Risks, options, and informed consent for blood transfusion in elective surgery.
Blood banking is undergoing a period of significant change as a result of several concurrent issues. Blood-transmitted diseases such as human immunodeficiency virus (HIV) and the alternatives to community-derived (homologous) blood such as autologous (patient's own) and designated (blood donor known to transfusion recipient) blood have had an impact on surgical transfusion practice. Many of these issues comprise the medicolegal elements of informed consent for elective blood transfusion, so that increasingly the need for a dialogue incorporating these issues between the transfusing physician and the potential transfusion recipient is recognized. If the process is to be effective, then early involvement of the patient in a dialogue concerning informed consent is necessary. An overview of the medical elements and content of informed consent for elective blood transfusion is presented.


Modern health worries in medical students.
The aim of this study was to investigate the association between modern health worries (MHW), subjective health complaints, and use of health care services in first-year Dutch medical students, and to compare MHW in Dutch and New Zealand cohorts. Two hundred and twenty-seven Dutch first-year medical students completed questionnaires assessing MHW, subjective health complaints, positive and negative affect (PA and NA, respectively), and use of health care services. Dutch medical students were most concerned about drug resistant bacteria and least concerned about vaccination programmes. Overall, female students were more concerned about modern health issues than were male students. Students' scores on the MHW scale were significantly associated with subjective health complaints. Subjective health complaints were also significantly related to the use of health care services. The factor structure of the MHW scale was replicated. Respondents reported significantly lower scores on all MHW items than did New Zealand students. Worries about modernity are reliably associated with subjective health complaints and use of health care services in Dutch medical students.


An integrative analysis of genotype-phenotype correlation in Charcot Marie Tooth type 2A disease with MFN2 variants: A case and systematic review.
Dominant genetic variants in the mitofusin 2 (MFN2) gene lead to Charcot-Marie-Tooth type 2A (CMT2A), a neurodegenerative disease caused by genetic defects that directly damage axons. In this study, we reported a proband with a pathogenic variant in the GTPase domain of MFN2, c.494A > G (p.His165Arg). To date, at least 184 distinct MFN2 variants identified in 944 independent probands have been reported in 131 references. However, the field of medical genetics has long been challenged by how genetic variation in the MFN2 gene is associated with disease phenotypes. Here, by collating the MFN2 variant data and patient clinical information from Leiden Open Variant Database 3.0, NCBI clinvar database, and available related references in PubMed, we determined the mutation frequency, age of onset, sex ratio, and geographical distribution. Furthermore, the results of an analysis examining the relationship between variants and phenotypes from multiple genetic perspectives indicated that insertion and deletions (indels), copy number variants (CNVs), duplication variants, and nonsense mutations in single nucleotide variants (SNVs) tend to be pathogenic, and the results emphasized the importance of the GTPase domain to the structure and function of MFN2. Overall, three reliable classification methods of MFN2 genotype-phenotype associations provide insights into the prediction of CMT2A disease severity. Of course, there are still many MFN2 variants that have not been given clear clinical significance, which requires clinicians to make more accurate clinical diagnoses.


Low expression of junctional adhesion molecule A is associated with metastasis and poor survival in pancreatic cancer.
Characterized by its highly aggressive tumor biology, pancreatic cancer still remains a fatal diagnosis. The junctional adhesion molecule A (JAM-A) is a type I transmembrane glycoprotein, which recently has been shown to affect the prognosis of several human malignancies. JAM-A antigen expression was investigated retrospectively by immunohistochemistry in paraffin-embedded primary tumor tissue samples from a series (n = 186) of consecutive patients with pancreatic adenocarcinoma. Survival was calculated by Kaplan-Meier curves. Parameters found to be of prognostic significance in univariate analysis were verified in a multivariate Cox regression model. Low expression of JAM-A was observed in 79 (42 %) of 186 pancreatic cancer specimens and was significantly associated with poor overall survival (P < 0.01). By univariate analysis, low expression of JAM-A was found to correlate with positive lymph node status (P = 0.02), the presence of distant metastasis (P = 0.05), and tumor grade (P = 0.04), suggesting it may be an important event involved in cancer progression. Furthermore, in the subgroup of patients with surgically resected pancreatic cancer, low expression of JAM-A significantly correlated with decreased progression-free survival (P < 0.01). Multivariate analysis revealed JAM-A to be an independent predictor of poor outcome. These findings suggest for the first time that low levels of JAM-A expression in pancreatic cancer are associated with poor clinical outcome. JAM-A may represents a target molecule for functional inactivation and serve as a novel biomarker of adverse prognosis in pancreatic cancer.


[Correlation between the age-related memory impairment and the level of free Ca(2+) in brain synaptosomes].
In this study, We investigated the changes in the ability of learning-memory of 12-month- and 18-month-old mice, and the intrasynaptosomal Ca(2+) levels of some mouse brain areas (hippocampus, cerebral cortex, corpus quadrigem and cerebellum) on the basis of our last behavior observation and biochemistry detection. Meanwhile, the intrasynaptosomal Ca(2+) levels of the four brain areas were compared between the mice of impaired and good memory. The main results are as follows. With the increase of age, the ability of learning-memory of mice decreased significantly; and the concentration of the intrasynaptosomal free Ca(2+) (i) in mouse brain areas (except for cerebral cortex) increased markedly, especially in the memory-impaired mice. The results suggest that age-related memory impairment may be associated with the overloading of intrasynaptosomal free Ca(2+) (i).


Protocol development, validation, and troubleshooting of in-situ fiber optic bathless dissolution system (FODS) for a pharmaceutical drug testing.
Currently, there is no systematic approach available for the validation, quantitative assessment, and troubleshooting for the in-situ fiber optic/bathless dissolution system (FODS). In this report, a dissolution protocol was developed and validated for a model product, chlorpheniramine maleate (CPM) 4 mg IR tablets. Dissolution runs were conducted at 37 ± 0.2 °C using a USP apparatus II, at 50 rpm in 500 mL of 0.01 N hydrochloric acid. The dissolution system was validated for linearity, accuracy, precision, specificity, and robustness analogously to an HPLC method validation. The linearity determination method was developed using five concentration levels between 25-125 % of the expected concentration, while for accuracy, 80 %, 100 %, and 120 % levels were used, and precision was determined using six runs at the 100 % level. Probe sampling depth, orientation, analytical wavelength, and paddle speed were varied to evaluate the robustness of the system tested. Method equivalence was established by comparing the dissolution results from FODS and the traditional dissolution method using UV spectrophotometry. Based on the statistics generated using the dissolution tests, the results are linear, accurate, precise, and specific. Robustness testing demonstrates that small changes in operating conditions did not significantly change the result. No significant difference in the amount dissolved at Q-timepoint was observed between FODS and traditional testing. Therefore, the FODS is a suitable alternative to traditional dissolution for CPM immediate-release tablets (many other drug products have been tested in the laboratory, and reports are in preparation). Additionally, the current work discusses problems related to media preparation, probe sensitivity, and excipient effects on data collected using FODS. The instrument-specific artifacts and data analysis problems are addressed and troubleshooting with possible solutions to eliminate or mitigate the errors. Although the FODS method was developed and evaluated using CPM in 500 mL dissolution volume, the dissolution method using a more common pharmacopoeial dissolution volume, i.e., 900 mL, was used to demonstrate the troubleshooting experiments for the drug products requiring 900 mL dissolution media.


Immunity to Trichinella spiralis. VII. Resistance stimulated by the parenteral stages of the infection.
In three experiments mice were given three intravenous injections of Trichinella spiralis newborn larvae produced in vitro. Following a challenge infection of newborn larvae the mice were shown to be on the average 85% resistant i.e., only 15% of the challenge larvae developed to encysted muscle stage larvae in these mice; when the challenge consisted of normal muscle larvae administered per os, the mice were 51% resistant. Neither the number nor longevity of adult worms in the intestines was affected by this immunization procedure.


[Genetic analysis of a child affected with Crigler-Najjar syndrome type II].
To detect potential mutation of the UGT1A1 gene in a child affected with Crigler-Najjar syndrome type II. Blood samples were collected from the patient and his parents for the extraction of genomic DNA. Potential mutation of the UGT1A1 gene was detected with polymerase chain reaction (PCR) and direct sequencing. The child was followed up until the age of 3 years and 6 months. The patient showed persistent unconjugated hyperbilirubinemia. Sequencing of the UGT1A1 gene has detected a rare heterozygous c.610 A>G (p.Met204Val) mutation in the exon 1, in addition with a heterozygous c.1091 C>T (p.Pro364Leu) mutation in exon 4. The two mutations were inherited from his father and mother, respectively. The patient was diagnosed with Crigler-Najjar syndrome type II and received oral phenobarbital treatment. The compound UGT1A1 gene mutation probably accounts for the disease in the patient manifesting persistent mild unconjugated hyperbilirubinemia. Genetic counseling and prenatal diagnosis should be provided for his family.


Imaging immunity in patients with cancer using positron emission tomography.
Immune checkpoint inhibitors and related molecules can achieve tumour regression, and even prolonged survival, for a subset of cancer patients with an otherwise dire prognosis. However, it remains unclear why some patients respond to immunotherapy and others do not. PET imaging has the potential to characterise the spatial and temporal heterogeneity of both immunotherapy target molecules and the tumor immune microenvironment, suggesting a tantalising vision of personally-adapted immunomodulatory treatment regimens. Personalised combinations of immunotherapy with local therapies and other systemic therapies, would be informed by immune imaging and subsequently modified in accordance with therapeutically induced immune environmental changes. An ideal PET imaging biomarker would facilitate the choice of initial therapy and would permit sequential imaging in time-frames that could provide actionable information to guide subsequent therapy. Such imaging should provide either prognostic or predictive measures of responsiveness relevant to key immunotherapy types but, most importantly, guide key decisions on initiation, continuation, change or cessation of treatment to reduce the cost and morbidity of treatment while enhancing survival outcomes. We survey the current literature, focusing on clinically relevant immune checkpoint immunotherapies, for which novel PET tracers are being developed, and discuss what steps are needed to make this vision a reality.


