagnosis. Most participants from the chosen countries expressed positive views of most elements and features of the intervention. Some interactive and audiovisual elements required modification to increase their usability and perceived credibility and relevance. There were some differences in views based on age and gender, but very few differences relating to health literacy level or time since diagnosis. In general, participants found the intervention content and format accessible, appropriate, engaging, and motivating. Digital interventions can and should be designed to be accessible and engaging for people with a wide range of health literacy levels.


Fluorescence Quenching of Carbazole by Selected Phenols in a Cationic Micellar System of Cetyltrimethyl Ammonium Bromide (CTAB).
A group of selected phenols i.e., picric acid, p-Nitrophenol, m-Nitrophenol, o-Nitrophenol, and phenol interactions were studied with a fluorescent probe carbazole in a micellar system of CTAB. CTAB concentration was optimized for maximum quenching of carbazole for each studied phenol. Interaction was studied in 0.02 and 0.1 mol/dm3 CTAB. All the studied phenols resulted in the quenching of carbazole in both CTAB concentrations though lower CTAB concentration was found optimum for highest quenching of the probe carbazole. Carbazole fluorescence quenching with phenols were explained with the help of Stern-Volmer equation that produced the constants of Stern-Volmer ([Formula: see text]). [Formula: see text] shows the sensitiveness of the method for the studied phenol and were observed in the order picric acid > phenol > m-Nitrophenol > p-Nitrophenol > o-Nitrophenol. Detection threshold (DT) and quantification threshold (QT) were observed in the order 1.76 [Formula: see text] 10-7 - 6.30 [Formula: see text] 10-7 mol/dm3 and 5.898 [Formula: see text] 10-7 - 2.11 [Formula: see text] 10-6 mol/dm3 respectively. The method is reproducible and is effective for the determination of studied phenols in the samples.


Mutagenesis and deoxyribonucleotide pool imbalance.
Numerous studies have demonstrated that DNA-precursor pool imbalances are mutagenic and can modulate the lethality and mutagenicity of DNA-damaging agents. In addition, physical and chemical mutagens can induce alterations in DNA-precursor levels. Such findings suggest that regulation of intracellular concentrations of DNA precursors may be an important factor in environmental mutagenesis. In this article, results linking mutation and disturbances in DNA-precursor pools are reviewed.


Balamuthia mandrillaris stimulates interleukin-6 release in primary human brain microvascular endothelial cells via a phosphatidylinositol 3-kinase-dependent pathway.
Balamuthia mandrillaris is an emerging protozoan parasite that can cause fatal granulomatous encephalitis. Haematogenous spread is a likely route prior to entry into the central nervous system (CNS), but it is not clear how circulating amoebae cross the blood-brain barrier. Using human brain microvascular endothelial cells (HBMEC), which constitute the blood-brain barrier, we determined HBMEC inflammatory response to B. mandrillaris and the underlying mechanisms associated with this response. We demonstrated that HBMEC incubated with B. mandrillaris released significantly higher levels of interleukin-6 (IL-6) (>400 pg/ml) as compared with less than 50 pg/ml in HBMEC incubated alone. Western blotting assays determined that B. mandrillaris specifically activates phosphatidylinositol 3-kinase (PI3K). By using LY294002, a PI3K inhibitor, as well as by using HBMEC expressing dominant-negative PI3K, we have identified PI3K as an important mediator of B. mandrillaris-mediated IL-6 release. We conclude that B. mandrillaris induces HBMEC signalling pathways, which lead to IL-6 release. This is the first time PI3K has been shown to play a crucial role in B. mandrillaris-mediated IL-6 release in HBMEC.


Dendritic solutions to the credit assignment problem.
Guaranteeing that synaptic plasticity leads to effective learning requires a means for assigning credit to each neuron for its contribution to behavior. The 'credit assignment problem' refers to the fact that credit assignment is non-trivial in hierarchical networks with multiple stages of processing. One difficulty is that if credit signals are integrated with other inputs, then it is hard for synaptic plasticity rules to distinguish credit-related activity from non-credit-related activity. A potential solution is to use the spatial layout and non-linear properties of dendrites to distinguish credit signals from other inputs. In cortical pyramidal neurons, evidence hints that top-down feedback signals are integrated in the distal apical dendrites and have a distinct impact on spike-firing and synaptic plasticity. This suggests that the distal apical dendrites of pyramidal neurons help the brain to solve the credit assignment problem.


