Rodent fibroblast tumours expressing human myc and ras genes: growth, metastasis and endogenous oncogene expression.
The effects of expression of human c-myc and both mutated (T24) and normal forms of human Ha-ras-1 were studied in an aneuploid rat fibroblast line (208F). Mutated T24 Ha-ras was also studied in a near-diploid cell derived from early passage Chinese hamster lung fibroblasts (CHL). In contrast to the parental fibroblasts, cells expressing any of the human oncogenes engendered rapidly growing tumours in immune-suppressed animals. Blood- and lymph-borne metastases were observed from both ras- and myc-expressing cells. In general ras-expressing cells were more aggressive than those expressing myc. In the 208F background, expression of c-myc was associated with an incidence of mitosis similar to that in tumours expressing T24 Ha-ras, but incidence of single cell death by apoptosis was higher. Quantitatively, expression of human oncogene mRNA was constant during growth in vivo, and similar to that sometimes observed in human neoplasms. Of 9 endogenous proto-oncogenes, 7 showed no change in expression from the parental fibroblasts, but c-abl and c-fos were strongly expressed in all cells expressing human ras or myc. Thus these tumorigenic cells, although transfected with single human oncogenes, all expressed oncogenes with both nuclear- and membrane-associated products.


Circulating short chain fatty acids and fatigue in patients with head and neck cancer: A longitudinal prospective study.
Fatigue among patients with head and neck cancer (HNC) has been associated with higher inflammation. Short-chain fatty acids (SCFAs) have been shown to have anti-inflammatory and immunoregulatory effects. Therefore, this study aimed to examine the association between SCFAs and fatigue among patients with HNC undergoing treatment with radiotherapy with or without concurrent chemotherapy. Plasma SCFAs and the Multidimensional Fatigue Inventory-20 were collected prior to and one month after the completion of treatment in 59 HNC patients. The genome-wide gene expression profile was obtained from blood leukocytes prior to treatment. Lower butyrate concentrations were significantly associated with higher fatigue (p = 0.013) independent of time of assessment, controlling for covariates. A similar relationship was observed for iso/valerate (p = 0.025). Comparison of gene expression in individuals with the top and bottom 33% of butyrate or iso/valerate concentrations prior to radiotherapy revealed 1,088 and 881 significantly differentially expressed genes, respectively (raw p < 0.05). The top 10 Gene Ontology terms from the enrichment analyses revealed the involvement of pathways related to cytokines and lipid and fatty acid biosynthesis. These findings suggest that SCFAs may regulate inflammatory and immunometabolic responses and, thereby, reduce inflammatory-related symptoms, such as fatigue.


[Laparoscopic partial nephrectomy. Analysis of first 30 cases of our series and review of the literature].
Our goal is to analyze the surgical and clinicopathological results of our first 30 laparoscopic partial nephrectomies (LPN) performed consecutively and correlate the results with the literature. This is a cases series, with 30 patients (20 men and 10 women) operated between 2006 and 2008. We assessed the clinicopathological factors and complications. The mean and median follow-up was 25 and 5 months. Resected tumors had an average size of 2.4 cm. 60% of the tumors were malignant. The pathological stage was pT1 in 100% of cases (47% grade I, 53% Fuhrman grade II).Surgical margins were positive in 3 cases, switching to open surgery. Intraoperative bleeding was 74.66 cc (35.7±SD) and 70 cc of mean and median. The mean operative time was 214.4min (±69) and ischemia time of 31.3min (±13.8). Our results are similar to those reported in the literature, except for positive margins and conversion attributable to the learning curve.


Functional analysis of the uL11 protein impact on translational machinery.
The ribosomal GTPase associated center constitutes the ribosomal area, which is the landing platform for translational GTPases and stimulates their hydrolytic activity. The ribosomal stalk represents a landmark structure in this center, and in eukaryotes is composed of uL11, uL10 and P1/P2 proteins. The modus operandi of the uL11 protein has not been exhaustively studied in vivo neither in prokaryotic nor in eukaryotic cells. Using a yeast model, we have brought functional insight into the translational apparatus deprived of uL11, filling the gap between structural and biochemical studies. We show that the uL11 is an important element in various aspects of 'ribosomal life'. uL11 is involved in 'birth' (biogenesis and initiation), by taking part in Tif6 release and contributing to ribosomal subunit-joining at the initiation step of translation. uL11 is particularly engaged in the 'active life' of the ribosome, in elongation, being responsible for the interplay with eEF1A and fidelity of translation and contributing to a lesser extent to eEF2-dependent translocation. Our results define the uL11 protein as a critical GAC element universally involved in trGTPase 'productive state' stabilization, being primarily a part of the ribosomal element allosterically contributing to the fidelity of the decoding event.


Do the neurologists recognize autoimmune epilepsy well enough? What is the effect of the pandemic on this matter?
The concept of "autoimmune epilepsy" (AE) has been emphasized more frequently through the recent increase in recognition of various autoantibodies specific to neuronal proteins. To evaluate the attitudes of neurologists in regard to AE, to review the differential diagnosis, treatment options, and to reveal the effect of COVID-19 on this matter. A detailed questionnaire prepared for AE was sent to neurologists via social media and WhatsApp after the approval of the Ethics Committee. The responses of 245 respondents working in different settings were analyzed, and the group with 15 years or less experience in neurology was statistically compared to the group with more than 15 years of experience. Awareness and knowledge levels on AE seemed high in all groups, while 11% had never thought about AE during the differential diagnosis in real life. Before starting treatment, 20% thought that the autoantibody result should definitely support it, and 77.6% reported that they did not recognize AE well. Participants stated that satisfactory guidelines for diagnosis and treatment (88.2%) and widespread laboratory support (83.7%) were lacking. Neurologists with less experience and those working outside of training hospitals get more often consultation from an experienced clinician while diagnosing and conduct more detailed investigations at the diagnosis stage (p = 0.0025, p = 0.0001). This first survey study conducted in a large group of neurologists on the attitudes for the concept of AE suggested that postgraduate education, and diagnostic and treatment guidelines should be organized and antibody screening tests need to be better disseminated.


An adenosine 3':5'-monophosphate-dependent protein kinase from the human erythrocyte membrane. Purification and characterization.
An adenosine 3':5'-monophosphate-dependent protein kinase (ATP:protein phosphotransferase, EC 220.127.116.11) has been isolated from the human erythrocyte memebrane and the phosphotransferase activity exhibited by this enzyme has been purified 800-fold. In concentrated solutions, the membrane-derived protein kinase undergoes aggregation with a concomitant loss in observed phosphotransferase activity. This loss of activity can be restored by means of inducing deaggregation. The phosphotransferase activity of the protein kinase is virtually obliterated in the presence of high (300 mM) concentrations of sodium chloride. This effect is also reversible. The pH optimum for the phosphotransferase reaction that is catalyzed by the membrane-derived protein kinase is approximately 8. Micromolar concentrations of cAMP are optimal with respect to promoting the phosphotransferase reaction. Initial velocity and product inhibition studies were conducted on the cAMP-independent protein kinase derived from the cAMP-dependent enzyme. These studies indicate that the phosphotransferase reaction proceeds by a sequential kinetic mechanism.


Anal-canal duplication in a 6-year-old child.
A 6-year-old girl with an anal deformity had been complaining of pruritus around the anus. A small pit at 6 o'clock was diagnosed as an anal duplication. Fistulography showed a 0.5-cm-depth fistula without communication to the rectum. A 1.5-cm diameter presacral mass was shown on computed tomography. There was no sacral anomaly. At fistulectomy, the fistula contained mucous, yellow-white fluid. The base was enlarged, probably because of inflammation, but was resected without any invasion of the rectum. Histology showed squamous epithelium on the surface of the fistula and columnar epithelium and goblet cells in the base, which confirmed the diagnosis of an anal-canal duplication.


Impact of MRI markers in subcortical vascular dementia: a multi-modal analysis in CADASIL.
CADASIL is an arteriopathy caused by mutations of the Notch3 gene. White matter hyperintensities (WMH), lacunar lesions (LL), cerebral microhemorrhages (CM), brain atrophy and tissue microstructural changes are detected on MRI. Using an integrated multi-modal approach, we examined the relative impact of lesion burden and location of these MRI markers on cognitive impairment and disability. Multi-modal imaging was performed on 147 patients from a two-center cohort study. Volume of LL, WMH and number of CM was determined. Whole brain mean apparent diffusion coefficient (mean-ADC) and brain parenchymal fraction (BPF) were measured. In multivariate models accounting for lesion burden and location, volume of LL, mean-ADC, and BPF each had an independent influence on global cognitive function and disability. BPF explained the largest portion of the variation in cognitive and disability scores (35-38%). Brain atrophy has the strongest independent influence on clinical impairment in CADASIL when all MRI markers in the disease are considered together. The results suggest that the clinical impact of cerebral tissue loss plays a principal role in this genetic model of subcortical ischemic vascular dementia.


Objective Assessment of Laparoscopic Force and Psychomotor Skills in a Novel Virtual Reality-Based Haptic Simulator.
Most of the commercially available virtual reality-based laparoscopic simulators do not effectively evaluate combined psychomotor and force-based laparoscopic skills. Consequently, the lack of training on these critical skills leads to intraoperative errors. To assess the effectiveness of the novel virtual reality-based simulator, this study analyzed the combined psychomotor (i.e., motion or movement) and force skills of residents and expert surgeons. The study also examined the effectiveness of real-time visual force feedback and tool motion during training. Bimanual fundamental (i.e., probing, pulling, sweeping, grasping, and twisting) and complex tasks (i.e., tissue dissection) were evaluated. In both tasks, visual feedback on applied force and tool motion were provided. The skills of the participants while performing the early tasks were assessed with and without visual feedback. Participants performed 5 repetitions of fundamental and complex tasks. Reaction force and instrument acceleration were used as metrics. Surgical Gastroenterology, Government Stanley Medical College and Hospital; Institute of Surgical Gastroenterology, Madras Medical College and Rajiv Gandhi Government General Hospital. Residents (N = 25; postgraduates and surgeons with <2 years of laparoscopic surgery) and expert surgeons (N = 25; surgeons with >4 and ≤10 years of laparoscopic surgery). Residents applied large forces compared with expert surgeons and performed abrupt tool movements (p < 0.001). However, visual + haptic feedback improved the performance of residents (p < 0.001). In complex tasks, visual + haptic feedback did not influence the applied force of expert surgeons, but influenced their tool motion (p < 0.001). Furthermore, in complex tissue sweeping task, expert surgeons applied more force, but were within the tissue damage limits. In both groups, exertion of large forces and abrupt tool motion were observed during grasping, probing or pulling, and tissue sweeping maneuvers (p < 0.001). Modern day curriculum-based training should evaluate the skills of residents with robust force and psychomotor-based exercises for proficient laparoscopy. Visual feedback on force and motion during training has the potential to enhance the learning curve of residents.


