Safety and efficacy of imatinib in chronic eosinophilic leukaemia and hypereosinophilic syndrome: a phase-II study.
This study evaluated the efficacy and safety of imatinib in chronic eosinophilic leukaemia (CEL, n = 23) and hypereosinophilic syndrome (HES, n = 13). In CEL with FIP1L1-PDGFRA (n = 16) or various PDGFRB fusion genes (n = 5), complete haematological remission (CHR) was achieved in 95% (20/21) after 3 months. Complete molecular remission (CMR) was seen in 75% (12/16) of cases with FIP1L1-PDGFRA positive CEL by 6 months, and in 87% (13/15) after 12 months. CMR was achieved in three of five PDGFRB fusion positive patients after 3, 9 and 18 months respectively. All patients are currently on imatinib (100 mg; n = 13, 400 mg; n = 8) and no molecular relapse has yet been observed (median 26.7 months; range, 6.9-39.9). Imatinib was less effective in HES and CEL without known molecular aberration (n = 15); CHR was observed in 40% (6/15) of patients, two patients relapsed after 4.8 and 24.5 months. Three patients died due to imatinib-resistant progressive CEL (n = 2) or myocardial infarction (n = 1) unrelated to study treatment. Overall, imatinib was well tolerated with a low incidence of grade III/IV toxicities. These data confirmed the long-term efficacy of imatinib for PDGFR-rearranged CEL patients, and also showed that a minority of HES cases without known molecular aberrations may benefit from imatinib.


Prognostic significance of serum annexin A7 in severe traumatic brain injury: A prospective longitudinal cohort study.
Annexin A7 (ANXA7) may have the potential to exacerbate brain injury. Our purpose was to investigate the role of serum ANXA7 as a biomarker of severity and prognosis after severe traumatic brain injury (sTBI). In this prospective cohort study, we consecutively enrolled 102 sTBI patients and 102 controls and measured their serum ANXA7 concentrations. Post-trauma 180-day poor prognosis was considered as extended Glasgow outcome scale score 1-4. Significantly increased serum ANXA7 concentrations of sTBI patients, as compared to controls (median, 74.1 vs 8.0 ng/ml; P < 0.001), had independent correlation with Rotterdam computed tomography score (t = 3.251, P = 0.002) and Glasgow coma scale score (t = -2.253, P = 0.027), as well as serum ANXA7 concentrations > 74.1 ng/ml were independently predictive of 180-day overall survival (hazard ratio, 3.356; 95 % confidence interval (CI), 1.233-9.138; P = 0.018), and poor prognosis (OR: 3.558; 95 % CI, 1.264-10.015; P = 0.016). Serum ANXA7 concentrations were of significant efficiency for discriminating risks of mortality (area under receiver operating curve (AUC), 0.808; 95 % CI; 0.718-0.879) and poor prognosis (AUC, 0.772; 95 % CI; 0.678-0.849). Moreover, its AUC was in range of Glasgow coma scale score and Rotterdam computed tomography score (all P > 0.05) CONCLUSIONS: Increased serum ANXA7 concentrations, in close relation to severity, were independently associated with prognosis, indicating that serum ANXA7 may represent a clinically valuable biomarker of sTBI.


Morphometric study on the postnatal growth of non-cortical brain regions in Australian aborigines and Caucasians.
In an autopsy study on 29 male and 27 female Aborigines and 57 male and 37 female Caucasians the volumes of a large number of brain regions were determined and fitted to logistic growth functions. For Aboriginal adults significantly smaller values were found for weight and volume of the whole brain, cerebrum, and cerebellum and for the volumes of cerebral white matter, thalamus, amygdaloid body (females only), and globus pallidus (males only). No significant differences were found for caudate nucleus, putamen, amygdaloid body (males only), and globus pallidus (females only). Almost every region studied showed later half-value times, slower growth rates, and prolonged growth phases for Aborigines compared to Caucasians. These results are discussed in relation to secular changes of growth parameters of the human brain during the last century, timing of growth phases for each area, and the socioeconomical and health status of Aborigines.


Preservice teacher knowledge of basic language constructs in Canada, England, New Zealand, and the USA.
The present study examined preservice teachers' (PSTs) knowledge of basic language constructs across four different English-speaking teacher preparations programs. A standardized survey was administered to participants from Canada (n = 80), England (n = 55), New Zealand (n = 26), and the USA (n = 118). All participants were enrolled in undergraduate university programs that led to teacher certification for general education in the primary grades. Our data reveal that preservice teachers from all four countries show patterns of relative strength in areas that were targeted to be crucial within their national initiatives. Nevertheless, in general, PSTs demonstrated a lack of knowledge of certain constructs needed to teach early reading skills. The results are discussed in relation to research reports and initiatives regarding beginning reading instruction from each of the four countries.


An intelligent Bayesian hybrid approach to help autism diagnosis.
This paper proposes a Bayesian hybrid approach based on neural networks and fuzzy systems to construct fuzzy rules to assist experts in detecting features and relations regarding the presence of autism in human beings. The model proposed in this paper works with a database generated through mobile devices that deals with diagnoses of autistic characteristics in human beings who answer a series of questions in a mobile application. The Bayesian model works with the construction of Gaussian fuzzy neurons in the first and logical neurons in the second layer of the model to form a fuzzy inference system connected to an artificial neural network that activates a robust output neuron. The new fuzzy neural network model was compared with traditional state-of-the-art machine learning models based on high-dimensional based on real-world data sets comprising the autism occurrence in children, adults, and adolescents. The results (97.73- Children/94.32-Adolescent/97.28-Adult) demonstrate the efficiency of our new method in determining children, adolescents, and adults with autistic traits (being among the top performers among all ML models tested), can generate knowledge about the dataset through fuzzy rules.


[Publicity campaign rheuma2025 of the Union for Rheumatology].
The publicity campaign "rheuma2025", initiated by the Union for Rheumatology, aims at improvement of patient-centered care. For this the number of positions for trainees in rheumatology needs to increase to a level which matches the public needs. Students in medical school must have even more interest for the discipline and they must be recruited. Regulatory constraints in the approval by the authorities for opening a private rheumatology practice must become much more flexible. The possibilities for in-patient acute care of patients in specialized hospitals have to be strengthened. Finally, the public image of rheumatology per se must be sharpened. To achieve these goals a homepage for the campaign was created ( https://rheuma2025.de ), which provides a toolkit of items for the public, for physicians and students. Various media channels for rheuma2025 were established with specific contents for each target group.


Innovative approach to sunlight activated biofungicides for strawberry crop protection: ZnO nanoparticles.
Strawberries are one of the most common and important fruits in the world, widely investigated for their nutritional and nutraceutical properties. However, after the emergence of several outbreaks of foodborne diseases some concerns regarding the microbiological safety of fresh strawberries have increased in recent years. In this paper new insights, based on application of ZnO nanoparticles (NPs) as alternative to chemical fungicides in the fields for preharvest preservation of strawberries are presented. Antifungal activity of ZnO NPs was tested on main strawberry plant pathogen Botrytis cinerea. Obtained data indicated that used ZnO NPs (5 × 10-3 M) in the dark just insignificantly (12%) inhibited the radial growth of B. cinerea. But photoactivated ZnO NPs (5 × 10-3 M, 405 nm, 34 J/cm2) inhibited the growth of B. cinera by 80%. Real-time field experiments revelead, that spraying of ZnO NPs in the strawberry field in sunny day reduced Botrytis incidences by 43%, enhanced the crop production by 28.5% and stoped the spoilage of harvested fruits during storage by 8 days, if compare with control. No harm to crowns and leaves of strawberry plant have been found, however this treatment increased the growth of inflorescence (37.5%) and reduced the growth of runners (32.8%). For comparison, spraying of conventionqal chemical fungicide fenhexamid (FEN) reduced Botrytis incidences in the same level as ZnO NPs, increased the harvest by 21.9% and delayed the spoilage of fruits by 8 days. The presented results look highly promising, since ZnO NPs in the presence of sunlight, activated by UV and visible light can protect strawberry fruits from Botrytis infection more effectively than conventional fungicide fenhexamid. This treatment significantly increased crop production and reduced spoilage of strawberries. It looks like ZnO NPs have great potential in the future to replace chemical fungicides.


α-Synuclein oligomers with broken helical conformation form lipoprotein nanoparticles.
α-Synuclein (αS) is a membrane-binding protein with sequence similarity to apolipoproteins and other lipid-carrying proteins, which are capable of forming lipid-containing nanoparticles, sometimes referred to as "discs." Previously, it has been unclear whether αS also possesses this property. Using cryo-electron microscopy and light scattering, we found that αS can remodel phosphatidylglycerol vesicles into nanoparticles whose shape (ellipsoidal) and dimensions (in the 7-10-nm range) resemble those formed by apolipoproteins. The molar ratio of αS to lipid in nanoparticles is ∼1:20, and αS is oligomeric (including trimers and tetramers). Similar nanoparticles form when αS is added to vesicles of mitochondrial lipids. This observation suggests a mechanism for the previously reported disruption of mitochondrial membranes by αS. Circular dichroism and four-pulse double electron electron resonance experiments revealed that in nanoparticles αS assumes a broken helical conformation distinct from the extended helical conformation adopted when αS is bound to intact vesicles or membrane tubules. We also observed αS-dependent tubule and nanoparticle formation in the presence of oleic acid, implying that αS can interact with fatty acids and lipids in a similar manner. αS-related nanoparticles might play a role in lipid and fatty acid transport functions previously attributed to this protein.


Nivolumab induced pulmonary sarcoid-like granulomas with a concurrent pleural schwannoma: A pathologic-radiologic correlation of a rare condition mimicking metastatic melanoma.
Nivolumab is an anti-PD-1 antibody. The mechanism of action of nivolumab is inhibition of binding between PD-1 and PD-1 ligand. This causes activation of antigen-specific T cells that were previously unresponsive to cancer cells. This unique mechanism of action attributes the widespread use of nivolumab for the treatment of a variety of neoplastic conditions. On the other hand, this mode of action is associated with adverse effects as well. Schwannoma, also called neurilemmoma, is a benign peripheral nerve sheath tumor. Pleural schwannomas are very rare and very few cases have been reported in the medical English literature so far. Herein, we report a very rare case of concurrent presence of Nivolumab induced pulmonary sarcoid-like granulomas along with primary benign pleural schwannoma in a 49-year-old male. He was diagnosed with malignant melanoma of the right upper arm for which he underwent surgery and was receiving adjuvant chemotherapy. He developed pneumonitis during chemotherapy, and on imaging multiple reticular and nodular interstitial infiltrates were seen along with an incidental pleural mass with a high suspicion for metastasis. Wedge biopsy of the interstitial infiltrates was done and they were found to be pulmonary granulomas related to the nivolumab therapy he was receiving. The patient underwent excision of the pleural mass which showed histopathological and immunohistochemical features of schwannoma. The two conditions are unrelated and rarely encountered simultaneously. The radiologic and pathologic correlation along with differential diagnosis of these conditions are discussed.