Randomized double-blind placebo-controlled trial of sublingual immunotherapy in children with house dust mite allergy in primary care: study design and recruitment.
For respiratory allergic disorders in children, sublingual immunotherapy has been developed as an alternative to subcutaneous immunotherapy. Sublingual immunotherapy is more convenient, has a good safety profile and might be an attractive option for use in primary care. A randomized double-blind placebo-controlled study was designed to establish the efficacy of sublingual immunotherapy with house dust mite allergen compared to placebo treatment in 6 to 18-year-old children with allergic rhinitis and a proven house dust mite allergy in primary care. Described here are the methodology, recruitment phases, and main characteristics of the recruited children. Recruitment took place in September to December of 2005 and 2006. General practitioners (in south-west Netherlands) selected children who had ever been diagnosed with allergic rhinitis. Children and parents could respond to a postal invitation. Children who responded positively were screened by telephone using a nasal symptom score. After this screening, an inclusion visit took place during which a blood sample was taken for the RAST test. A total of 226 general practitioners invited almost 6000 children: of these, 51% was male and 40% <12 years of age. The target sample size was 256 children; 251 patients were finally included. The most frequent reasons given for not participating were: absence or mildness of symptoms, absence of house dust mite allergy, and being allergic to grass pollen or tree pollen only. Asthma symptoms were reported by 37% of the children. Of the enrolled children, 71% was sensitized to both house dust mite and grass pollen. Roughly similar proportions of children were diagnosed as being sensitized to one, two, three or four common inhalant allergens. Our study was designed in accordance with recent recommendations for research on establishing the efficacy of sublingual immunotherapy; 98% of the target sample size was achieved. This study is expected to provide useful information on sublingual immunotherapy with house dust mite allergen in primary care. The results on efficacy and safety are expected to be available by 2010. the trial is registered as ISRCTN91141483 (Dutch Trial Register).


Targeting cellular senescence in cancer by plant secondary metabolites: A systematic review.
Senescence suppresses tumor growth, while also developing a tumorigenic state in the nearby cells that is mediated by senescence-associated secretory phenotypes (SASPs). The dual function of cellular senescence stresses the need for identifying multi-targeted agents directed towards the promotion of cell senescence in cancer cells and suppression of the secretion of pro-tumorigenic signaling mediators in neighboring cells. Natural secondary metabolites have shown favorable anticancer responses in recent decades, as some have been found to target the senescence-associated mediators and pathways. Furthermore, phenolic compounds and polyphenols, terpenes and terpenoids, alkaloids, and sulfur-containing compounds have shown to be promising anticancer agents through the regulation of paracrine and autocrine pathways. Plant secondary metabolites are potential regulators of SASPs factors that suppress tumor growth through paracrine mediators, including growth factors, cytokines, extracellular matrix components/enzymes, and proteases. On the other hand, ataxia-telangiectasia mutated, ataxia-telangiectasia and Rad3-related, extracellular signal-regulated kinase/mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin, nuclear factor-κB, Janus kinase/signal transducer and activator of transcription, and receptor tyrosine kinase-associated mediators are main targets of candidate phytochemicals in the autocrine senescence pathway. Such a regulatory role of phytochemicals on senescence-associated pathways is associated with cell cycle arrest and the attenuation of apoptotic/inflammatory/oxidative stress pathways. The current systematic review highlights the critical roles of natural secondary metabolites in the attenuation of autocrine and paracrine cellular senescence pathways, while also elucidating the chemopreventive and chemotherapeutic capabilities of these compounds. Additionally, we discuss current challenges, limitations, and future research indications.


A Rare Case of Donor-Origin Intrahepatic Cholangiocarcinoma After Liver Transplantation for Hepatocellular Carcinoma: A Case Report.
Tumors may develop in the grafted liver after liver transplantation for hepatocellular carcinoma, most of which are hepatocellular carcinoma recurrences and are rarely of donor origin. We report a rare case of donor-origin intrahepatic cholangiocarcinoma in a liver allograft after liver transplantation for hepatocellular carcinoma. A man in his 60s underwent liver transplantation for hepatocellular carcinoma with hepatitis C virus cirrhosis. The donor was a braindead woman in her 60s who had no history of malignancy. Three years and 5 months after liver transplantation, a tumor developed in the allograft. Computed tomography scans showed a 40-mm tumor that was atypical for hepatocellular carcinoma. Tumor biopsy was most suggestive of intrahepatic cholangiocarcinoma. Fluorescence in situ hybridization of the tumor showed an XX signal pattern, suggesting that it originated from the donor liver. Whole exome sequencing analysis strongly suggested that the tumor was an intrahepatic cholangiocarcinoma derived from the donor. Although donor-origin cancer after liver transplantation is extremely rare, it should be considered for adequate treatment.


Age at onset and gender resemblance in bipolar siblings.
In order to measure the intrafamilial correlation for age at onset and to examine gender resemblance among bipolar siblings, we assessed a sample of 130 bipolar patients belonging to 59 multiple affected sibships. To study the intrafamilial resemblance for age at onset and gender, we used the intraclass correlation and the sibship method, respectively. Within the whole sample, age at onset for affected siblings was correlated (rho = 0.42, P = 0.0001). Gender was randomly distributed among bipolar sibships, demonstrating the absence of gender resemblance among affected siblings. The existence of an intrafamilial correlation for age at onset among bipolar siblings suggests that this variable may assist in the identification of more heritable forms of the illness. No intrafamilial correlation was found for the gender of affected siblings, suggesting that familial vulnerability factors are not gender-specific.


Comprehensive review on Caelsalpinioideae lectins: From purification to biological activities.
Lectins are a class of proteins with specific and reversible carbohydrate binding properties. Plant lectins constitute the group of these proteins most studied, placing emphasis on the legume family. The Caesalpinioideae subfamily is part of Leguminosae and second only to Papilionoideae with more published works on lectins. Classically, Caesalpinioideae is formed by 171 genera and 2250 species. It presents 13 genera with reports of lectins, featuring the Bauhinia genus with the greatest number of species having purified and characterized lectins. Comparing genera, the lectins in this subfamily do not have similar physicochemical or structural properties. Collectively, however, antibacterial, antiviral, and anticancer activities have been reported, as well as applications as biosensors and biomarkers. This review aims to summarize the available data on purified lectins from species of the Caesalpinioideae subfamily, demonstrating the characteristics of these molecules and the potential for their application in future studies of new lectins, as well as of application in several areas.


Cerebral aneurysm evolution modeling from microstructural computational models to machine learning: A review.
Predicting the future behavior of cerebral aneurysms was the target of several studies in recent years. When an unruptured cerebral aneurysm is diagnosed, the physician has to decide about the treatment method. Often more giant aneurysms are diagnosed at higher risk of rupture and are candidates for intervention. However, several clinical and morphological parameters are introduced as risk factors. Therefore, some small size aneurysms with a higher growth rate and rupture risk may be missed. Nowadays, computational models and artificial intelligence can help physicians make more precise decisions, not only according to the aneurysm size. Therefore, the target can be developing a tool that receives the patient history and medical images as input and gives the aneurysm growth rate and rupture risk as output. Achieving this target can be possible by developing a proper computational growth model and using artificial intelligence. This requires knowledge of the vascular microstructure and the procedure of disease development, including degradation and remodeling mechanisms. Moreover, geometrical and clinical risk factors should also be recognized and considered. The present article is a step-by-step indication of this concept. In this paper, first, a review of different computational growth models is presented. Then, the morphological and clinical risk factors are described, and at last, the methods of combining the computational growth models with machine learning are discussed. This review can help the researchers learn the fundamentals and take the proper future steps.


Pharmacokinetics, pharmacodynamics and safety evaluation of 5,5'-methylenebis(2-acetoxybenzoic acid) in dogs following intravenous administration.
Complement-mediated intravascular hemolysis occurs in canine immune-mediated hemolytic anemia (IMHA). Complement inhibitors might enhance treatment of this disease. Dimers of acetylsalicylic acid such as 5,5'-methylenebis(2-acetoxybenzoic acid) (DAS) have been reported to inhibit complement. This study aimed to characterize the pharmacokinetics and safety profile of a single 3 mg/kg IV dose of DAS in 6 healthy mixed-breed dogs. Serum concentrations of DAS and its primary metabolites were measured by liquid chromatography-tandem mass spectrometry at baseline and at 5, 10 and 30 min, and 1, 2, 4, 6, 8, 12, 18 and 24 h post-administration. Additional blood samples were collected 7 and 14 days after drug administration. Complete blood counts, serum chemistry panels, C-reactive protein measurements, coagulation testing and cytokine analyses were used for safety monitoring. Following IV administration of 3 mg/kg DAS, the estimated mean maximum plasma concentration was 54,709 ng/mL. Pharmacokinetic modeling suggested that DAS was eliminated with a half-life value of 8.1 h, equivalent to a clearance of 6.93 L/hr kg and a volume of distribution of 56 mL/kg. Plasma concentrations of the metabolites were measured rapidly (within 15-60 min for M1 and M2 respectively). Overall, the relative exposure to M1 and M2 suggest significant biotransformation of DAS occurred, but DAS was the most abundant circulating species. No adverse clinical reactions were noted following DAS administration and safety studies suggested DAS caused no inflammatory response or coagulation disturbance. Further clinical evaluation of DAS is warranted.


Simultaneous determination of penthiopyrad enantiomers and its metabolite in vegetables, fruits, and cereals using ultra-high performance liquid chromatography-tandem mass spectrometry.
Penthiopyrad is a novel succinate dehydrogenase inhibitor that has one chiral center and exists a metabolite, 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxamide in its residue definition. An efficient analytical method for the simultaneous determination of penthiopyrad enantiomers and its metabolite in eight matrices were developed using modified quick, easy, cheap, effective, rugged, safe method, coupled with chiral stationary phase and ultra-high performance liquid chromatography-tandem mass spectrometry. The absolute configuration of penthiopyrad enantiomers was confirmed by polarimetry and electronic circular dichroism. Eight polysaccharide-based chiral stationary phases were evaluated in terms of the enantioseparation of penthiopyrad and separation-related factors (the mobile phase, flow rate and the column temperature) were optimized. To obtain an optimal purification, different sorbent combinations were assessed. The linearities of this method were acceptable in the range of 0.005 to 1 mg/L with R2 > 0.998, while the limits of detection and quantification were 0.0015 mg/kg and 0.01 mg/kg for two enantiomers and its metabolite. The average recoveries of R-(-)-penthiopyrad, S-(+)-penthiopyrad and the metabolite ranged from 75.4 to 109.1, 69.5 to 112.8, and 70.0 to 108.5%, respectively. The intra-day and inter-day relative standard deviations were less than 18.8%. The analytical method was accurate and convenient, which can support their further research on stereoselective degradation, residual monitoring and risk assessment.