Economics and obesity: costing the problem or evaluating solutions?
There is no doubt that obesity is a major public health problem. However, what is the contribution of economics to solving it? In this report, we make the case that the role of economics is not in measuring the economic burden of obesity, through so-called cost-of-illness studies. Such studies merely confirm that obesity is a serious societal issue; adding a monetary figure to this does not add much. The economic foundations of such estimates can also be questioned, thus lessening their policy relevance. The real value of economics in the arena of obesity care is in evaluating, through formal economic evaluation, the use of our scarce health care resources in different strategies to prevent and treat obesity.


S-cones do not contribute to the OFF-midget pathway in the retina of the marmoset, Callithrix jacchus.
It is well established that in primate retina both medium- and long-wavelength-sensitive cone types provide input to the midget-parvocellular pathway. The question, however, whether short-wavelength-sensitive (S or 'blue') cones provide input to the OFF-division of the midget-parvocellular pathway is still controversial. In the present study, we investigated the connections of nearly 400 S-cones with OFF-midget bipolar cells in central and peripheral retina of a New World monkey, the marmoset. Horizontal sections or pieces of whole retinae were double-labelled with an antiserum to S-cone opsin to identify S-cones and antibodies to the cell adhesion molecule CD15 to identify OFF-midget bipolar cells. Peanut agglutinin coupled to a fluorescent tag was used to label the cone pedicles of all cone types. Peanut agglutinin was also used to distinguish S-cones from the other cone types. The sections were analysed with deconvolution microscopy. We found that nearly all pedicles of medium- and long-wavelength-sensitive cones are located opposite distinct dendritic clusters formed by OFF-midget bipolar cells. By contrast, the S-cone pedicles are not located opposite dendritic clusters. Instead, S-cones make sparse contacts with CD15-labelled processes. Some of these processes protruded from OFF-midget bipolar clusters, whereas others could be traced to a diffuse bipolar cell type. Thus, in the marmoset retina the midget-parvocellular system does not carry a blue-OFF signal.


Comparison of plasma exchange with different membrane pore sizes in the treatment of severe viral hepatitis.
Plasma exchange has become an effective mode of blood purification in patients suffering from liver failure. To assist in patient recovery, we compared two plasma separators to identify a plasma separator with suitable pore sizes to remove toxic substances effectively, and retain important plasma components. The study focused on severe viral hepatitis patients. Of 206 rounds of plasma exchange, 137 were completed with the PS-06 plasma separator (membrane pore size=0.2 microm) and 69 with the EC-4A plasma separator (membrane pore size=0.03 microm). The efficacy of different plasma separators was compared using survival rate, changes in liver biochemistry, immunoglobulin, and complement parameters. The survival rate of patients treated with PS-06 was 43.3% (13 of 30 patients). For patients treated with EC-4A, two patients were bridged to liver transplantation successfully, and 57.9% (11 of 19 patients) survived. In both groups, the levels of total bilirubin, prothrombin time, and bile acid declined significantly. Compared to PS-06, EC-4A could retain significantly larger amounts of immunoglobulin and complements. Our study revealed that plasma exchange implementation with membrane pore size 0.03 microm could remove adequate bilirubin and bile acid, a class of toxins bound to plasma protein in severe viral hepatitis patients, and reduce the loss of essential plasma macromolecules.


Association of mTOR pathway with risk of gastric cancer in male smoker with potential prognostic significance.
Aberrant expression of mTOR signaling pathway is significantly associated with gastric cancer. However, the effect of smoking on mTOR expression and its downstream signaling molecules in gastric cancer has not been explored. Our study aims to investigate the effect of smoking on p-mTOR and its correlation with various downstream targets and survival of the smoker and never-smoker in advanced gastric cancer patients. Forty-one smokers and 41 never-smokers patient sample with the advanced gastric carcinoma were chosen for this study. Immunohistochemistry and western blot analysis were performed to check the expression of p-mTOR and its downstream targets. The correlation of p-mTOR with its downstream targets was analyzed by linear regression analysis in Graph Pad Prism software. Survivability analysis was examined by Kaplan-Meier method with log rank test in SPSS. High expression of p-mTOR and its downstream targets were observed in advanced gastric cancer smoker patients as compared to never-smokers by immunohistochemistry and western blot analysis. Results revealed that over expressed p-mTOR in smoker patients were positively correlated with its downstream targets (P < 0.05) and poor survival (P = 0.034). Over expression of p-mTOR in gastric cancer male smoker patients had the worse outcome.


Structural Differences in Translation Initiation between Pathogenic Trypanosomatids and Their Mammalian Hosts.
Canonical mRNA translation in eukaryotes begins with the formation of the 43S pre-initiation complex (PIC). Its assembly requires binding of initiator Met-tRNAiMet and several eukaryotic initiation factors (eIFs) to the small ribosomal subunit (40S). Compared to their mammalian hosts, trypanosomatids present significant structural differences in their 40S, suggesting substantial variability in translation initiation. Here, we determine the structure of the 43S PIC from Trypanosoma cruzi, the parasite causing Chagas disease. Our structure shows numerous specific features, such as the variant eIF3 structure and its unique interactions with the large rRNA expansion segments (ESs) 9S, 7S, and 6S, and the association of a kinetoplastid-specific DDX60-like helicase. It also reveals the 40S-binding site of the eIF5 C-terminal domain and structures of key terminal tails of several conserved eIFs underlying their activities within the PIC. Our results are corroborated by glutathione S-transferase (GST) pull-down assays in both human and T. cruzi and mass spectrometry data.


Osteoporosis Self-Assessment Tool As a Screening Tool for Predicting Osteoporosis in Elderly Chinese Patients With Established Rheumatoid Arthritis.
Osteoporosis Self-Assessment Tool for Asians (OSTA) is an indicator for assessing osteoporosis in postmenopausal women. The aim of this study was to investigate the value of OSTA index on predicting osteoporosis in elderly Chinese patients with established rheumatoid arthritis (RA). A total of 320 patients with RA and 158 normal individuals were recruited from January 2015 to October 2017. Bone mineral density (BMD) at the femur and lumbar spine was measured by dual-energy X-ray absorptiometry. RA group and control group were divided into low risk (values≥-1), medium risk (values between -4 and -1), and high risk (values ≤-4) group according to the value of OSTA index. One-way analysis of variance showed that BMD at all detected regions among the 3 groups were obviously different (p < 0.0001). Incidences of osteoporosis among different OSTA groups were 21.76% (47/216), 56.41% (44/78), and 80.77% (21/26), separately (x2 = 67.389, p < 0.0001). In RA group including premenspausal or postmenspausal female subgroup, prevalences of osteoporosis among different OSTA groups were different (p < 0.05-0.0001). We also found a positive linear correlation between OSTA index and BMD (p < 0.0001) both in RA and in control groups. Logistic regression revealed OSTA index (odds ratio = 0.734, p < 0.0001, 95% confidence interval: 0.657-0.819) was a protective factor for occurrence of RA-induced osteoporosis. OSTA had the highest discriminatory power, with an estimated Area Under Curve (AUC) of 0.750 (95% confidence interval 0.694-0.807, p < 0.0001), sensitivity of 76.9% and specificity of 66.5%. Our findings indicated that OSTA index was closely associated with BMD in RA patients, the degree of correlation was much stronger than age or BMI. OSTA index was a predictor for osteoporosis in RA, but it might have little relationship with disease status in RA.


[Tree-Augmented NaÏve Bayesian network model for predicting prostate cancer].
To evaluate the integrated performance of age, serum PSA, and transrectal ultrasound images in the prediction of prostate cancer using a Tree-Augmented NaÏve (TAN) Bayesian network model. We collected such data as age, serum PSA, transrectal ultrasound findings, and pathological diagnoses from 941 male patients who underwent prostate biopsy from January 2008 to September 2011. Using a TAN Bayesian network model, we analyzed the data for predicting prostate cancer, and compared them with the gold standards of pathological diagnosis. The accuracy, sensitivity, specificity, positive prediction rate, and negative prediction rate of the TAN Bayesian network model were 85.11%, 88.37%, 83.67%, 70.37%, and 94.25%, respectively. Based on age, serum PSA, and transrectal ultrasound images, the TAN Bayesian network model has a high value for the prediction of prostate cancer, and can help improve the clinical screening and diagnosis of the disease.


Idiopathic hypoparathyroidism with gestational diabetes.
A case of gestational diabetes complicating the pregnancy of a hypoparathyroid gravid patient is presented. Labor was induced by prostaglandin E2 vaginal tablets, but delivery was by cesarean section. Separate treatment of the two endocrinopathies was successful. After the induction of labor, hypocalcemia and hypoglycemia were seen, and they may have been caused by the prostaglandin E2.


Transgenesis and gene targeting in the mouse; tools for studying genetic determinants of hypertension.
As more effort is made to identify genes responsible for hypertension in human populations and genetically hypertensive animal models, the need for experimental systems in which the functional significance of genes, gene variants, and quantitative trait loci (QTL) can be determined is becoming increasingly important. Over the past five years, transgenic and gene-targeting technology has been utilized to study the cardiovascular effects of over-expression or ablation of genes which have been considered candidates in the genetic basis of hypertension. This review focuses on the most recent major advances in this area, and how this technology aids in our understanding of the molecular mechanisms by which newly discovered genes or gene variants affect blood pressure in the whole organism. We also discuss the potential use of transgenic models in refining the location of a QTL, and discuss some of the limitations and potential pitfalls in the application of these tools to the field of hypertension research. The coupling of genetic manipulations afforded by transgenesis and gene targeting, along with advances in our ability to assess the cardiovascular phenotype in the mouse, provides us with a powerful system for examining the genes responsible for causing essential hypertension.


[ETAP: A smoking scale for Primary Health Care].
To obtain a scale of tobacco exposure to address smoking cessation. Follow-up of a cohort. Scale validation. Primary Care Research Unit. Tenerife. A total of 6729 participants from the "CDC de Canarias" cohort. A scale was constructed under the assumption that the time of exposure to tobacco is the key factor to express accumulated risk. Discriminant validity was tested on prevalent cases of acute myocardial infarction (AMI; n=171), and its best cut-off for preventive screening was obtained. Its predictive validity was tested with incident cases of AMI (n=46), comparing the predictive power with markers (age, sex) and classic risk factors of AMI (hypertension, diabetes, dyslipidaemia), including the pack-years index (PYI). The scale obtained was the sum of three times the years that they had smoked plus years exposed to smoking at home and at work. The frequency of AMI increased with the values of the scale, with the value 20 years of exposure being the most appropriate cut-off for preventive action, as it provided adequate predictive values for incident AMI. The scale surpassed PYI in predicting AMI, and competed with the known markers and risk factors. The proposed scale allows a valid measurement of exposure to smoking and provides a useful and simple approach that can help promote a willingness to change, as well as prevention. It still needs to demonstrate its validity, taking as reference other problems associated with smoking.