Quenching-induced surface modulation of perovskite oxides to boost catalytic oxidation activity.
Quenching is a powerful method for modulating surface structures of metal oxide nanocatalysts to achieve high catalytic oxidation activities, but it is still challenging. Herein, a catalyst of ultrafine Co3O4 nanoparticles decorated on Co-doped LaMnO3 (Co3O4/LaCoxMn1-xO3) is synthesized via one-step quenching perovskite-type LaMnO3 nanocatalyst into an aqueous solution of cobalt nitrate, which exhibits significantly improved catalytic performance with toluene (1000 ppm) conversion of 90% at 269 °C under the gas hourly space velocity of 72000 mL g-1 h-1. The high catalytic activity correlates with large surface area, abundant oxygen vacancies and good reducibility. Furthermore, density functional theory calculations disclose that Co doping and interfacial effect of Co3O4/LaCoxMn1-xO3 can achieve lower C-H bond activation energy. These findings provide a unique and effective route towards surface modification of nanocatalysts.


Incidence of congenital toxoplasmosis in the City of Belém, State of Pará, Northern Brazil, determined by a neonatal screening program: preliminary results.
The aim of this study was to determinate the incidence of congenital toxoplasmosis among a group of newborns (NBs) from Belém using neonatal screening. Among the 6,000 newborns referred for investigation of genetic and metabolic diseases, 1,000 were selected for screening for congenital toxoplasmosis by determining the amount of IgM in the eluates of blood collected on filter paper. Positive tests were confirmed using paired serology of the NB and his mother. Out of the 1,000 NBs assessed, one had a positive screening result that was confirmed by paired serology. The incidence of congenital toxoplasmosis in Belém was 10/10,000 live NBs.


The detection of Alcelaphine herpesvirus-1 DNA by in situ hybridization of tissues from rabbits affected with malignant catarrhal fever.
Tissue sections and cultured lymphocytes from rabbits clinically affected following experimental infection with Alcelaphine herpesvirus-1 (AHV-1) were assessed for the presence of viral DNA by in situ hybridization with the cloned major HindII repeat sequence of this virus. Small numbers of virus-infected cells were consistently detected only in submandibular lymph nodes, while other tissues showed no evidence of viral DNA. Virus titration in culture suggested that there were higher titres of virus in the lymph nodes, spleen and lung of infected animals than in the kidney or peripheral blood lymphocytes and confirmed the low level of virus in these animals. Substantially more viral DNA was detected by in situ hybridization in lymphocytes following at least 24 h of culture, suggesting that viral replication is normally repressed by the host.


[Influence of social support on the life quality of burn survivors].
To investigate the influence of social support on the life quality of burn survivors. Three hundred and sixty patients admitted to our hospital from July of 1995 to July of 2002 were investigated by social support questionnaire (PRQ-85 Part2) and life quality self-evaluation questionnaire (GQOLL) 1 to 2 years after burns. The patients were divided into 3 groups (high, middle and low level of social support groups) according to the scores in the survey. The influence of different levels of social support on the degree of satisfaction of life and living quality were analyzed with SPSS11.0 software. The living satisfaction score and living quality score of patients with high and middle levels of social support were 54.6 +/- 7.1, 57.4 +/- 8.1 and 46.8 +/- 5.2, 51.3 +/- 5.7, respectively. On the other hand, those with low level of social support, the scores were 51.2 +/- 8.1 and 43.6 +/- 5.0, respectively. The life quality of burn patients can be improved through reinforcement of the social support.


Hyperglycemia alters N-glycans on colon cancer cells through increased production of activated monosaccharides.
Diabetes Mellitus (DM) is both, correlated and a known risk factor for colorectal cancer (CRC). Besides favoring the incidence of CRC, DM also accelerates its progression, worsening its prognosis. Previously, hyperglycemia, the DM hallmark, has been shown to lead to aberrant glycosylation of CRC cells, heightening their malignancy both in vivo and in vitro. Here we use mass spectrometry to elucidate the composition and putative structures of N-glycans expressed by MC38 cultured in normoglycemic (LG) and hyperglycemic-like conditions (HG). N-glycans, 67, were identified in MC38 cells cultured in LG and HG. The cells grown in HG showed a greater abundance of N-glycans when compared to LNG cells, without changes in the proportion of sialylated, fucosylated and mannosylated N-glycans. Among the identified N-glycans, 16 were differentially expressed, mostly mannosylated and fucosylated, with a minority of them being sialylated. Metabolomics analysis indicates that the alterations observed in the N-glycosylation may be mostly due to increase of the activated monosaccharides pool, through an increased glucose entrance into the cells. The alterations found here corroborate data from the literature regarding the progression of CRC, advocating for development or repositioning of effective treatments against CRC in diabetic patients.


Internal inguinal hernia on the transplant side after kidney transplantation: a case report.
The patient was a 52-year-old man who presented with right inguinal swelling and pain. He had undergone kidney transplantation in 2005 and bypass surgery using a vascular prosthesis from the left axillary artery to the bilateral femoral arteries in 2008. The vascular prosthesis had invaded the right inguinal canal ventrally. The transplanted ureter had a hazy appearance on a non-enhanced abdominal CT scan. A Lichtenstein operation was performed under a diagnosis of inguinal hernia. A skin incision with pulling of tissue and subcutaneous fat was devised to avoid exposure of the vascular prosthesis. The inguinal canal and spermatic cord were found to have coalesced. The hernia was diagnosed as a supravesical hernia, class II-1. This case shows that a Lichtenstein operation is a suitable procedure for avoidance of damage to the transplanted ureter in treatment of a transplant-side inguinal hernia in a kidney transplant recipient.


Chronic renal dysfunction following liver transplantation.
With most of the immunosuppressive protocols consisting of calcineurin inhibitors (CI), nephrotoxicity has become a major long-term complication often compromising outcome. In a single-center retrospective study, we reviewed 1173 liver transplantations to identify variables indicative for the occurrence of chronic renal dysfunction (CRD) (defined as > or = 1 episode of serum creatinine increase > or = 1.8 mg/dL > or = 2 wk). Chronic renal dysfunction was found in 137 (11.7%) of all transplants [82 (7%) early (after 3-12 months), 55 (4.7%) late-onset (> 12 months)]. Compared to 5-/10-yr survival rates in non-CRD transplants (84/74%) survival was significantly decreased in early (66/46%), but unchanged in late-onset CRD (98/86%). Rates of alcoholic cirrhosis and prior renal dysfunction were significantly increased in patients with CRD. In a multivariate logistic regression analysis, only cyclosporine A (CyA) as immunosuppression remained an independent risk factor. No correlations to age, gender, rejection/retransplantation or diabetes were found. Surprisingly, renal function (creatinine) showed no difference between patients on CI monotherapy (FK/CyA) compared to those who had mycophenolate mofetil (MMF) added. In liver transplantation, early onset CRD significantly compromises survival. CyA-based immunosuppression appears to have a stronger impact than FK. The fact that patients with long-term severe chronic renal dysfunction failed to improve under MMF rescue therapy emphasizes the importance of new diagnostic strategies to earlier identify at-risk patients.


Des-Leu angiotensin I: biosynthesis and drinking response.
The crude rat and bovine synaptosomal lysate from brain can hydrolyze angiotensin I (AI) to des-Leu angiotensin I (AI-dL) and no further. This cytosolic enzyme has a specificity for angiotensin-related sequences, R-His-Pro-Phe-His-Leu and therefore named angiotensin-related carboxypeptidase (ARC). These studies led to the biosynthesis and purification of AI-dL in order to determine if it can provoke a drinking response. This nonapeptide is a potent dipsogen when injected into the cerebroventricles of rats. The drinking response probably requires a second hydrolysis to angiotensin II (AII) since both captopril and saralasin can inhibit this response.


Heavy metal, microbial and pesticides residue contaminations are limiting the potential consumption of green leafy vegetables in Ghana: An overview.
Green leafy vegetables (such as cocoyam (Colocasia spp) leaves, spinach (Spinach spp), amaranths (Amaranthus spp), roselle leaves (Hibiscus spp), and lettuce (Lactuca spp)) form a major part of Ghanaian meals providing essential vitamin such as A, B and C and minerals including iron and calcium as well as essential bioactive compounds. However, the practices involved in the production, distribution and handling of these nutrient rich vegetables, by most value chain actors in Ghana, unfortunately pre-dispose them to contamination with pathogens, heavy metals and pesticides residues. These have therefore raised public health concerns regarding the safety and quality of these green leafy vegetables. Understanding the current perspectives of the type of pathogens, heavy metals and pesticide contaminants that are found in leafy vegetables and their health impacts on consumers will go a long way in helping to identify appropriate mitigation measures that could be used to improve the practices involved and thereby help safeguard human health. This review examined reported cases of microbial, heavy metal and pesticides residue contamination of green leafy vegetables in Ghana from 2005 to 2022. Notable pathogenic microorganisms were Ascaris eggs and larvae, faecal coliform, Salmonella spp., Staphylococcus aureus Streptococci, Clostridium perfringes, and Escherichia coli. In addition, Lead (Pb), Cadmium (Cr), Chromium (Cr), Zinc (Zn), Iron (Fe), Copper (Cu) and Manganese (Mn) have been detected in green leafy vegetables over the years in most Ghanaian cities. Pesticides residues from organochlorine, organophosphorus and synthetic pyrethroid have also been reported. Overall, microbial, heavy metals and pesticide residue contamination of Ghanaian green leafy vegetables on the farms and markets were significant. Hence, mitigation measures to curb the contamination of these vegetables, through the food chain, is urgently required to safeguard public health.


Elevated serum levels of anti-Müllerian hormone can be introduced as a new diagnostic marker for polycystic ovary syndrome.
To determine the possible role of anti-Müllerian hormone (AMH) in the diagnosis of polycystic ovary syndrome (PCOS) with a larger population of women and to evaluate its role as a new diagnostic marker. Cross-sectional study. University hospital. A total of 570 women, with PCOS (n = 419) and without PCOS (n = 151). Serum basal hormone; AMH, follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, and thyroid-stimulating hormone (TSH) levels were measured. Mean hormone levels were compared and the predictive value of serum AMH level was evaluated with the use of the receiver operating characteristic (ROC) curve analysis. No statistically significant differences were found between PCOS women and control groups in terms of age, body mass index and TSH levels. Differences between mean serum, FSH, LH and estradiol levels and LH/FSH ratio were found to be statistically significant (p < 0.001). Mean serum AMH level was higher in PCOS women than in controls (7.34 vs. 2.24 ng/mL, p < 0.001). The area under the ROC curve assay yielded a satisfactory result of 0.916 (95% confidence interval 0.897-0.935, p < 0.0001). The best compromise between 89.8% specificity and 80% sensitivity was obtained with a cut-off value of 3.94 ng/mL for PCOS diagnosis. Serum AMH measurement is very valuable in the diagnosis of PCOS women. The serum AMH level in women with hyperandrogenism or oligo-anovulation could indicate the diagnosis of PCOS when reliable ultrasonography data are not available or when typical clinical and laboratory findings are not available. The serum AMH level is a new and useful diagnostic tool in PCOS diagnosis.


