Germline CDH1 variants in hereditary diffuse gastric cancer syndrome with focus on younger women.
The objective of this study was to determine the male and female frequency of diffuse gastric cancer (DGC), the age at diagnosis, and the country of origin in a selected population with germline CDH1 variants from families with the hereditary diffuse gastric cancer (HDGC) syndrome. Relevant literature dating from 1998 to 2021 was systematically searched for data on CDH1 gene. The Wilcoxon rank sum test and the Chi-square test were used to estimate if the difference observed between patients with gastric cancer (GC) and unaffected individuals was significant. We identified 80 families fulfilling the established clinical criteria for HDGC CDH1 genetic screening. There were more women than men with DGC and germline CDH1 variant (65.5%). Stratifying the age at diagnosis, we identified an association between DGC, positive CDH1 screening and young women (≤ 40 years) (p = 0.015). The mean age at diagnosis was 39.6 ys for women and 42.5 ys for men. There was an association between CDH1 carrier status and DGC (p = 0.021). Young women carrying germline CDH1 variants with DGC are comparatively frequent in the HDGC syndrome, and potentially at higher risk to develop DGC particularly in low-incidence areas for GC.


Aequorin-detected calcium changes in stimulated thrombasthenic platelets. Aggregation-dependent calcium movement in response to ADP.
Calcium changes in normal and thrombasthenic platelets were recorded using the PICA-apparatus. Aequorin was loaded in the presence of DMSO, EGTA and PGE1. Platelets of three patients with type I thrombasthenia stimulated with A-23, 187, thrombin, PMA in the presence 1 mM Ca++ and 1 mM Mg++ were able to normally raise their calcium concentrations. The maximal values could be found below the normal range with collagen, ADP and PAF-acether. Calcium mobilization from internal stores in response to thrombin was normal. There were two calcium peaks in normal platelets stimulated with ADP. The second one was suppressed by omitting fibrinogen, stirring, or by adding aspirin, and was absent in thrombasthenic platelets. Thus the GP IIb-IIIa complex is not a prerequisite for calcium fluxes but is involved, when weak agonists such ADP are used, through an aggregation-dependent reinforcement of platelet activation.


Diagnostic assays applied in BVDV control in The Netherlands.
In The Netherlands, a voluntary bovine virus diarrhoea virus (BVDV)-free certification programme was started in 1997. After an intake procedure in which all cattle are tested for the presence of BVD virus, a herd obtains the status "BVD-virus-free". To maintain this status a monitoring procedure is executed to verify absence of BVDV circulation in the herd. Several diagnostic tests are used: RT-PCR in bulk milk and pooled blood samples, antigen-ELISA (Ag-ELISA) and antibody ELISA in individual blood samples. Sensitivity and specificity of these tests are discussed. In addition, a diagnostic quick scan has been introduced, consisting of a combination of bulk milk tests for virus and antibody, and antibody tests in samples from young stock. Preliminary results are presented.


Effect of acute exposure to cold on the levels of corticosterone and pituitary hormones in plasma collected from free conscious cannulated rats.
To investigate the initial response of the pituitary and adrenal cortex functionings of rats acutely exposed to cold, we developed a technique for cannulation which allowed sequential blood collection from conscious and freed rats. Two cannulae were inserted, one into the carotid artery used for collection and the other into the femoral vein for blood transfusion to keep the blood volume constant. Significant increases in plasma corticosterone and thyrotropin were evoked within 15 min after exposure. While plasma growth hormone (GH) slightly decreased, and the prolactin level tended to fall by 1 hr after cold exposure but the difference was not significant as compared with control values.


The actions of C-peptide in HEK293 cells are dependent upon insulin and extracellular glucose concentrations.
Connecting peptide, or C-peptide, is a part of the insulin prohormone and is essential for the proper folding and processing of the mature insulin peptide. C-peptide is released from the same beta cell secretory granules as insulin in equimolar amounts. However, due to their relative stabilities in plasma, the two peptides are detected in the circulation at ratios of approximately 4:1 to 6:1 (C-peptide to insulin), depending on metabolic state. C-peptide binds specifically to human cell membranes and induces intracellular signaling cascades, likely through an interaction with the G protein coupled receptor, GPR146. C-peptide has been shown to exert protective effects against the vascular, renal, and ocular complications of diabetes. The effects of C-peptide appear to be dependent upon the presence of insulin and the absolute, extracellular concentration of glucose. In this study, we employed HEK293 cells to further examine the interactive effects of C-peptide, insulin, and glucose on cell signaling. We observed that C-peptide's cellular effects are dampened significantly when cells are exposed to physiologically relevant concentrations of both insulin and C-peptide. Likewise, the actions of C-peptide on cFos and GPR146 mRNA expressions were affected by changes in extracellular glucose concentration. In particular, C-peptide induced significant elevations in cFos expression in the setting of high (25 mmol) extracellular glucose concentration. These data indicate that future experimentation on the actions of C-peptide should control for the presence or absence of insulin and the concentration of glucose. Furthermore, these findings should be considered prior to the development of C-peptide-based therapeutics for the treatment of diabetes-associated complications.


Poly(ADP-ribose) polymerase-1 and its clinical applications in brain injury.
Traumatic brain injury (TBI) is a devastating occurrence that may result in short- and long-term complications. Oxidative stress (an imbalance between oxidants and antioxidants) plays a critical role in the development of secondary injuries following TBI and, consequently, in patient outcomes. Secondary injuries resulting from oxidative stress produce DNA strand breaks that activate poly(adenosine diphosphate [ADP]-ribose) polymerase-1 (PARP-1) and produce another level of injury. PARP-1 functions as a DNA-damage sensor and signaling molecule. In response to the severe DNA damage after brain injury, PARP-1 becomes overactivated and depletes the cells' energy sources, which leads to cellular and neuronal death. Recently, PARP-1 inhibition has been studied in various animal models of brain injury with promising results. TBI treatments based on PARP-1 inhibition in humans are far from the clinical arena, although descriptive studies of PARP-1 activation in humans are beginning to emerge. Nurses should become involved in this area of collaborative research in human response to brain injury by helping design and implement safe and meaningful clinical trials.


Intravitreal aflibercept for diabetic macular oedema: Moorfields' real-world 12-month visual acuity and anatomical outcomes.
To assess structural and functional outcomes of treatment with intravitreal aflibercept (Eylea®) for diabetic macular oedema in treatment-naive patients. This is a retrospective, real-life, cohort study. In all, 92 diabetic patients (102 eyes) receiving intravitreal anti-vascular endothelial growth factor therapy were included. A total of 99 aflibercept-treated eyes were included in the statistical analysis. Each patient had corrected visual acuity in Early Treatment Diabetic Retinopathy Study letters and optical coherence tomography central foveal thickness and macular volume performed at baseline and 12 months. Patients were initiated on a loading phase of five monthly intravitreal aflibercept injections, followed by injections if needed as per clinicians' discretion. The mean number of aflibercept injections received was 6.92. At baseline, the mean visual acuity (standard deviation; Snellen) was 59.7 (16.1) (20/63) Early Treatment Diabetic Retinopathy Study letters, the mean central foveal thickness (standard deviation) was 431 (129) µm, while the mean macular volume (standard deviation) was 9.53 (1.79) mm3. At 12 months, the mean visual acuity (standard deviation; Snellen) was 69.6 (15.2; 20/40) Early Treatment Diabetic Retinopathy Study letters (p < .0001). Mean central foveal thickness (standard deviation) was 306 (122) μm (p < .0001) and mean macular volume (standard deviation) was 8.43 (1.58) mm3 (p < .0001) at 12 months; 33 (33.67%) eyes gained ⩾15 Early Treatment Diabetic Retinopathy Study letters at month 12, and 50 (55.55%) eyes had a decrease in central foveal thickness of ⩾100 µm. There was a significant improvement in visual acuity and in anatomical outcomes in aflibercept-treated eyes at 12 months after commencing treatment for diabetic macular oedema in real-life settings.