Staging surgery in early-stage ovarian mucinous tumors according to expansile and infiltrative types.
The aim of this study is to determine the value of surgical staging for the two histologic types (expansile or infiltrative) of apparent stage I mucinous ovarian carcinoma. We retrospectively analyzed patients treated from 1976 and 2016 for apparent macroscopic stage I ovarian mucinous carcinoma. Extra-ovarian disease and tumors that metastasized to the ovaries were excluded. Two expert pathologists performed pathologic reviews of tumor data, according to 2014 WHO classification criteria. Tumors were typed as expansile or infiltrative and clinical and histologic characteristics were studied. The value of staging procedures (peritoneal and nodal) was based on the rate of microscopic involvement in macroscopically normal specimens. Of 114 cases reviewed, 46 were excluded (26 with macroscopic stage > I; 20 inaccessible for pathologic review). Of 68 patients included, 29 had expansile and 39 had infiltrative types. 27 patients received one-step surgery and 41 received restaging surgery. 52 patients received "complete" peritoneal surgical staging (including cytology, peritoneal biopsies, and an omentectomy or large omental biopsies). 24 underwent appendectomies and 31 underwent lymphadenectomies (8 expansile and 23 infiltrative). Before histologic analyses of staging specimens, 35 had "initial" stage IA and 33 had IC disease. After histologic analyses of lymph nodes, 4 cases (17%, all infiltrative) had nodal involvement, and 2 showed microscopic peritoneal disease (1 omentum and 1 right diaphragm peritoneum). Three patients were upstaged based on isolated positive peritoneal cytology. To conclude, peritoneal staging procedures are required for both types of mucinous ovarian carcinoma. Lymphadenectomy could be omitted in expansile, but required in infiltrative type.


Simulation-Based Breast Biopsy Training Using a Low-Cost Gelatin-Based Breast Model in Rwanda.
An interdisciplinary team of healthcare providers and simulation specialists adopted and modified a protocol for the creation of a low-cost, gelatin-based breast model for teaching ultrasound-guided breast biopsy and assessed first-time user experience. An interdisciplinary team of healthcare providers and simulation specialists adopted and modified a protocol for the creation of a low-cost, gelatin-based breast model for teaching ultrasound-guided breast biopsy for approximately $4.40 USD. Components include medical-grade gelatin, Jell-O™, water, olives, and surgical gloves. The model was used to train two cohorts comprising 30 students total during their junior surgical clerkship. The learners' experience and perceptions on the first Kirkpatrick level were evaluated using pre- and post-training surveys. Response rate was 93.3% (n = 28). Only three students had previously completed an ultrasound-guided breast biopsy, and none had prior exposure to simulation-based breast biopsy training. Learners that were confident in performing biopsies under minimal supervision rose from 4 to 75% following the session. All students indicated the session increased their knowledge, and 71% agreed that the model was an anatomically accurate and appropriate substitute to a real human breast. The use of a low-cost gelatin-based breast model was able to increase student confidence and knowledge in performing ultrasound-guided breast biopsies. This innovative simulation model provides a cost-effective and more accessible means of simulation-based training especially for low- and middle-income settings.


Agrobacterium tumefaciens-mediated transformation of Botryosphaeria dothidea.
Botryosphaeria dothidea is a severe causal agent of die-back and cankers of many woody plants and causes great losses in many regions. The pathogenic mechanism of this pathogen has not been well explored due to lack of mutants and genetic information. In this study, we developed an Agrobacterium tumefaciens-mediated transformation (ATMT) protocol for B. dothidea protoplasts using vector pBHt2 containing the hph gene as a selection marker under the control of trp C promoter. Using this protocol we successfully generated the B. dothidea transformants with efficiency about 23 transformants per 10(5) protoplasts. This is the first report of genetic transformation of B. dothidea via ATMT and this protocol provides an effective tool for B. dothidea genome manipulation, gene identification and functional analysis.


Epstein-Barr virus lymphoproliferative disease after solid organ transplantation.
Epstein-Barr virus (EBV) was the first identified human oncovirus and is also one of the most ubiquitous viral infections known with established infections in more than 90% of individuals by early adulthood. EBV establishes latency by controlling expression of the viral genome making it silent to immune surveillance. In immunocompetent individuals, up to 1% of circulating T cells are directed at maintaining control over EBV replication. In addition to being involved in oncogenesis of lymphoid and epithelial tumors in immune-competent individuals, loss of immune surveillance over EBV predisposes individuals to EBV malignancies. Lymphoid proliferations from EBV-infected B cells arise in up to 20% of recipients of solid organ transplants (SOTs). One question not answered is why, when EBV requires such active immune surveillance, EBV malignancies are not even more prevalent in severely immune-compromised individuals. A better understanding of who develops complications related to EBV and what the immunologic risks are will ultimately make it feasible to perform prophylactic trials in those at highest risk. This review summarizes our current understanding of factors in SOT recipients that predispose them to the development of an EBV malignancy and that predict response to initial therapy. We then review the current landscape of those therapies, focusing on the goal of restoring long-term EBV-directed immunity to patients at risk.


Ecological genetics of Bromus tectorum : III. The demography of reciprocally sown populations.
By incorporating demographic analyses of fitness components (e.g., survival and reproduction) within a reciprocal sowing design, we tested for 3 consecutive years whether local adaptation has occurred in the alien grass Bromus tectorum (cheatgrass) within 7 habitats along an environmental gradient from arid steppe to subalpine forest in the Intermontain Region of western North America. Patterns of emergence and survival were strongly influenced by the local environment. In terms of survival, expression of significant local adaptation in Tsuga heterophylla habitat varied among years. In contrast, relative differences in flowering time among seed sources were stable across sites and years. Populations from the arid steppe were the earliest to flower; flowering was latest in populations from the mesic Tsuga heterophylla habitat. In terms of net reproductive rate, evidence for local adaptation in B. tectorum was obtained in populations from habitats representing environmental extremes: an arid, saline site dominated by the shrub Sarcobatus vermiculatus and clearings within the cool, mesic Tsuga heterophylla forest habitat. Unlike the plants introduced from other sites, members of the resident population at the Sarcobatus site flowered and produced seeds before soil water became limiting. In contrast, net reproductive rates in other habitats were sometimes the lowest for populations in their home site. This lack of an advantage for local populations within more environmentally moderate sites suggests that limited dispersal may restrict the rate at which superior genotypes are introduced into a particular site.


Thermoregulation as a limit to habitat use in alpine marmots (Marmota marmota).
The body temperature (T b) of free-living alpine marmots rose with activity; the higher the effective environmental temperature (T e), the higher the rise. Maximum T bof 40° C was reached at the time of greatest activity in late afternoon or evening. The activity pattern was strongly influenced by the microclimate. Up to an T eof 25° C the animals spent more time above ground and were more active the higher T ewas, but above 25° C this trend was reversed, and the animals withdrew increasingly into their burrows. On warm days the activity pattern was therefore bimodal and above ground presence was reduced, in contrast to cool days. Hence behavioural thermoregulation limits the available time for above ground activity on days with high T ein this strictly diurnal species. We suggest that the alpine marmots' preference for south oriented slopes is due to the better conditions for hibernation there, the microclimate during summer is more favourable on northerly slopes. Thermoregulatory constraints could also keep alpine marmots away from lower elevations.


Identification and characterization of a transcriptional regulator, SucR, that influences sucCD transcription in Corynebacterium glutamicum.
We have identified and characterized a novel transcriptional regulator that binds to the promoter region of succinyl-CoA synthetase (sucCD) in Corynebacterium glutamicum. Using biotin-labeled DNA affinity beads, we identified a DeoR-type transcriptional regulator, SucR (Cg0146), which is a protein consisting of 282 amino acids with a mass of 31 kDa and RamB (Cg0444). The results of electrophoretic mobility shift assays verified that these regulators specifically bind to the sucCD promoter region. The putative SucR binding region extends from position -155 to -146 (a 10 bp sequence, ACTCTAGGGG) relative to the transcriptional start point of the sucCD operon. The expression level of sucCD in a sucR deletion mutant was seven times higher than that in wild-type cells grown on acetate. The increase in succinyl-CoA synthetase levels caused by inactivation of sucR. These assays revealed that SucR acts as a repressor of sucCD expression during acetate metabolism.


1-D Compression Behaviour of Acid Sulphate Soils Treated with Alkali-Activated Slag.
Improvements of soft soils by mechanically mixing cementitious additives have been widely practised for construction of infrastructure. Mixing of additives improves strength and compressibility properties of soils through the development of soil structure. This study investigates the 1-D compression behaviour of alkali-activated slag treated acid sulphate soils (ASS) cured up to 365 days. The void ratio-logarithm of pressure (e-logσ') behaviour of treated ASS, including the destructuration behaviour, with additive contents and curing time have been analysed. X-ray diffraction (XRD) and scanning electron microscopy (SEM) analyses have been undertaken to explain the observed variations of the 1-D compression behaviour. This paper presents the results of these analyses in view of obtaining an insight into the 1-D compression behaviour of treated ASS with the help of mineralogical analysis.


Mechanisms and therapy of osmotic demyelination.
Central pontine myelinolysis (CPM) is a rare but serious demyelinative disease that is associated with rapid correction of chronic hyponatremia. Disruption of the blood-brain barrier (BBB) following a rapid increase in serum sodium concentration is considered to play a critical role in the pathogenesis of osmotic demyelination. We investigated the protective effect of dexamethasone (DEX) on osmotic demyelination in rats. After rapid correction of chronic hyponatremia, rats displayed serious neurologic impairments and demyelinative lesions were observed in various brain regions. Conversely, DEX-treated rats exhibited minimal neurologic impairments and demyelinative lesions were rarely seen in the brain. A marked extravasation of endogenous immunoglobulin G and Evans blue dye were observed in the brains of rats that did not receive DEX, indicating disruption of the BBB, but this was not observed in DEX-treated rats. These results indicate that DEX is effective in preventing osmotic demyelination by inhibiting BBB disruption, and suggest that DEX might be useful for the prevention of CPM in clinical practice.


Walks with Small Steps in the 4D-Orthant.
We provide some first experimental data about generating functions of restricted lattice walks with small steps in N 4 .