A novel protocol for antibiotic prophylaxis based on preoperative kidney function in patients undergoing open heart surgery under cardiopulmonary bypass.
This study aimed to develop and assess the effectiveness of a protocol for antibiotic prophylaxis based on preoperative kidney function in patients undergoing open heart surgery. We established a protocol for antibiotic prophylaxis based on preoperative kidney function in patients undergoing open heart surgery. This novel protocol was assessed by comparing patients undergoing open heart surgery before (control group; n = 30) and after its implementation (protocol group; n = 31) at Kyoto University Hospital between July 2012 and January 2013. Surgical site infections (SSIs) were observed in 4 control group patients (13.3 %), whereas no SSIs were observed in the protocol group patients (P < 0.05). The total duration of antibiotic use decreased significantly from 80.7 ± 17.6 h (mean ± SD) in the control group to 55.5 ± 14.9 h in the protocol group (P < 0.05). Similarly, introduction of the protocol significantly decreased the total antibiotic dose used in the perioperative period (P < 0.05). Furthermore, antibiotic regimens were changed under suspicion of infection in 5 of 30 control group patients, whereas none of the protocol group patients required this additional change in the antibiotic regimen (P < 0.05). Our novel antibiotic prophylaxis protocol based on preoperative kidney function effectively prevents SSIs in patients undergoing open heart surgery.


Association of functional genetic variants in TFF1 and nephrolithiasis risk in a Chinese population.
Trefoil Factor 1 (TFF1) is considered to be able to inhibit the formation of kidney stone. However, genetic variants in TFF1 and corresponding function in kidney stone development are still not well studied. In this study, the discovery set including 230 cases and 250 controls was used to analyze the association between seven tagSNPs of TFF1 gene and the nephrolithiasis risk. Further evaluation was confirmed by the validation set comprising 307 cases and 461 controls. The consequences of the two-stage case-control study indicated that individuals with the rs3761376 A allele have significantly increased nephrolithiasis risk than those with the GG genotypes [adjusted odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.05-1.73]. Moreover, we also carried out a stratified analysis and found the increased nephrolithiasis risks at A allele among males, overweight individuals, no hypertensive individuals, nondiabetic individuals, smokers, and drinkers. In the following functional experiments, the notably lower expression of TFF1 was exhibited by the vectors carrying A allele compared with those carrying G allele in both luciferase (P = 0.022) and expression vectors (P = 0.041). In addition to tissue detection, we confirmed a significant inverse association of rs3761376 G > A and TFF1 gene expression (P < 0.001). These results suggest that TFF1 rs3761376 may serve as a potential biomarker to predict the risk of nephrolithiasis.


Systematically characterization of in vivo substances of Ziziphi Spinosae Semen in rats by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry analysis.
Ziziphi Spinosae Semen (ZSS), the seeds of Ziziphus jujuba var. spinosa, is widely used in China or other Asian countries for the treatment of insomnia and palpitation. In our previous work, chemical constituents in ZSS were profiled by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UHPLC/Q-TOF MS). Notably, characterization of substances in vivo was of great importance to reveal the therapy basis or mechanism in further work. Till now, there were few reports about in vivo substances' investigation of ZSS. In the present study, an integrated strategy contained represented compounds and diagnostic ions extraction was applied to characterize metabolism feature of ZSS in rats based on UHPLC/Q-TOF MS method. First, the metabolic information of four compounds (spinosin, isovitexin, jujuboside B, betulinic acid) featuring three representative chemical structures (flavonoids, saponins, terpenes) in ZSS was conducted, and their metabolism features were summarized, especially for flavonoid C-glycosides. Second, the absorbed compounds and representative compounds-related metabolites were quickly screened out; during this time, the diagnostic ions were sorted out. Last, with the help of diagnostic ions and summarized metabolic reactions, other metabolites were characterized. As a result, a total of 151 xenobiotics (58 prototypes and 93 metabolites) were identified or tentatively characterized in rats after ingestion of ZSS. Among them, 16 substances were presented in plasma, 114 in urine, 51 in bile, and 120 in feces, respectively. Hydrogenation, hydrolysis, and glucuronidation were the major metabolic reactions of ZSS in rats. The present study provided meaningful data for further pharmacological mechanism research or pharmacokinetics evaluation of ZSS.


Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis.
We used the Immunochip array to analyze 2,816 individuals with juvenile idiopathic arthritis (JIA), comprising the most common subtypes (oligoarticular and rheumatoid factor-negative polyarticular JIA), and 13,056 controls. We confirmed association of 3 known JIA risk loci (the human leukocyte antigen (HLA) region, PTPN22 and PTPN2) and identified 14 loci reaching genome-wide significance (P < 5 × 10(-8)) for the first time. Eleven additional new regions showed suggestive evidence of association with JIA (P < 1 × 10(-6)). Dense mapping of loci along with bioinformatics analysis refined the associations to one gene in each of eight regions, highlighting crucial pathways, including the interleukin (IL)-2 pathway, in JIA disease pathogenesis. The entire Immunochip content, the HLA region and the top 27 loci (P < 1 × 10(-6)) explain an estimated 18, 13 and 6% of the risk of JIA, respectively. In summary, this is the largest collection of JIA cases investigated so far and provides new insight into the genetic basis of this childhood autoimmune disease.


Detection of TNF alpha and Fas ligand mRNA within synovial mononuclear cells by fluorescence in-cell labeling PCR (FICL-PCR).
T cells that infiltrate the synovial lesions of rheumatoid arthritis may play a key role in its pathogenesis. To learn more about their functional nature, we determined the frequency of synovial T cells that harbored the TNF alpha and Fas ligand transcript by a technique, called Fluorescence In-Cell Labeling Polymerase Chain Reaction (FICL-PCR). The mRNA of interest was detected in fixed cells by the incorporation during PCR of a fluorescein-12-dUTP label following an initial reverse transcription PCR step. Using this technique the CD3 transcript was detected in the T leukemic cell line, MOLT-4, with calculated sensitivity and specificity values of 91% and 100%, respectively. The percentage mean (+/-S.D.) of TNF alpha mRNA positive cells and Fas ligand mRNA positive cells in peripheral blood mononuclear cells from 12 rheumatoid arthritis patients were 5.1+/-2.3% and 4.8+/-3.1%, respectively. The percentage mean (+/-S.D.) of TNF alpha mRNA positive cells and Fas ligand mRNA positive cells among synovial mononuclear cells from six rheumatoid arthritis patients was 16.8+/-8.3% and 10.8+/-1.8%, respectively. This result indicates that the cytotoxic T cells expressing TNF alpha accumulate in rheumatoid arthritic lesions where they may play a pathogenic role.


Rab GTPases and kinesin motors in endosomal trafficking.
The endocytic pathway is composed of distinct types of endosomes that vary in shape, function, and molecular composition. In addition, endosomes are highly dynamic structures that continuously receive, sort, and deliver molecules to other organelles. Among organizing machineries that contribute to endosomal functions, Rab GTPases and kinesin motors play critical roles. Rab proteins define the identity of endosomal subdomains by recruiting set of effectors among which kinesins shape and transport membranous carriers along the microtubule network. In this review, we provide detailed protocols from live cell imaging to electron microscopy and biochemical approaches to address how Rab and kinesin proteins cooperate molecularly and functionally within the endocytic pathway.


Audiogenic seizures in rats: relation to noradrenergic neurons of the locus coeruleus.
Bilateral lesions involving the nucleus locus coeruleus produced a substantial decrease in the forebrain noradrenaline concentrations. Lesioned animals showed an increased susceptibility to audiogenic seizures. It is supposed that noradrenergic neurons, belonging to the locus coeruleus, play an inhibitory role in the seizure mechanism.


IL-4Rα expression by airway epithelium and smooth muscle accounts for nearly all airway hyperresponsiveness in murine allergic airway disease.
Airway hyperresponsiveness (AHR) often defines asthma. Murine allergic airway disease (AAD), like human eosinophilic asthma, is characterized by AHR, eosinophilia, goblet cell metaplasia (GCM), smooth muscle hypercontractility, and increased production of IL-4 and IL-13-cytokines that induce these characteristics by binding to the IL-4Rα chain. We evaluated the epithelial and smooth muscle IL-4Rα-dependent contributions to AHR of BALB/c mice that possessed 0-2 functional IL-4Rα alleles and had airway disease induced by house dust mite extract (HDM) or exogenous IL-13. Two functional IL-4Rα alleles were required for maximal AHR, while only one functional allele was required for maximal GCM and systemic IL-4/IL-13 levels. Deletion of IL-4Rα from both smooth muscle and epithelial cells inhibited AHR >83% in mice with two functional IL-4Rα alleles. In mice with one functional IL-4Rα allele, selective epithelial cell IL-4Rα deletion maximally inhibited AHR, while selective smooth muscle IL-4Rα deletion decreased IL-13-induced, but not HDM-induced, AHR. Less IL-4Rα signaling is required to maximize the epithelial cell contribution to AHR compared to the smooth muscle contribution to AHR. In addition, epithelial cell responses to IL-4/IL-13 can increase the IL-4Rα-dependent smooth muscle contribution to AHR. These findings carry increasing relevance as IL-4Rα-targeted therapy is administered to human asthmatics.