SARS-CoV-2 variants of concerns in animals: An unmonitored rising health threat.
Recent findings have highlighted the urgency for rapidly detecting and characterizing SARS-CoV-2 variants of concern in companion and wild animals. The significance of active surveillance and genomic investigation on these animals could pave the way for more understanding of the viral circulation and how the variants emerge. It enables us to predict the next viral challenges and prepare for or prevent these challenges. Horrible neglect of this issue could make the COVID-19 pandemic a continuous threat. Continuing to monitor the animal-origin SARS-CoV-2, and tailoring prevention and control measures to avoid large-scale community transmission in the future caused by the virus leaping from animals to humans, is essential. The reliance on only developing vaccines with ignoring this strategy could cost us many lives. Here, we discuss the most recent data about the transmissibility of SARS-CoV-2 variants of concern (VOCs) among animals and humans.


Estrogen induces phosphorylation of cyclic AMP response element binding (pCREB) in primary hippocampal cells in a time-dependent manner.
Using hippocampal primary cell cultures at 14 days in vitro (div), we have investigated actions of 17-beta estradiol (E; 10 nM) on the phosphorylation of CREB and on signaling pathways that regulate CREB phosphorylation. After demonstrating that 14 div is optimal for these studies, we examined the time course of E induction of CREB phosphorylation (pCREB) at serine residue 133. The induction of pCREB occurs as early as 1 h following E treatment, presumably via a mechanism involving an E-stimulated signal transduction system, which is sustained for at least 24 h but inhibited by 48 h. The early activity may represent an initial signal required for events leading to phosphorylation of CREB while the sustained signal may lead to CREB-mediated gene expression for cell survival and synapse formation. Furthermore, we examined the pathways for E action preceding pCREB induction by blocking three major kinases (protein kinase; mitogen activated protein kinase, MAPK; and calcium-calmodulin kinase II, CaMKII) upstream of pCREB. We found that E stimulates each pathway at 24 h and that phosphorylation of CREB is dependent on both MAPK and CaMK activities, but less dependent on the Akt pathway. Because CREB has been linked to E induction of excitatory spine synapses, we used a spine marker, spinophilin, to establish E effects on spine formation. Spinophilin expression was up-regulated in response to E and this effect was blocked by an inhibitor of (CaMKII). These studies demonstrate the central role played by CaMKII pathway in the actions of E on both transcriptional regulation and structural reorganization in neurons.


Enteroparasites from the American White Pelican (Pelecanus erythrorhynchos) in Toluca Valley, Mexico.
We examined 82 fresh fecal samples from American White Pelican (Pelecanus erythrorhynchos) at San Pablo Autopan, Toluca Valley, central Mexico, December 2021 to April 2022. Eggs of Contracaecum spp. were observed in 100%, Capillaria spp. in two (2.5%), Strongyloides spp. in eight (9.7%), and coccidial oocysts in 12 (15%).


Amniotic stromal stem cell-loaded hydrogel repairs cardiac tissue in infarcted rat hearts via paracrine mediators.
The use of stem cells to repair the heart after a myocardial infarction (MI) remains promising, yet clinical trials over the past 20 years suggest that cells fail to integrate into the native tissue, resulting in limited improvements in cardiac function. Here, we demonstrate the cardioprotective potential of a composite inserting human amniotic stromal mesenchymal stem cells (ASMCs) in a chitosan and hyaluronic acid (C/HA) based hydrogel in a rat MI model. Mechanical characterization of the C/HA platform indicated a swift elastic conversion at 40°C and a rapid sol-gel transition time at 37°C. Cell viability assay presented active and proliferating AMSCs in the C/HA. The ASMCs + C/HA injected composite significantly increased left ventricular ejection fraction, fractional shortening, and neovessel formation. The encapsulated AMSCs were abundantly detected in the infarcted myocardium 6 weeks post-administration and co-expressed cardiac proteins and notably proliferative markers. Proteomic profiling revealed that extracellular vesicles released from hypoxia preconditioned ASMCs contained proteins involved in cytoprotection, angiogenesis, cardiac differentiation and non-canonical Wnt-signaling. Independent activation of non-canonical Wnt-signaling pathways in ASMCs induced cardiogenesis. Despite a low injected cellular density at baseline, the encapsulated AMSCs were abundantly retained and increased cardiac function. Furthermore, the C/HA hydrogel provided an active milieu for the AMSCs to proliferate, co-express cardiac proteins, and induce new vessel formation. Hence, this novel composite of AMSCs + C/HA scaffold is a conceivable candidate that could restore cardiac function and reduce remodeling.


Sickness and satiety: physiological mechanisms underlying perceptions of nausea and stomach fullness.
The pathophysiology of nausea and the physiological mechanisms underlying perceptions of stomach emptiness and fullness are not clearly understood, but several potentially important factors have been identified. Gastric dysrhythmias are believed to contribute to the subjective experience of nausea and may also be involved with perceptions of stomach emptiness, hunger, and even dyspepsia symptoms like bloating and early satiety. Normal gastric neuromuscular function is more evident in the absence of nausea and is also thought to be related to feelings of satiety or comfortable stomach fullness. Autonomic and endocrine influences may also play a critical role in the pathophysiology of nausea and abnormal perceptions of stomach emptiness or fullness. Achieving a better understanding of the gastric neuromuscular and neurohormonal influences on perceptions arising from the viscera may prove invaluable in the development of novel treatments for such conditions as unexplained nausea, functional dyspepsia, and obesity.


Effect of SGLT2 Inhibitors on Cardiovascular Outcomes Across Various Patient Populations.
The effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on heart failure (HF) outcomes and cardiovascular (CV) death in patients with varying combinations of type 2 diabetes mellitus (T2DM), HF, and chronic kidney disease (CKD) are uncertain. The authors conducted a meta-analysis assessing the effects of SGLT2 inhibitors on HF outcomes and CV death across different patient populations. Online databases were queried up to November 2022 for primary and secondary analyses of trials of SGLT2 inhibitors in patients with HF, T2DM, or CKD. Outcomes of interest were composite of first heart failure hospitalization (HFH) or CV death (first HFH/CV death), first HFH, and CV death. Data were pooled by means of a random-effects model to derive HRs and 95% CIs. Thirteen trials (n = 90,413) were included. Compared with placebo, SGLT2 inhibitors reduced the risk of first HFH/CV death by 24% in HF (HR: 0.76; 95% CI: 0.72-0.81), 23% in T2DM (HR: 0.77; 95% CI: 0.73-0.81), and 23% in CKD (HR: 0.77; 95% CI: 0.72-0.82). The benefit was consistent in HF with reduced or preserved ejection fraction, HF with or without T2DM, and HF with or without CKD. The benefit was also consistent in T2DM with or without CKD, T2DM without HF, CKD without HF, and in patients with all 3 comorbidities. SGLT2 inhibitors significantly reduced CV death by 16% in HF, 15% in T2DM, and 12% in CKD. SGLT2 inhibitors reduce HF events and CV death in cohorts of HF, T2DM and CKD, and these effects appear consistent in patients with varying combinations of these diseases.


Management of pancreatic pseudocysts in children.
The management of 25 children with pseudocyst of the pancreas presenting over a 30-year period is reviewed. Nearly a third could be managed nonoperatively, monitoring clinical signs, serum amylase, and in recent years the findings of ultrasound and CT scan. Persistence of symptoms, signs, and hyperamylasemia for more than 4 weeks indicated failed resolution in all but one case. Endoscopic retrograde cholangiopancreatography (ERCP) done in those who did not improve spontaneously facilitated operative strategy. Early operation and internal drainage in selected cases was well tolerated. Individualization of treatment is emphasized.


Can we use the Omron T9P automated blood pressure monitor in pregnancy?
Recent events in our hospital, combined with international recommendations, catalyzed the need to move from mercury sphygmomanometry to automated blood pressure (BP) recording in pregnancy. To test the accuracy of the Omron T9P automated BP recorder in pregnant women, using mercury sphygmomanometry as the gold standard. Antenatal clinics and obstetric day assessment unit, St George Hospital, Sydney. Eighty-five pregnant women, 11% of whom were receiving antihypertensives. Differences in both systolic and diastolic BP between the T9P Omron device and mercury sphygmomanometer were obtained for each woman, using sequential automated and mercury BP recordings, as required by a modified British Hypertension Society (BHS) protocol. The accuracy of the device was graded according to the BHS and the Association for the Advancement of Medical Instrumentation (AAMI) standards. The Omron T9P device received an A/A grade according to this modified BHS and AAMI testing process, though the range of the 255 differences was 1-13 for systolic BP and 1-10 for diastolic BP. The Omron T9P device is an accurate device for use predominantly in an outpatient antenatal clinical setting. Further studies are required solely within hypertensive pregnant women before its use can be recommended with certainty in this group.