Raman microspectrometric investigation of wall paintings in S. Giovanni Evangelista Abbey in Parma: a comparison between two artists of the 16th century.
Micro-Raman spectroscopy, combined with gas chromatography and ultra-violet fluorescence photography, was used to study some wall paintings in the S. Giovanni Evangelista Abbey in Parma, Italy. The restoration of some painted chapels enabled a comparison between two painters of the 16th century: Parmigianino (Girolamo Francesco Maria Mazzola, 1503-1540) and Michelangelo Anselmi (1492?-1556?). Micro-Raman spectroscopy determined the palette used by the artists, leading to the identification of different white, yellow, red, brown, green, blue and black pigments. Some pigments are evidence of later restorations. Gas chromatography combined with mass spectroscopy revealed the presence of organic binding media and enabled to distinguish between fresco and secco paintings.


Brain-derived neurotrophic factor is associated with sarcopenia and frailty in Japanese hemodialysis patients.
We evaluated several sarcopenia-related hormones, cytokines and uremic toxins to identify the humoral factors associated with sarcopenia and frailty in Japanese hemodialysis patients. Twenty Japanese patients aged ≥65 years who underwent maintenance hemodialysis therapy at Uonuma Kikan Hospital for more than 6 months were included in this retrospective cross-sectional study. Clinical data, including physical function and mental state, were obtained from the clinical records collected during the regular evaluation at the beginning of each hemodialysis therapy session, 3 days after the previous hemodialysis therapy. The diagnosis of sarcopenia and frailty was based on the Asian Working Group for Sarcopenia 2019 and the Japanese version of the Cardiovascular Health Study, respectively. The mental state of patients was evaluated using the Japanese version of the Patient Health Questionnaire 9 (J-PHQ-9). In univariate analyses, plasma brain-derived neurotrophic factor (BDNF) levels were significantly lower in patients with severe sarcopenia and frailty. The plasma BDNF concentration was correlated with muscle strength and physical performances, such as the 6-m walk test, Short Physical Performance Battery and 5-time chair stand test. BDNF was also correlated with body weight, hemodialysis vintage, and serum levels of total protein and indoxyl sulfate but not with body mass index, appendicular skeletal muscle mass, serum interleukin 6 levels, or J-PHQ-9 scores. The odds ratio per 100 pg/mL of BDNF for the prevalence of frailty was 0.353. BDNF is associated with decreased physical performance and the prevalence of severe sarcopenia and frailty in Japanese maintenance hemodialysis patients. Geriatr Gerontol Int 2021; 21: 27-33.


Multi-factor reconciliation of discrepancies in ozone-precursor sensitivity retrieved from observation- and emission-based models.
Ground-level O3 pollution has been continuously worsening in China despite gradual improvement in other major pollutant levels. Understanding the sensitivity of O3 production to its precursors (OPS) is a prerequisite for formulating effective O3 control measures, but this has been hampered by significant discrepancies in OPS produced by traditional identification approaches using observation-based models (OBM) and emission-based models (EBM). In this study, by applying OBM and EBM in parallel within a month having significant O3 pollution in Shanghai, China, we demonstrated that a lack of carbonyl input, overestimation in NO2 monitoring data, and differences in simulation period and emission reduction area were the core factors leading to OPS discrepancies, and that a reliable OPS cannot be obtained unless these factors are reconciled. By collectively addressing these factors, the number of days with a consistent OPS from both models increased from 6-7 to 20-21 in a month, and the R value defined to quantify the discrepancy decreased by ∼55%. The contributions of these factors to OPS discrepancy differed greatly in urban and suburban settings, mainly caused by differences in pollutant emission and transport characteristics. Overall, OPS identified solely by OBM or EBM is associated with great uncertainty, while reliable OPS estimation can be achieved by a collective application of OBM and EBM with consensus on the above factors. The method demonstrated here could be applied to other photo-chemically active regions worldwide as part of efforts to address ozone pollution.


Iridium-Catalyzed Synthesis of Acylpyridines by [2 + 2 + 2] Cycloaddition of Diynes with Acyl Cyanides.
2-Acylpyridines were prepared by iridium-catalyzed [2 + 2 + 2] cycloaddition of α,ω-diynes with acyl cyanides. [Ir(cod)Cl]2/rac-BINAP or F-DPPE is an efficient catalyst for this reaction. The scope and limitations of this reaction have been disclosed.


A negative T-wave in electrocardiogram at 50 years predicted lifetime mortality in a random population-based cohort.
Severe electrocardiographic (ECG) abnormalities in asymptomatic subjects correlate with cardiovascular risk. The role of minor ECG abnormalities is less well-known. We evaluated the association between a negative T-wave and mortality, as a possible marker for prognosis. A prospective, population-based cohort, examined at 50 years, and followed until death. Time to death (event rates) and predictive role of a negative T-wave (Cox regression) were analyzed. Participants (n = 839) with a negative T-wave (7.3%) had significantly higher blood pressure (BP) (mean systolic 157.9 mmHg vs 136.8 mmHg without negative T-wave, P = <.0001). A negative T-wave correlated with elevated risk (hazard ratio [HR] [95% CI] [confidence interval]) for all-cause and cardiovascular (CV) death (1.59 (1.20-2.11) P = .0012 vs 1.91 (1.34-2.73) P = .0004). The association remained after excluding coexisting Q/QS patterns and ST-junction/segment depression ECG abnormalities (1.66 [1.13-2.44] P = .0098 for all-cause vs 1.87 [1.13-3.09] P = .015 for CV death). Death from other causes was not associated with a negative T-wave. A major negative T-wave carried higher risk than a minor (2.17 [1.25-3.76] P = .0062 vs 1.78 [1.13-2.79] P = .012) for CV death. A negative T-wave at 50 years, in asymptomatic individuals, carried an increased risk of all-cause and CV death during lifetime follow-up.


Tracheal resection and reconstruction for post-tracheostomy tracheal stenosis treated with T-tube stenting for 10 years.
We describe the case of a patient who underwent tracheal resection for post-tracheostomy stenosis following T-tube stenting for 10 years. A 32-year-old female patient with a T-tube in the trachea was referred to us. She had brain surgery for intracranial hemorrhage 10 years ago and developed a post-tracheostomy tracheal stenosis, for which she had been treated with a T-tube. At the time of referral, she was ambulatory with a cane and otherwise independent in her daily life. We assessed her stenosis and determined that it was amenable to tracheal resection as a definitive treatment. We resected the tracheal stenosis including the stoma site and performed an end-to-end tracheal anastomosis. The anastomosis was widely patent at 6 months follow-up. Long-term treatment of tracheal stenosis with T-tube does not preclude tracheal resection as a definitive treatment. A careful review of airway stenosis for resectability on a case-by-case basis is imperative.


Programmed Recognition between Complementary Dinucleolipids To Control the Self-Assembly of Lipidic Amphiphiles.
One of the major goals in systems chemistry is to create molecular assemblies with emergent properties that are characteristic of life. An interesting approach toward this goal is based on merging different biological building blocks into synthetic systems with properties arising from the combination of their molecular components. The covalent linkage of nucleic acids (or their constituents: nucleotides, nucleosides and nucleobases) with lipids in the same hybrid molecule leads, for example, to the so-called nucleolipids. Herein, we describe nucleolipids with a very short sequence of two nucleobases per lipid, which, in combination with hydrophobic effects promoted by the lipophilic chain, allow control of the self-assembly of lipidic amphiphiles to be achieved. The present work describes a spectroscopic and microscopy study of the structural features and dynamic self-assembly of dinucleolipids that contain adenine or thymine moieties, either pure or in mixtures. This approach leads to different self-assembled nanostructures, which include spherical, rectangular and fibrillar assemblies, as a function of the sequence of nucleobases and chiral effects of the nucleolipids involved. We also show evidence that the resulting architectures can encapsulate hydrophobic molecules, revealing their potential as drug delivery vehicles or as compartments to host interesting chemistries in their interior.


Identification and mapping of resistance gene analogs (RGAs) in Prunus: a resistance map for Prunus.
The genetically anchored physical map of peach is a valuable tool for identifying loci controlling economically important traits in Prunus. Breeding for disease resistance is a key component of most breeding programs. The identification of loci for pathogen resistance in peach provides information about resistance loci, the organization of resistance genes throughout the genome, and permits comparison of resistance regions among other genomes in the Rosaceae. This information will facilitate the breeding of resistant species of Prunus. A candidate gene approach was implemented for locating resistance loci in the genome of peach. Candidate genes representing NBS-LRR, kinase, transmembrane domain classes, as well as, pathogen response (PR) proteins and resistance-associated transcription factors were hybridized to a peach BAC library and mapped by using the peach physical map database and the Genome Database for Rosaceae (GDR). A resistance map for Prunus was generated and currently contains 42 map locations for putative resistance regions distributed among 7 of the 8 linkage groups.


Rapamycin-induced tumor vasculature remodeling in rhabdomyosarcoma xenografts increases the effectiveness of adjuvant ionizing radiation.
Rapamycin inhibits vascular endothelial growth factor expression. Vascular endothelial growth factor is a tumor-elaborated protein that stimulates neovascularization. This inhibition can cause transient "normalization" of the generally dysfunctional tumor vasculature, resulting in improved tumor perfusion and oxygenation. We hypothesized that this may potentiate the antitumor effects of adjuvant ionizing radiation. Mice bearing orthotopic Rh30 alveolar rhabdomyosarcomas were treated with rapamycin (5 mg/kg intraperitoneally daily ×5). Tumors were then evaluated for changes in intratumoral oxygenation, perfusion, vessel permeability, and microvessel density. Additional tumor-bearing mice were treated with 5 doses of rapamycin, irradiation (4 Gy), or 5 doses of rapamycin with irradiation administered on the first or sixth day of rapamycin treatment. Although tumor vessel permeability changed only minimally, microvessel density decreased (3153 ± 932 vs 20,477 ± 3717.9 pixels per high-power field), whereas intratumoral oxygenation increased significantly (0.0385 ± 0.0141 vs 0.0043 ± 0.0023 mm Hg/mm(3)) after 5 doses of rapamycin. Contrast-enhanced ultrasound demonstrated a significantly increased rate of change of signal intensity after 5 days of rapamycin, suggesting improved intratumoral perfusion. Tumor volume 14 days after treatment was smallest in mice treated with the combination of rapamycin given before irradiation. Combination therapy with rapamycin given before irradiation to normalize the tumor vasculature, thereby improving tumor oxygenation, increased the sensitivity of alveolar rhabdomyosarcoma xenografts to adjuvant irradiation.