Anion triggered metallogels: demetalation and crystal growth inside the gel matrix and improvement in viscoelastic properties using Au-NPs.
Progelator complex Zn-TRPA-2 undergoes Cl(-) triggered gelation to afford ZTP2G, while Zn-TRPA-2 capped Au-NPs under similar conditions gave another gel GNZTP2G which also represents a rare nano-composite metallogel. When Zn-TRPA-2 was triggered by Cl(-) and NO3(-) simultaneously, crystals of demetalated species NA-TRPA-2 grew inside the ZTP2G matrix. Interestingly, GNZTP2G exhibits superior viscoelastic properties over ZTP2G.


Effectiveness of repeated influenza vaccination among the elderly population with high annual vaccine uptake rates during the three consecutive A/H3N2 epidemics.
Annually, about 80% of the Korean elderly aged ≥65 years receive influenza vaccination. Repeated annual vaccination has been suggested as an important factor of poor influenza vaccine effectiveness (VE), though reported conflicting results. During the consecutive A/H3N2-dominant influenza seasons between 2012 and 2015, we comparatively evaluated the VE (repeated vs. current season only) against laboratory-confirmed influenza, pneumonia and hospitalization in the elderly aged ≥65 years with influenza-like illness (ILI). Clinical and demographic data were collected prospectively, and vaccination status of prior and current seasons was verified using the immunization registry data of Korean Centers for Disease Control and Prevention. During the first A/H3N2-dominant season in 2012-2013, influenza vaccine showed statistically significant effectiveness against influenza A infection only and when vaccinated in the current season only (VE 53%, 95% CI 15-77). In the latter two seasons (2013-2015 years), the adjusted VE for influenza A was indistinguishable between repeated vaccination and vaccination in the current season only. During consecutive influenza A/H3N2 epidemics, poor influenza vaccine effectiveness may be more pronounced among the elderly population with a high annual vaccine uptake rate.


Persistent Overexposure to N-Methyl-D-Aspartate (NMDA) Calcium-Dependently Downregulates Glutamine Synthetase, Aquaporin 4, and Kir4.1 Channel in Mouse Cortical Astrocytes.
Astrocytes express N-methyl-D-aspartate (NMDA) receptor (NMDAR) but its functions in these cells are not well defined. This study shows that the sustained exposure (8-72 h) of mouse astrocytes to NMDA decreases the expression of the functional astroglia-specific proteins, glutamine synthetase (GS), and the water channel protein aquaporin-4 (AQP4) and also reduces GS activity. Similar to rat astrocytes (Obara-Michlewska et al. Neurochem Int 88:20-25, 2015), the exposure of mouse astrocytes to NMDA also decreased the expression of the inward rectifying potassium channel Kir4.1. NMDA failed to elicit the effects in those cells incubated in the absence of Ca2+ and in those in which the GluN1 subunit of the NMDAR was silenced with GluN1 siRNA. The downregulation of GS, AQP4, and Kir4.1 observed in vitro may reflect NMDAR-mediated alterations of astrocytic functions noted in central nervous system pathologies associated with increased glutamate (Glu) release and excitotoxic tissue damage.


Genome-wide association and replication studies for handedness in a Korean community-based cohort.
Handedness is a conspicuous characteristic in human behavior, with a worldwide proportion of approximately 90% of people preferring to use the right hand for many tasks. In the Korean population, the proportion of left-handedness is relatively low at approximately 7%-10%, similar to that in other East-Asian cultures in which the use of the left hand for writing and other public activities has historically been oppressed. In this study, we conducted two genome-wide association studies (GWASs) between right-handedness and left-handedness, and between right-handedness and ambidexterity using logistic regression analyses using a Korean community-based cohort. We also performed association analyses with previously reported variants and our findings. A total of 8806 participants were included for analysis, and the results identified 28 left-handedness-associated and 15 ambidexterity-associated loci; of these, two left-handedness loci (NEIL3 [rs11726465] and SVOPL [rs117495448]) and one ambidexterity locus (PDE8B/WDR41 [rs118077080]) showed near genome-wide significance. Association analyses with previously reported variants replicated ANKS1B (rs7132513) in left-handedness and ANKIB1 (rs2040498) in ambidexterity. The variants and positional candidate genes identified and replicated in this study were largely associated with brain development, cerebral asymmetry, neurological processes, and neuropsychiatric diseases in line with previous findings. As the first East-Asian GWAS related to handedness, these results may provide an intriguing reference for further human neurologic research in the future.


CCT4 suppression inhibits tumor growth in hepatocellular carcinoma by interacting with Cdc20.
The chaperonin containing t-complex (CCT) proteins play an important role in cell cycle-related protein degradation in yeast and mammals. The role of the chaperonin containing t-complex 4 (CCT4), one subtype of CCT proteins, in the progress of hepatocellular carcinoma (HCC) was not fully elucidated. Here, we aimed to explore the mechanisms of CCT4 in HCC. In this study, we used the UALCAN platform to analyze the relationship between CCT4 and HCC, and the association of CCT4 with the overall survival (OS) of HCC patients was also analyzed. CCT4 expression in HCC tumor tissues and normal tissues was also determined by western blot (WB) assay. Lentivirus vector was used to knock down the CCT4 expression, and quantitative polymerase chain reaction and WB were used to determine the level of CCT4 in HCC cell lines. Cell counting kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays were used to detect the cell proliferation, and flow cytometry (FCM) was performed to evaluate the effect of CCT4 on the apoptosis of HCC cells. Co-immunoprecipitation (co-IP) assay and WB were used to explore the mechanisms of CCT4 regulating the growth of HCC. Data were calculated from at least three replicate experiments and expressed as mean ± standard deviation. Student's t test, paired t test, and Kaplan-Meier analysis were used to compare across different groups. We found CCT4 was upregulated in HCC tissues compared with normal tissues, and its high expression was associated with poor prognosis (P < 0.001). CCT4 was significantly increased in HCC tumor tissues compared with normal tissues (0.98 ± 0.12 vs. 0.23 ± 0.05, t = 7.73, P < 0.001). After being transfected with CCT4 short-hairpin RNA (shRNA), CCT4 was decreased in mRNA level and protein level in both Huh7 (mRNA level: 0.41 ± 0.07 vs. 1.01 ± 0.11, t = 8.09, P = 0.001; protein level: 0.61 ± 0.03 vs. 0.93 ± 0.07, t = 7.19, P = 0.002) and Hep3b cells (mRNA level: 0.55 ± 0.11 vs. 1.04 ± 0.15, t = 4.51, P = 0.011; protein level: 0.64 ± 0.10 vs. 0.95 ± 0.08, t = 4.32, P = 0.012). CCK8 assay indicated that CCT4 knockdown inhibited cell proliferation in both Huh7 (OD value of 3 days: 0.60 ± 0.14 vs. 0.97 ± 0.16, t = 3.13, P = 0.036; OD value of 4 days: 1.03 ± 0.07 vs. 1.50 ± 0.12, t = 5.97, P = 0.004) and Hep3b (OD value of 3 days: 0.69 ± 0.14 vs. 1.10 ± 0.11, t = 3.91, P = 0.017; OD value of 4 days: 1.12 ± 0.12 vs. 1.48 ± 0.13, t = 3.55, P = 0.024) cells. EdU assay showed that CCT4 knockdown inhibited the cell proliferation in both Huh7 (EdU positive rate: [31.25 ± 3.41]% vs. [58.72 ± 3.78]%, t = 9.34, P = 0.001) and Hep3b cells (EdU positive rate: [44.13 ± 7.02]% vs. [61.79 ± 3.96]%, t = 3.79, P = 0.019). FCM assay suggested that CCT4 knockdown induced apoptosis in HCC cells (apoptosis rate of Huh7: [9.10 ± 0.80]% vs. [3.66 ± 0.64]%, t = -9.18, P = 0.001; apoptosis rate of Hep3b: [6.69 ± 0.72]% vs. [4.20 ± 0.86]%, t = -3.84, P = 0.018). We also found that CCT4 could regulate anaphase-promoting complex (APC)Cdc20 activity via interacting with Cdc20. Furthermore, CCT4 knockdown induced securin (0.65 ± 0.06 vs. 0.44 ± 0.05, t = -4.69, P = 0.009) and B-cell lymphoma-2 (Bcl-2) interacting mediator of cell death (Bim; 0.96 ± 0.06 vs. 0.61 ± 0.09, t = -5.65, P = 0.005) accumulation. The upregulation of securin inhibited cell growth by downregulating cyclin D1 (0.65 ± 0.05 vs. 1.04 ± 0.07, t = 8.12, P = 0.001), and the accumulation of Bim inhibited Bcl-2 (0.77 ± 0.04 vs. 0.87 ± 0.04, t = 3.00, P = 0.040) and activated caspase 9 (caspase 9: 0.77 ± 0.04 vs. 0.84 ± 0.05, t = 1.81, P = 0.145; cleaved caspase 9: 0.64 ± 0.06 vs. 0.16 ± 0.07, t = 1.81, P = 0.001), which led to elevated apoptosis. Overall, these results showed that CCT4 played an important role in HCC pathogenesis through, at least partly, interacting with Cdc20.


Development and characterization of a new gill cell line from air breathing fish Channa striatus (Bloch 1793) and its application in toxicology: direct comparison to the acute fish toxicity.
A new cell line, Channa striatus gill (CSG), derived from the gill tissue of murrel, was established and characterized. The CSG cell line was maintained in Leibovitz's L-15 supplemented with 10% fetal bovine serum and has been subcultured more than 92 times. This cell line was able to grow in a range of temperatures from 22 to 32°C with optimal growth at 28°C. The plating efficiency was very high (52.21%) and doubling time was approximately 37h. The gill cell line was cryopreserved at different passage levels and revived successfully with 85% survival. Polymerase chain reaction amplification of mitochondrial 16S rRNA using primer specific to C. striatus confirmed the origin of this cell line from murrel. The cell line was further characterized by immunocytochemical analysis, chromosome number, transfection and mycoplasma detection. The cytotoxicity of endosulfan was assessed in CSG cell line using apoptosis assay, comet assay, mitochondrial alteration and five other endpoints such as Rhodamine 123 uptake, 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, neutral red assay, Alamar Blue assay and Methylene Blue protein assay. Acute toxicity study on fish was conducted by exposing murrel for 96h to endosulfan under static conditions. Statistical analysis revealed good correlation with r(2)=0.972-0.997 among the five endpoints. Linear correlations between the in vivo lethal concentration 50 (LC50) and each in vitro effective concentration 50 (EC50) were highly significant. The present study highlights the development of a new gill cell line from an air breathing fish that could be used as an alternative in vitro tools for studying pesticide toxicity in fish.