[Pyoderma gangrenosum revealing colonic diverticulitis: Two cases].
The association of pyoderma gangrenosum (PG) with colonic diverticulitis infection (DI) is relatively unknown. Herein, we describe two cases of PG with full recovery after colonic surgery. Case 1: an 83-year-old man presented with lesions on his legs that had been present for several weeks, and a diagnosis of PG was confirmed histologically. Abdominopelvic computed tomography (CT) performed on account of biological inflammatory syndrome revealed DI complicated by abscesses. Following the failure of two different antibiotic regimens, sigmoidectomy was performed. Postoperatively, the skin lesions healed without local or systemic corticosteroids. Case 2: a 63-year-old woman presented PG resistant to local and systemic corticosteroids and dapsone for several months. A particularly severe flare was accompanied by abdominal pain and inflammatory syndrome. CT revealed perforated sigmoid DI. Sigmoidectomy was performed after failure of drug therapy. The patient's PG subsequently improved and had disappeared without recurrence at 24months. Both of these cases of PG revealed DI. The hypothesis is that DI constituted a source of colonic inflammation, sending out bacterial antigenic stimuli that resulted in PG through deposition of circulating immune complexes. Removal of this inflammatory source appears to have enabled healing of PG. DI must be added to the list of systemic diseases associated with PG. In the case of isolated PG, CT may be used to detect asymptomatic DI. Early diagnosis could prevent serious gastrointestinal complications.


Toward genome editing in X-linked RP-development of a mouse model with specific treatment relevant features.
Genome editing represents a powerful tool to treat inherited disorders. Highly specific endonucleases induce a DNA double strand break near the mutant site, which is subsequently repaired by cellular DNA repair mechanisms that involve the presence of a wild type template DNA. In vivo applications of this strategy are still rare, in part due to the absence of appropriate animal models carrying human disease mutations and knowledge of the efficient targeting of endonucleases. Here we report the generation and characterization of a new mouse model for X-linked retinitis pigmentosa (XLRP) carrying a point mutation in the mutational hotspot exon ORF15 of the RPGR gene as well as a recognition site for the homing endonuclease I-SceI. Presence of the genomic modifications was verified at the RNA and protein levels. The mutant protein was observed at low levels. Optical coherence tomography studies revealed a slowly progressive retinal degeneration with photoreceptor loss starting at 9 months of age, paralleling the onset of functional deficits as seen in the electroretinogram. Early changes to the outer retinal bands can be used as biomarker during treatment applications. We further show for the first time efficient targeting using the I-SceI enzyme at the genomic locus in a proof of concept in photoreceptors following adeno-associated virus mediated gene transfer in vivo. Taken together, our studies not only provide a human-XLRP disease model but also act as a platform to design genome editing technology for retinal degenerative diseases using the currently available endonucleases.


The diminishing effects of winter heating on air quality in northern China.
Cleaner winter heating has been promoted to abate the winter air pollution in northern China. Although improvements in air quality have been observed, the effectiveness and mechanism of cleaner heating measures on air quality have not been examined on the empirical ground. In this study, we estimate the annual effects of winter heating policy on air quality from 2014 to 2017 using a regression discontinuity design (RDD) and dynamic regression model. The results show that winter heating aggravates Air Quality Index (AQI). Specifically, the AQI raised by winter heating reduce from 85.3 in 2014 to 24.1 in 2017, indicating diminishing effects of winter heating with the implementation of clean heating measures. The heterogeneous characteristics of winter heating in terms of different pollutants and city scales are further quantified. The effects of clean heating are more evident for particulate pollutants (PM2.5 and PM10) than for SO2, NO2, CO and O3. The promotion of clean heating is more effective in larger cities. These findings provided insights into the diminishing air pollution change with continuous advancement in clean heating policy and the heterogeneity among cities and pollutants should be taken into account when formulating future policies in response to energy transition and climate change.


Advanced hepatocellular carcinoma and palliative care: a scoping review.
Patients with advanced hepatocellular carcinoma (HCC) have specific palliative care needs owing to the influence of the disease on abdominal pain, jaundice, bleeding, appetite, ascites, liver function and hepatic encephalopathy. This research would help develop care models and identify knowledge gaps in the field. To identify the palliative care needs and experiences of patients with advanced HCC. CINAHL, EMBASE and MEDLINE were used to search English literature from January 1998 to March 2022 for 'Palliative care' and 'Hepatocellular cancer' using precise inclusion and exclusion criteria. The retrieves identified 2710 records, including 33 studies used in our research. Two additional studies were grey items. Among 35 studies, 13 studies were performed in Asia, 11 studies in North America, 8 studies in Europe and 3 studies in Australia. Quantitative investigations were mostly descriptive or observational. Eight studies were conducted on a national scale, while two were in specific regions. 20 studies were conducted by a single institution. 22 studies focused only on patients, 2 on family caregivers and 2 on healthcare professionals. 2 more studies concentrated on patients and family caregivers, while 6 concentrated on patients and healthcare professionals. This scoping study illustrates the complexity of advanced HCC treatment and challenges in modern healthcare systems. Formulating appropriate referral criteria, integrating and coordinating care, and assessing care contents are crucial. To enhance the treatment of patients with advanced HCC, it is important to understand the relationships between research and service design across teams, disciplines and care settings.


Hummingbird: monitoring and analyzing flash X-ray imaging experiments in real time.
Advances in X-ray detectors and increases in the brightness of X-ray sources combined with more efficient sample delivery techniques have brought about tremendous increases in the speed of data collection in diffraction experiments. Using X-ray free-electron lasers such as the Linac Coherent Light Source (LCLS), more than 100 diffraction patterns can be collected in a second. These high data rates are invaluable for flash X-ray imaging (FXI), where aerosolized samples are exposed to the X-ray beam and the resulting diffraction patterns are used to reconstruct a three-dimensional image of the sample. Such experiments require immediate feedback on the quality of the data collected to adjust or validate experimental parameters, such as aerosol injector settings, beamline geometry or sample composition. The scarcity of available beamtime at the laser facilities makes any delay extremely costly. This paper presents Hummingbird, an open-source scalable Python-based software tool for real-time analysis of diffraction data with the purpose of giving users immediate feedback during their experiments. Hummingbird provides a fast, flexible and easy-to-use framework. It has already proven to be of great value in numerous FXI experiments at the LCLS.


Poly-victimization and mental health of street children in Lahore city.
Street children are vulnerable to a number of problems throughout their lives. Poly-victimization covers the different domains of the difficulties they face on streets, it is also notable to find out the impact of poly-victimization on the mental health of street children. The purpose of the study was to examine the relationship between poly-victimization and mental health in street children of Lahore city. It was hypothesized that there is likely to be a predictive relationship between poly-victimization and mental health of street children. Through purposive sampling a sample of 77 street boys was collected from Lahore city, with the help of three government and private organizations working with street children. Sample included only boys within the age range of 9-13 years (M = 10.66, SD = 1.26) who have been residing on streets for more than one month. Juvenile Victimization Questionnaire and Mental Health Inventory were used for assessment of poly-victimization and mental health respectively. The results indicated that poly-victimization positively predicted the psychological distress and negatively predicted psychological wellbeing in street children. The most common type of victimization was conventional crime which negatively predicts mental health of street children. The results have important implications for the policy makers to develop improved services for this vulnerable group.