A dietary embryo/fetal developmental toxicity study of arruva, an R,R-monatin salt isomer, in Crl:CD(SD) rats.
R,R-Monatin is an intensely sweet substance originally identified in the root bark of Sclerochiton ilicifolius. R,R-Monatin salt, commonly known as "arruva", has potential for use as a high-potency sweetener food ingredient. Previously, arruva was concluded to present no toxicologically relevant effects to Crl:CD(SD) rats and Crl:CD-1(ICR) mice fed up to 35,000 ppm arruva in the diet for 90 days. In the present study, groups of mated Sprague-Dawley rats (25 Crl:CD(SD) females/group) were exposed continuously to 0 (control), 15,000, 30,000, or 50,000 ppm arruva in the diet during gestation days 6-21. There were no fetal malformations or developmental variations that were attributable to arruva at any exposure level, nor were there any test article-related effects on intrauterine survival. Maternal toxicity, evidenced by lower mean body weights, body weight gains and feed efficiency, was observed at 50,000 ppm. A developmental effect, in the form of lower mean fetal body weight, was noted in the 50,000 ppm group in the presence of maternal toxicity. Therefore, the dietary no-observed-adverse-effect level (NOAEL) for maternal and embryo/fetal developmental toxicity of arruva in pregnant rats during gestation days 6-21 was 30,000 ppm (equivalent to 2564 mg/kg bw/day) based on reductions in maternal and fetal body weights.


Notch pathway inhibition with LY3039478 in soft tissue sarcoma and gastrointestinal stromal tumours.
LY3039478 is an orally bioavailable selective Notch inhibitor. This phase 1a/b trial evaluated the safety, pharmacokinetics and antitumour activity of LY3039478 in patients with soft tissue sarcoma (STS) and gastrointestinal stromal tumour (GIST). This multipart, phase 1 trial enrolled patients with refractory advanced/metastatic STS and GIST, measurable disease, Eastern Cooperative Oncology Group ≤1 and baseline tumour tissue. Eligible patients received LY3039478 50mg/75 mg three times per week, for 28-day cycle until disease progression. Safety assessments were based on Common Terminology Criteria for Adverse Events, V4.0. Tumour responses were assessed using Response Evaluation Criteria in Solid Tumours (RECIST 1.1) and Choi criteria. Primary objectives were to confirm the recommended phase 2 dose of LY3039478 and document the antitumour activity. Secondary objectives were safety and toxicity, pharmacokinetics (PK), progression-free survival (PFS) and overall survival (OS). Sixty-nine patients were enrolled and received LY3039478 (27 males, 42 females; median age 58, range 31-78). 16/37 (43%) patients with evaluable samples were positive for Notch 1 immunohistochemistry. Per RECIST 1.1, in leiomyosarcoma (LMS) group (n = 29), ten (36%) had stable disease (SD) and one (4%) had unconfirmed partial response (PR). In GIST group (n = 13), four (31%) had SD. Among other STS subtypes (n = 27), one patient with angiosarcoma had unconfirmed PR, six (21%) had SD. Median PFS was 1.9 months (95% confidence interval:1.6-3.3) for LMS, 1.9 months (0.3-6.1) for GIST and 1.7 months (1.4-2.2) for other STS groups. Median OS was 7.4 months (4.3-non-evaluable [NE]) for LMS, 16.5 months (3.9-16.5) for GIST and 5.6 months (3.4-NE) for other STS groups. Most common adverse events were diarrhoea, nausea, vomiting and decreased appetite. LY3039478 suggested a modest clinical activity in patients with STS and GIST and had a manageable safety profile.


On categorizing aphasic speech errors.
Acoustic studies of voice-onset-time in aphasics' speech suggest that fluent aphasics' errors are misselected phonemic targets whereas nonfluent aphasics' errors are of articulatory origin. However, we must be cautious when extrapolating a theory from only one measure of articulation. In this experiment, I examined utterances produced by five fluent aphasics, five nonfluent aphasics and two controls. First, the voice-onset-time findings were replicated. Second, I examined the duration of vowels preceding word-final stop consonants as an index of the consonant's voicing category. The pattern of voice-onset-times produced did not predict the pattern of vowel durations. Thus, voice-onset-time cannot be used to characterize more generally the output of the speaker.


The relationship between diabetic retinopathy and nephropathy in Sudanese adult with diabetes: population based study.
Diabetic nephropathy is responsible for nearly third of the world cases of end stage renal disease; it becomes a major public health problem with social and economic burden. The aim of this study is to explore if there is an association between retinopathy and nephropathy. In a cross sectional hospital based study a total of 316 individuals with diabetes were recruited from Makkah eye complex retina clinic. Demographic data, medical history and life style characteristics were taken through standard questionnaire. In addition, urine samples were collected to check for presence of albuminuria, blood samples were taken to measure HbA1c, lipid profile and renal function test. The mean age of participants was 58±10 years old. Only 39.8 and 40.2% of females were diagnosed with retinopathy and nephropathy, respectively. In addition, 60.2 and 59.8% of males were diagnosed with retinopathy and nephropathy, respectively. Hypertension was identified as risk factors for both retinopathy and nephropathy (P<0.001 and P<0.07). Serum creatinine and blood urea are significantly associated with retinopathy (P<0.01 and P<0.01). Body mass index (BMI) and HbA1c are not significantly associated with retinopathy and nephropathy. The prevalence of nephropathy among individuals with retinopathy was 35.6%. There was significant association between nephropathy and development of retinopathy (P<0.01). Logistic regression showed that two absolute risk factors are: nephropathy and having hypertension with P value of 0.009 and 0.003, respectively. Almost third of diabetic patients developed nephropathy, significant association between nephropathy and development of retinopathy was found.


Action verb processing specifically modulates motor behaviour and sensorimotor neuronal oscillations.
Understanding action-related language recruits the brain's motor system and can interact with motor behaviour. The current study shows MEG oscillatory patterns during verb-motor priming. Hand and foot verbs were followed by hand or foot responses, with faster reaction times for congruent conditions. In ROIs placed in the hand/arm and foot/leg portions of the sensorimotor cortex, this behavioural priming effect was accompanied by modulations in MEG oscillatory patterns preceding the responses. Power suppression in the alpha/beta frequency bands was reduced in congruent conditions in the body-part-specific ROIs. These results imply that the verb-motor priming effect may be a direct consequence of motor cortex contributions to action word processing.


Effect of phorbol-12-myristate-13-acetate (PMA) on the fine structure of Trypanosoma cruzi and its interaction with activated and resident macrophages.
Epimastigotes of Trypanosoma cruzi showed many filopodium-like projections from the flagellar membrane when incubated in the presence of 100 ng/ml (a concentration which does not interfere with cell motility and viability) phorbol-12-myristate-13-acetate (PMA). PMA is a substance which binds to the membrane-associated protein kinase C. Few of these projections were observed in control parasites. PMA, when added to the interaction medium, significantly increased the attachment of epimastigotes to the surface and their ingestion by resident or activated mouse peritoneal macrophages maintained in vitro. PMA, however, did not interfere with the ingestion of trypomastigotes.


Effect of Mg2+ on the structure and function of ribulose-1,5-bisphosphate carboxylase/oxygenase.
Mg(2+) in various concentrations was added to purified Rubisco in vitro to gain insight into the mechanism of molecular interactions between Mg(2+) and Rubisco. The enzyme activity assays showed that the reaction between Rubisco and Mg(2+) was two order, which means that the enhancement of Rubisco activity was accelerated by low concentration of Mg(2+) and slowed by high concentration of Mg(2+). The kinetics constant (K (m)) and V (max) was 1.91 microM and 1.13 micromol CO(2) mg(-1) protein.min(-1), respectively, at a low concentration of Mg(2+), and 3.45 microM and 0.32 micromol CO(2)mg(-1) protein.min(-1), respectively, at a high concentration of Mg(2+). By UV absorption and fluorescence spectroscopy assays, the Mg(2+) was determined to be directly bound to Rubisco; the binding site of Mg(2+) to Rubisco was 0.275, the binding constants (K (A)) of the binding site were 6.33 x 10(4) and 5.5 x 10(4) l.mol(-1). Based on the analysis of the circular dichroism (CD) spectra, it was concluded that the binding of Mg(2+) did not alter the secondary structure of Rubisco, suggesting that the observed enhancement of Rubisco carboxylase activity was caused by a subtle structural change in the active site through the formation of the complex with Mg(2+).


Cerebrospinal fluid tau in dementia disorders: a large scale multicenter study by a Japanese study group.
A large scale multicenter study of cerebrospinal fluid (CSF) tau levels was conducted to determine the cut-off value, sensitivity and specificity for clinical usage as a biomarker of Alzheimer's disease (AD). Its use for early and differential diagnosis and the factors that increase CSF tau levels were also examined. CSF samples from a total of 1,031 subjects including 366 patients with AD, 168 patients with non-Alzheimer type dementia (NA), 316 patients with non-dementia neurological diseases (ND) and 181 normal controls (NC) were measured using ELISA for tau. The cut-off value of tau, 375 pg/ml, showed 59.1% sensitivity and 89.5% specificity for diagnosis of AD compared with the other groups. The tau levels were increased from the early to late stages of AD. Elevation of CSF tau in the non-tauopathy and tauopathy dementia groups, chronic and acute damage to the cerebrum, and meningeal disturbance were other factors that required attention for clinical practice. Measurement of CSF tau was useful as a biomarker for early and differential diagnosis of AD.