Reproductive performance of ewes grazing lucerne during different periods around mating.
High intake of lucerne pastures or feeding of other high quality diets during early pregnancy may increase embryo mortality, negating any benefit of improved nutrition on ovulation rate in ewes. This study was conducted to determine whether grazing ewes on lucerne (Medicago sativa) pastures for 7 days prior to and throughout joining would result in greater foetal numbers than if ewes were removed 7 days after the commencement of joining, or if ewes grazed senescent pasture throughout the joining period. Merino ewes (300) were allocated to two replicates of three treatments, grazing pastures between Days -7 and 36 of an unsynchronised, natural autumn joining. Grazing lucerne to Day 7 of joining resulted in 30% more (P<0.05) foetuses per ewe than grazing senescent pasture (1.60±0.07 and 1.31±0.07, respectively), and 19% more lambs marked per ewe joined. Extending grazing of lucerne past Day 7 of joining did not result in additional foetuses per ewe (1.61±0.06) in comparison with only grazing lucerne to Day 7 of joining. Greater than 80% of ewes mated during the first 14 days of joining, and the proportions of ewes returning to oestrus and re-mating (0.18±0.022) and of non-pregnant (0.09±0.017) ewes were similar (P>0.05) among all treatment groups, suggesting no differences between treatments in embryo mortality. Grazing naturally cycling ewes on lucerne prior to and during joinings in autumn is recommended as a means to increase the number of lambs born, although additional gains may not be obtained by grazing past day seven of joining.


Quantitative trait loci on barley (Hordeum vulgare L.) chromosome 7 associated with components of winterhardiness.
Quantitative trait loci (QTL) controlling traits associated with winterhardiness in barley (field survival, LT50, growth habit, and crown fructan content) were mapped to chromosome 7 in a population of 100 F1-derived doubled haploid lines. The largest QTL effects for all traits were detected in a 21% recombination interval on the long arm of chromosome 7. QTL in this region accounted for 37-68% of the variation for three measures of cold tolerance, 47% of the variation for growth habit, and 28% of the variation in crown fructan content. Trait association may be due to linkage rather than pleiotropy.


The levels of zinc, copper, manganese, selenium, chromium, nickel, cobalt, and aluminium in the meat, liver and kidney of swedish pigs and cattle.
The levels of zinc, copper, manganese, selenium, chromium, nickel, cobalt, and aluminium were determined in samples of meat, liver and kidney from pigs and cattle from Swedish slaughterhouses. The results have been compared with those reported from other investigations carried out in recent years. For zinc, copper, manganese and selenium, the mean levels found in the different tissues were very similar to those reported in previous studies. The mean levels of chromium and nickel were found to be in the range less than 0.010-0.015 mg/kg, regardless of the type of tissue. Cobalt levels ranged from 0.001 to 0.043 mg/kg, the highest levels being in the liver samples. The mean levels of aluminium were between 0.024 and 0.068 mg/kg. Tissues from cattle contained approximately twice as much aluminium as tissues from pigs. Analytical quality assurance was carried out by analysing standard reference materials. A great effort was made to minimize and check contamination. This may partly explain the fact that the levels of chromium, nickel, and aluminium found in the present study are among the lowest reported.


In vitro malignant transformation of in vivo ENU-induced rat ovarian Sertoli cell tumor (adenoma).
An N-ethyl-N-nitrosourea-induced rat ovarian Sertoli cell tumor was grown in tissue culture in Dulbecco's modified Eagle's medium (DMEM) supplemented with 25% horse serum (HS) and a hormone combination of 20 ng/ml each of hydrocortisone, insulin, and prolactin. This tissue culture derived from a nonsteroid hormone-producing tumor. Cytofluorometry and karyotyping of the nonhormone-producing tumor cell line (SCTL-1) revealed a diploid pattern for the early passage (P1), which became hyperdiploid (P10), and then aneuploid (P20). These cells had an epitheloid pattern, grew in a monolayer at early passages. After P10 the cells were transplanted into newborn rats and nude mice and resulted in high incidences of tumors (up to 100%). The cell line (SCTL-1) continued to grow in DMEM, 10% HS, and no hormone supplementation after P10. This study revealed that a benign rat ovarian Sertoli cell tumor after multiple passages in vitro underwent sequential genotypic and phenotypic changes and became highly malignant.


Should the followup of patients with bladder cancer include routine excretory urography?
This retrospective study was done to determine if patients who present with bladder tumors should be followed with routine excretory urograms to detect subsequent upper tract tumors at an early stage. The charts of 337 patients who have been followed for up to 9 years were reviewed. Excluding 1 patient with invasive transitional cell carcinoma of the distal ureter, no documented renal pelvic or ureteral tumor was discovered in any of the followup data. This finding is in contradistinction to patients who present with upper tract tumors and who are known to have a 44 to 54 per cent incidence of bladder tumor either pre-dating or post-dating the upper tract tumor. We conclude that routine excretory urography is neither cost-effective nor necessary for the followup of patients who present with bladder tumors.


Uterine artery embolization in patients with symptomatic diffuse leiomyomatosis of the uterus.
Six patients with symptomatic diffuse uterine leiomyomatosis underwent technically successful uterine artery embolization. After a median follow-up of 16 months, five women presented with permanent alleviation of symptoms and a normalized quality of life according to the Uterine Fibroid Symptom and Quality of Life questionnaire. Magnetic resonance imaging showed impressive recovery of the myometrium, and the infarcted leiomyomas shrank and were partially expelled. No additional treatment was necessary. Failure of therapy occurred in one patient with atypical growth of fibroid tumor tissue shortly after embolization, which was suspicious for malignancy. Hysterectomy was performed and pathologic evaluation revealed benign leiomyomatosis.


Mineralocorticoid interaction with glycated albumin downregulates NRF - 2 signaling pathway in renal cells: Insights into diabetic nephropathy.
In diabetic nephropathy, hyperglycemia elevates albumin glycation and also results in increased plasma aldosterone. Both glycation and aldosterone are reported to cause oxidative stress by downregulating the NRF-2 pathway and thereby resulting in reduced levels of antioxidants and glycation detoxifying enzymes. We hypothesize that an interaction between aldosterone and glycated albumin may be responsible for amplified oxidative stress and concomitant renal cell damage. Hence, human serum albumin was glycated by methylglyoxal (MGO) in presence of aldosterone. Different structural modifications of albumin, functional modifications and aldosterone binding were analyzed. HEK-293 T cells were treated with aldosterone+glycated albumin along with inhibitors of receptors for mineralocorticoid (MR) and advanced glycation endproducts (RAGE). Cellular MGO content, antioxidant markers (nitric oxide, glutathione, catalase, superoxide dismutase, glutathione peroxidase), detoxification enzymes (aldose reductase, Glyoxalase I, II), their expression along with NRF-2 and Keap-1 were measured. Aldosterone binds to albumin with high affinity which is static and spontaneous. Cell treatment by aldosterone+glycated albumin increased intracellular MGO, MR and RAGE expression; hampered antioxidant, detoxification enzyme activities and reduced NRF-2, Keap-1 expression. Thus, the glycated albumin-aldosterone interaction and its adverse effect on renal cells were confirmed. The results will help in developing better pharmacotherapeutic strategies for diabetic nephropathy.


Adrenergic neurons in the nucleus tractus solitarius receive GABAergic synapses. Demonstration by dual immunocytochemistry in the rat.
By means of a dual immunocytochemical labeling for phenylethanolamine-N-methyltransferase and glutamate decarboxylase, synaptic associations between adrenaline-synthesizing neurons and GABAergic terminals are demonstrated in the medial nucleus tractus solitarius of the rat. These relationships could constitute an anatomical substrate for the presumed role of GABA in modulation of baroreceptor reflexes at this level.


High-fat diet may impair K(ATP) channels in vascular smooth muscle cells.
K(ATP) channel in vascular smooth muscle cell (VSMC) is closely linked to the etiology of hypertension. The aim of this study was to investigate effect of the high-fat diet-induced obesity on K(ATP) channel and blood pressure. Obesity was induced by a 24-week high-fat diet feeding in rats. Function and expression of K(ATP) channel in mesenteric arteries were examined using myography system, patch clamp and Western blotting. We show that high-fat diet increased blood pressure, decreased K(ATP) channel-mediated relaxation responses and currents, and down-regulated K(ATP) expression in VSMC. In conclusion, diet-induced obesity impairs K(ATP) channels in VSMC, which may underscore obesity-triggered increase in blood pressure.


Interventional radiology using endoscopy: Blood supply route-targeted endoscopic injection sclerotherapy with multiple ligations for giant esophagogastric varices.
A case of high-risk giant esophagogastric varices was treated by blood supply route-targeted endoscopic injection sclerotherapy with multiple ligations (EISML). An endoscope was inserted in the left lower semi-lateral position under general anesthesia in the digital subtraction angiography room. The C-arm was rotated to obtain a frontal view for fluoroscopy. Before puncturing the esophageal varices, the balloon attached to the tip of the endoscope was inflated to block the variceal blood flow. At puncture, an intravascular injection was confirmed fluoroscopically, and a total of 18 m of 5% ethanolamine oleate with iopamidol was injected retrogradely at 5-minute intervals from the esophagogastric varices to the root of the left gastric vein, maintaining stagnation for 25 minutes. The variceal site of the injection was ligated immediately after the removal of the needle to prevent variceal bleeding. Multiple variceal ligations were added to stop the variceal blood flow. Contrast-enhanced CT 3 days after EISML showed the thrombus formation in esophagogastric varices and the left gastric vein. The blood supply route-targeted EISML can be a feasible procedure for giant esophagogastric varices.


Plasmid-borne colistin resistance gene mcr-1 in a multidrug resistant Salmonella enterica serovar Typhimurium isolate from an infant with acute diarrhea in China.
Antimicrobial resistance of Salmonella enterica is a major global concern. Recent findings suggest that colistin as a last resort treatment for multidrug-resistant gram-negative bacteria is seriously threatened by the report of plasmid-mediated colistin resistance gene mcr-1 in China. A total of 827 S. Typhimurium isolates were recovered from 4 cities of China, including Henan, Shanghai, Zhejiang, and Hubei provinces. Subsequently, mcr-1 presence was identified by PCR screening. Antimicrobial susceptibility testing was performed by broth microdilution using a 96-well microtiter plate. Plasmid conjugation transfer experiments were conducted using Escherichia coli J53 as the recipient. Only one mcr-1 positive strain from the stool sample of an infant with acute diarrhea was isolated. Apart from colistin, the mcr-1-positive isolate showed co-resistance to the third-generation cephalosporins, ampicillin, nalidixic acid, tetracycline, chloramphenicol, sulfisoxazole, gentamicin, and cefotaxime revealing a multidrug-resistant phenotype. This strain harbored mcr-1 on a 227 kb IncHI2 plasmid, termed pJZ26, which could be transferred to E. coli J53. In addition to mcr-1, pJZ26 coharbored other resistance genes, including aph(4)-Ia, aac(3)-IVa, fosA, floR, sul2, and blaCTX-M-14. Compared with p2474-MCR1 and pHYEC7-IncHI2, pJZ26 contains an additional 4.6 kb fragment harboring the resistance gene tet(A) and its regulator tetR located on TnAs1 transposable element, which could mediate resistance to tetracycline. These findings highlight that the fact the mcr-1-harboring plasmid pJZ26 has a high potential to disseminate the mcr-1 gene and further challenge the clinical treatment.