Impact of type 2 diabetes mellitus on short-term and long-term outcomes of stage iv colorectal cancer patients after primary surgery: a propensity score matching analysis.
This study aims to investigate the influence of type 2 diabetes mellitus (T2DM) on stage IV colorectal cancer (CRC) patients performed primary surgery in terms of short-term and long-term outcomes. Patients diagnosed with stage IV CRC and received primary CRC surgery at a single clinical center from Jan, 2013 to Jan, 2020 were included in this study. Baseline characteristics, short-term and long-term outcomes were compared between the T2DM group and the Non-T2DM group. Univariate and multivariate analysis were used to find risk factors for overall survival (OS). Propensity score matching (PSM) using a 1:1 ratio was used to minimize selective bias between the two groups. Statistical analysis was performed using SPSS (version 22.0) software. A total of 302 eligible patients were enrolled, and there were 54 (17.9%) patients with T2DM, and 248 (82.1%) patients without T2DM. The T2DM group had more older patients (P < 0.01), higher body mass index (BMI) (P < 0.01), and a higher proportion of hypertension (P < 0.01) than the Non-T2DM group. After PSM, there were 48 patients in each group. There were no significant differences in short-term outcomes or OS between the two groups, either before or after PSM (P > 0.05). In multivariate analysis, older age (P < 0.01, HR = 1.032, 95% CI = 1.014-1.051) and larger tumor size (P < 0.01, HR = 1.760, 95% CI = 1.179-2.626) were independent factors for OS. Although T2DM did not influence short-term outcomes or OS in stage IV CRC patients after primary surgery, age and tumor size might have predictive value for OS.


The effect of self-directed virtual reality simulation on dissection training performance in mastoidectomy.
To establish the effect of self-directed virtual reality (VR) simulation training on cadaveric dissection training performance in mastoidectomy and the transferability of skills acquired in VR simulation training to the cadaveric dissection training setting. Prospective study. Two cohorts of 20 novice otorhinolaryngology residents received either self-directed VR simulation training before cadaveric dissection training or vice versa. Cadaveric and VR simulation performances were assessed using final-product analysis with three blinded expert raters. The group receiving VR simulation training before cadaveric dissection had a mean final-product score of 14.9 (95 % confidence interval [CI] [12.9-16.9]) compared with 9.8 (95% CI [8.4-11.1]) in the group not receiving VR simulation training before cadaveric dissection. This 52% increase in performance was statistically significantly (P < 0.0001). A single dissection mastoidectomy did not increase VR simulation performance (P = 0.22). Two hours of self-directed VR simulation training was effective in increasing cadaveric dissection mastoidectomy performance and suggests that mastoidectomy skills are transferable from VR simulation to the traditional dissection setting. Virtual reality simulation training can therefore be employed to optimize training, and can spare the use of donated material and instructional resources for more advanced training after basic competencies have been acquired in the VR simulation environment. NA. Laryngoscope, 126:1883-1888, 2016.


[Production of wheat-rye substitution lines based on winter rye cultivars with karyotype identification by means of C-banding, GISH, and SSR markers].
The study presents a continuation of the research aimed at producing of wheat-rye substitution lines based on the cross (Triticum aestivum L. x Secale sereale L.) x Triticum aestivum L., and using winter rye cultivars Vyatka and Vietnamskaya Mestnaya. In BC1F5 two lines were identified, having karyotypes in which a pair of homologous wheat chromosomes was substituted by a homeologous pair of rye chromosomes. The chromosome composition of these lines was analyzed using C-banding, GISH, and SSR markers. It was demonstrated that karyotype of each line included a single pair of rye chromosomes and lacked wheat-rye translocations. The rye chromosomes were identified, and the chromosomes of wheat, at which the substitutions occurred, were determined. The lines generated by crosses with rye of Vyatka and Vietnamskaya Mestnaya cultivars were designated 1Rv(1A) and 5Rviet(5A), respectively. Chromosome identification and classification of the lines makes it possible to use them in breeding programs and genetic studies.


Study on the Microstructure of Polyether Ether Ketone Films Irradiated with 170 keV Protons by Grazing Incidence Small Angle X-ray Scattering (GISAXS) Technology.
Polyether ether ketone (PEEK) films irradiated with 170 keV protons were calculated by the stopping and ranges of ions in matter (SRIM) software. The results showed that the damage caused by 170 keV protons was only several microns of the PEEK surface, and the ionization absorbed dose and displacement absorbed dose were calculated. The surface morphology and roughness of PEEK after proton irradiation were studied by atomic force microscope (AFM). GISAXS was used to analyze the surface structural information of the pristine and irradiated PEEK. The experimental results showed that near the surface of the pristine and irradiated PEEK exists a peak, and the peak gradually disappeared with the increasing of the angles of incidence and the peak changed after irradiation, which implies the 170 keV protons have an effect on PEEK structure. The influences of PEEK irradiated with protons on the melting temperature and crystallization temperature was investigated by differential scanning calorimetry (DSC). The DSC results showed that the crystallinity of the polymer after irradiation decreased. The structure and content of free radicals of pristine and irradiated PEEK were studied by Fourier transform infrared spectroscopy (FTIR) and electron paramagnetic resonance (EPR). The stress and strain test results showed that the yield strength of the PEEK irradiated with 5 × 1015 p/cm2 and 1 × 1016 p/cm2 was higher than the pristine, but the elongation at break of the PEEK irradiated with 5 × 1015 p/cm2 and 1 × 1016 p/cm2 decreased obviously.


Nonconformance of standard metabolic rate with body mass in Hawaiian Honeycreepers.
Among four species of Hawaiian Honeycreepers, three from Hawaii (Vestiaria coccinea, 15.0 g; Himatione sanguinea, 12.9 g; Loxops virens, 10.7 g) and one from Kauai (Loxops parva, 7.9 g), standard metabolic rate (in ml O2/g·h) was positively related to body mass, the opposite of that predicted by conventional endothermic allometry. SMR of V. coccinea conformed to the predicted value, but in the remaining species was progressively reduced below expected levels as body mass decreased. All four species occur predominantly in Metrosideros collina forests, where their preferred food is the nectar of its blooms. At least on Hawaii and during periods of moderate bloom the species are aligned along a dominance hierarchy, with the largest species most dominant and most successful at nectar exploitation. I believe that nonconformancy of SMR with body mass in the smaller species reflects an energy-conserving measure, the degree of which is dictated by social position and relative success in nectar exploitation.


Computed tomography of cervical and retropharyngeal lymph nodes: normal anatomy, variants of normal, and applications in staging head and neck cancer. Part I: normal anatomy.
The retropharyngeal and cervical lymph-node-bearing areas in 30 patients were examined with computed tomography (CT) to determine the range of normal variation in these nodal groups. The data agree with those in the pathologic, anatomic, and surgical literature, and indicate that CT can very precisely determine the size and gross morphology of normal nodes in the retropharyngeal region and the neck. This should have important applications in the management of patients with head and neck cancer.


Breast cancer risk in usual ductal hyperplasia is defined by estrogen receptor-alpha and Ki-67 expression.
The hypothetical multistep model for breast carcinogenesis indicates that invasive carcinoma arises via a series of intermediate hyperplastic lesions through various grades of atypia to in situ and invasive carcinoma. Non-atypical hyperplasia [hyperplasia of usual type (HUT)] is a nonobligate precursor of breast cancer. Although its further morphological subclassification is unlikely, refining is more likely to depend on defining biological markers of risk. Having assembled a cohort of benign proliferative breast lesions of known outcome, we studied the expression of estrogen receptor-alpha (ER-alpha) and Ki-67 using morphometric image analysis as well as dual-labeled immunofluorescence in HUT foci and in surrounding normal lobules of 25 patients that progressed to breast cancer and 19 controls. Those patients that progressed to breast cancer (cases) showed significantly higher ER-alpha [median, 57.00% of cells within individual HUT foci; interquartile range (IQ), 33.48 to 67.78] and Ki-67 (median, 3.82%; IQ, 0.85 to 11.28) expression in their HUT foci compared with controls (ER-alpha median, 30.27%; IQ, 19.75 to 52.50 and Ki-67 median, 0.77%; IQ, 0.0458 to 1.72, P = 0.008 and <0.001). No significant difference in expression of dual-stained cells was found between cases and controls. Although normal lobules from cases showed higher ER-alpha expression compared with controls, this was not statistically significant. Our data point to a previously undescribed hormone-dependent pathway in this particular group of breast neoplasms and suggest the possibility of selective hormonal therapy to suppress the proliferative potential of these benign but high-risk breast lesions. The findings of this study might have important implications for improving breast cancer screening and management strategies.