Distribution of lactate dehydrogenase isoenzymes in normal and inflamed bovine udders and milk.
The patterns of distribution of lactate dehydrogenase (LDH) isoenzymes were determined in normal and inflamed bovine udder tissues, in normal and mastitic milk-leucocytes and serum. LDH1 was the most common isoenzyme found in all the types of tissues examined, normal tissues contained the lowest proportions of LDH5 whereas the inflamed tissues and leucocytes from mastitic milk showed a higher proportion of LDH4 and LDH5. It seems that the origin of the elevated LDH in mastitic milk is the leucocytes and the parenchyma cells of the udder. The significance of the shift in the molecular forms of LDH isoenzymes is discussed in relation to possible alternations in energy metabolism in the inflamed bovine mammary gland.


Incidence and risk factors of late adverse reactions to low-osmolar contrast media: A prospective observational study of 10,540 exposures.
To evaluate the incidence and risk factors of late adverse reactions (ARs) to non-ionic low-osmolar contrast media (LOCM). The occurrence of late AR was monitored on day 1 and from day 7 to day 28 in all patients who received enhanced computed tomography using LOCM during a 5-week study period in a single tertiary hospital. Patients who experienced late AR were followed up for three years. Among the total 10,540 LOCM exposures, 315 ARs (3.0%) were reported; acute ARs occurred in 108 LOCM exposures (1.0%) and late ARs occurred in 207 LOCM exposures (2.0%) (90.9% within one week, 9.1% developed afterwards by day 20). Previous history of drug allergy (odds ratio [OR] = 4.59; 95% confidence interval [CI] 2.17-9.71) and allergic diseases (OR = 2.54; 95% CI 1.32-4.91) were risk factors of late ARs to LOCM. Although the recurrence rate was lowered with premedication from 8.5% to 1.7% (8/94 vs. 3/178; p = 0.016), LOCM change did not make difference compared to reuse of the culprit LOCM (2/38 vs. 9/234; p = 0.655). In patients with a history of late AR to LOCM, the risk of recurrent reactions decreased with longer time intervals between exposures (OR = 0.86; 95% CI: 0.77-0.97; p = 0.025) and with the use of antihistamine premedication (OR = 0.27; 95% CI: 0.06-0.99; p = 0.049). Late ARs to LOCM occurred mostly within one week. The use of premedication may be helpful in reducing the recurrence of late ARs.


Use of Smartphones in Telemedicine: Comparative Study Between Standard and Teledermatological Evaluation of High-Complex Care Hospital Inpatients.
It is estimated that there are around 7 billion mobile phone subscriptions worldwide. Considering the availability and convenience, it appears to be a suitable device for store-and-forward (SF) consultations. Although teledermatology has been suggested as an effective way of reducing costs and providing otherwise inaccessible expert evaluation, most studies have relied on high cost and high technological means. We conducted a study with inpatients that required dermatological evaluation in a high-complexity university hospital, accessing the correlation between traditional face-to-face evaluation and SF teledermatology, with data and pictures collected by medical students using smartphone cameras and then sent to consultants by e-mail. For 2 months, we evaluated 100 patients and, as a result, the total agreement between both consultation modalities was 54%, the partial agreement was 27%, and the disagreement was 19%. This study points out that SF teledermatology with the use of mobile phone is comparable to traditional face-to-face evaluation. Furthermore, most of the disagreements were probably related to the inexperience of the medical residents. Our study suggests that a smartphone-based teledermatology inpatient consultation model could be a reasonable option for hospitals lacking dermatological services. Also, it may be as or more effective than face-to-face consultations, if performed by a more experienced dermatologist. When feasible, photographing training should be performed.


Disseminated intravascular coagulation in the pathogenesis of adult respiratory distress syndrome: 2. Experimental study.
The role of disseminated intravascular coagulation (DIC) in the pathogenesis of adult respiratory distress syndrome (ARDS) was studied in the experimental animals. ARDS was simulated in dogs by the administration of various doses of Escherichia coli endotoxin (Difco). The alveolar surface activity in the group which received lethal dose of endotoxin (3 mg/kg) exhibited no significant alterations with mild pulmonary insufficiency and little pathologic change five hours after the induction of shock. On the other hand, a significant decrease in alveolar surface activity was found to develop in the group which received sublethal dose of endotoxin (1 mg/kg) accompanying enlarged alveolar-arterial oxygen tension differences (A-aDO2) and elevated pulmonary vascular resistance after 24 hours. These changes occurred concomitantly with pathologic findings of DIC, interstitial edema and atelectasis. The disturbance in ventilatory function observed in prolonged shock appeared to be related to the impairment of pulmonary microcirculation caused by DIC and subsequent hypoxia of lung tissue which led to a loss of alveolar surfactant.


Biotransformation of explosive-grade nitrocellulose under denitrifying and sulfidogenic conditions.
Waste nitrocellulose (NC) is regulated as a hazardous material. The objective of this study was to determine if NC exposed to denitrifying and sulfidogenic conditions would undergo sufficient removal of the nitro groups to yield a material that is no longer explosive. Enrichment cultures were established with methanol as the electron donor for nitrate-reducing conditions and lactate for sulfate-reducing conditions. NC was added to the cultures at 10 g/l. A statistically significant decrease in the nitrogen (N) content of NC occurred in both enrichment cultures, from approximately 13.1-13.2% in virgin NC to 12.2-12.4%. This was accompanied by an increase in nitrogen gas formation. The presence of a primary substrate (methanol and lactate) was necessary to affect this change; NC itself did not serve as an electron donor. In cultures that were carrying out denitrification but were then depleted of nitrate, with methanol still present, a slightly greater removal of nitro groups from NC occurred along with additional formation of nitrogen gas. NC did not have an inhibitory affect on the denitrification process but it did significantly slow the rate of lactate consumption and sulfate reduction. Fourier Transform Infrared Spectroscopy (FTIR) results indicated that NC exposed to denitrifying conditions was enriched in hydroxyl groups, consistent with removal of some of the nitro groups by hydrolysis of the nitrate esters. NC exposed to nitrate- and sulfate-reducing conditions and virgin NC were also compared based on their explosive properties using a small-scale burning test. The biologically treated NC exhibited somewhat less reactivity, but was still rated as explosive. The decrease in%N, increase in N2, and FTIR results demonstrated that NC does undergo biotransformation in the presence of nitrate- and sulfate-reducing enrichment cultures, but the extent of denitration does not appear to be adequate to yield a nonhazardous product.


Regulation strategy, bioactivity, and physical property of plant and microbial polysaccharides based on molecular weight.
Structural features affect the bioactivity, physical property, and application of plant and microbial polysaccharides. However, an indistinct structure-function relationship limits the production, preparation, and utilization of plant and microbial polysaccharides. Molecular weight is an easily regulated structural feature that affects the bioactivity and physical property of plant and microbial polysaccharides, and plant and microbial polysaccharides with a specific molecular weight are important for exerting their bioactivity and physical property. Therefore, this review summarized the regulation strategies of molecular weight via metabolic regulation; physical, chemical, and enzymic degradations; and the influence of molecular weight on the bioactivity and physical property of plant and microbial polysaccharides. Moreover, further problems and suggestions must be paid attention to during regulation, and the molecular weight of plant and microbial polysaccharides must be analyzed. The present work will promote the production, preparation, utilization, and investigation of the structure-function relationship of plant and microbial polysaccharides based on their molecular weight.


PAI-1/PIAS3/Stat3/miR-34a forms a positive feedback loop to promote EMT-mediated metastasis through Stat3 signaling in Non-small cell lung cancer.
This study intented to clarify the intracellular effect of PAI-1 on Non-small cell lung cancer (NSCLC) metastasis and the precise mechanism involved. The metastatic properties of NSCLC cells were determined by transwell assays and wound-healing assay in vitro. The mRNA and protein expressions of genes were analyzed by Real-time qPCR and western blot, respectively. Pulmonary metastasis model of NSCLC cells was established to evaluate the pro-metastasis effect of PAI-1 and anti-metastatic effect of miR-34a in vivo. The gene targets of miR-34a were confirmed by luciferase reporter assays. Chromatin immunoprecipitation assay was employed to detect the transcriptional regulation of miR-34a. Co-immunoprecipitation assay was performed to observe the interaction of proteins. PAI-1, which was elevated in NSCLC patients with recurrence and metastasis, augmented NSCLC metastasis and was negatively related to the prognosis of NSCLC. miR-34a, which was decreased in NSCLC patients with metastasis, attenuated NSCLC metastasis and was positively correlated with the prognosis of NSCLC. Moreover, PAI-1 was identified as the target gene of miR-34a and activated the Stat3 signaling pathway to promote epithelial-mesenchymal transition (EMT) in NSCLC cells. PAI-1 interacted with PIAS3 to regulate Stat3-dependent gene expression and miR-34a was transcriptionally suppressed by Stat3 to form a positive regulatory loop through Stat3 signaling. Our findings suggest that PAI-1 and miR-34a, which can be clinically utilized as biomarkers for the clinical prognosis or diagnosis of NSCLC, are potential targets for the treatment of NSCLC.


Comparison of fentanyl and droperidol mixture (neuroleptanalgesia II) with morphine on clinical outcomes in unstable angina patients.
The objective of the study was to compare the influence of a fentanyl and droperidol mixture (neuroleptanalgesia) with morphine on the in-hospital instability, development of acute myocardial infarction (AMI), and mortality during a 30-day and 12-month follow-up in unstable angina patients. The study was performed in 112 unstable angina patients. In addition to standard therapy for unstable angina (aspirin, heparin, nitroglycerin, and oxygen), 53 patients (63.2 +/- 9.7 years; 32 males) were randomized to receive neuroleptanalgesia (0.025 mg fentanyl and 1.25 mg droperidol in a volume of 1 mL) and 59 patients (58.6 +/- 11.5 years; 41 males) to receive morphine. Neuroleptanalgesia was started i.v. with 2 mL and could be followed by 1 mL every 4 hours. Morphine was started i.v. with 10 mg and could be followed by 5 mg every 4 hours up to angina resolution during 24 hours of hospitalization. Another 1 mL of neuroleptanalgesia or 5 mg of morphine could be administered on demand if angina lasted or reappeared earlier than the next scheduled dose. Odds ratios with 95% confidence intervals (95% CI) adjusted for the age, sex, smoking, previous myocardial infarction, and hypertension were evaluated for all study outcomes. The odds ratios for clinical in-hospital instability (5.93, 95% CI: 2.49-14.15; P = 0.0001), 12-month AMI development (3.57, 95% CI: 1.51-8.45; P = 0.0038), and 12-month mortality (6.00, 95% CI: 1.63-22.09; P = 0.0070) were significantly increased in the neuroleptanalgesia group compared with the patients on morphine. It is concluded that neuroleptanalgesia negatively influences disease course, AMI development, and total mortality in unstable angina patients.