Ozone weekend effect in cities: Deep insights for urban air pollution control.
Studying weekend-weekday variation in ground-level ozone (O3) allows one to better understand O3 formation conditions, with a potential for developing effective strategies for O3 control. Reducing inappropriately the O3 precursors emissions can either produce no reduction or increase surface O3 concentrations. This paper analyzes the weekend-weekday differences of O3 at 300 rural and 808 urban background stations worldwide from 2005 to 2014, in order to investigate the O3 weekend effect over time and assess the effectiveness of the precursors emissions control policies for reducing O3 levels. Data were analyzed with the non-parametric Mann-Kendall test and Theil-Sen estimator. Rural sites typically did not experience a weekend-weekday effect. In all urban stations, the mean O3 concentration on the weekend was 12% higher than on weekdays. Between 2005 and 2014, the annual mean of daily O3 concentrations increased at 74% of urban sites worldwide (+ 0.41 ppb year-1) and decreased in the United Kingdom (- 0.18 ppb year-1). Over this time period, emissions of O3 precursors declined significantly. However, a greater decline in nitrogen oxides (NOx) emissions caused an increase in Volatile Organic Compounds (VOCs) to NOx ratios leading to O3 formation. In France, South Korea and the United Kingdom, most urban stations showed a significant upward trend (+ 1.15% per year) for O3 weekend effect. Conversely, in Canada, Germany, Japan, Italy and the United States, the O3 weekend effect showed a significant downward trend (- 0.26% per year). Further or inappropriate control of anthropogenic emissions in Canada, Southern Europe, Japan, South Korea and the United States might result in increased daily O3 levels in urban areas.


The effect of hemiplegia on bone mass and soft tissue body composition.
The content of bone mineral (BMC), lean tissue, and fat tissue were measured by single and dual photon absorptiometry in both the paretic and the non-paretic limbs of 15 patients, hemiplegic due to cerebrovascular accident 23-38 weeks earlier. Compared with the non-paretic arm, the paretic arm had approximately 10% lower (P less than 0.01) BMC. This difference was largest at the measuring site with the highest ratio of trabecular to compact bone. The paretic leg had a 4% (P less than 0.001) lower BMC than the non-paretic leg. For both the arms and the legs, the lean content was lower (P less than 0.05) and the fat content higher (P less than 0.01) in the paretic than in the non-paretic. This was relatively more pronounced in the arms than in the legs. We conclude that partial immobilization, owing to paresis after a cerebrovascular accident, results in characteristic changes in the affected limbs, with a marked decrease in the content of bone and lean tissue and a pronounced increase in fatty tissue.


Differences of connectivity between ESRD patients with PD and HD.
The aim of this study was to investigate alterations in structural and functional brain connectivity between patients with end-stage renal disease (ESRD) who were undergoing peritoneal dialysis (PD) and hemodialysis (HD). We enrolled 40 patients with ESRD who were undergoing PD (20 patients) and HD (20 patients). We also enrolled healthy participants as a control group. All of the subjects underwent diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (rs-fMRI). Using data from the structural and functional connectivity matrix based on DTI and rs-fMRI, we calculated several network measures using graph theoretical analysis. The measures of global structural connectivity were significantly different between the patients with ESRD who were undergoing PD and healthy subjects. The global efficiency and local efficiency in the patients with PD were significantly decreased compared with those in healthy participants. However, all of the measures of global structural connectivity in the patients with HD were not different from those in healthy participants. Conversely, in the global functional connectivity, the characteristic path length was significantly increased and the small-worldness index was decreased in patients with HD. However, the measures of the global functional connectivity in the patients with PD were not different from those in healthy subjects. This study revealed that alterations in structural and functional connectivity in patients who were undergoing PD and HD were different than those in healthy controls. These findings suggest that brain networks may be affected by different types of renal replacement therapy.


[Knee range of motion as a marker of the effectiveness of medical intervention in multiple sclerosis].
To measure the knee range of motion (ROM) in the sagittal plane by video analysis in patients with multiple sclerosis (MS) after a course of medical rehabilitation and determine the minimal clinically important differences (MCID). We examined 45 patients (37 women, 8 men) with relapsing-remitting (n=38) and secondary-progressive MS before and after a course of medical rehabilitation. Gait parameters were recorded on video analysis system Physiomed Smart («Physiomed», Germany, the Davis protocol). The course of complex medical rehabilitation contributes to an increase knee ROM in MS patients in a wide range of disability (EDSS <6.5 points). MCID is estimated as 7.14° in mild (EDSS ≤4.0) and as 7.67° in moderate (EDSS=4.5-5.5) gait impairment. The results will assist clinicians and researchers in interpreting the significance of observed kinematic changes in the knee joint in MS patients after medical intervention.


Influence of relative humidity during coating on polymer deposition and film formation.
The influence of relative humidity in the pan during coating on polymer deposition and film formation was investigated. Four tablet substrates, differing in hydrophobicity, porosity, and surface roughness, were prepared and coated with Eudragit(®) RS/RL 30 D (8:2 ratio). The spray rate and atomization air pressure were varied to create two distinct micro-environmental conditions in the coating pan. PyroButton data logging devices placed directly in the pan were found to more accurately reflect the relative humidity to which tablets were exposed in comparison to measurements taken at the exhaust. Polymer deposition was shown to be influenced by the properties of the substrate, rather than the processing conditions used during coating, with higher polymer weight gains observed for the more porous tablets. Differences in the film-tablet interface and in the release performance of the coated products, however, were attributed to both the relative humidity in the pan and tablet porosity. Overall, this study demonstrated that a more humid coating process (86% vs 67%) promoted surface dissolution and physical mixing of the tablet ingredients with the forming film and the extent of this phenomenon was dependent on the tablet porosity.


A genetical study of DDT resistance in the mosquito Aedes aegypti.
Crosses have been carried out to determine the relationship between adult DDT resistance and the three linkage groups of the mosquito Aedes aegypti. Two linkage groups were implicated in the control of DDT resistance. In the Bangkok-HR strain resistance derived mainly from linkage group III, probably with the maor effect from the gene R-DDT2. When resistance was transferred into a susceptible background, by outcrossing Bangkok-HR to strain 64 and reselecting, resistance in the resulting Bangkok-MR strain came from both linkage groups II and III.


Event-related desynchronization in the EEG during emotional and cognitive information processing: differential effects of extraversion.
The aim of the present study was to analyze the influence of the personality dimension extraversion/introversion (E) on the level and topographical distribution of event-related desynchronization (ERD) in the EEG whilst participants were engaged in emotional face and cognitive information processing. In this context we build up on former studies dealing with the role of E as a possible moderator variable in cortical activation patterns during performance of mental speed, reasoning and working memory tasks (i.e., cognitive information processing). In a sample of 33 introverts and 33 extraverts (31 were male, 35 female) we found extraverted individuals displaying a lower (left-hemispheric) cortical activation than introverts when their task was to judge the identity of two simultaneously presented facial emotions. This effect was only observed in the upper alpha frequency band ( approximately 9.6-11.6 Hz). In analyzing E differences during cognitive information processing (i.e., performance of a verbal and a figural-spatial task) E effects - which were moderated by participants' sex - were restricted to lower EEG (alpha) frequency ranges ( approximately 5.6-9.6 Hz). The results generally suggest that E is differently involved when different kinds of information are processed.


Inherited syndrome of infantile olivopontocerebellar atrophy, micronodular cirrhosis, and renal tubular microcysts: review of the literature and a report of an additional case.
An 8-month-old male infant who presented in the neonatal period with failure to thrive, bilateral pleural and pericardial effusions, and hepatic insufficiency characterized by elevated liver functions tests and hypoalbuminemia was found at autopsy to have an unusual combination of olivopontocerebellar atrophy (OPCA), micronodular cirrhosis, and renal tubular microcysts. Metabolic evaluation was significant only for elevated urine dicarboxylic acids. In the brain, sections from the cerebellum showed marked atrophy of folia most severe in the vermal and paravermal regions. In addition, mild neuronal loss was present in the basis pontis and inferior olivary nuclei accompanied by gliosis. Residual Purkinje cells in the cerebellar hemispheres exhibited greatly expanded and swollen arbors, which ultrastructurally were found to contain densely packed membranous cytoplasmic body-like inclusions that had the appearance of unwinding, lamellar coils. Review of the literature shows that this constellation of findings has been associated with carbohydrate-deficient transferrin. This biochemical marker along with the distinctive clinical presentation and pathological features clearly delineates a unique subset of OPCA.


Fabrication of activated carbon from pomegranate husk by dual consecutive chemical activation for 4-chlorophenol adsorption.
In the present work, the fabrication of activated carbon (AC) from pomegranate husk (PHAC) by dual consecutive activation processes with ZnCl2 and NaOH as a chemical agent was studied. After that, the synthesized PHAC was used for adsorption of 4-chlorophenol (4CP) as a highly toxic compound for the human health and the environment. Different analytical techniques characterized the synthesized PHAC using ZnCl2/NaOH. The isotherms of N2 adsorption and desorption showed that total pore volume (Vtotal) and specific surface area (SBET) of PHAC were 0.404 cm3/g and 811.12 m2/g, respectively. The 4CP adsorption by PHAC studies revealed that the highest 4CP removal efficiency was 100% and obtained at 50, 100, and 150 mg/L of 4CP concentration with 2.5 g/L of PHAC. Based on the batch experiments, the highest 4CP removal was achieved at pH 6, 2.5 g/L of PHAC, and contact time of 60 min. The 4CP adsorption data of equilibrium and kinetics were successfully fitted to Langmuir's isotherm and Avrami fractional order.


Effects of a Remotely Delivered Cognitive Behavioral Coaching Program on the Self-Rated Functional Disability of Participants with Low Back Pain.
A remotely delivered cognitive behavioral coaching (CBC) program was offered as a service benefit for commercial health plan members with low back pain (LBP). This study describes changes in self-rated functional disability in a sample of plan members participating in the program (N=423). Independent measures included demographics, length of program enrollment, total CBC sessions, and baseline self-reported patient activation and presenteeism levels. Participants rated their functional disability level due to LBP using the Oswestry Disability Index (ODI). Dependent outcomes quantified change in participant functional disability rating (final ODI score minus baseline ODI score). Nonparametric tests compare differences between groups and within-group ODI score change. Two generalized linear models test for associations between independent variables and the ODI change score. A significant difference between baseline and final ODI scores was observed at the overall program level (p<.001) and within all independent variable categories of interest. Over 68% of total participants (n=289) reported improved functional ability from baseline to final (decrease in ODI score). Participants who completed more CBC sessions demonstrated significantly greater improvement in functional ability (p=.038) compared to those who completed fewer sessions. Participants aged 55 and older were significantly more likely to show deterioration in functional ability from baseline to final (p=.021). Outcomes suggest that program participation can influence self-rated functional disability in the management of LBP.


Free floating pigment cyst of the anterior chamber ten years after miotic therapy.
A free-floating pigment cyst has been present in the anterior chamber of the eye of a 14-year-old patient with numerous pigment nodules on the border of both pupils for about ten years. As a small child this patient has been treated very successfully with miotics for accommodative esotropia.