Sinus histiocytosis with massive lymphadenopathy presenting as a meningioma.
This report documents a case of sinus histiocytosis with massive lymphadenopathy (SHML) which was unusual in that it produced a localized mass on the intracranial dura, simulating a meningioma. The clinical, histological and ultrastructural features of this case are presented.


Backward multiple imputation estimation of the conditional lifetime expectancy function with application to censored human longevity data.
The conditional lifetime expectancy function (LEF) is the expected lifetime of a subject given survival past a certain time point and the values of a set of explanatory variables. This function is attractive to researchers because it summarizes the entire residual life distribution and has an easy interpretation compared with the popularly used hazard function. In this paper, we propose a general framework of backward multiple imputation for estimating the conditional LEF and the variance of the estimator in the right-censoring setting. Simulation studies are conducted to investigate the empirical properties of the proposed estimator and the corresponding variance estimator. We demonstrate the method on the Beaver Dam Eye Study data, where the expected human lifetime is modeled with smoothing-spline ANOVA given the covariates information including sex, lifestyle factors, and disease variables.


Docking, synthesis and antimalarial activity of novel 4-anilinoquinoline derivatives.
A series of 4-anilinoquinoline triazine derivatives were designed, synthesized and screened for in vivo antimalarial activity against a chloroquine-sensitive strain of Plasmodium berghei. The compounds were further subjected to in vitro antimalarial activity against chloroquine-resistant W2 strain of Plasmodium falciparum and β-haematin inhibition studies. All the compounds exhibited in vivo antimalarial activity better than that shown by the standard drug, chloroquine. Twelve out of fifteen compounds showed better inhibition than that of chloroquine against chloroquine-resistant W2 strain of Plasmodium falciparum. Ten compounds showed β-haematin inhibition, better than that of chloroquine, with IC50 values in the range of 18-25µM. One compound, 3k, was found to be better than artemisinin against W2 strain of Plasmodium falciparum and also displayed the best β-haematin inhibitory activity, thereby becoming eligible to be explored as a potential lead for antimalarial chemotherapy.


Social position modifies the association between severe shoulder/arm and knee/leg pain, and quality of life after retirement.
Musculoskeletal disorders are extremely frequent and account for an important part of the global burden of disease. Risk factors for musculoskeletal disorders include sustained occupational exposure to physically demanding jobs. The effects of sustained occupational physical exposures on knee and shoulder pain are known to persist after retirement; also, several studies have shown a socio-economic gradient in health and quality-of-life outcomes, including for musculoskeletal pain. It is thus possible that prolonged occupational exposures affect workers differently in the long-term along a socio-economic gradient. This study was conducted to investigate whether the impacts of severe shoulder/arm and knee/leg pain on the quality of life of retired workers follow a socio-economic gradient. Data from the French GAZEL cohort study (n = 14,249) were used to compare the impacts of severe shoulder/arm and knee/leg pain separately on the SF-36, Nottingham Health Profile and limitations in activities of daily living measured in 2006 and 2007, between four groups of social position (measured in 1989). Analyses were made in 2014 with multiple linear and logistic regressions and stratified by sex. For both pain sites, in men and women, there was a strong general tendency for the impacts of severe pain to be smaller among participants in higher social positions. Most important differences were related to pain and physical limitations. These results suggest inequalities in the impacts of severe joint pain by socio-economic status. The source of these inequalities is still speculative and merits the scientific attention.


Evaluation of the cardiovascular function of older adult Rhesus monkeys by ultrasonography.
To evaluate the cardiovascular structure and function of older adult Rhesus monkey by utrasonography. Sixteen monkeys aged from 17 to 20 years and weighing from 8.2 to 15.3 kg, six adults aged 7-8 years and weighing from 8.1 to 9.2 kg. All monkeys were determined to be free from hypertension, hyperglycaemia and cardiac disease. The normal values of index related to heart and blood vessels including structure, haemodynamics and systolic or diastolic function were detected by 2D, M-mode, pulsed Doppler and tissue Doppler echocardiography respectively under ketamine hydrochloride sedation. Meanwhile, blood pressures were also measured by electronic sphygmomanometer. Each monkey underwent repeated detections in 2 weeks and all data were analysed with statistical methods. Compared with young adult monkeys, the older's heart rate (HR), the left ventricular diastolic function and the compliance of big artery including right and left common carotid artery, bulbus caroticus, internal carotid artery and abdominal aorta were decreased and the associated indexes changed significantly (P < 0.05 or P < 0.01). Meanwhile, older monkeys exhibited significant increase in the aorta diameter (AO), amplitude of aortic wall (AAO), left atrial diameter (LAD), end diastolic volume of left ventricle (EDV), stroke volume (SV), left ventricular mass (LVM) (P < 0.05 vs. young adult monkeys); however, cardiac output (CO) only slightly increased but the difference did not reach the statistical significance (P = 0.418, P = 0.644 respectively). The present results demonstrated the profiles of cardiovascular function and structure in the older Rhesus monkeys. Older monkey is accompanied by diminished left ventricular diastolic function and big artery compliance. Ultrasonography provides a means to non-invasively evaluate the anatomy and function of the heart and blood vessel, and plays an increasingly important role in the drug evaluation against cardiovascular dysfunction.


Developmental trajectories of body mass index in early childhood and their risk factors: an 8-year longitudinal study.
To identify groups of children with distinct developmental trajectories of body mass index (BMI), calculated as weight in kilograms divided by height in meters squared, between the ages of 5 months and 8 years and identify early-life risk factors that distinguish children in an atypically elevated BMI trajectory group. Prospective cohort study. Families with a child born between October 1997 and July 1998 in the province of Quebec, Canada. A representative sample of children (N = 2120) selected through birth registries for the Quebec Longitudinal Study of Child Development. Children for whom BMI data were available for at least 5 time points were retained in the present study (n = 1957). Early-life factors putatively associated with BMI, assessed by maternal report. Group-based trajectories of children's BMI, identified with a semiparametric modeling method from raw BMI values at each age. Three trajectories of BMI were identified: low-stable (54.5% of children), moderate (41.0%), and high-rising (4.5%). The high-rising group was characterized by an increasing average BMI, which exceeded international cutoff values for obesity by age 8 years. Two maternal risk factors were associated with the high-rising group as compared with the low-stable and moderate groups combined: maternal BMI (odds ratio, 2.38; 95% confidence interval, 1.38-4.54 for maternal overweight and 6.33; 3.82-11.85 for maternal obesity) and maternal smoking during pregnancy (2.28; 1.49-4.04). Children continuing on an elevated BMI trajectory leading to obesity in middle childhood can be distinguished from children on a normative BMI trajectory as early as age 3.5 years. Important and preventable risk factors for childhood obesity are in place before birth.


The interest of intraoperative scanner coupled to neuronavigation in traumatic or oncologic fractures of the cervical and upper thoracic spine requiring vertebral body height restoring procedures.
In recent years, the classical vertebroplasty has tended to be replaced by vertebral augmentation procedures. This article discusses the reliability of vertebral augmentation procedures using balloon kyphoplasty or a spine jack system, with intraoperative CT scan control coupled with the neuronavigation system as a treatment option for cervical and upper thoracic spine lesions. In our neurosurgical department, in the past two years, 11 patients underwent either a kyphoplasty or a vertebral augmentation by a Spine Jack via a transpedicular route, under perioperative 3D imaging, for a total of 15 cervical/upper thoracic lesions. For these patients, we evaluated the clinical symptoms before and after surgery, the intraoperative and postoperative complications as well as the radiation exposure and the duration of their hospitalisation. We noted for all of the patients an improvement of the mean Karnofsky index, which improved from 50 to 80, and of the VAS that decreased from a mean of 75 to 15, as they were clearly alleviated after the operation. The radiation was lower for patients that were treated for 2 or more vertebrae, and much lower for the medical staff. The intraoperative complications rate (4 cement leakages for 15 vertebrae, 26%), was low and completely asymptomatic in all cases. The radiological follow-up examinations were satisfactory for all the patients. Our results suggest that percutaneous transpedicular vertebral augmentation techniques using intraoperative CT scan are a viable treatment for secondary lesions or traumatic compression fractures of the cervical and upper thoracic spine.


[Acute pulmonary edema occurred during tocolytic treatment using nicardipine in a twin pregnancy. Report of three cases].
We report three cases of acute pulmonary edema that occurred during treatment by intravenous tocolysis using nicardipine in twin pregnancy patients with no previous heart problems. The three patients were admitted into our unit on account of the risk of premature birth after 29 to 32 weeks of amenorrhea. The treatment by intravenous tocolysis using nicardipine combined with glucocorticoids therapy had been undertaken in the previous maternity ward. The three patients presented symptoms of acute dyspnea 48 hours after the beginning of the treatment. Paraclinical examinations eliminated the diagnosis of pulmonary embolism. The patients'condition improved rapidly with appropriate diuretic treatment and by modifying the tocolysis. There are currently few studies proving the benefits of nicardipine in tocolysis treatment. Few similar cases of acute pulmonary edema have been noted in twin pregnancy patients treated with nicardipine. Haemodynamic modifications specific to twin pregnancy, intravenous hydratation and glucocorticoid maturation may explain a part of this complication. Therefore, it is appropriated to limit the use of intravenous nicardipine in the sole indication of tocolysis in twin pregnancy, and to prefer the use of nifedipine and atosiban, that have proven their effectiveness in this indication.