Towards a dialogue between psychoanalysis and neuroscience: connections that are both possible and necessary.
The author, a child psychiatrist, calls for a dialogue between psychoanalysis and neuroscience (both from his clinical joint practices with neuropediatricians and on a theoretical level) to found a new approach to the questions of neurodevelopmental and psychopathological disorders. He briefly discusses two examples. The first example is developmental and concerns the links between the archaic grasping reflex and adhesive identification. He shows how the phenomena observed in the two fields can find a logical sequence. The second example concerns a therapeutic technique (wrapping) that is used to soothe self-injurious behaviours in children with autism. Here, again, both approaches are used to better understand the phenomenon in question. Bridges must be built to open new theoretico-clinical and therapeutic collaborations. One could imagine data integration from these two heterogeneous subdomains to form a new complex subdomain, from which productivity is guaranteed.


Obesity and Sexual Functioning.
Sexual functioning is an important, yet often overlooked, aspect of quality of life for many individuals with obesity. With the growing recognition of obesity as a significant, international public health issue, a developing body of research has investigated the relationship between obesity and sexual functioning. Several studies have found that obesity is associated with impairments in sexual functioning. The mechanisms of this relationship, whether physiological, psychosocial, or a combination of the two, are yet to be fully elucidated. Other studies have suggested that weight loss, whether induced by bariatric surgery or less intensive interventions, is associated with significant and clinically meaningful change in sexual functioning and relevant reproductive hormones. This chapter reviews the research in these areas and provides recommendations for future research on these relationships.


Temporal stability and assembly mechanisms of gut microbiota in sea cucumbers response to nanoplastics treatment.
Aquaculture provides essential food for humans, and the health of farmed species is particularly important for the aquaculture industry. Aquaculture environment could be a sink of plastic debris (PDs) due to the enclosed character and heavy use of plastics. Gut microbiota of aquaculture species could respond to the exogenous pollutants and regulate the health of hosts. Here, variations in gut microbiota of Apostichopus japonicus induced by the ingested nanoplastics (NPs) were investigated by a lab experiment. We selected a NPs concentration gradient of 100 mg/kg and 500 mg/kg to simulate microplastic pollution to A. japonicus, and the significant differences in gut microbiota composition after 21 days of NP exposure were evaluated. According to the high-throughput sequencing from time series samples, a decrease of diversity in gut microbiota of A. japonicus with dietary NPs was observed. In addition, the gut microbiota compositions of sea cucumbers with and without NPs exposure were also distinct, expressing as enrichment of Bacteroidota while reducement of Proteobacteria under NPs stresses. Combined the results of network analysis, the less complexity and stability of gut microbiota in sea cucumbers with dietary NPs were proved. Based on the neutral community model, the ingested NPs elevated the contribution of stochastic processes for the gut microbiota assembly in sea cucumbers. Our study showed that substantial variations in gut microbiota of A. japonicus under NPs stresses, and also explored the underlying mechanisms regulating these changes. This research would offer new meaningful insights into the toxicity of NPs on sea cucumbers, contributing a solid fundament to improve the health of sea cucumbers under NPs stresses.


Pre-medication with pronase reduces artefacts during endoscopic ultrasonography.
Gastric mucus usually induces artefacts during endoscopic ultrasonography. To investigate the effectiveness of pre-medication with the proteolytic enzyme, pronase, before endoscopic ultrasonography. Out-patients scheduled for endoscopic ultrasonography were randomly assigned to oral pre-medication with the anti-foam agent, dimethylpolysiloxane, alone (treatment A; n = 29), with dimethylpolysiloxane plus sodium bicarbonate (treatment B; n = 29) or with dimethylpolysiloxane, sodium bicarbonate and pronase (treatment C; n = 29). All drinks were given about 10 min before the start of the procedure. After insertion of the endoscope, endoscopists recorded visibility scores before the procedure, imaging scores at endoscopic ultrasonography and the numbers of high-echo spots in the gastric cavity and on the gastric wall surface after the procedure. Pre-medication with pronase (treatment C) significantly reduced (both at P < 0.05) the visibility score (score 4, 46%) in comparison with that obtained for pre-medication without pronase (10% for both treatments A and B). Treatment with pronase significantly reduced (both at P < 0.05) the endoscopic ultrasonography score in the gastric cavity (score 4, 34%) in comparison with that found for treatments A (7%) and B (0%). It also significantly reduced (P < 0.05) the endoscopic ultrasonography score on the gastric wall surface (score 4, 14%) in comparison with that observed for treatment A (3%). The numbers of high-echo spots in the gastric cavity and on the gastric wall surface were significantly less (both at P < 0.001) for pre-medication with pronase (treatment C) than for pre-medication with treatments A and B. There were no complications associated with the solutions. Pre-treatment with pronase reduced the artefacts during endoscopic ultrasonography.


Smaller visual arrays are harder to integrate in schizophrenia: Evidence for impaired lateral connections in early vision.
Long-range horizontal connections in early vision undergird a well-studied "collinear facilitation" effect, wherein a central low-contrast target becomes more detectable when flanked by collinear elements. Collinear facilitation is weaker in schizophrenia. Might lateral connections be responsible? To consider the possibility, we had 38 schizophrenia patients and 49 well-matched healthy controls judge the presence of a central low-contrast element flanked by collinear or orthogonal high-contrast elements. The display (target+flankers) was scaled in size to produce a lower and higher spatial frequency ("SF") condition (4 and 10 cycles/deg, respectively). Larger stimulus arrays bias processing towards feedback connections from higher-order visual areas; smaller arrays bias processing toward lateral connections. Patients had impaired facilitation relative to controls at higher but not lower SFs. Combining data from a past study on "contour integration" (in which subjects sought to detect chains of co-circular elements), we found correlated integration and facilitation performance at the higher SF and a similar effect of spatial scaling across SF, suggesting a common mechanism. In an exploratory analysis, worse contrast thresholds (without facilitation) correlated strongly with more premorbid dysfunction. In schizophrenia, inter-element filling-in worsens at smaller spatial scales potentially because of its increased reliance on impaired lateral connections in early vision.


Genetic analysis of the isolated Faroe Islands reveals SORCS3 as a potential multiple sclerosis risk gene.
In search of the missing heritability in multiple sclerosis (MS), additional approaches adding to the genetic discoveries of large genome-wide association studies are warranted. The objective of this research paper is to search for rare genetic MS risk variants in the genetically homogenous population of the isolated Faroe Islands. Twenty-nine Faroese MS cases and 28 controls were genotyped with the HumanOmniExpressExome-chip. The individuals make up 1596 pair-combinations in which we searched for identical-by-descent shared segments using the PLINK-program. A segment spanning 63 SNPs with excess case-case-pair sharing was identified (0.00173 < p > 0.00212). A haplotype consisting of 42 of the 63 identified SNPs which spanned the entire the Sortilin-related vacuolar protein sorting 10 domain containing receptor 3 (SORCS3) gene had a carrier frequency of 0.34 in cases but was not present in any controls (p = 0.0008). This study revealed an oversharing in case-case-pairs of a segment spanning 63 SNPs and the entire SORCS3. While not previously associated with MS, SORCS3 appears to be important in neuronal plasticity through its binding of neurotrophin factors and involvement in glutamate homeostasis. Although additional work is needed to scrutinise the genetic effect of the SORCS3-covering haplotype, this study suggests that SORCS3 may also be important in MS pathogenesis.


Quinolone analogues of benzothiazinone: Synthesis, antitubercular structure-activity relationship and ADME profiling.
Mycobacterium tuberculosis (Mtb) has an impermeable cell wall which gives it an inherent ability to resist many antibiotics. DprE1, an essential enzyme in Mtb cell wall synthesis, has been validated as a target for several TB drug candidates. The most potent and developmentally advanced DprE1 inhibitor, PBTZ169, is still undergoing clinical development. With high attrition rate, there is need to populate the development pipeline. Using a scaffold hopping strategy, we imprinted the benzenoid ring of PBTZ169 onto a quinolone nucleus. Twenty-two compounds were synthesised and screened for activity against Mtb, with six compounds exhibiting sub micromolar activity of MIC90 <0.244 μM. Compound 25 further demonstrated sub-micromolar activity when evaluated against wild-type and fluoroquinolone-resistant Mtb strains. This compound maintained its sub-micromolar activity against a DprE1 P116S mutant strain but showed a significant reduction in activity when tested against the DprE1 C387S mutant.


First report on the occurrence of Rickettsia slovaca and Rickettsia raoultii in Dermacentor silvarum in China.
Rickettsioses are among both the longest known and most recently recognized infectious diseases. Although new spotted fever group rickettsiae have been isolated in many parts of the world including China, Little is known about the epidemiology of Rickettsia pathogens in ticks from Xinjiang Autonomous Region of China. In an attempt to assess the potential risk of rickettsial infection after exposure to ticks in Xinjiang Uygur Autonomous Region of China, a total of 200 Dermacentor silvarum ticks collected in Xinyuan district were screened by polymerase chain reaction based on the outer membrane protein A gene. 22 of the 200 specimens (11%) were found to be positive by PCR. Phylogenetic analysis of OmpA sequences identified two rickettsial species, Rickettsia raoultii (4.5%) and Rickettsia slovaca (6.5%). This study has reported the occurrence of Rickettsia raoultii and Rickettsia slovaca in Xinjiang Autonomous Region of China and suggests that Dermacentor silvarum could be involved in the transmission of rickettsial agents in China. Further studies on the characterization and culture of rickettsial species found in Dermacentor silvarum should be performed to further clarify this. Additionally, the screening of human specimens for rickettsial disease in this region will define the incidence of infection.