Accelerated loss of hearing and vision in the DNA-repair deficient Ercc1(δ/-) mouse.
Age-related loss of hearing and vision are two very common disabling conditions, but the underlying mechanisms are still poorly understood. Damage by reactive oxygen species and other reactive cellular metabolites, which in turn may damage macromolecules such as DNA, has been implicated in both processes. To investigate whether DNA damage can contribute to age-related hearing and vision loss, we investigated hearing and vision in Ercc1(δ/-) mutant mice, which are deficient in DNA repair of helix-distorting DNA lesions and interstrand DNA crosslinks. Ercc1(δ/-) mice showed a progressive, accelerated increase of hearing level thresholds over time, most likely arising from deteriorating cochlear function. Ercc1(δ/-) mutants also displayed a progressive decrease in contrast sensitivity followed by thinning of the outer nuclear layer of the eyeball. The strong parallels with normal ageing suggest that unrepaired DNA damage can induce age-related decline of the auditory and visual system.


Delayed ectopic antler growth and formation of a double-head antler in the metacarpal region of a fallow buck (Dama dama L.) following transplantation of antlerogenic periosteum.
Autologous transplantation of antlerogenic periosteum to the metacarpal region of a fallow buck resulted in the formation of an ectopic pedicle within a few months after transplantation. In the following years the pedicle increased in size, but no ectopic antler development occurred. However, in the ninth year after transplantation a first antler of about 3 cm length grew from the ectopic pedicle. The hard ectopic first antler was not cast, and renewed antler growth, starting in late spring of the following year, led to the formation of a larger subsequent antler of 7.3 cm length. The latter exhibited a distal flattening (palmation) and a rudimentary basal coronet, thereby displaying morphological features typical of the subsequent antlers of fallow bucks. The results of the experiment indicate (1) that transformation from pedicle to antler growth can occur several years after pedicle initiation, when the pedicle has reached a certain threshold size, (2) that species and age specific features of antler morphology tend to be realized even in ectopic locations, and (3) that primary and subsequent antler growth was apparently triggered by cells of the pedicle periosteum, being derived from the transplanted antlerogenic periosteum. The findings thereby emphasize the importance of local factors in the control of pedicle/first antler transformation and antler morphogenesis.


Autophagy benefits the in vitro and in vivo clearance of Talaromyces marneffei.
Talaromycosis, namely Talaromyces marneffei infection, is increasing gradually and has a high mortality rate even under antifungal therapy. Although autophagy acts differently on different pathogens, it is a promising therapeutic strategy. However, information on autophagy in macrophages and animals upon infection by T. marneffei is still limited. Therefore, several models were employed here to investigate the role of autophagy in host defense against T. marneffei, including RAW264.7 macrophages as in vitro models, different types of Caenorhabditis elegans and BALB/c mice as in vivo models. We applied the clinical T. marneffei isolate SUMS0152 in this study. T. marneffei-infected macrophages exhibit increased formation of autophagosomes. Further, macrophage autophagy promoted by rapamycin or Earle's balanced salt solution (EBSS) inhibited the viability of intracellular T. marneffei. In vivo, compared with uninfected Caenorhabditis elegans, the wild-type nematodes upregulated the expression of the autophagy-related gene lgg-1 and atg-18, and nematodes carrying GFP reporter were induced to form autophagosomes (GFP::LGG-1) after T. marneffei infection. Furthermore, the knockdown of lgg-1 significantly reduced the survival rate of T. marneffei-infected nematodes. Likewise, the autophagy activator rapamycin reduced the fungal burden and suppressed lung inflammation in a mouse model of infection. In conclusion, autophagy is essential for host defense against T. marneffei in vitro and in vivo. Therefore, autophagy may be an attractive target for developing new therapeutics to treat talaromycosis.


The discovery of colchicine-SAHA hybrids as a new class of antitumor agents.
A novel class of colchicine-SAHA hybrids were designed and synthesised based on the synergistic antitumor effect of tubulin inhibitors and histone deacetylases (HDAC) inhibitors. To the best of our knowledge, this is the first design of molecules that are dual inhibitors of tubulin and HDAC. Biological evaluations of these compounds included the inhibitory activity of HDAC, in vitro cell cycle analysis in BEL-7402 cells as well as cytotoxicity in five cancer cell lines.


Attenuation of acute morphine withdrawal in the neonatal rat by the competitive NMDA receptor antagonist LY235959.
The present study examined the ability of LY235959, a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, to attenuate behaviors and c-fos mRNA expression associated with acute morphine withdrawal in the infant rat. Rat pups were given a single dose of morphine (10.0 mg/kg, s.c.) or saline. Two hours later, pups were removed from the dam and injected with either LY235959 (10.0 mg/kg, s.c.) or saline. Fifteen minutes later acute morphine withdrawal was precipitated with naltrexone (10.0 mg/kg, s.c.) and behaviors were recorded every 15 s for the next 60 min. Immediately after behavioral testing, brain and spinal cord were assayed for c-fos mRNA analysis by solution hybridization. The intensity of the morphine withdrawal syndrome was reduced in pups pre-treated with LY235959. Withdrawal behaviors such as head moves, moving paws, rolling, and walking were decreased, and vocalizations were completely eliminated in pups pre-treated with LY2359559. Acute morphine withdrawal increased c-fos mRNA expression in the brain and the spinal cord, which was attenuated by pre-treatment of LY235959. Thus, in the 7-day-old rat, as in the adult, NMDA receptors play a role in the behavioral and molecular manifestations of acute morphine withdrawal.


[Participation of hypothalamic adrenergic and cholinergic systems in the regulation of pituitary adrenocorticotropic function].
Experiments were conducted on male rats; a study was made of the activity of pituitary-adrenal cortex system under conditions of electrolyte destruction of various hypothalamic areas. Pharmacological analysis pointed to the irregular distribution in the hypothalamus of the cholinergic and adrenergic systems controlling the secretion of ACTH-glucocorticoids. As suggested, the cholinergic systems are situated in the mammillary region, alpha-adrenergic ones--in the anterior or the posterior regions of the hypothalamus, and beta-adrenergic receptors--in the ventromedial nuclei of the hypothalamus. The latter possibly play an inhibitory role.


Detection and recognition of auditory patterns.
The detection/recognition theorem (Starr, Metz, Lusted, & Goodenough, 1975) provides a signal detection theory prediction of an observer's ability to identify one of a set of possible signals on the basis of the observer's ability to detect whether any signal is presented. The present findings show that the theorem can be applied to complex auditory stimuli in a fashion that is not merely a trivial extension of the results obtained with simple auditory stimuli.


[NiFe], [FeFe], and [Fe] hydrogenase models from isomers.
The study of hydrogenase enzymes (H2ases) is necessary because of their importance to a future hydrogen energy economy. These enzymes come in three distinct classes: [NiFe] H2ases, which have a propensity toward H2 oxidation; [FeFe] H2ases, which have a propensity toward H2 evolution; and [Fe] H2ases, which catalyze H- transfer. Modeling these enzymes has so far treated them as different species, which is understandable given the different cores and ligand sets of the natural molecules. Here, we demonstrate, using x-ray analysis and nuclear magnetic resonance, infrared, Mössbauer spectroscopies, and electrochemical measurement, that the catalytic properties of all three enzymes can be mimicked with only three isomers of the same NiFe complex.


Cleavage of the soluble (pro)renin receptor (sATP6AP2) in the placenta.
The (pro)renin receptor (ATP6AP2) is cleaved and released as soluble ATP6AP2 (sATP6AP2). The sATP6AP2 is detected in plasma and urine and is elevated in women with gestational diabetes and preeclampsia. The source and cleavage pathway of sATP6AP2 in pregnancy is unknown. The syncytiotrophoblast is the major placental secretory layer and is in direct contact with maternal blood. Both FURIN and Site 1 protease (MBTPS1) cleave sATP6AP2 in non-placental cells. We postulated that ATP6AP2 was cleaved by FURIN and/or MBTPS1 and that sATP6AP2 is secreted by the placental syncytiotrophoblast. Term primary trophoblast cells were transfected with FURIN siRNA, negative control siRNA or vehicle. In a separate experiment, primary trophoblasts were treated with a pro-protein convertase inhibitor (DEC-RVKR-CMK), an MBTPS1 inhibitor (PF 429242) or vehicle. Trophoblasts were left to spontaneously syncytialise before cells and supernatants were collected and intracellular and extracellular sATP6AP2 levels analysed by immunoblot. sATP6AP2 is secreted by placental trophoblasts. Levels of intra and extra-cellular sATP6AP2 decrease with syncytialisation (P = 0.01 and P = 0.02, respectively), as do FURIN mRNA (P = 0.0003) and protein (P = 0.0007). FURIN siRNA decreased FURIN mRNA and protein levels (both P < 0.0001). Neither FURIN siRNA or PF 429242 affected sATP6AP2 levels. DEC-RVKR-CMK significantly decreased extracellular sATP6AP2 protein levels (P = 0.02). Soluble ATP6AP2 is secreted by placental trophoblasts and levels decrease with syncytialisation. DEC-RVKR-CMK, a broad inhibitor of pro-protein convertases reduced extracellular sATP6AP2 levels, but FURIN siRNA and MBTPS1 inhibition had no effect. Hence, a convertase other than FURIN or MBTPS1 is most likely responsible for placental sATP6AP2 secretion.


Comparative immunoreactivity of mouse and hamster sperm proteins recognized by an anti-P26h hamster sperm protein.
The binding of the spermatozoon to the zona pellucida is a species-specific phenomenon. We have previously shown that the binding of hamster sperm to the homologous zona pellucida involves a sperm 26-kDa glycoprotein, the P26h, originating in the epididymis. In order to establish to what extent this sperm protein is involved in the species-specific recognition of the egg's extracellular coat, we have compared the inhibitory properties of anti-P26h antibodies in a sperm-zona pellucida assay using hamster and mouse gametes. Anti-P26h IgGs inhibit, in a dose-dependent manner, gamete interactions in both species, although in a less efficient manner in the mouse than in the hamster. While anti-26kDa Fab fragments are as efficient as the intact IgG to inhibit hamster sperm-zona pellucida binding, they have no effect on mouse gamete interaction. ELISA, Western blot, and immunohistochemical experiments have been performed in order to characterize the mouse antigen(s) recognized by the anti-P26h antiserum. ELISA and Western blots showed that this antiserum recognized two proteins on mouse spermatozoa that are less reactive than the hamster P26h. These antigens are localized in the acrosomal region of epididymal spermatozoa of both species. These results indicate that the hamster P26H involved in zona pellucida interaction has certain unique epitopes, while others are common to the sperm of both species.