Impact of bone health on the mechanics of plate fixation for Vancouver B1 periprosthetic femoral fractures.
Condyle-spanning plate-screw constructs have shown potential to lower the risks of femoral refractures after the healing of a primary Vancouver type B1 periprosthetic femoral fracture. Limited information exists to show how osteoporosis (a risk factor for periprosthetic femoral fractures) may affect the plate fixation during activities of daily living. Using total hip arthroplasty and plate-implanted finite element models of three osteoporotic femurs, this study simulated physiological loads of three activities of daily living, as well as osteoporosis associated muscle weakening, and compared the calculated stress/strain, load transfer and local stiffness with experimentally validated models of three healthy femurs. Two plating systems and two construct lengths (a diaphyseal construct and a condyle-spanning construct) were modeled. Osteoporotic femurs showed higher bone strain (21.9%) and higher peak plate stress (144.3%) as compared with healthy femurs. Compared with shorter diaphyseal constructs, condyle-spanning constructs of two plating systems reduced bone strains in both healthy and osteoporotic femurs (both applying 'the normal' and 'the weakened muscle forces') around the most distal diaphyseal screw and in the distal metaphysis, both locations where secondary fractures are typically reported. The lowered resultant compressive force and the increased local compressive stiffness in the distal diaphysis and metaphysis may be associated with strain reductions via condyle-spanning constructs. Strain reductions in condyle-spanning constructs agreed with the clinically reported lowered risks of femoral refractures in the distal diaphysis and metaphysis. Multiple condylar screws may mitigate the concentrated strains in the lateral condyle, especially in osteoporotic femurs.


The Mystery of the Benzene-Oxide/Oxepin Equilibrium-Heavy-Atom Tunneling Reversed by Solvent Interactions.
The equilibrium between benzene oxide (1) and oxepin (2) is of large importance for understanding the degradation of benzene in biological systems and in the troposphere. Our studies reveal that at cryogenic temperatures, this equilibration is governed by rare heavy-atom tunneling. In solid argon at 3 K, 1 rearranges to 2 via tunneling with a rate constant of approximately 5.3×10-5 s-1 . Thus, in a nonpolar environment, 2 is slightly more stable than 1, in agreement with calculations at the CCSD(T) level of theory. However, if the argon is doped with 1 % of H2 O or CF3 I as typical hydrogen or halogen bond donors, respectively, weak complexes of 1 and 2 are formed, and now 2 is tunneling back to form 1. Thus, by forming non-covalent complexes, 1 becomes slightly more stable than 2 and the direction of the heavy-atom tunneling is reversed.


An activatable fluorescent probe enables in vivo evaluation of peroxynitrite levels in rheumatoid arthritis.
An activatable probe able to detect RONS level underlying the development of rheumatoid arthritis (RA) would be far-reaching for the diagnosis and drug efficacy assessment of RA. Despite more and more evidence suggests that ONOO- is an important signaling molecule participating in the RA disease, only rare fluorescent probes can detect ONOO- in this disease with satisfying performance. To this end, we designed and synthesized a novel activatable AIE fluorescent probe (DPPO-PN) for the detection of ONOO- levels in RA. The probe linearly responds to 0-10 μM ONOO- with a significant far-red fluorescence enhancement at 632 nm in 30 s (F/F0 = 161-fold, LOD = 10 nM) upon the excitation of 490 nm, elucidating excellent sensing abilities for ONOO- in cuvettes. Moreover, the fluctuations of intracellular ONOO- levels caused by adscititious adding or stimulant provoking could be real-time captured and visualized with this probe by confocal imaging. Further, the intravital imaging of ONOO- in LPS-induced and CFA-induced RA mouse models also can be achieved with the aid of the probe, substantiating the burst of ONOO- in the RA process. Therefore, this work not only offers an auxiliary tool for the diagnosis of RA but also would benefit our understanding of the ONOO-'s roles in RA.


Organization and neurochemical properties of intersegmental interneurons in the lumbar enlargement of the adult rat.
Intersegmental interneurons with relatively short axons perform an important role in the coordination of limb movement but surprisingly little is known about their organization and how they contribute to neuronal networks in the adult rat. We undertook a series of anatomical tract-tracing studies to label cell bodies and axons of intersegmental neurons in the lumbar cord and characterized their neurochemical properties by using immunocytochemistry. The b-subunit of cholera toxin was injected into L1 or L3 segments of seven rats in the vicinity of lateral or medial motor nuclei. In L5 lumbar segments, cells were found to be concentrated in contralateral lamina VIII, and in ipsilateral lamina VII and laminae V-VI following injections into the lateral and medial motor nuclei respectively. About 25% of labelled cells contained calbindin or calretinin or a combination of both. Calbindin positive cells were mainly distributed within the ipsilateral side of the L5 segment, especially within the ipsilateral dorsal horn whereas there was a concentration of calretinin cells in contralateral lamina VIII. A small population of cells around the central canal were cholinergic. We also examined axon terminals that projected from L1/3 to the L5 contralateral lateral motor nucleus. The majority of these axons were excitatory (75%) and made direct contacts with motoneurons. However, most inhibitory axons in L5 contained a mixture of GABA and glycine (20%) and about 22% of the total population of axons contained calbindin. In contrast, 19% of all intra-segmental axons in the L3 contralateral lateral motor nucleus were found to be purely glycinergic and 17% contained a mixture of GABA and glycine. This study shows that short range interneurons form extensive ipsi- and contralateral projections within the lumbar enlargement and that many of them contain calcium binding proteins. Those projecting contralaterally to motor nuclei are predominantly excitatory.


Anti-interleukin 33 treatment alleviates psoriatic dermatitis in mice induced imiquimod.
Interleukin-33(IL-33), is constitutively expressed in the epithelial cells of the skin. It has been reported that IL-33 contributed to the severity of the disease in psoriasis-like mouse models. In the current study, we evaluated the effect of anti-IL-33 antibody (Ab) in imiquimod-induced psoriatic dermatitis in mice. Our observations showed that anti-IL-33 Ab ameliorated the erythema, scaling, epidermal thickness and spleen index. Additionally, we found anti-IL-33 Ab significantly decreased the expression of psoriasis-related cytokines. Moreover, anti-IL-33 Ab significantly reduced Ki-67 positive cells, CD3+CD4+T cells, and CD3+CD8+T cells in the skin lesions. Furthermore, anti-IL-33 Ab treatment down-regulated the expression of phosphorylation of STAT3 and IL-33 in model mouse. These results indicated that the anti-IL-33 Ab alleviated the seriousness of skin lesions, inhibited the activation of the STAT3, lymphocyte infiltration and the secretion of pro-inflammatory cytokines in imiquimod-induced psoriatic dermatitis in mice, suggesting IL-33 may be a therapeutic target for the treatment of psoriasis.


[Periodontal surgical approach to the vertical fracture of the root. The application of composite resin to the fractured root surface].
For a patient who had a deep periodontal pocket without an attached gingiva on labial central area of left upper canine, a free gingival graft from the palate was done. After that, a flap was reflected and the cause of the lesion was determined. It became clear that there was a vertical fracture of the root and a composite resin (Clearfil-SC) was used to fill the fractured area. It has been 2 1/2 years since the therapy and the prognosis is good.


Resolvin E1 (RX-10001) reduces corneal epithelial barrier disruption and protects against goblet cell loss in a murine model of dry eye.
Resolvin E1 (RvE1; RX-10001) belongs to a new class of endogenous immunoregulating mediators, originally identified as a metabolite of the omega-3 polyunsaturated fatty acid, eicosapentaenoic acid. Based on its proven efficacy in models of chronic inflammation, this study investigated the efficacy of resolvin E1 in a murine model of dry eye. C57/B6 mice, aged 6 to 8 weeks, were treated with systemic scopolamine and exposed to air draft and low humidity for 16 hours/day for 5 days and allocated to the following groups: unexposed controls, disease controls, treatment with vehicle or RvE1 delivered topically as its methyl ester prodrug, RX-10005, to enhance corneal surface penetration. Treatment was initiated at the time of desiccating stress induction. Treatment efficacy was assessed by corneal permeability using Oregon Green Dextran and by conjunctival goblet cell density using periodic acid-Schiff reagent. RvE1 reduced the increase in corneal staining by 80% compared with untreated disease controls. Goblet cell density was reduced by 20% in disease controls but fully maintained in the group receiving RvE1. RvE1, delivered as its methyl ester prodrug, improved the outcome measures of corneal staining and goblet cell density in this murine model of dry eye, indicating the potential utility of endogenous resolvins and resolvin analogues in the treatment of dry eye.


Dentists in the US should be integrated into the hospital team.
Few dentists play integrated roles within hospital settings and few hospital emergency rooms have dentists. Existing research shows that only 67% of ER visits for dental problems are managed appropriately. Every year Americans die in hospital after being admitted because of dental disease and a recent study found that 20 people died after such hospitalisations in the United States in 2008. Authors of the current correspondence have conducted extensive research on characteristics of emergency room visits and hospitalisations due to various dental conditions using a nationwide dataset for the United States. This opinion article is intended to provoke discussion about the restructuring of hospitals to integrate oral health professionals into the hospital team.


Evaluating potential of tissue-engineered cryogels and chondrocyte derived exosomes in articular cartilage repair.
Treatment of articular cartilage injuries especially osteochondral tissue requires intervention of bioengineered scaffold. In this study, we investigated the potential of the tissue-engineered cryogel scaffold fabricated using cryogelation technology. Two types of cryogels viz. chitosan-gelatin-chondroitin sulfate (CGC) for articular cartilage and nano-hydroxyapatite-gelatin (HG) for subchondral bone were fabricated. Further, novel bilayer cryogel designed using single process fabrication of two layers (CGC as top layer and HG as the lower layer) was designed to mimic osteochondral unit. CGC cryogel was tested for their biocompatibility using the enzymatically isolated chondrcoytes from goat articular cartilage while HG cryogel was tested using pre-osteoblast cell line. Extracellular vesicles, specifically exosomes were isolated from the spent media of chondrocytes to validate their effect over cell proliferation and migration which are required for defect healing and infiltration respectively. These isolated exosomes were characterized and analyzed for confirming their size distribution profile and visualized morphologically using advanced microscopy techniques. For cartilage part, CGC cryogels were examined as delivery system for delivering exosomes at defect site, where 80% of release was observed in 72 h. Release of 18.7 µg chondroitin sulfate/mg cryogel was obtained in a period of one week from CGC cryogel (termed cryogel extract) which has chondroprotective effect. Further, effect of exosome concentration (10 and 20 µg/ml), CGC extract and combination of exosome and CGC extract (Exo-Ex) were assessed over the chondrocytes. In addition, in vitro scratch wound assay was performed to analyse the migration capacity over the micro-injury when treated with exosomes, cryogel extract and Exo-Ex. The overall results thus answer key questions of therapeutic potential of chondrocyte exosomes, cryogel extract in addition to potential of CGC and HG cryogel for osteochondral repair.