Foreign body aspiration in children: value of radiography and complications of bronchoscopy.
The authors undertook a 10-year review of bronchoscopies for airway foreign bodies in children to test assertions in previous reports that (1) characteristic abnormalities in chest radiographs are important indicators of the need for bronchoscopy and (2) experienced operators incur negligible complications. The medical records of 293 children who underwent bronchoscopies by experienced pediatric surgeons for suspected airway foreign bodies were reviewed for patient age, symptoms, duration of symptoms before bronchoscopy, prebronchoscopy radiographs, type of foreign body, anatomic location of foreign body, success of bronchoscopic removal, length of hospital stay, and complications. Of the 293 bronchoscopies, 265 showed airway foreign bodies. A choking episode was recorded in 228 of the 265 patients with foreign bodies and 5 of the 28 with negative bronchoscopy. The surgeon thought that radiographs were normal at the time of bronchoscopy in 110 patients who had foreign bodies. Nine patients with foreign bodies had atypical radiographs; three had bilateral emphysema and six had upper lobe or bilateral atelectasis or pneumonia. There were three complications: one vocal cord injury requiring temporary tracheostomy, one tracheal laceration from removal of an aspirated tooth, and one severe postoperative subglottic edema requiring a 4-day hospital stay. The age of the patients, symptoms, types of foreign bodies, locations of foreign bodies, management, and outcomes were similar to those of previous reports. In children with airway foreign bodies, chest radiograph findings are frequently normal and can display abnormalities uncharacteristic for foreign body aspiration. Children witnessed to choke while having small particles in their mouths and noted subsequently to have raspy respiration, wheezing, or coughing should undergo prompt bronchoscopy regardless of radiographic findings. Complications of bronchoscopy for foreign body aspiration are uncommon but occur even in experienced hands.


Drinking water turbidity and emergency department visits for gastrointestinal illness in Atlanta, 1993-2004.
The extent to which drinking water turbidity measurements indicate the risk of gastrointestinal illness is not well understood. Despite major advances in drinking water treatment and delivery, infectious disease can still be transmitted through drinking water in the United States, and it is important to have reliable indicators of microbial water quality to inform public health decisions. The objective of our study was to assess the relationship between gastrointestinal illness, quantified through emergency department visits, and drinking water quality, quantified as raw water and filtered water turbidity measured at the treatment plant. We examined the relationship between turbidity levels of raw and filtered surface water measured at eight major drinking water treatment plants in the metropolitan area of Atlanta, Georgia, and over 240,000 emergency department visits for gastrointestinal illness during 1993-2004 among the population served by these plants. We fit Poisson time-series statistical regression models that included turbidity in a 21-day distributed lag and that controlled for meteorological factors and long-term time trends. For filtered water turbidity, the results were consistent with no association with emergency department visits for gastrointestinal illness. We observed a modest association between raw water turbidity and emergency department visits for gastrointestinal illness. Our results suggest that source water quality may contribute modestly to endemic gastrointestinal illness in the study area. The association between turbidity and emergency department visits for gastrointestinal illness was only observed when raw water turbidity was considered; filtered water turbidity may not serve as a reliable indicator of modest pathogen risk at all treatment plants.


Fabrication and examination of polyorganophosphazene/polycaprolactone-based scaffold with degradation, in vitro and in vivo behaviors suitable for tissue engineering applications.
The present study aimed to synthesis a proper scaffold consisting of hydroxylated polyphosphazene and polycaprolactone (PCL), focusing on its potential use in tissue engineering applications. The first grafting of PCL to poly(propylene glycol)phosphazene (PPGP) was performed via ROP of ε-caprolactone, whereas PPGP act as a multisite macroinitiator. The prepared poly(propylene glycol phosphazene)-graft-polycaprolactone (PPGP-g-PCL) were evaluated by essential tests, including NMR, FTIR, FESEM-EDS, TGA, DSC and contact angle measurement. The quantum calculations were performed to investigate molecular geometry and its energy, and HOMO and LUMO of PPGP-g-PCL in Materials Studio2017. MD simulations were applied to describe the interaction of the polymer on phospholipid membrane (POPC128b) in Material Studio2017. The C2C12 and L929 cells were used to probe the cell-surface interactions on synthetic polymers surfaces. Cells adhesion and proliferation onto scaffolds were evaluated using FESEM and MTT assay. In vitro analysis indicated enhanced cell adhesion, high proliferation rate, and excellent viability on scaffolds for both cell types. The polymer was further tested via intraperitoneal implantation in mice that showed no evidence of adverse inflammation and necrosis at the site of the scaffold implantation; in return, osteogenesis, new-formed bone and in vivo degradation of the scaffold were observed. Herein, in vitro and in vivo assessments confirm PPGP-g-PCL, as an appropriate scaffold for tissue engineering applications.


Radiological and clinical predictors of long-term outcome in rotator cuff calcific tendinitis.
Knowledge on the epidemiology and long-term course of rotator cuff calcific tendinitis (RCCT) is scarce. We assessed demographics, radiological characteristics, and their association with long-term outcomes in a large patient group. Baseline demographics, radiological characteristics and treatment were recorded in 342 patients. Interobserver agreement of radiological measures was analyzed. Long-term outcome was evaluated with questionnaires (WORC, DASH). The association of baseline characteristics with outcome was assessed. Mean age was 49.0 (SD = 10.0), and 59.5 % were female. The dominant arm was affected in 66.0 %, and 21.3 % had bilateral disease. Calcifications were on average 18.7 mm (SD = 10.1, ICC = 0.84 (p < 0.001)) and located 10.1 mm (SD = 11.8) medially to the acromion (ICC = 0.77 (p < 0.001)). Gärtner type I calcifications were found in 32.1 % (Kappa = 0.47 (p < 0.001)). After 14 years (SD = 7.1) of follow-up, median WORC was 72.5 (range, 3.0-100.0; WORC < 60 in 42 %) and median DASH 17.0 (range, 0.0-82.0). Female gender, dominant arm involvement, bilateral disease, longer duration of symptoms, and multiple calcifications were associated with inferior WORC. DASH results were similar. Many subjects have persisting shoulder complaints years after diagnosis, regardless of treatment. Female gender, dominant arm involvement, bilateral disease, longer duration of symptoms, and multiple calcifications were associated with inferior outcome. Radiological measures had moderate-to-good reliability and no prognostic value. • Most RCCT studies report on short-term outcome and/or small patients groups. • In this large, long-term observational study, RCCT appeared to not be self-limiting in many subjects. • Negative prognostic factors included female gender, more calcifications, dominant arm affected, and longer duration of symptoms. • Interobserver agreement of general radiological RCCT measures is moderate to good. • More rigorous diagnostics and treatment might be needed in specific RCCT cases.


Influence of modified atmosphere and vacuum packaging with and without nanosilver-coated films on different quality parameters of pork.
Pork is often marketed in packages with high oxygen atmosphere (MAP) or vacuum to improve shelf life and appearance. As silver ions have antibacterial effects, food contact films coated with silver might improve the shelf life of meat. In the present study, pork was wrapped in commercially available films, coated with nanosilver particles, and stored in the two packaging variants MAP and vacuum for 12 days. During storage, samples were analyzed on days 1 (before packaging), 4, 8 and 12 for microbiological contamination, meat quality (e.g., pH, color), and for the percentages of the myoglobin (Mb) redox forms. In addition, the effects of the film were examined after inoculation of the meat with high quantities of methicillin-resistant Staphylococcus aureus (MRSA) cells before vacuum storage for 8 days. MAP storage resulted in higher lightness (L*) values, lower liquid loss and higher Mb oxidation compared to vacuum. Microbiological spoilage was partly affected by the packaging variants with reducing effects of the MAP. The nanosilver-coating only affects the Mb redox form percentages of the pork cutlets and on day 4 the L* values, whereas microbiological parameters were not influenced. As the nanosilver coating had no influence on the total viable bacteria counts as well as Pseudomonas spp., Enterobacteriaceae and MRSA counts, an advantage of the nanosilver coating on the shelf life could be excluded.


Comparison of the Efficacy of Amniotic Membrane Versus Buccal Fat Pad in Treatment of Oral Submucous Fibrosis.
Oral and maxillofacial surgery deals with wide range of oral defects, wound closure, tissue resection, and tissue reconstruction. The purpose of our study is to use amniotic membrane for closure of post surgery defect in patient of oral submucous fibrosis to utilize its growth factor and scaffold nature for effective healing and to evaluate effectiveness of amniotic membrane in treatment outcome. The objectives are to compare post-operative mouth opening, healing of amniotic membrane and buccal fat pad. Diagnosed patients with OSMF are divided into two surgical site Group I (n = 5patients)-Left side buccal mucosa in which resection of fibrous band with coronoidectomy followed by reconstruction of the mucosal defect with BFP. Group II-Right side buccal mucosa in which resection of fibrous band with coronoidectomy followed by reconstruction of the mucosal defect with freeze dried irradiated amniotic membrane. This study suggested that in comparison to buccal fat pad flap, the HAM graft is a better option for oral reconstruction in terms of infection, graft failure, MMO, inflammation, pain. Outcome indicated that the HAM is biologically ideal graft for oral wounds and could be used as clinical alternative for various repair surgery for oral defects. The amniotic membrane was found easy to handle and easy to use with inherent hemostatic property which is observed in all patients. No patients had shown any evidence of any complications. Good pain control observed in patients throughout postoperative period.


ACE2 deficiency induced perivascular fibrosis and cardiac hypertrophy during postnatal development in mice.
In order to investigate the role of angiotensin-converting enzyme 2 (ACE2) in cardiac development, we examined the effects of ACE2 deficiency on postnatal development of the heart using ACE2-knockout (ACE2KO) mice. Heart samples of wild type (WT; C57BL/6J) mice and ACE2KO mice were taken at 1, 4, and 10 weeks of age. In WT mice, expression of ACE2 mRNA increased from 1 week to 10 weeks. A similar increase was observed in immunostaining of ACE2 in the heart, in which ACE2 was strongly expressed in coronary arteries. Compared with WT mice, heart weight was greater in ACE2KO mice at 4 weeks, and coronary artery thickening and perivascular fibrosis were also already enhanced from 4 weeks. Consistent with the increase of fibrosis, cardiac expression of collagen and TIMP was higher, and expression of MMP was lower in ACE2KO mice at 4 weeks. In addition, TGF-β mRNA was also higher, and lower expression of PPARγ mRNA was observed at 4 weeks in ACE2KO mice. These results suggest that ACE2 plays an important role in postnatal development of the heart, and that lack of ACE2 enhances coronary artery remodeling with an increase in perivascular fibrosis and cardiac hypertrophy already around the weaning period.