An empirical evaluation of functional alignment using inter-subject decoding.
Inter-individual variability in the functional organization of the brain presents a major obstacle to identifying generalizable neural coding principles. Functional alignment-a class of methods that matches subjects' neural signals based on their functional similarity-is a promising strategy for addressing this variability. To date, however, a range of functional alignment methods have been proposed and their relative performance is still unclear. In this work, we benchmark five functional alignment methods for inter-subject decoding on four publicly available datasets. Specifically, we consider three existing methods: piecewise Procrustes, searchlight Procrustes, and piecewise Optimal Transport. We also introduce and benchmark two new extensions of functional alignment methods: piecewise Shared Response Modelling (SRM), and intra-subject alignment. We find that functional alignment generally improves inter-subject decoding accuracy though the best performing method depends on the research context. Specifically, SRM and Optimal Transport perform well at both the region-of-interest level of analysis as well as at the whole-brain scale when aggregated through a piecewise scheme. We also benchmark the computational efficiency of each of the surveyed methods, providing insight into their usability and scalability. Taking inter-subject decoding accuracy as a quantification of inter-subject similarity, our results support the use of functional alignment to improve inter-subject comparisons in the face of variable structure-function organization. We provide open implementations of all methods used.


Electron microscopic observations on the elimination of the oocyte through the peritoneal epithelium in the neonatal mouse ovary.
Numerous ovarian oocytes of primordial follicles are lost postnatally by their elimination into the peritoneal cavity during days 1-6 in young mice. It is rarely found in animals over 2 weeks old. This phenomenon has been investigated by light and EM techniques. Oocytes that become extruded from the ovary this way appear to pass between the cells of the covering epithelium. The ultrastructural changes that take place during this process are described.


Hydration of NaDNA by neutron quasi-elastic scattering.
Preliminary results of neutron quasi-elastic scattering experiments are reported for hydrated paracrystals of sodium deoxyribonucleic acid (NaDNA). The samples were investigated at two water contents: 3.5 +/- 1.0 and 9.5 +/- 1.5 mol H2O per mole nucleotide. The results of the scattering experiments were almost independent of whether the NaDNA fibers were oriented parallel or perpendicular to the momentum transfer. The data indicate that at the lower hydration the water molecules do not diffuse appreciably on the time scale of the neutron measurements (approximately 3 X 10(-10) s). At the higher hydration the water molecules diffuse isotropically in a sphere of 9 A in diameter with a diffusion coefficient of (5 +/- 2) X 10(-6) cm2 s-1.


Daily low-dose administration of growth hormone secretagogue stimulates pulsatile growth hormone secretion and elevates plasma insulin-like growth factor-1 levels in pigs.
Repeated administration of growth hormone secretagogues (GHSs) has proven to be a delicate matter owing to development of tolerance. The aim of the present study was to define conditions during which the responsiveness to the orally active NN703 was maintained over several days. Growing pigs were fitted with stomach and vascular catheters, permitting unstressed intragastric administrations and blood sampling. NN703 or vehicle was administered once daily. When NN703 was given at a dose of 18 mg/kg, there was a massive acute increase in plasma growth hormone (GH) levels, but this was only seen on the first day of administration. A dose of 1.8 mg/kg did not cause a significant acute increase in plasma GH concentrations, whereas stimulation of pulsatile GH release was sustained over a 4-d period. During the first 7 h following injection of vehicle, the area under the curve of plasma GH was 1211+/-144 (microg/[L x 7 h]), but increased to 1770+/-269 and 1824+/-198 (microg/[L x 7 h]) on the first and fourth day of NN703 administration, respectively. Deconvolution analysis of the 7-h profiles revealed that the GH mass per burst as well as the GH burst amplitude were significantly (p < 0.001) increased during treatment with NN703, which led to an increase in pulsatile GH secretion rate (p < 0.001). Insulin-like growth factor-1 plasma concentrations increased steadily during NN703 administration (p < 0.01) and decreased after termination of treatment. The sustained increase in GH pulsatility observed with low-dose NN703 treatment suggests that development of tolerance to this GHS may be obviated by minimization of dose.


Nutrient utilisation in muscle and in the whole body of patients receiving total parenteral nutrition.
Forearm metabolite exchange was assessed by the arterio-venous catheterization technique in 5 parenterally fed patients (weight 55.22 kg +/- 4.18 kg; height 1.71 m +/- 0.04 m), who received an 'all-in-one' nutrition regimen whilst in remission from Crohn's disease. All patients received 12.8 g N, 4725 kJ from carbohydrate and 4200 kJ from fat (10416 kJ total energy). The exchanges were related to nutrient oxidation and nutrient balances in the whole body as assessed by indirect calorimetry and nitrogen excretion. At rest, the subjects were found to be in positive balances for carbohydrate (+0.78 +/- 0.13 kJ/min), fat (+1.85 +/- 0.26 kJ/min) and protein (+0.240 +/- 0.04 kJ/min). Resting forearm muscle was also in positive amino acid balance and positive carbohydrate balance. Despite the large estimated uptake of glucose by forearm muscle (+1860 +/- 84 nmol/100 ml tissue/min) there was no net release of pyruvate and lactate. Glutamate and the branched chain amino acids (BCAA) were the dominant amino acids taken up by muscle (26% and 30% of total uptake respectively) and glutamine was the dominant amino acid carrying nitrogen out of muscle (78% of total amino acid nitrogen release). The energy taken up by muscle as non-esterified fatty acids, triacylglycerol and ketone bodies was small relative to that associated with glucose uptake. The results suggest that during the hypercaloric parenteral nutrition regimen, a) increased peripheral glucose uptake is not necessarily associated with increased release of glycolytic products, b) in the absence of glutamine intake for at least 10 days, muscle retains enough capacity to synthesise and release sufficient quantities of glutamine so that it remains the dominant amino acid carrying nitrogen out of muscle, c) despite the use of the intravenous route for administration of nutrients, and unusual amino acid composition of the regimen, the overall pattern of forearm metabolism bears many similarities to that which occurs after a mixed meal in normal subjects.


Passive immunization: a method of enhancing the immune response against antigen mixtures.
Antigenic competition is known to be a widespread phenomenon when using crude extracts of antigens (e.g., Escherichia coli cytoplasmic proteins) for immunization. This non-specific form of immune suppression can be partially overcome by passive immunization with antibodies against dominant antigens (which are the suppressive molecules) before injection of the antigenic mixture. Blocking these immunodominant antigens or antigenic determinants by a passively administered antibody permits antibody responses against hitherto weakly or non-immunogenic molecules.


Body size and weight status of adult Indian males born in the 1890s-1950s: Age and secular change in the context of demographic, economic, and political transformation.
To evaluate secular change in body size and weight status of adult Indian males born in 1891-1957 and surveyed in the 1970s. Data are from Anthropological Surveys. Only men were included in the surveys due to high female illiteracy and lack of female researchers. Indian society was also strongly conservative at the time, especially in rural areas, and the measurement of women by men was not permitted. Heights and weights of 43 950 males 18-84 years (born 1891-1957) were measured. The BMI was calculated; weight status of individuals was classified relative to WHO criteria and suggested criteria for the Asia-Pacific region. Heights of men 35+ years were also adjusted for age-related stature loss. Trends in measured and adjusted heights, body weight and the BMI, and in weight status were evaluated by age groups. Linear regression of measured height and adjusted height on year of birth was used to estimate secular effects. Mean heights declined slightly with age to 50 years and declined sharply through 60+ years, while mean weights increased into the 40s and then declined. Mean BMIs were relatively stable from 30 to 60 years. The prevalence of thinness and normal weight was high, while that of overweight and obesity was low. Regression analyses indicated limited secular change across the total range of birth years but suggested a decline in adjusted heights among men born in 1891 through the 1930s, and little change among men born subsequently. Age-related trends and results of the regression analyses by year of birth indicated negligible secular change in heights of Indian men 18-84 years born between 1891 and 1957. BMIs indicated a high prevalence of thinness and normal weight and low prevalence of overweight and obesity.