Central Hepatectomy versus Extended Hepatectomy for Malignant Tumors: A Propensity Score Analysis of Postoperative Complications.
The specific definition of central hepatectomy (CH) (i.e., resection of segments 4-5-8 ± 1) is not uniformly used, resulting in conflicting comparisons with the more commonly performed extended hepatectomy (EH). The study aimed to compare, using propensity score matching (PSM) analysis, the incidence of postoperative complications between CH and EH for centrally located liver tumors (CLLT). All consecutive CH and EH procedures for CLLT performed from 1980 to 2011 were retrospectively reviewed. Independent predictors of postoperative complications were identified. CH was compared to EH after PSM. The study population consisted of 373 patients, 44 (11.8 %) of whom underwent CH and 329 (88.2 %) of whom underwent EH. Before PSM, the overall 90-day mortality was 7.2 % (27 patients) without a group difference (2 (4.5 %) for CH vs. 25 (7.6 %) for EH, p = 0.756). The CH and EH groups had similar postoperative morbidity rates (43.2 vs. 55.3 %; p = 0.108). Blood transfusion was the only independent predictor of postoperative complications (Hazard Ratio: 1.73; 95 % confidence interval: 1.11-2.68; p = 0.014). After PSM, 43 CH patients were matched with 43 EH patients. No group difference was observed for the postoperative mortality, morbidity, or duration of hospital stay. A higher number of EH patients (30.2 vs. 9.3 %, p = 0.028) presented with more than one postoperative complication. CH and EH yield similar mortality and morbidity. For CLLT, CH may be an attractive procedure with the advantage of sparing the liver parenchyma compared with EH.


Multiple metastases after laparoscopic surgery for early-stage endometrial cancer: A case report.
Laparoscopic surgery for early-stage endometrial cancer is associated with lower morbidity compared to open surgery and has comparable oncologic outcomes. We observed unexpected multiple metastases after laparoscopic surgery for endometrial cancer, the recurrence risk of which has previously been estimated to be low. Herein, we present this case and discuss the optimal management of endometrial cancer. A 58-year-old woman complaining of atypical genital bleeding lasting for 5 months was diagnosed with stage IA endometrioid carcinoma grade 1. According to our primary strategy, she underwent a total laparoscopic hysterectomy and bilateral salpingo-oophorectomy. The post-operative diagnosis was consistent with the pre-operative diagnosis. Since the recurrence risk was post-operatively revised to an intermediate level, she was administered adjuvant chemotherapy. However, multiple metastases were observed 4 months post-operatively, and despite treatment for recurrent disease, she died 2 months later. The uterine specimen was re-examined after the diagnosis of recurrence, and the post-operative diagnosis was revised to endometrioid carcinoma grade 3, indicating that her recurrence risk might have been underestimated. The multiple metastases observed in this case, including those in the subcutaneous tissue, were presumably caused by pneumoperitoneum. Aspiration biopsy was used to confirm the histological diagnosis pre-operatively. However, dilation and curettage would have been preferable, considering aspiration biopsy provides limited diagnostic accuracy in some cases. Laparoscopic surgery is less invasive; however, it leads to a peculiar recurrence pattern, which is sometimes difficult to assess pre-operatively. Physicians should carefully consider indications for laparoscopic surgery for malignant diseases.