Wild mice in the cold: some findings on adaptation.
The house mouse, Mus domesticus, can thrive in natural environments much below its optimum temperature. Thermogenesis is then above that at more usual temperatures. In addition, body weight, and the weights of brown adipose tissue and the kidneys, may be higher than usual. In free populations of house mice cold lowers fertility and may prevent breeding. Other possible limiting factors on breeding are food supply, shelter for nesting and social interactions. In captivity, wild-type house mice exposed to severe cold (around 0 degrees C) at first adapt ontogenetically by shivering and reduced activity. But raised thermogenesis is soon achieved without shivering; nest-building improves; and readiness to explore may be enhanced. Endocrine changes probably include, at least initially, a rise in adrenal cortical activity and in catecholamine secretion. Some females become barren, but many remain fertile. The maturity of fertile females is, however, delayed and intervals between births are lengthened; nestling mortality rises. A limiting factor during lactation may be the capacity of the gut. Similar adaptive changes are observed during winter in some species of small mammals that do not hibernate. But neither the house mouse nor other species present a single, universal pattern of cold-adaptation. Wild-type mice bred for about 10 generations in a warm laboratory environment (20-23 degrees C) change little over generations. In cold they become progressively heavier and fatter at all ages; they mature earlier, and nestling mortality declines. The milk of such 'Eskimo' females is more concentrated than that of controls. If 'Eskimo' mice are returned to a warm environment, they are more fertile, and rear heavier young, than controls that remained in the warm. Despite the heavier young, litter size is not reduced: it may be increased, probably as a result of a higher ovulation rate. Parental effects have been analyzed by cross-fostering and hybridizing. Survival, growth and fertility are all favourably influenced by the intra-uterine and nest environments provided by 'Eskimo' females. 'Eskimo' males are also better fathers. Hence after ten generations the phenotype of cold-adapted house mice shows the combined effects of (a) an ontogenetic response to cold, (b) a superior parental environment and (c) a change genotype. The secular changes in the cold that lead to this phenotype give the appearance of evolution in miniature; but it is equally possible that they represent a genetical versatility that allows rapid, reversible shifts in response to environmental demands.(ABSTRACT TRUNCATED AT 400 WORDS)


Fusion variations of pancreatic ducts in patients with anomalous arrangement of pancreaticobiliary ductal system.
Fusion variations of the pancreatic ducts were studied to elucidate the significance of such variations. We classified structural fusion anomalies of the main and accessory pancreatic ducts on endoscopic retrograde cholangio-pancreatography (ERCP) in 37 patients with anomalous arrangement of the pancreaticobiliary ductal system (AAPB). The fusion variations of the pancreatic ducts were classified into five types: common, ansa pancreatica, branch fusion, looped, and separated. These fusion variations, except for common type, were found in 68% of the 37 patients with AAPB on ERCP. Fusion variations of the pancreatic ducts were very frequent (93%) in the 30 patients with congenital cystic dilatation of the common bile duct (CCD). The branch confluence fashion, in which the terminal bile duct communicated with a pancreatic duct branch, was found only in patients with cystic dilatation cyst of the CCD, and it appeared that cystic dilatation cyst of CCD might differ from spindle or cylindrical cyst originating from embryonic formation of an anomalous confluence. It was also suggested that in patients with fusion variations of the pancreatic ducts, the flow of pancreatic juice might be disordered, leading to the development of acute pancreatitis or pancreatic dysfunction. Consequently, it appears to be necessary to carefully examine patients with AAPB for the presence or absence of any fusion variations of the pancreatic ducts and to observe such patients with long-term monitoring by ERCP, and computed temography, and with pancreatic function tests.


Novel DNA amplification on chromosomes 2p25.3 and 7q11.23 in cholangiocarcinoma identified by arbitrarily primed polymerase chain reaction.
To detect and characterize amplified DNA sequences in cholangiocarcinoma (CCA). We extracted DNA from tumor and corresponding normal tissues of 30 patients with CCA and amplified with 30 random ten-mer arbitrary primers by the arbitrarily primed polymerase chain reaction (AP-PCR) technique. Our results showed gains of genomic sequences at high frequency. Using the AX-11 arbitrary primer, we determined an amplified DNA fragment occurred frequently in the tumors analyzed. The DNA fragment was isolated and identified as two sequences mapped to chromosomes 2p25.3 and 7q11.23. Specific primers were designed employing these sequences and used for detecting amplification by real-time quantitative PCR. The amplification of the DNA sequences on chromosomes 2p25.3 and 7q11.23 was detected in 10 (33%) and 6 (20%) cases, respectively. Thirteen (43%) cases showed amplification on both or one of the chromosomes. In addition, amplification of the DNA on chromosome 2p25.3 was predominantly observed in poorly differentiated tumors. Our findings suggest that the novel amplified DNA on chromosomal regions at 2p25.3 and 7q11.23 might be involved in the development and progression of CCA.


Boric-acid-modified Fe3O4@PDA@UiO-66 for enrichment and detection of glucose by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
Herein, boric-acid-modified multifunctional Zr-based metal-organic frameworks (denoted as Fe3O4@PDA@B-UiO-66) were synthesized by hydrothermal reaction and surface modification. Compared to traditional matrix, Fe3O4@PDA@B-UiO-66 has the advantages of high ionization efficiency, high surface area, low matrix background, porous structure, and numerous boric-acid-active sites. By combining matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), Fe3O4@PDA@B-UiO-66 was used as an adsorbent and matrix for enrichment and detection of glucose, based on a specific reaction between boric acid and glucose. The limit of detection was 58.5 nM. The proposed method provides a simple and efficient approach for the sensitive and quantitative detection of glucose in complex samples based on MALDI-TOF MS. Design and synthesis of boric-acid-modified multifunctional magnetic metal-organic frameworks (designated as Fe3O4@PDA@B-UiO-66) applied as adsorbent and matrix for the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis of glucose in complex biosamples.


Direct effects of manganese compounds on dopamine and its metabolite Dopac: an in vitro study.
Following combustion of fuel containing the additive methylcyclopentadienyl-manganese-tricarbonyl (MMT), manganese phosphate (MnPO(4)) and manganese sulfate (MnSO(4)) are emitted in the atmosphere. Manganese chloride (MnCl(2)), another Mn(2+) species, is widely used experimentally. Using rat striatal slices, we found that MnPO(4) decreased tissue and media dopamine (DA) and media Dopac (a DA metabolite) levels substantially more than either MnCl(2) or MnSO(4); antioxidants were partially protective. Also, both MnCl(2) and MnPO(4) (more potently) oxidized DA and Dopac even in the absence of tissue in the media, suggesting a direct interaction between Mn and DA/Dopac. Because aminochrome is a major oxidation product of DA, we next determined whether MnPO(4) will be more potent in forming aminochrome than MnCl(2) or MnSO(4) which, indeed, was the case. Thus, a potential additional mechanism for the neurotoxic effects of environmentally-relevant forms of Mn, MnPO(4) in particular, is the generation of reactive DA intermediates.


Validation of Machine Learning-Based Individualized Treatment for Depressive Disorder Using Target Trial Emulation.
This study aims to develop and validate the use of machine learning-based prediction models to select individualized pharmacological treatment for patients with depressive disorder. This study used data from Taiwan's National Health Insurance Research Database. Patients with incident depressive disorders were included in this study. The study outcome was treatment failure, which was defined as psychiatric hospitalization, self-harm hospitalization, emergency visits, or treatment change. Prediction models based on the Super Learner ensemble were trained separately for the initial and the next-step treatments if the previous treatments failed. An individualized treatment strategy was developed for selecting the drug with the lowest probability of treatment failure for each patient as the model-selected regimen. We emulated clinical trials to estimate the effectiveness of individualized treatments. The area under the curve of the prediction model using Super Learner was 0.627 and 0.751 for the initial treatment and the next-step treatment, respectively. Model-selected regimens were associated with reduced treatment failure rates, with a 0.84-fold (95% confidence interval (CI) 0.82-0.86) decrease for the initial treatment and a 0.82-fold (95% CI 0.80-0.83) decrease for the next-step. In emulation of clinical trials, the model-selected regimen was associated with a reduced treatment failure rate.


Association of High Sensitivity C-Reactive Protein Concentrations and Metabolic Syndrome among Thai Adults.
OBJECTIVE: To investigate the association of high sensitivity C-reactive protein (hsCRP) concentrations and metabolic syndrome among Thai adults. METHODS: This cross-sectional study is comprised of 467 Thai participants (209 men and 258 women) receiving annual health check-up. Spearman's rank correlation coefficients were used to assess associations of metabolic parameters (age, waist circumference, blood pressure, triglycerides, HDL-C, fasting plasma glucose, fasting insulin and uric acid) with hsCRP concentrations for men and women, respectively. Multivariable logistic regression procedures were used to estimate the risk (odds ratios [OR] and 95% confidence intervals [95% CI]) of metabolic syndrome according to low, moderate and high hsCRP concentrations (<1.0, 1.0-3.0 and >3.0 mg/l, respectively). RESULTS: Measures of adiposity and fasting insulin were positively and significantly correlated with hsCRP concentrations among women with and without metabolic syndrome. Similar associations were observed among men without metabolic syndrome. After controlling for confounders, moderately elevated hsCRP concentrations were associated with a 2.38-fold increased risk of metabolic syndrome (OR=2.38, 95% CI: 1.20-4.72) among men. Men with high hsCRP concentrations had a 5.45-fold increased risk of metabolic syndrome (OR=5.45, 95% CI: 2.24-13.27) when compared with those who had low hsCRP concentrations. The corresponding odds ratios for women with moderately elevated and high hsCRP concentrations were 4.92 (OR=4.92, 95% CI: 2.34-10.35) and 11.93 (OR=11.93, 95% CI: 5.54-25.72), respectively. CONCLUSIONS: These findings are consistent with the literature suggesting a role of hsCRP as a biomarker for metabolic syndrome.


EphA2 Receptor Unliganded Dimers Suppress EphA2 Pro-tumorigenic Signaling.
The EphA2 receptor tyrosine kinase promotes cell migration and cancer malignancy through a ligand- and kinase-independent distinctive mechanism that has been linked to high Ser-897 phosphorylation and low tyrosine phosphorylation. Here, we demonstrate that EphA2 forms dimers in the plasma membrane of HEK293T cells in the absence of ephrin ligand binding, suggesting that the current seeding mechanism model of EphA2 activation is incomplete. We also characterize a dimerization-deficient EphA2 mutant that shows enhanced ability to promote cell migration, concomitant with increased Ser-897 phosphorylation and decreased tyrosine phosphorylation compared with EphA2 wild type. Our data reveal a correlation between unliganded dimerization and tumorigenic signaling and suggest that EphA2 pro-tumorigenic activity is mediated by the EphA2 monomer. Thus, a therapeutic strategy that aims at the stabilization of EphA2 dimers may be beneficial for the treatment of cancers linked to EphA2 overexpression.