Comparison of the pressor effects of angiotensin II and III in the rostral ventrolateral medulla.
Microinjection of angiotensin II and III into the rostral ventrolateral medulla of anesthetized barodenervated rabbits elicited in both cases pressor responses, which were of similar magnitude and time course. The responses to angiotensin II and III were either unchanged or increased in the presence of compounds which inhibit their degradation to shorter length peptides. The results indicate that both angiotensin peptides are independently capable of eliciting pressor responses in the rostral ventrolateral medulla.


Development of quinoline-based hybrid as inhibitor of methionine aminopeptidase 1 from Leishmania donovani.
Methionine aminopeptidase 1 (MetAP1) is a target for drug discovery against many adversaries and a potential antileishmanial target for its role in N-terminal methionine processing. As an effort towards new inhibitor discovery against methionine aminopeptidase 1 from Leishmania donovani (LdMetAP1), we have synthesized a series of quinoline-based hybrids, that is (Z)-5-((Z)-benzylidine)-2-(quinolin-3-ylimino)thiazolidin-4-ones (QYT-4a-i) whose in vitro screening led to the discovery of a novel inhibitor molecule (QYT-4h) against LdMetAP1. The compound QYT-4h showed nearly 20-fold less potency for human MetAP1 and had drug-like features. Time-course kinetic assays suggested QYT-4h acting through a competitive mode by binding to the metal-activated catalytic site. Notably, QYT-4h was most potent against the physiologically relevant Mn(II) and Fe(II) supplemented forms of LdMetAP1 and less potent against Co(II) supplemented form. Surface plasmon resonance and fluorescence spectroscopy demonstrated high affinity of QYT-4h for LdMetAP1. Through molecular modelling and docking studies, we found QYT-4h binding at the LdMetAP1 catalytic pocket occupying both the catalytic and substrate binding sites mostly with hydrogen bonding and hydrophobic interactions which provide structural basis for its promising potency. These results demonstrate the feasibility of employing small-molecule inhibitors for selective targeting of LdMetAP1 which may find use to effectively eliminate leishmaniasis.


Molecularly Imprinted Polymers Doped with Carbon Nanotube with Aid of Metal-Organic Gel for Drug Delivery Systems.
The incidence of breast cancer worldwide has been on the rise since the late 1970s, and it has become a common tumor that threatens women's health. Aminoglutethimide (AG) is a common treatment of breast cancer. However, current treatments require frequent dosing that results in unstable plasma concentration and low bioavailability, risking serious adverse reactions. Our goal was to develop a molecularly imprinted polymer (MIP) based delivery system to control the release of AG and demonstrate the availability of this drug delivery system (DDS), which was doped with carbon nanotube with aid of metal-organic gel. Preparation of MIP was optimized by key factors including composition of formula, ratio of monomers and drug loading concentration. By using multi-walled carbon nanotubes (MWCNT) and metal-organic gels (MOGs), MIP doubled the specific surface area, pore volume tripled and the IF was 1.6 times than the reference. Compared with commercial tablets, the relative bioavailability was 143.3% and a more stable release appeared. The results highlight the influence of MWCNT and MOGs on MIP, which has great potential as a DDS.


Periosteal chondroma of the rib--report of a case and literature review.
Periosteal chondroma is a rare benign tumor of hyaline cartilage. It develops adjacent to the cortex of the bone and is rimmed by an intact periosteal membrane. Periosteal chondromas are most common in the metaphyses of long bones followed by the small tubular bones of the hands and feet. Periosteal chondroma arising in the rib is an extremely rare event. We could only find 10 reported cases in the English literature. We present a case of periosteal chondroma in the rib discovered incidentally on chest x-ray of an 11-year-old girl.


Evidence for prostaglandin mediated prejunctional control of renal sympathetic transmitter release and vascular tone.
1 Prostaglandin E(2) dose-dependently and reversibly inhibited the noradrenaline overflow resulting from nerve stimulation of the rabbit kidney.2 The magnitude of this inhibition varied inversely with the frequency of stimulation employed.3 The prostaglandin synthesis inhibitors, indomethacin and meclofenamic acid, both increased the transmitter overflow resulting from renal nerve stimulation, suggesting that endogenous prostaglandin has a role in the regulation of transmitter release.4 In the presence of indomethacin, the inhibitory effect of exogenous prostaglandin E(2) was enhanced.5 The prostaglandin precursor, arachidonic acid, also caused a significant, dose-dependent and reversible inhibition of transmitter overflow. This inhibition became insignificant when arachidonic acid was applied in the presence of indomethacin, suggesting that the inhibition was mediated by newly formed prostaglandin rather than by arachidonic acid itself.6 It is proposed that newly formed prostaglandin controls noradrenaline release primarily from inner cortical nerve endings, thereby maintaining juxtamedullary blood flow under periods of increased sympathetic nerve activity.


Color tunable emission in Ce3+ and Tb3+ co-doped Ba2Ln(BO3)2Cl (Ln=Gd and Y) phosphors for white light-emitting diodes.
Ce(3+) and Tb(3+) co-doped Ba2Ln(BO3)2Cl (Ln=Y and Gd) green emitting phosphors were prepared by solid state reaction in reductive atmosphere. The emission and excitation spectra as well as luminescence decays were investigated, showing the occurrence of efficient energy transfer from Ce(3+) to Tb(3+) in this system. The phosphors exhibit both a blue emission from Ce(3+) and a green emission from Tb(3+) under near ultraviolet light excitation with 325-375 nm wavelength. Emission colors of phosphors could be tuned from deep blue through cyan to green by adjusting the Tb(3+) concentrations. The energy transfer efficiency and emission intensity of Ba2Y(BO3)2Cl:Ce(3+), Tb(3+) precede those of Ba2Gd(BO3)2Cl:Ce(3+), Tb(3+), and the sample Ba2Y(BO3)2Cl:0.03Ce(3+), 0.10Tb(3+) is the best candidate for n-UV LEDs.


Autonomic nervous system control of heart rate during baroreceptor activation in conscious and anesthetized rats.
Heart rate and blood pressure were recorded in conscious, freely behaving rats through a catheter in the tail artery during administration of nitroprusside or phenylephrine through a catheter in the jugular vein. The sympathetic and parasympathetic components were distinguished by treating the rats with atenolol or methyl-atropine. Reflex bradycardia induced by all doses of phenylephrine was almost totally blocked blocked following methyl-atropine treatment. Reflex tachycardia induced by small to moderate doses of nitroprusside was attenuated to an equal extent following atropine or atenolol treatment. A similar experimental schedule was followed with a separate group of rats to determine the effects of pentobarbital and urethane anesthesia on the baroreceptor reflex. Both pentobarbital and urethane equally attenuated the tachycardia response to a decrease in blood pressure. However, pentobarbital anesthesia resulted in a greater attenuation of the bradycardia response to an increase in blood pressure than did urethane anesthesia. These data support the conclusion that the parasympathetic nervous system is primarily responsible for baroreceptor reflex-induced bradycardia in conscious rats. The sympathetic and parasympathetic systems contribute equally to control baroreceptor reflex-induced tachycardia except in extreme acute hypotension when the tachycardia is predominantly due to the activation of sympathetic nerves. The findings of the second experiment indicate that pentobarbital and urethane affect sympathetic systems differently.


Conditional control of gene expression in the mammary gland.
Identifying gene function during mammary gland development and function remains a technical challenge. For example, if a gene deletion is lethal during early embryogenesis, there is no opportunity to study its effects on the development or function of the gland. Similarly, if a dominant gain of gene function alters early mammary gland development, then its specific role during lactation cannot be assessed. Conditional gene expression systems can be used to circumvent these problems. Gene deletions or dominant gain experiments can be performed in an organ or cell type specific manner at specific timepoints using inducible gene expression systems. This review focuses on tetracycline responsive transactivation and Cre-lox systems. Other tetracycline regulatable (tet system) or hormone inducible systems and the Flp recombinase system are discussed as alternative approaches. Each system is described. The advantages and disadvantages of each for studying gene function in the mammary gland are discussed. Finally, the role of mammary gland transplantation in these genetic studies is examined.