Charting ELSI's future course: lessons from the recent past.
We sought to examine the ethical, legal, and social implications (ELSI) literature research and scholarship types, topics, and contributing community fields of training as a first step to charting the broader ELSI community's future priorities and goals. We categorized 642 articles and book chapters meeting inclusion criteria for content in both human genetics or genomics and ethics or ELSI during a 5-year period (2003-2008) according to research and scholarship types, topics, and the area of advanced training of the first-listed author. Research and scholarship type categories were developed and characterized through in-depth review of 95 randomly sampled publications from the larger group. There is a single dominant approach to ELSI, which focuses on ethical and other social issues "downstream" of advances in genomics, the contributors to which predominately have advanced training in medicine or science fields other than social science. A comparatively low percentage of publications primarily offer policy recommendations, and these are much more likely to be written by those with advanced training in law than is the case for the literature as a whole. Social science studies predominately employ qualitative methods and vary significantly with respect to the extent and types of recommendations offered. Two further types of ELSI research and scholarship offer alternative models for so-called "normative" work in this field. Considering topics, training, and types of ELSI research and scholarship from the most recent past allows for a baseline perspective that is sorely needed in charting this field's future course.


(Na, Pb)-Jarosite nucleation and growth on anglesite: Implications for inhibition of Pb releasing.
The mobility and bioavailability of Pb can be significantly reduced by Pb-bearing minerals encapsulation in jarosite-group minerals, especially in sulfate-rich environments. However, the kinetic pathways and mechanisms of jarosite-group minerals formations on Pb-bearing mineral surfaces are not well understood. Here, time-resolved heterogeneous (Na, Pb)-jarosite nucleation and growth on anglesite were explored to gain insights into the encapsulation mechanisms. The initial dissolution of anglesite were clearly distinguished, and for the first time, the facet-specific heterogeneous nucleation of (Na, Pb)-jarosite on anglesite was demonstrated. Density functional theory calculations revealed higher adsorption energies and electronic interactions of FeSO4+ complex on anglesite (020), (140), (110) facets, attributed to the preferential nucleation of (Na, Pb)-jarosite on these facets, which resulted in effective passivation of the facets resistant to dissolution. An interpretation was proposed where (Na, Pb)-jarosite grew via a particle-attachment pathway involving the formation of amorphous intermediate, and subsequently, it transformed to the crystalline phase by solid-state conversion. These observations might improve the mechanistic understanding of interface interactions between slightly soluble Pb-bearing minerals and iron minerals, with implications for Pb immobilization in sulfate-rich environments.


Major correlates of male height: A study of 105 countries.
The purpose of this study is to explore the main correlates of male height in 105 countries in Europe & overseas, Asia, North Africa and Oceania. Actual data on male height are compared with the average consumption of 28 protein sources (FAOSTAT, 1993-2009) and seven socioeconomic indicators (according to the World Bank, the CIA World Factbook and the United Nations). This comparison identified three fundamental types of diets based on rice, wheat and milk, respectively. The consumption of rice dominates in tropical Asia, where it is accompanied by very low total protein and energy intake, and one of the shortest statures in the world (∼162-168cm). Wheat prevails in Muslim countries in North Africa and the Near East, which is where we also observe the highest plant protein consumption in the world and moderately tall statures that do not exceed 174cm. In taller nations, the intake of protein and energy no longer fundamentally rises, but the consumption of plant proteins markedly decreases at the expense of animal proteins, especially those from dairy. Their highest consumption rates can be found in Northern and Central Europe, with the global peak of male height in the Netherlands (184cm). In general, when only the complete data from 72 countries were considered, the consumption of protein from the five most correlated foods (r=0.85) and the human development index (r=0.84) are most strongly associated with tall statures. A notable finding is the low consumption of the most correlated proteins in Muslim oil superpowers and highly developed countries of East Asia, which could explain their lagging behind Europe in terms of physical stature.


Heterocyclic pharmacochemistry of new rhinovirus antiviral agents: A combined computational and experimental study.
Rhinovirus (RV), member of the Enterovirus genus, is known to be involved in more than half of the common colds. Through advances in molecular biology, rhinoviruses have also been associated with exacerbations of chronic pulmonary diseases (e.g. asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis). In the current investigation, we develop a novel series of 4,5-dimethoxybenzyl derivatives that potently inhibits rhinovirus replication. Compound (S)-7f blocks RV-B14 replication with an EC50 value of 0.25 μM and shows a low toxicity in HeLa cells (CC50 > 271 μM). Enantioseparation followed by an absolute configuration determination by a Mosher's method revealed the interest of enantiopure compounds. Molecular docking studies permitted the identification of key biological interactions within the drug-binding pocket and an in silico drug-like study revealed a good potential for the development of these derivatives.