Pulp regeneration in a full-length human tooth root using a hierarchical nanofibrous microsphere system.
While pulp regeneration using tissue engineering strategy has been explored for over a decade, successful regeneration of pulp tissues in a full-length human root with a one-end seal that truly simulates clinical endodontic treatment has not been achieved. To address this challenge, we designed and synthesized a unique hierarchical growth factor-loaded nanofibrous microsphere scaffolding system. In this system, vascular endothelial growth factor (VEGF) binds with heparin and is encapsulated in heparin-conjugated gelatin nanospheres, which are further immobilized in the nanofibers of an injectable poly(l-lactic acid) (PLLA) microsphere. This hierarchical microsphere system not only protects the VEGF from denaturation and degradation, but also provides excellent control of its sustained release. In addition, the nanofibrous PLLA microsphere integrates the extracellular matrix-mimicking architecture with a highly porous injectable form, efficiently accommodating dental pulp stem cells (DPSCs) and supporting their proliferation and pulp tissue formation. Our in vivo study showed the successful regeneration of pulp-like tissues that fulfilled the entire apical and middle thirds and reached the coronal third of the full-length root canal. In addition, a large number of blood vessels were regenerated throughout the canal. For the first time, our work demonstrates the success of pulp tissue regeneration in a full-length root canal, making it a significant step toward regenerative endodontics. The regeneration of pulp tissues in a full-length tooth root canal has been one of the greatest challenges in the field of regenerative endodontics, and one of the biggest barriers for its clinical application. In this study, we developed a unique approach to tackle this challenge, and for the first time, we successfully regenerated living pulp tissues in a full-length root canal, making it a significant step toward regenerative endodontics. This study will make positive scientific impact and interest the broad and multidisciplinary readership in the dental biomaterials and craniofacial tissue engineering community.


Effect of deltorphin on pituitary-adrenal response to insulin-induced hypoglycemia and ovine corticotropin-releasing hormone in healthy man.
To determine the role of delta-opioid receptors in the modulation of hypothalamic-pituitary-adrenal activity, we studied in normal subjects the effect of the highly selective delta-opioid receptor agonist deltorphin (DT) on the secretion of ACTH, cortisol, and arginine vasopressin in response to insulin-induced hypoglycemia. In an attempt to clarify the site of opiate modulation of ACTH secretion, we also studied in normal subjects the effect of DT on the ACTH response to ovine CRH-41. DT blunted the ACTH, cortisol, and arginine vasopressin responses to insulin-induced hypoglycemia, whereas it had no effect on the ACTH and cortisol responses to CRH. We conclude that DT-induced activation of delta-opioid receptors exerts an inhibitory influence on hypoglycemia-stimulated ACTH secretion. Based on the lack of an effect of DT on the ACTH response to CRH, we postulate that DT may modulate the secretion of ACTH through suprapituitary mechanisms.


Brain Stimulation's expanding impact - Now immediately free to download by anyone, anywhere and at anytime.
The brain stimulation revolution continues to grow and even accelerate. Business models around academic publishing are also changing. Beginning Jan 1, 2020, Brain Stimulation content will become fully open access. The author argues that this change will likely expand the overall impact of the journal, without compromising editorial quality. However there are some concerns to consider with this transition to full open access. This editorial looks back on the history of brain stimulation academic publishing and summarizes the reasons for this optimistic view of the open access future.


Polyamine metabolism in Setaria cervi, the bovine filarial worm.
Spermine and spermidine were found to be the principal polyamines in the bovine filarial parasite Setaria cervi, whereas putrescine was observed in very low amounts. Studies conducted on the enzymes of polyamine biosynthesis revealed low activity for S-adenosyl-methionine decarboxylase, questionable and negligible activities for the decarboxylation of ornithine and arginine, and appreciable activity for ornithine aminotransferase. Uptake studies with radiolabeled putrescine, spermidine and spermine showed that these amines are rapidly taken up from the medium by an active uptake process. The uptake was temperature-sensitive and abolished at 0-4 degrees C. The questionable presence of biosynthetic enzymes such as ornithine and arginine decarboxylase and, on the other hand, an effective uptake mechanism indicate that the parasite may depend on the host for its polyamine requirement, thereby indicating a possible target for chemotherapy.


Photoreaction of caged ATP studied by the time-resolved transient grating method.
The photoreaction of caged ATP, P3-[1-(2-nitrophenyl)ethyl]adenosine-5'-triphosphate, has been investigated using the time-resolved transient grating (TG) method. We found that a feature of the TG signal time profile depends sensitively on the grating wavenumber (q) after the photoexcitation of caged ATP. This q-dependent feature of the TG signal was interpreted based on a model where the ATP release rate is comparable to the molecular diffusion process. We found that the TG signals at various q can be consistently analyzed based on this model and the ATP release rate determined. The enthalpy and volume changes of the reaction have been determined by quantitative measurement of the grating and photoacoustic signals.


Functional roles of the pepper antimicrobial protein gene, CaAMP1, in abscisic acid signaling, and salt and drought tolerance in Arabidopsis.
Biotic signaling molecules including abscisic acid (ABA) are involved in signal transduction pathways that mediate the defense response of plants to environmental stresses. The antimicrobial protein gene CaAMP1, previously isolated from pepper (Capsicum annuum), was strongly induced in pepper leaves exposed to ABA, NaCl, drought, or low temperature. Because transformation is very difficult in pepper, we overexpressed CaAMP1 in Arabidopsis. CaAMP1-overexpressing (OX) transgenic plants exhibited reduced sensitivity to ABA during the seed germination and seedling stages. Overexpression of CaAMP1 conferred enhanced tolerance to high salinity and drought, accompanied by altered expression of the AtRD29A gene, which is correlated with ABA levels and environmental stresses. The transgenic plants were also highly tolerant to osmotic stress caused by high concentrations of mannitol. Together, these results suggest that overexpression of the CaAMP1 transgene modulates salt and drought tolerance in Arabidopsis through ABA-mediated cell signaling.


A novel approach to control Botrytis cinerea fungal infections: uptake and biological activity of antifungals encapsulated in nanoparticle based vectors.
Botrytis cinerea, responsible for grey mold diseases, is a pathogen with a broad host range, affecting many important agricultural crops, in pre and post harvesting of fruits and vegetables. Commercial fungicides used to control this pathogen are often subjected to photolysis, volatilization, degradation, leaching, and runoff during application. In this context, the use of a delivery system, based on poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) represents an innovative approach to develop new pesticide formulations to successfully fight B. cinerea infections. In order to study NPs uptake, B. cinerea conidia and mycelium were treated with PLGA NPs loaded with the high fluorescent probe coumarin 6 (Cu6-PLGA NPs) and analyzed under ApoTome fluorescence microscopy. The observations revealed that 50 nm Cu6-PLGA NPs penetrated into B. cinerea conidia and hyphae, as early as 10 min after administration. Pterostilbene, a natural compound, and fluopyram, a synthetic antifungal, were entrapped in PLGA NPs, added to B. cinerea conidia and mycelium, and their antifungal activity was tested. The results revealed that the compounds loaded in NPs exhibited a higher activity against B. cinerea. These results lay the foundations for the use of PLGA NPs as a new strategy in plant pest management.


So what if parasites vary?
The British Society for Parasitology Autumn Symposium was held on 14 September 2001 at the Linnean Society of London, UK, only a few yards from the room in which Darwin and Wallace presented their joint papers on organic variation. Fittingly, the symposium--Parasite variation: immunological and ecological significance--considered the consequences of parasite variation.


Bioengineering of non-pathogenic Escherichia coli to enrich for accumulation of environmental copper.
Heavy metal sequestration from industrial wastes and agricultural soils is a long-standing challenge. This is more critical for copper since copper pollution is hazardous both for the environment and for human health. In this study, we applied an integrated approach of Darwin's theory of natural selection with bacterial genetic engineering to generate a biological system with an application for the accumulation of Cu2+ ions. A library of recombinant non-pathogenic Escherichia coli strains was engineered to express seven potential Cu2+ binding peptides encoded by a 'synthetic degenerate' DNA motif and fused to Maltose Binding Protein (MBP). Most of these peptide-MBP chimeras conferred tolerance to high concentrations of copper sulphate, and in certain cases in the order of 160-fold higher than the recognised EC50 toxic levels of copper in soils. UV-Vis spectroscopic analysis indicated a molar ratio of peptide-copper complexes, while a combination of bioinformatics-based structure modelling, Cu2+ ion docking, and MD simulations of peptide-MBP chimeras corroborated the extent of Cu2+ binding among the peptides. Further, in silico analysis predicted the peptides possessed binding affinity toward a broad range of divalent metal ions. Thus, we report on an efficient, cost-effective, and environment-friendly prototype biological system that is potentially capable of copper bioaccumulation, and which could easily be adapted for the removal of other hazardous heavy metals or the bio-mining of rare metals.


[18F]-FMISO PET study of hypoxia in gliomas before surgery: correlation with molecular markers of hypoxia and angiogenesis.
Hypoxia in gliomas is associated with tumor resistance to radio- and chemotherapy. However, positron emission tomography (PET) imaging of hypoxia remains challenging, and the validation of biological markers is, therefore, of great importance. We investigated the relationship between uptake of the PET hypoxia tracer [18F]-FMISO and other markers of hypoxia and angiogenesis and with patient survival. In this prospective single center clinical study, 33 glioma patients (grade IV: n = 24, III: n = 3, and II: n = 6) underwent [18F]-FMISO PET and MRI including relative cerebral blood volume (rCBV) maps before surgery. Maximum standardized uptake values (SUVmax) and hypoxic volume were calculated, defining two groups of patients based on the presence or absence of [18F]-FMISO uptake. After surgery, molecular quantification of CAIX, VEGF, Ang2 (rt-qPCR), and HIF-1α (immunohistochemistry) were performed on tumor specimens. [18F]-FMISO PET uptake was closely linked to tumor grade, with high uptake in glioblastomas (GB, grade IV). Expression of biomarkers of hypoxia (CAIX, HIF-1α), and angiogenesis markers (VEGF, Ang2, rCBV) were significantly higher in the [18F]-FMISO uptake group. We found correlations between the degree of hypoxia (hypoxic volume and SUVmax) and expression of HIF-1α, CAIX, VEGF, Ang2, and rCBV (p < 0.01). Patients without [18F]-FMISO uptake had a longer survival time than uptake positive patients (log-rank, p < 0.005). Tumor hypoxia as evaluated by [18F]-FMISO PET is associated with the expression of hypoxia markers on a molecular level and is related to angiogenesis. [18F]-FMISO uptake is a mark of an aggressive tumor, almost always a glioblastoma. Our results underline that [18F]-FMISO PET could be useful to guide glioma treatment, and in particular radiotherapy, since hypoxia is a well-known factor of resistance.


Peripheral blood serum from healthy donors contains antibodies against the fragment of transcribed region of ribosomal repeat.
Enzyme immunoassay showed that blood serum from healthy donors contains specific high-affinity antibodies (apparent association constant > or = 5 x 10(9) M(-1)) against a fragment of transcribed region of ribosomal DNA repeat of human serum, which are present in a free form or are bound to extracellular DNA. Preheating of the serum at 55 degrees C and high ionic strength (1.5 M NaCl) had no effect on the interaction of antibodies with this fragment. Competitive binding assay showed that these antibodies recognize DNA epitopes, which differ from the epitopes recognized by most anti-DNA antibodies in systemic lupus erythematosus.