Pharmacokinetics of calcium dobesilate in beagle dogs after repeated administration.
Many pharmacological findings suggest that repeated intravenous administration of calcium dobesilate improves myocardial lymphatic drainage, accelerates removal of degradation products and other toxic substances by increasing the number of functioning lymphatics and thus limits infarct size after experimental coronary artery occlusion. The aim of the present study was to investigate the relationship between the blood levels of calcium dobesilate and the pharmacological effect described above using the same dosage schedule. During the first six hours after intravenous administrations, at one hour interval, of three doses each of 100 mg/kg of calcium dobesilate, the average plasma level ranged from 414 micrograms/ml to 95 micrograms/ml with a plateau between the second and fourth hour. During this period, which is the most crucial for the ischemic myocardium, the effect of calcium dobesilate attained its optimum as evidenced by a statistically significant increase in the number of lymphatics visualized by lymphangiography and the reduction of infarct size measured by planimetry, by weight or by tomography. The plasma levels before the 18th hour were still higher than 10 micrograms/ml but no measurable calcium dobesilate was detected in the plasma at the 20th hour which indicates total elimination of the drug from the blood and thus precluding any risk of accumulation. The present results confirm that the doses of calcium dobesilate used in the pharmacological studies correspond to an adequate blood level.


The etiology of alcohol-induced breast cancer.
Breast cancer is the most common cancer in women in the United States, and it is second among cancer deaths in women. Results of most epidemiologic studies, as well as of most experimental studies in animals, have shown that alcohol intake is associated with increased breast cancer risk. Alcohol consumption may cause breast cancer through different mechanisms, including through mutagenesis by acetaldehyde, through perturbation of estrogen metabolism and response, and by inducing oxidative damage and/or by affecting folate and one-carbon metabolism pathways. Alcohol-metabolizing enzymes are present in human breast tissue. Acetaldehyde is a known, although weak, mutagen. However, results of some studies with human subjects implicate this agent in the context of genetic susceptibilities to increased ethanol metabolism. Reactive oxygen species, resulting from ethanol metabolism, may be involved in breast carcinogenesis by causing damage, as well as by generating DNA and protein adducts. Alcohol interferes with estrogen pathways in multiple ways, influencing hormone levels and effects on the estrogen receptors. With regard to one-carbon metabolism, alcohol can negatively affect folate levels, and the folate perturbation affects DNA methylation and DNA synthesis, which is important in carcinogenesis. Some study results indicate that genetic variants of one-carbon metabolism genes might increase alcohol-related breast cancer risk. For all these pathways, genetic polymorphisms might play a role in increasing further a woman's risk for breast cancer. Additional studies are needed to determine the relative importance of these pathways, as well as the modifying influence by genetic variation.


Sensitivity analysis and inverse uncertainty quantification for the left ventricular passive mechanics.
Personalized computational cardiac models are considered to be a unique and powerful tool in modern cardiology, integrating the knowledge of physiology, pathology and fundamental laws of mechanics in one framework. They have the potential to improve risk prediction in cardiac patients and assist in the development of new treatments. However, in order to use these models for clinical decision support, it is important that both the impact of model parameter perturbations on the predicted quantities of interest as well as the uncertainty of parameter estimation are properly quantified, where the first task is a priori in nature (meaning independent of any specific clinical data), while the second task is carried out a posteriori (meaning after specific clinical data have been obtained). The present study addresses these challenges for a widely used constitutive law of passive myocardium (the Holzapfel-Ogden model), using global sensitivity analysis (SA) to address the first challenge, and inverse-uncertainty quantification (I-UQ) for the second challenge. The SA is carried out on a range of different input parameters to a left ventricle (LV) model, making use of computationally efficient Gaussian process (GP) surrogate models in place of the numerical forward simulator. The results of the SA are then used to inform a low-order reparametrization of the constitutive law for passive myocardium under consideration. The quality of this parameterization in the context of an inverse problem having observed noisy experimental data is then quantified with an I-UQ study, which again makes use of GP surrogate models. The I-UQ is carried out in a Bayesian manner using Markov Chain Monte Carlo, which allows for full uncertainty quantification of the material parameter estimates. Our study reveals insights into the relation between SA and I-UQ, elucidates the dependence of parameter sensitivity and estimation uncertainty on external factors, like LV cavity pressure, and sheds new light on cardio-mechanic model formulation, with particular focus on the Holzapfel-Ogden myocardial model.


A novel root analogue dental implant using CT scan and CAD/CAM: selective laser melting technology.
Direct laser metal forming (DLMF) is a new technique which allows solids with complex geometry to be produced by annealing metal powder microparticles in a focused laser beam, according to a computer-generated three-dimensional (3D) model. For dental implants, the fabrication process involves the laser-induced fusion of titanium microparticles, in order to build, layer by layer, the desired object. Modern computed tomography (CT) acquisition and 3D image conversion, combined with the DLMF process, allows the fabrication of custom-made, root-analogue implants (RAI), perfect copies of the radicular units that need replacing. This report demonstrates the successful clinical use of a custom-made, root-analogue DLMF implant. CT images of the residual non-restorable root of a right maxillary premolar were acquired and modified with specific software into a 3D model. From this model, a custom-made, root-analogue, DLMF implant was fabricated. Immediately after tooth extraction, the root-analogue implant was placed in the extraction socket and restored with a single crown. At the 1-year follow-up examination, the custom-made implant showed almost perfect functional and aesthetic integration. The possibility of fabricating custom-made, root-analogue DLMF implants opens new interesting perspectives for immediate placement of dental implants.


Pharmacologic therapies.
Medical treatment of low back pain is at best palliative. While no drugs are specifically labeled for back pain treatment, analgesics, muscle relaxants, and corticosteroids are used in practice to augment rest and exercise programs. Invasive therapy remains contentious. This article reviews the available literature on the various pharmacologic therapies. In addition, newly postulated outcome measures for future back pain studies are discussed.


Publisher Correction: Concerns with yeast mitochondrial ADP/ATP carrier's integrity in DPC.
In the version of this article originally published, references 6 and 7 were interchanged in the reference list. The error has been corrected in the HTML and PDF versions of the article.


An Innovative Approach to Resident Scheduling: Use of a Point-Based System to Account for Resident Preferences.
The scheduling of residents for rotation assignments and on-call responsibilities is a time-consuming process that challenges the resources of residency programs. Assignment of schedules is traditionally done by chief residents or program administration with variable input from the residents involved. We introduced an innovative point-based scheduling system to increase transparency in the scheduling process, foster a sense of fairness and equality in scheduling, and increase resident ownership for making judicious scheduling choices. We devised a point-based system in which each resident in our 40-member program was allocated an equal number of points. The residents assigned these points to their preferred choices of rotations. Residents were then surveyed anonymously on their perceptions of this new scheduling system and were asked to compare it with their traditional scheduling system. The schedule was successfully implemented, and it allowed residents to express their scheduling preferences using an innovative point-based approach. Residents were generally satisfied with the new system, would recommend it to other programs, and perceived a greater sense of involvement. However, resident satisfaction with the new system was not significantly greater compared with the previous approach to scheduling (P = .20). Chief residents expressed satisfaction with the new scheduling model. Residents were equally satisfied with the traditional preference-based scheduling approach and the new point-based system. Chief residents' feedback on the new system reflected reduced stress and time commitment in the new point-based system.


Students help raise awareness of AMR.
Holly Hills, a veterinary student at the University of Nottingham, reports on events held by students at the university to mark European Antibiotic Awareness Day last month.


Current perspectives of New Zealand physiotherapists on rehabilitation and return to sport following anterior cruciate ligament reconstruction: A survey.
To investigate the clinical beliefs and practices of New Zealand physiotherapists regarding pre- and post-surgical rehabilitation and return to sport (RTS) criteria following anterior cruciate ligament reconstruction (ACLR). Online cross-sectional survey. A survey was adapted from a previously published survey and disseminated to New Zealand physiotherapists who were considered more likely to be involved in post-ACLR rehabilitation. The number of completed surveys was 318. Most physiotherapists (85%) preferred to first consult patients within 14 days of ACLR. In the first six weeks following ACLR, 89% of physiotherapists see patients at least once per week. Between 3- and 6-months post-ACLR, 76% of physiotherapists see patients at least once a fortnight. Pre-operative rehabilitation and post-operative rehabilitation exceeding six months are considered essential or important to patient outcomes by over 95% of physiotherapists. While 63% of physiotherapists support RTS 9-12 months after ACLR, 11% permit RTS within 6-9 months of surgery. Common RTS considerations include functional capacity, movement quality during functional tasks, time from ACLR, and knee strength. The survey revealed variability in the beliefs and practices of NZ physiotherapists regarding post-ACLR rehabilitation, and these beliefs and practices are at times inconsistent with best practice recommendations.


Taiwaniaquinoid and abietane quinone derivatives with trypanocidal activity against T. cruzi and Leishmania spp.
The in vitro leishmanicidal (Leishmania infantum and Leishmania braziliensis) and trypanocidal (Trypanosoma cruzi) activities of different compounds were evaluated. These compounds, of vegetal origin but synthesised in our laboratory, included five taiwaniaquinoid derivatives (S-567; S-569; S-589; S-602 and A-246) and one abietane quinone (P-1). The in vitro activity of the compounds on extracellular and intracellular forms of the two Leishmania species and T. cruzi was assayed. Infectivity and cytotoxicity tests for the Leishmania species were conducted on J774.2 macrophage cells using Glucantime as the reference drug. From all the compounds assayed, the derivatives P-1>S-567 were more active and less toxic than Glucantime. Infection rates and amastigote means indicated that these two compounds were the most active in both Leishmania species. In the case of T. cruzi, the best derivatives were P-1 and S-567, at the same levels as for the Leishmania species. These compounds exhibited the most potent anti-proliferative activity against the extracellular vector form (the epimastigote), the extracellular host form (the trypomastigote), and the intracellular host form (the amastigote), with lower toxicity than that of the reference drug Benznidazole. Metabolite excretion studies showed that alterations mainly at the level of the mitochondria may explain observed metabolic changes in succinate and acetate production, perhaps due to the disturbance of enzymes involved in sugar metabolism within the mitochondrion. The in vivo studies for T. cruzi provided results consistent with those found in vitro. No signs of toxicity were detected in mice treated with the compounds tested, and the parasitic charge was slightly lower than in the control. The effects of these two compounds were also demonstrated with the change in the anti-T. cruzi antibody levels during the chronic stage.