Autistic Traits and Prosocial Behaviour in the General Population: Test of the Mediating Effects of Trait Empathy and State Empathic Concern.
Although the core characteristics associated with autistic traits are impaired social interactions, there are few studies examining how autistic traits translate into prosocial behaviour in daily life. The current study explored the effect of autistic traits on prosocial behaviour and the mediating role of multimodal empathy (trait empathy and state empathic concern). The results showed that autistic traits reduced prosocial behaviour directly and indirectly through complex mediation by multimodal empathy. The findings revealed the internal mechanism of autistic traits impeding prosocial behaviour and expanded our understandings of social behaviour in autism spectrum conditions (ASCs) and autistic traits in the general population. Furthermore, the results have implications for social adaptability interventions for individuals with ASCs and high levels of autistic traits.


The use of oral contraceptives to regulate oocyte retrieval.
This study was designed to determine the efficacy of using OCs prior to ovulation induction in an IVF-ET program. A total of 26 cycles were initiated after gonadotropin suppression with OCs and 22 laparoscopies (84.6%) were performed. A pregnancy rate of 22.7% per laparoscopy and 23.8% per ET was achieved. The results suggest that the use of OCs to regulate oocyte retrieval can result in acceptable pregnancy rates and facilitate efficient time use of IVF-ET personnel.


Two designs of platysma myocutaneous flap for reconstruction of oral and facial defects following cancer surgery.
This study evaluates the effects of two different designs of platysma myocutaneous flap, vertical and transverse, used in the reconstruction of defects following the excision of oral and facial tumors. Modified radical neck dissection or selected neck dissection was also performed. Out of the 48 patients, vertical and transverse platysma myocutaneous flaps were used for 41 and 7, respectively. The postoperative outcome for the vertical flaps was 37 cases surviving, two cases of complete necrosis, and two cases of partial necrosis. With the transverse flaps, six survived and there was one case of complete necrosis. The success rate was 90.2% and 85.7% for the vertical and the transverse flap, respectively. The form and function of recipient sites were well recovered. In conclusion, the platysma myocutaneous flap has clinical value in selected patients needing reconstruction of small and medium-sized intraoral or facial defects. It is recommended that the vertical design be used for reconstruction of buccal mucosa defects, and the transverse design for mouth-floor and facial defects.


Predictive genetic testing of at-risk relatives requires analysis of all CCM genes after identification of an unclassified CCM1 variant in an individual affected with cerebral cavernous malformations.
The mutation detection rate for familial cerebral cavernous malformations (CCM) is extremely high, being about 90 % if direct sequencing of the three genes, CCM1, CCM2, and CCM3, is used in conjunction with quantitative analyses to detect larger CCM1-3 deletions/duplications. We here report on an individual who had presented with more than 30 cerebral and spinal cavernous malformations, two intracranial meningiomas, and disease manifestation only in the mid-forties. A CCM1 missense variant of unclear relevance was found during the first sequencing step. Thereafter, direct sequencing of all three CCM genes revealed the typical pathogenic loss-of-function mutation c.598C > T/p.Q200* in the CCM3 gene. Our results demonstrate that mutation analyses of all three CCM genes in the index patient regardless of previous identification of an unclassified CCM1 variant is crucial for reliable predictive testing of at-risk relatives.


Posttraumatic autoimmune reaction in peripheral nerve: effect of two successive injuries at the same site.
We studied local autoimmune reactions in rat sciatic nerve after two successive injuries at the same site. The behavioral consequences of these injuries were also examined. We found that repetitive injuries had a moderately adverse effect on function and were accompanied by local autoimmune reactions. A causal relation between the two phenomena was possible but not clearly established.


Bis(2-amino-benzimidazolium) sulfate monohydrate.
In the title hydrated mol-ecular salt, 2C7H8N3 +·SO4 2-·H2O, the components are linked by numerous N-H⋯O and O-H⋯O hydrogen bonds.


New flat air injection cannula.
I developed a 6-mm long, flattened, 30-gauge air cannula with a polished tip for instillation and extraction of air and fluids from the anterior chamber during intraocular surgery. The polished flattened tip prevents Descemet's membrane detachments and the extra length allows easy instillation of air over an intraocular lens.


HMGA2 gene is a promising target for ovarian cancer silencing therapy.
Ovarian cancer is one of the most lethal gynecological malignancies and the small success rate of routine therapeutic methods justifies efforts to develop new approaches. Evaluation of targets for effective inhibition of ovarian cancer cell growth should precipitate clinical application of gene silencing therapy. In our previous work, we showed upregulation of HMGA2 gene expression as a result of Ras-induced rat ovarian surface epithelial cell transformation. This gene codes the HMGA2 protein, a member of the high-mobility group AT-hook (HMGA) family of nonhistone chromatin proteins. Genome-wide studies revealed upregulation of the HMGA2 gene in human ovarian carcinomas. Herein we have evaluated over-expression of the HMGA2 gene, relevant to ovarian cancer, in subsets of human specimens and cell lines by in situ RNA hybridization and RT-PCR. Transient silencing of HMGA2 gene by means of siRNA inhibited proliferation of those ovarian cancer cells, which over-express this gene initially. Growth suppression was mediated by cell-cycle arrest. Stable silencing of highly expressed HMGA2 gene by shRNAi in A27/80, Ovcar-3 and OAW-42 ovarian cancer cell lines resulted in growth inhibition because of G1 arrest and increase of apoptosis as well. The tumor growth inhibition effect of HMGA2 silencing for Ovcar-3 cells was validated in vivo. Our findings revealed that the HMGA2 gene represents a promising target for gene silencing therapy in ovarian cancer.


Emerging New Diagnostic Modalities and Therapies of Nonalcoholic Fatty Liver Disease.
Nonalcoholic fatty liver disease (NAFLD) has emerged as the leading cause of chronic liver disease in both adults and children. In this article, we review recent developments in the screening, diagnosis, and treatment of pediatric NAFLD. Although alanine aminotransferase (ALT) remains the best screening test for NAFLD in children, and liver biopsy is still required for the diagnosis of nonalcoholic steatohepatitis (NASH), other noninvasive biomarker/imaging studies (MRI-PDFF and VCTE) have emerged as diagnostic methods for pediatric NAFLD. Two large clinical therapeutic trials testing vitamin E, metformin, and cysteamine in pediatric NAFLD yielded mostly inconclusive results. Bariatric surgery has begun to be used in adolescents with severe obesity. An adult phase 2 study using obeticholic acid (OCA) to treat NASH patients with fibrosis showed some positive results. As we continue to await the first FDA-approved therapeutic agent for NASH, lifestyle change remains the main modality of treatment. Newer diagnostic and treatment modalities for pediatric NAFLD continue to be in development under FDA guidance.


Study on Serum Markers of Morphology and Peripheral Neuropathy in Patients with Type 2 Diabetic Nephropathy Evaluated by Ultrasound Image Based on Optimized Denoising Algorithm.
The paper uses an optimized denoising algorithm, combined with spiral CT coronary angiography (CCTA) in conjunction with carotid ultrasound, serological markers relevance for the assessment of coronary artery disease was analysed early T2DM and coronary heart disease (CHD) in patients with coronary and carotid artery disease to provide diagnostic evidence. Papers selected from January 2017 to December 2019 in hospital diagnosed 95 patients CHD, CHD were divided into three groups (n = 45) and T2DM with CHD group (n depending on whether T2DM disease = 50), were compared coronary arteries, the degree of carotid lesions, high-sensitivity C- reactive protein (hsC-RP) and the difference of FFA. CCTA display, combined with CHD of T2DM in double-vessel coronary artery disease and three main right coronary artery, left circumflex artery plaques appear more CHD combined group of T2DM, and three double-vessel coronary disease carotid plaque compared with the number of single-vessel disease and more. Spearman correlation analysis showed, hsC-RP positively correlated with FFA, hsC-RP and coronary artery lesion count was positively correlated. CCTA display, T2DM with CHD in coronary plaque with soft plaque and mixed plaque mainly extensive coronary artery disease, carotid artery ultrasound prompted the more peripheral vascular plaque number, the more the number of diseased vessels, the more severe the disease. Joint CCTA Clinically, carotid ultrasound and hsC-RP, FFA level detection can improve the rate of diagnosis of T2DM with CHD, reduce false positives, should be widely applied.