Moving vision zero programs forward: What pedestrian-focused countermeasure combinations work best and where? A dynamic copula-based time-series approach.
Vision Zero stands out as one of the most promising systemic safety action plans. A crucial step to ensure the successful implementation of Vision Zero is to continuously assess the efficiency of the implemented treatments. Traditionally, this is achieved using before-and-after analyses or cross-sectional studies. However, the applicability of these approaches can be limited in assessing Vision Zero initiatives, which usually involve installing multiple treatments at a location, leading to a significant interdependency between treatments. This study proposes a dynamic R-vine copula-based time series model to evaluate the efficiency of treatments implemented as a part of Vision Zero. The proposed approach enables the accurate assessment of the treatments, understanding of their long-term impacts, and identifying the most effective combination of treatments at a location. The study also investigated the association between location characteristics and the performance of treatments. The proposed framework was applied to the City of Toronto at the macro-level (neighbourhood level) and focused on pedestrian-related treatments. Collision data and the implemented countermeasures were obtained from Toronto's Vision Zero Mapping Tool. The results show that the combination of speed limit reduction, leading pedestrian intervals (LPI), and community safety zones was the most frequent combination in terms of efficiency. Enforcement and speed limit reduction were the most effective combination in neighbourhoods with high school density, while LPI was effective in neighbourhoods with high densities of subway stations, and office density, especially when integrated with speed limit reduction and community zones. Driver feedback signs were effective in neighbourhoods with a high density of intersections, but only when combined with automated enforcement, community safety zones, and speed limit reduction. The results of the study would assist decision-makers in selecting the most effective treatment in a neighbourhood based on the neighbourhood characteristics and the countermeasures that are already installed.


Machine learning-based prediction model for postoperative delirium in non-cardiac surgery.
Postoperative delirium is a common complication that is distressing. This study aimed to demonstrate a prediction model for delirium. Among 203,374undergoing non-cardiac surgery between January 2011 and June 2019 at Samsung Medical Center, 2,865 (1.4%) were diagnosed with postoperative delirium. After comparing performances of machine learning algorithms, we chose variables for a prediction model based on an extreme gradient boosting algorithm. Using the top five variables, we generated a prediction model for delirium and conducted an external validation. The Kaplan-Meier and Cox survival analyses were used to analyse the difference of delirium occurrence in patients classified as a prediction model. The top five variables selected for the postoperative delirium prediction model were age, operation duration, physical status classification, male sex, and surgical risk. An optimal probability threshold in this model was estimated to be 0.02. The area under the receiver operating characteristic (AUROC) curve was 0.870 with a 95% confidence interval of 0.855-0.885, and the sensitivity and specificity of the model were 0.76 and 0.84, respectively. In an external validation, the AUROC was 0.867 (0.845-0.877). In the survival analysis, delirium occurred more frequently in the group of patients predicted as delirium using an internal validation dataset (p < 0.001). Based on machine learning techniques, we analyzed a prediction model of delirium in patients who underwent non-cardiac surgery. Screening for delirium based on the prediction model could improve postoperative care. The working model is provided online and is available for further verification among other populations. KCT 0006363.


TRPV4 and TRPC1 channels mediate the response to tensile strain in mouse Müller cells.
Müller glia, a pillar of metabolic, volume regulatory and immune/inflammatory signaling in the mammalian retina, are among the earliest responders to mechanical stressors in the eye. Ocular trauma, edema, detachment and glaucoma evoke early inflammatory activation of Müller cells yet the identity of their mechanotransducers and signaling mechanisms downstream remains unknown. Here, we investigate expression of genes that encode putative stretch-activated calcium channels (SACs) in mouse Müller cells and study their responses to dynamical tensile loading in cells loaded with a calcium indicator dye. Transcript levels in purified glia were Trpc1>Piezo1>Trpv2>Trpv4>>Trpv1>Trpa1. Cyclic radial deformation of matrix-coated substrates produced dose-dependent increases in [Ca2+]i that were suppressed by the TRPV4 channel antagonist HC-067047 and by ablation of the Trpv4 gene. Stretch-evoked calcium responses were also reduced by knockdown and pharmacological inhibition of TRPC1 channels whereas the TRPV2 inhibitor tranilast had no effect. These data demonstrate that Müller cells are intrinsically mechanosensitive, with the response to tensile loading mediated through synergistic activation of TRPV4 and TRPC1 channels. Coupling between mechanical stress and Müller Ca2+ homeostasis has treatment implications, since many neuronal injury paradigms in the retina involve calcium dysregulation associated with inflammatory and immune signaling.


Injuries and Health Considerations in Ultramarathon Runners.
Ultramarathon runners are a relatively small and unique group of distance runners with somewhat different medical issues than other distance runners. This article outlines some of those differences so that clinicians caring for these runners in the clinic or at competitions might be better prepared.


Targeting lactate-related cell cycle activities for cancer therapy.
Lactate has long been considered as a metabolic by-product of aerobic glycolysis for cancer. However, more and more studies have shown that lactate can regulate cancer progression via multiple mechanisms such as cell cycle regulation, immune suppression, energy metabolism and so on. A recent discovery of lactylation attracted a lot of attention and is already a hot topic in the cancer field. In this review, we summarized the latest functions of lactate and its underlying mechanisms in cancer. We also included our analysis of protein lactylation in different rat organs and compared them with other published lactylation data. The unresolved challenges in this field were discussed, and the potential application of these new discoveries of lactate-related cell cycle activities for cancer target therapy was speculated.


Guidelines for the use of local anesthesia in office-based dermatologic surgery.
There are an increasing number and variety of dermatologic surgical procedures performed safely in the office setting. This evidence-based guideline addresses important clinical questions that arise regarding the use and safety of local anesthesia for dermatologic office-based procedures. In addition to recommendations for dermatologists, this guideline also takes into account patient preferences while optimizing their safety and quality of care. The clinical recommendations presented here are based on the best evidence available as well as expert opinion.


Guideline-Based Critical Care Pathway Improves Long-Term Clinical Outcomes in Patients with Acute Coronary Syndrome.
Implementation of a critical care pathway (CCP) for acute coronary syndrome (ACS) has been shown to improve early compliance to guideline-directed therapies and reduce early mortality. Nevertheless its long-term impact on the compliance with medications or clinical outcomes remains unknown. Between 2004 and 2015, 2023 consecutive patients were admitted to our coronary care unit with ACS. We retrospectively compared the outcomes of 628 versus 1059 patients (mean age 66.1 ± 13.3 years, 74% male) managed before and after full implementation of a CCP. Compared with standard care, implementation of the CCP significantly increased coronary revascularization and long-term compliance with guideline-directed medical therapy (both P < 0.01). After a mean follow-up of 66.5 ± 44.0 months, 46.7% and 22.2% patients admitted before and after implementation of the CCP, respectively, died. Kaplan-Meier analyses showed that patients managed by CCP had better overall survival (P = 0.03) than those managed with standard care. After adjustment for clinical covariates and coronary anatomy, CCP remained independently predictive of better survival from all-cause mortality [hazard ratio (HR): 0.75, 95%confidence intervals (CI): 0.62-0.92, P < 0.01]. Stepwise multivariate cox regression model showed that both revascularization (HR: 0.55, 95%CI: 0.45-0.68, P < 0.01) and compliance to statin (HR: 0.70, 95%CI: 0.58-0.85, P < 0.01) were accountable for the improved outcome.


Insulin Resistance and Inflammation in Hypogonadotropic Hypogonadism and Their Reduction After Testosterone Replacement in Men With Type 2 Diabetes.
One-third of men with type 2 diabetes have hypogonadotropic hypogonadism (HH). We conducted a randomized placebo-controlled trial to evaluate the effect of testosterone replacement on insulin resistance in men with type 2 diabetes and HH. A total of 94 men with type 2 diabetes were recruited into the study; 50 men were eugonadal, while 44 men had HH. Insulin sensitivity was calculated from the glucose infusion rate (GIR) during hyperinsulinemic-euglycemic clamp. Lean body mass and fat mass were measured by DEXA and MRI. Subcutaneous fat samples were taken to assess insulin signaling genes. Men with HH were randomized to receive intramuscular testosterone (250 mg) or placebo (1 mL saline) every 2 weeks for 24 weeks. Men with HH had higher subcutaneous and visceral fat mass than eugonadal men. GIR was 36% lower in men with HH. GIR increased by 32% after 24 weeks of testosterone therapy but did not change after placebo (P = 0.03 for comparison). There was a decrease in subcutaneous fat mass (-3.3 kg) and increase in lean mass (3.4 kg) after testosterone treatment (P < 0.01) compared with placebo. Visceral and hepatic fat did not change. The expression of insulin signaling genes (IR-β, IRS-1, AKT-2, and GLUT4) in adipose tissue was significantly lower in men with HH and was upregulated after testosterone treatment. Testosterone treatment also caused a significant fall in circulating concentrations of free fatty acids, C-reactive protein, interleukin-1β, tumor necrosis factor-α, and leptin (P < 0.05 for all). Testosterone treatment in men with type 2 diabetes and HH increases insulin sensitivity, increases lean mass, and decreases subcutaneous fat.


Genome editing of the disease susceptibility gene CsLOB1 in citrus confers resistance to citrus canker.
Citrus is a highly valued tree crop worldwide, while, at the same time, citrus production faces many biotic challenges, including bacterial canker and Huanglongbing (HLB). Breeding for disease-resistant varieties is the most efficient and sustainable approach to control plant diseases. Traditional breeding of citrus varieties is challenging due to multiple limitations, including polyploidy, polyembryony, extended juvenility and long crossing cycles. Targeted genome editing technology has the potential to shorten varietal development for some traits, including disease resistance. Here, we used CRISPR/Cas9/sgRNA technology to modify the canker susceptibility gene CsLOB1 in Duncan grapefruit. Six independent lines, DLOB 2, DLOB 3, DLOB 9, DLOB 10, DLOB 11 and DLOB 12, were generated. Targeted next-generation sequencing of the six lines showed the mutation rate was 31.58%, 23.80%, 89.36%, 88.79%, 46.91% and 51.12% for DLOB 2, DLOB 3, DLOB 9, DLOB 10, DLOB 11 and DLOB 12, respectively, of the cells in each line. DLOB 2 and DLOB 3 showed canker symptoms similar to wild-type grapefruit, when inoculated with the pathogen Xanthomonas citri subsp. citri (Xcc). No canker symptoms were observed on DLOB 9, DLOB 10, DLOB 11 and DLOB 12 at 4 days postinoculation (DPI) with Xcc. Pustules caused by Xcc were observed on DLOB 9, DLOB 10, DLOB 11 and DLOB 12 in later stages, which were much reduced compared to that on wild-type grapefruit. The pustules on DLOB 9 and DLOB 10 did not develop into typical canker symptoms. No side effects and off-target mutations were detected in the mutated plants. This study indicates that genome editing using CRISPR technology will provide a promising pathway to generate disease-resistant citrus varieties.