Localization of photosynthetic electron transport components in mesophyll and bundle sheath chloroplasts of Zea mays.
The organization of the electron transport components in mesophyll and bundle sheath chloroplasts of Zea mays was investigated. Grana-containing mesophyll chloroplasts (chlorophyll a to chlorophyll b ratio of about 3.0) possessed the full complement of the various electron transport components, comparable to chloroplasts from C3 plants. Agranal bundle sheath chloroplasts (Chl a/Chl b greater than 5.0) contained the full complement of photosystem (PS) I and of cytochrome (cyt) f but lacked a major portion of PS II and its associated Chl a/b light-harvesting complex (LHC), and most of the cyt b559. The kinetic analysis of system I photoactivity revealed that the functional photosynthetic unit size of PS I was unchanged and identical in mesophyll and bundle sheath chloroplasts. The results suggest that PS I is contained in stroma-exposed thylakoids and that it does not receive excitation energy from the Chl a/b LHC present in the grana. A stoichiometric parity between PS I and cyt f in mesophyll and bundle sheath chloroplasts indicates that biosynthetic and functional properties of cyt f and P700 are closely coordinated. Thus, it is likely that both cyt f and P700 are located in the membrane of the intergrana thylakoids only. The kinetic analysis of PS II photoactivity revealed the absence of PS II alpha from the bundle sheath chloroplasts and helped identify the small complement of system II in bundle sheath chloroplasts as PS II beta. The distribution of the main electron transport components in grana and stroma thylakoids is presented in a model of the higher plant chloroplast membrane system.


Sleep disturbance and rage attacks in opsoclonus-myoclonus syndrome: response to trazodone.
Parents of children with opsoclonus-myoclonus syndrome (OMS) frequently describe poor sleep and rage attacks. We hypothesized that these manifestations are related and could result from underlying monoaminergic dysfunction. We clinically characterized the sleep and behavioral characteristics of 51 young children with OMS; 19 of those with the most disruptive sleep patterns were treated with trazodone, a soporific serotonergic agent. Sleep disturbances, including prolonged sleep latency, fragmented sleep, reduced quantity of sleep, snoring, and non-restorative sleep, were reported in 32 children, and frequent rage attacks were reported in 25. In 59% of the poor sleepers, parents felt that the problem was severe enough to warrant treatment. Children sleeping <10 hours/night had a higher rage frequency than those who slept more. Of the children who required trazodone, 84% were receiving corticosteroids or adrenocorticotropic hormone (corticotrophin), compared with 37% in the subgroup with normal sleep. Trazodone (3.0 +/- 0.4 mg/kg/day) improved sleep and behavior in 95% of the children, significantly increasing total sleep time by 72%, decreasing the number of awakenings by 76%, and reducing rage attacks by 33%. Children with OMS exhibited multiple types of sleep disturbances, which contributed to rage attacks. Trazodone was effective in improving sleep and decreasing rage attacks and was well tolerated, even in toddlers.


A comparative study of bypass versus percutaneous intervention for left main disease.
Left main coronary artery disease is known as the highest risk lesion subset of ischemic heart disease. Several studies have shown a significant benefit following treatment with coronary artery bypass grafting compared with medical treatment. As a result, surgery has been the standard of care for the revascularization of left main disease for a long time. However, with the remarkable improvements in interventional cardiology, percutaneous coronary intervention has become technically feasible and showed favorable clinical outcomes. We sought to evaluate trends in treatment strategies of left main coronary artery disease over time in Sahloul University Hospital and to compare patient's characteristics as well as early, mid-term and long-term adverse outcomes of each therapeutic option. From 2005 to 2016, 260 patients with unprotected left main disease (defined as stenosis of at least 50%) were included. 109 patients underwent PCI (group 1), 102 patients underwent Surgery (group 2) and 49 patients were medically treated (group 3). Major cardiac and cerebrovascular events were defined as the composite of: mortality, nonfatal myocardial infarction, stroke, and need for repeat revascularization. Event rates were estimated with Kaplan-Meier analyses. Over time, the proportion of patients treated with percutaneous coronary intervention rather than coronary artery bypass grafting increased substantially, whereas the proportion of patients who received medical therapy remained steady. Group 1 patients had more cardiogenic shock (6.4% vs 0%, p=0,01) at presentation compared to group 2. More patients treated with surgery had multivessel disease (73% vs 40%; p <0.001), more distal left main bifurcation lesions (52.3% vs 73.5%; p=0.001) and higher SYNTAX scores (23.3±9.96 vs 32.5±8.7; p <0.001). All the other baseline variables were similar. At follow up, there were no differences, at the adjusted analysis, in the rate of myocardial infarction, cerebrovascular accidents, and the composite endpoint of major cardiovascular and cerebrovascular events (HR: 1, 04; 95% CI: 0.59 to 1.83; p=0.88). Compared to percutaneous coronary intervention group, group 2 has a higher all-cause mortality (p=0.017) driven exclusively by an elevated incidence of operative mortality (13.7% vs. 6.4%; HR: 0.08; 95% CI: 0.017 to 0.43; p=0.003). Nevertheless, long-term advantage of coronary artery bypass grafting over percutaneous coronary intervention was the less need for repeat revascularization (HR: 3.1; 95% CI: 1.26 to 8.12; p=0.014). Our data show that revascularization therapy have evolved remarkably in the favor of percutaneous coronary intervention over the last decade. Angioplasty and coronary artery bypass graft show comparable safety. However, the need for revascularization is more common after percutaneous treatment.


Is pulmonary tuberculosis a true risk-factor for chronic obstructive pulmonary disease?
This viewpoint discusses the possible relationship of tuberculosis with chronic obstructive pulmonary disease. Pulmonary tuberculosis as a risk factor and/or complication of COPD is reported in several reports from African and Asian countries. History of TB seems to have an important role in the natural history of COPD. It is difficult to conclude whether this is a true causal relationship or merely an incidental observation due to the concurrent presence of the two commonly prevalent diseases and their risk factors. Many of these disease and treatment-related factors can promote and/or aggravate disease condition.


[Myringoplasty and its effect on a vestibular function in patients with otitis media purulenta chronica (OMPC)].
A complex vestibulologic and audiologic examination was made in 25 patients with OMPC free of mesotympanitis before and after experimental myringoplasty with hen's egg amnion. The patients were divided into two groups depending on the presence of vestibular complaints. Partial or complete disappearance of subjective vestibular symptoms, reduced stimulation of the vestibular receptors (by 19%, on the average) were detected by experimental vestibular tests on the side of the affected ear. The asymmetry coefficient by labyrinth lowered by 31.1%, on the average.


Rejuvenating hepatic tumor microenvironment immunity with a phosphatidylserine-targeting small molecule drug conjugate.
We report the design, synthesis and evaluation of a class of phosphatidylserine-targeting zinc (II) dipicolylamine drug conjugates and show that conjugate 16b elicits immune cell infiltration and remodels the "cold" hepatic tumor microenvironment to the inflamed "hot" tumor. Structure-property relationship study via linker modifications and subsequent pharmacokinetics profiling were carried out to improve the solubility and stability of the conjugates in vivo. In a spontaneous hepatocellular carcinoma mouse model, we showed that conjugate 16b exhibited better antitumor efficacy than sorafenib. In particular, significant increase of CD8+ T cell infiltration and granzyme B level was observed, providing insights in sensitizing tumors from intrinsic immune suppressive microenvironment. Evaluation of tumor inflammation-related mRNA expression profile revealed that conjugate 16b, through inductions of key gene expressions including STAT1, CXCL9, CCL5, and PD-L1, rejuvenated tumor microenvironment with enhancement in T cell-, macrophage-, NK cell-, chemokines and cytokines'- functions. Our study establishes that an apoptosis-targeting theranostic enables enrichment of multifaceted immune cells into the tumor mass, which provides potential therapeutic strategies in the combination with immune checkpoint blockade treatment.


LAX PANICLE2 of rice encodes a novel nuclear protein and regulates the formation of axillary meristems.
Aerial architecture in higher plants is dependent on the activity of the shoot apical meristem (SAM) and axillary meristems (AMs). The SAM produces a main shoot and leaf primordia, while AMs are generated at the axils of leaf primordia and give rise to branches and flowers. Therefore, the formation of AMs is a critical step in the construction of plant architecture. Here, we characterized the rice (Oryza sativa) lax panicle2 (lax2) mutant, which has altered AM formation. LAX2 regulates the branching of the aboveground parts of a rice plant throughout plant development, except for the primary branch in the panicle. The lax2 mutant is similar to lax panicle1 (lax1) in that it lacks an AM in most of the lateral branching of the panicle and has a reduced number of AMs at the vegetative stage. The lax1 lax2 double mutant synergistically enhances the reduced-branching phenotype, indicating the presence of multiple pathways for branching. LAX2 encodes a nuclear protein that contains a plant-specific conserved domain and physically interacts with LAX1. We propose that LAX2 is a novel factor that acts together with LAX1 in rice to regulate the process of AM formation.


Quantifying the Dynamics of HIV Decline in Perinatally Infected Neonates on Antiretroviral Therapy.
Mathematical modeling has provided important insights into HIV infection dynamics in adults undergoing antiretroviral treatment (ART). However, much less is known about the corresponding dynamics in perinatally infected neonates initiating early ART. From 2014 to 2017, HIV viral load (VL) was monitored in 122 perinatally infected infants identified at birth and initiating ART within a median of 2 days. Pretreatment infant and maternal covariates, including CD4 T cell counts and percentages, were also measured. From the initial cohort, 53 infants demonstrated consistent decline and suppressed VL below the detection threshold (20 copies mL) within 1 year. For 43 of these infants with sufficient VL data, we fit a mathematical model describing the loss of short-lived and long-lived infected cells during ART. We then estimated the lifespans of infected cells and the time to viral suppression, and tested for correlations with pretreatment covariates. Most parameters governing the kinetics of VL decline were consistent with those obtained previously from adults and other infants. However, our estimates of the lifespan of short-lived infected cells were longer than published values. This difference may reflect sparse sampling during the early stages of VL decline, when the loss of short-lived cells is most apparent. In addition, infants with higher pretreatment CD4 percentage or lower pretreatment VL trended toward more rapid viral suppression. HIV dynamics in perinatally infected neonates initiating early ART are broadly similar to those observed in other age groups. Accelerated viral suppression is also associated with higher CD4 percentage and lower VL.


Four previously undescribed diketopiperazines from marine fungus Aspergillus puniceus FAHY0085 and their effects on liver X receptor α.
Four previously undescribed diketopiperazine-type alkaloids including one oxepin-containing diketopiperazine-type alkaloid, oxepinamide L (1), three 4-quinazolinone alkaloids, puniceloids E-G (10-12), together with 12 known analogues, protuboxepin D (2), oxepinamides D-G, J-K and I (3-9), puniceloids B-D (13-15) and protubonine B (16), were isolated from the culture of the marine-derived fungus Aspergillus puniceus FAHY0085. The structures of the previously undescribed compounds were comprehensively elucidated by detailed interpretation of their NMR and HRESIMS data. Their absolute configurations were unambiguously determined by ROESY experiments, Marfey's method, calculated ECD experiments and single-crystal X-ray diffraction analysis. Compounds (3-4, 6-8, 14-15) were evaluated for their cytotoxic activity against HepG2, MCF-7, SW1116 and HeLa cells and compound 6 and 14 showed moderate cytotoxic activity against HeLa cells with IC50 49.61 ± 2.91 and 28.38 ± 1.57 μM, respectively. Compounds (1-8, 11-15) were screened for their transcriptional activation of liver X receptor α and compound 11 with known compounds 13-15 showed significant transcriptional activation of liver X receptor α with EC50 values in the range 2-50 μM.


Inflammatory proteins in nasal lavage of workers exposed to occupational agents.
Low-molecular-weight (LMW) and high-molecular-weight (HMW) agents have been recognized as causes of occupational rhinitis (OR). Immunological mechanisms underlying OR differ according to the type of exposure. While HMW agents act mainly through IgE-mediated mechanisms, LMW agents appear to act through both immunological and non-immunological mechanisms. The objective of this study was to identify potential differences in the upper airways inflammatory response after exposure to LMW and HMW agents by specific inhalation challenge test (SIC). Nasal lavage (NL) samples from 20 subjects who were exposed to HMW (n = 10, Group I) and LMW (n = 10, Group II) at their workplaces were collected after SIC with control and specific occupational agents. These samples were analysed for 47 inflammatory markers using multiplex bead technology. After exposure to specific agent, Group I exhibited higher concentrations of the following proteins compared to Group II: fibrinogen (median (interquartile range) Group I: 0.09 (0.00) μg/mL, Group II: 0.04 (0.05) μg/mL, P = .05); haptoglobin (Group I: 0.86 (0.01) μg/mL, Group II: 0.14 (0.20) μg/mL, P = .02); vascular cell adhesion molecule-1 (VCAM-1) (Group I: 0.34 (0.67) ng/mL, Group II: 0.11 (0.11) ng/mL, P = .01); vascular endothelial growth factor (VEGF) (Group I: 157.0 (154.0) pg/mL, Group II: 98.0 (20.25) pg/mL, P = .01); and vitamin D (VDBP) (Group I: 0.06 (0.13) μg/mL, Group II: 0.03 (0.03) μg/mL, P = .04). No statistically significant differences in proteins profiles were observed between the groups after exposure to control agent. Also, subjects exposed to HMW agents showed a significant increase in NL levels of C-reactive protein compared to control-day exposure. Exposure to HMW and LMW agents by SIC induced a differential nasal airway response including acute-phase reactants proteins (fibrinogen, haptoglobin and CRP), cell adhesion molecules (VCAM-1), endothelial growth factors (VEGF) and VDBP.


Synthesis and evaluation of 3-[(2,4-dioxo-1,3,8-triazaspiro[4.6]undec-3-yl)methyl]benzonitrile derivatives as potential anticonvulsants.
New 3-[(2,4-dioxo-1,3,8-triazaspiro[4.6]undec-3-yl)methyl]benzonitrile derivatives 8-37 were synthesized and their pharmacological activities were determined with the objective to better understand their structure-activity relationship (SAR) for anticonvulsant activity. All the compounds were evaluated for their possible anticonvulsant activity by maximal electroshock seizure (MES) and pentylenetetrazole (PTZ) test. Compounds 11, 18, 31, and 32 showed significant and protective effect on seizure, when compared with the standard drug valproate. The same compounds were found to exhibit advanced anticonvulsant activity as well as lower neurotoxicity than the reference drug. From this study, it is quite apparent that there are at least three parameters for the activity of anticonvulsant drugs, that is, a lipophilic domain, a hydrophobic center, and a two-electron donor.


Changes in color and color coordinates of an indirect resin composite during curing cycle.
To measure the color changes of indirect resin composites during curing cycle and to determine the influence of shade group on these changes. One brand (belleGlass NG), divided into three shade groups (EN, OD and TL), was investigated. Resin composite was packed into a mold (BC) and was cured with a light-curing unit (C1). Secondary curing was performed in the proprietary curing chamber (C2). Color was measured at BC, C1 and C2 conditions. Changes in color and color coordinates were calculated and repeated measures three-way ANOVA was performed. Each pair of compared-condition in the curing cycle was set as a repeated variable. Net curing color change (C2-BC) was in the range of 1.0-10.1DeltaEab* units. Based on ANOVA for the color changes, DeltaEab* was influenced by the compared-condition, the shade group and the shade designation (p<0.01). Changes in color coordinates varied by the shade group. Changes in color during curing cycle were perceptible in several shades by the condition (DeltaEab*>3.7); therefore, clinical practice of shade matching should consider these color changes.


Hysteroscopic endometrial tumor localization and sentinel lymph node mapping. An upgrade of the hysteroscopic role in endometrial cancer patients.
Given the growing interest in sentinel node mapping (SLN) biopsy in Endometrial Cancer (EC) patients, many efforts have been made to maximize the SLN bilateral detection rate. However, at present, no previous research assessed the potential correlation between primary EC location in the uterine cavity and SLN mapping. In this context, this study aims to investigate the possible role of intrauterine EC hysteroscopic localization in predicting SLN nodal placement. EC patients surgically treated from January 2017 to December 2021 were retrospectively analyzed. All patients underwent hysterectomy, bilateral salpingo-oophorectomy, and SLN mapping. During hysteroscopy, the location of the neoplastic lesion was described as follows: uterine fundus (comprising the most cranial portion of the uterine cavity up to the tubal ostium including the cornual areas), corpus uteri (from the tubal ostium to the inner uterine orifice), and diffuse (when the tumor invades more than 50% of the uterine cavity). Three hundred ninety patients met the inclusion criteria. The tumor pattern diffused to the whole uterine cavity was statistically associated with SLN uptake on common iliac lymph nodes (OR 2.4, 95%CI 1-5.8, p = 0.05). Patients'age is an independent factor associated with SLN failure (OR: 0.95, 95%CI 0.93-0.98, p < 0.001). The study showed a statistically significant association between EC hysteroscopically spread throughout the whole uterine cavity and SLN uptake at the common iliac lymph nodes. Furthermore, patient age negatively affected the SLN detection rate.


The susceptibility of strains of mice to infection with Trypanosoma congolense.
The survival times of a number of strains of mice after infection with a stabilate of Trypanosoma brucei or of T congolense were examined. The mean survival times of all the strains when infected with T brucei TREU 667 ranged from 27 to 63 days. Greater disparity was observed after infection with T congolense GVR1 where the mean survival time ranged from seven (BALB/c) to 74 days (C57 Bl). It is suggested that the C57 Bl mouse might provide a laboratory model for the study of trypanotolerance in cattle.


Molecular basis of receptor/G-protein-coupling selectivity.
Molecular cloning studies have shown that G-protein-coupled receptors form one of the largest protein families found in nature, and it is estimated that approximately 1000 different such receptors exist in mammals. Characteristically, when activated by the appropriate ligand, an individual receptor can recognize and activate only a limited set of the many structurally closely related heterotrimeric G-proteins expressed within a cell. To understand how this selectivity is achieved at a molecular level has become the focus of an ever increasing number of laboratories. This review provides an overview of recent structural, molecular genetic, biochemical, and biophysical studies that have led to novel insights into the molecular mechanisms governing receptor-mediated G-protein activation and receptor/G-protein coupling selectivity.


Serum leucine-rich alpha-2 glycoprotein is a disease activity biomarker in ulcerative colitis.
Reliable biomarkers for monitoring disease activity have not been clinically established in ulcerative colitis (UC). This study aimed to investigate whether levels of serum leucine-rich alpha-2 glycoprotein (LRG), identified recently as a potential disease activity marker in Crohn's disease and rheumatoid arthritis, correlate with disease activity in UC. Serum LRG concentrations were determined by enzyme-linked immunosorbent assay (ELISA) in patients with UC and healthy controls (HC) and were evaluated for correlation with disease activity. Expression of LRG in inflamed colonic tissues from patients with UC was analyzed by western blotting and immunohistochemistry. Interleukin (IL)-6-independent induction of LRG was investigated using IL-6-deficient mice by lipopolysaccharide (LPS)-mediated acute inflammation and dextran sodium sulfate (DSS)-induced colitis. Serum LRG concentrations were significantly elevated in active UC patients compared with patients in remission (P < 0.0001) and HC (P < 0.0001) and were correlated with disease activity in UC better than C-reactive protein (CRP). Expression of LRG was increased in inflamed colonic tissues in UC. Tumor necrosis factor alpha (TNF-α), IL-6, and IL-22, serum levels of which were elevated in patients with active UC, could induce LRG expression in COLO205 cells. Serum LRG levels were increased in IL-6-deficient mice with LPS-mediated acute inflammation and DSS-induced colitis. Serum LRG concentrations correlate well with disease activity in UC. LRG induction is robust in inflamed colons and is likely to involve an IL-6-independent pathway. Serum LRG is thus a novel serum biomarker for monitoring disease activity in UC and is a promising surrogate for CRP.


Intracerebral hemorrhage after prophylactic revascularization in a patient with adult moyamoya disease.
The effect of revascularization surgery for a patient with moyamoya disease remains controversial. A 60-year-old man presented with bleeding from asymptomatic moyamoya vessels 10 years after prophylactic revascularization surgery. Cerebral angiography 10 years after the surgery demonstrated that the bilateral direct anastomoses remained effective and a small aneurysm persisted in the anterior choroidal artery. The territories of perfusion through the anastomoses and the size of the aneurysm remained unchanged compared with the angiograms performed 10 years ago. Direct revascularization surgery may not always resolve microaneurysms in the moyamoya vessels and prevent rebleeding in patients with hemorrhagic moyamoya disease or bleeding in the nonaffected side.


Direct examination of chemical kinetic laws by visual imagery. IV. Association processes between antigen- and fragmented antibody carrying fluorescent latex particles.
The binary association process was further examined by direct visual observation using a fluorescence microscope connected to an image-processing system and by a spectrophotometric method. In the present paper, we used human serum albumin (HSA)- and fragmented anti-HSA antibody-carrying fluorescent latex particles in order to attain higher sensitivities and exclude complexities that might be caused by dissociation of the association product. The rate constant of the binary association process was estimated to be 6.0 x 10(8) M-1 s-1 at 30 degrees C and pH 7.6. The activation parameters of the association process were evaluated. The effects of pH and viscosity of the suspension on the association process were also examined.