Quantitative Analysis of Objective Forward Scattering and Its Relevant Factors in Eyes with Cataract.
This study was aimed to quantitatively assess objective forward scattering and its relevant factors in eyes having cataract. Our study comprised 192 eyes of 192 patients (mean age, 71.3 ± 9.2 (standard deviation) years) who have cataract formation for surgical consultation. We determined uncorrected and corrected distance visual acuities (UDVA and CDVA), manifest refraction, the grade of nuclear sclerosis, objective scattering index (OSI) with the OQAS II (Visiometrics, Spain), log(s) with the C-Quant (Oculus, Germany), and ocular higher-order aberrations (HOAs) using the wavefront sensor (KR-1W, Topcon, Japan). The mean OSI was 5.11 ± 3.19 (0.90 to 20.90). We found explanatory variables relevant to the OSI to be, logMAR CDVA (p < 0.0001, partial regression coefficient B = 5.917) and log(s) (p = 0.0006, B = 0.911) (adjusted R2 = 0.333), in order of influence. No significant correlation was found with other clinical factors such as gender, age, manifest refraction, UDVA, ocular HOAs, or nuclear sclerosis. Eyes with worse CDVA and higher log(s) are more predisposed to show higher OSI in cataractous eyes. It is suggested that objective forward scattering was associated, not only with CDVA, but also with subjective forward scattering, in cataractous subjects.


Cardiovascular risk factors for early carotid atherosclerosis in the general population: the Edinburgh Artery Study.
Recent attempts to identify cardiovascular risk factors affecting early-stage carotid atherosclerosis, measured by ultrasonographically assessed intima-media thickness, have been inconclusive. To study the relationship between traditional cardiovascular risk factors and intima-media thickness. Ultrasonic evaluation of the intima-media thickness of the common carotid artery was included in the 5-year follow-up examination of participants of the Edinburgh Artery Study. We had valid readings of intima-media thickness for 1106 men and women aged 60-80 years. Information on a range of cardiovascular risk factors had been collected during the baseline examination. For men, in addition to age, lifetime smoking (measured in terms of pack years) was the only cardiovascular risk factor associated with increased intima-media thickness (P< or = 0.01) in the univariate analysis. Both systolic blood pressure (P < or = 0.001) and the high-density lipoprotein (HDL: total cholesterol ratio (P < or = 0.01) were correlated with intima-media thickness for women. When all the variables had been included in a multivariate analysis, pack years of smoking and the HDL:total cholesterol ratio were associated with early atherosclerotic development in men. In an equivalent analysis for women, alcohol consumption, systolic blood pressure and the HDL:total cholesterol ratio were associated with intima-media thickness. These data suggest that risk factors affecting intima-media thickness differ for men and women. Further sex-specific analyses of prospective population studies are required in order to clarify the role of 'traditional' cardiovascular risk factors in the early stages of carotid atherosclerosis.


Retracted: Spatial Pattern Evolution and Influencing Factors on Industrial Agglomeration: Evidence from Pearl River Delta Urban Agglomeration.
[This retracts the article DOI: 10.1155/2022/6477495.].


Normal & reversed spin mobility in a diradical by electron-vibration coupling.
π-conjugated radicals have great promise for use in organic spintronics, however, the mechanisms of spin relaxation and mobility related to radical structural flexibility remain unexplored. Here, we describe a dumbbell shape azobenzene diradical and correlate its solid-state flexibility with spin relaxation and mobility. We employ a combination of X-ray diffraction and Raman spectroscopy to determine the molecular changes with temperature. Heating leads to: i) a modulation of the spin distribution; and ii) a "normal" quinoidal → aromatic transformation at low temperatures driven by the intramolecular rotational vibrations of the azobenzene core and a "reversed" aromatic → quinoidal change at high temperatures activated by an azobenzene bicycle pedal motion amplified by anisotropic intermolecular interactions. Thermal excitation of these vibrational states modulates the diradical electronic and spin structures featuring vibronic coupling mechanisms that might be relevant for future design of high spin organic molecules with tunable magnetic properties for solid state spintronics.


SPONTANEOUS LAMELLAR MACULAR HOLES CLOSURE.
To report two cases of spontaneous closure of lamellar macular holes with epiretinal proliferation (ERP). Observational cases report. Two patients affected with lamellar macular hole showed progressive and spontaneous closure of the hole associated with ERP development. At presentation, both patients presented with irregular foveal contour, and foveal cavitation with apparent loss of retinal tissue. In both cases, ERP, also called "lamellar hole-associated epiretinal proliferation", was present and increased in size over time. This proliferation progressively developed across the hole with apparent restoration of the foveal contour and preservation of visual acuity. This report describes two cases of lamellar macular hole in which ERP increased over time, resulting in lamellar macular hole closure. Such observations may suggest a spontaneous healing process driven by glial cell proliferation.


In vitro Doppler ultrasound investigation of turbulence intensity in pulsatile flow with simulated cardiac variability.
An in vitro investigation of turbulence intensity (TI) associated with a severe carotid stenosis in the presence of physiological cardiac variability is described. The objective of this investigation was to determine if fluctuations due to turbulence could be quantified with conventional Doppler ultrasound (DUS) in the presence of normal physiological cycle-to-cycle cardiac variability. An anthropomorphic model of a 70% stenosed carotid bifurcation was used in combination with a programmable flow pump to generate pulsatile flow with a mean flow rate of 6 mL/s. Utilizing the pump, we studied normal, nonrepetitive cycle-to-cycle cardiac variability (+/-3.9%) in flow, as well as waveform shapes with standard deviations equal to 0, 2 and 3 times the normal variation. Eighty cardiac cycles of Doppler data were acquired at two regions within the model, representing either laminar or turbulent flow; each measurement was repeated six times. Turbulence intensity values were found to be 11 times higher (p < 0.001), on average, in the turbulent region than in the laminar region, with a mean difference of 24 cm/s. Twenty cardiac cycles were required for confidence in TI values. In conclusion, these results indicate that it is possible to quantify TI in vitro, even in the presence of normal and exaggerated cycle-to-cycle cardiac variability.


Genome-wide survey of mRNA half-lives in Bacillus subtilis identifies extremely stable mRNAs.
We have used DNA microarrays to survey rates of mRNA decay on a genomic scale in early stationary-phase cultures of Bacillus subtilis. The decay rates for mRNAs corresponding to about 1500 genes could be estimated. About 80% of these mRNAs had a half-life of less than 7 min. More than 30 mRNAs, including both mono- and polycistronic transcripts, were found to be extremely stable, i.e. to have a half-life of > or =15 min. Only two such transcripts were known previously in B. subtilis. The results provide the first overview of mRNA decay rates in a gram-positive bacterium and help to identify polycistronic operons. We could find no obvious correlation between the stability of an mRNA and the function of the encoded protein. We have also not found any general features in the 5' regions of mRNAs that distinguish stable from unstable transcripts. The identified set of extremely stable mRNAs may be useful in the construction of stable recombinant genes for the overproduction of biomolecules in Bacillus species.


A comparison between short-term evolution of micronuclei induced by X-rays and colchicine in root tips of Vicia faba.
The short-term evolution of micronuclei derived from acentric fragments and whole chromosomes was studied in root tips of Vicia faba. Micronuclei were induced by X-rays (30 cGy and 120 cGy) and colchicine (10(-5) M and 3 X 10(-4) M). Frequencies of chromosome breakage or loss of micronuclei in interphase and mitotic cells were studied. The DNA content of micronuclei in interphase cells was also measured. Micronuclei derived from whole chromosome showed a higher probability to survive and to undergo mitotic condensation in synchrony with main nuclei than micronuclei derived from an acentric fragment. PCC (Premature Chromosome Condensation) was not observed for both types of micronuclei in Vicia faba, in contrast to the ones reported in mammalian cells in culture.


Intracarotid infusions of protamine sulfate disrupt the blood-brain barrier of rabbits.
This study examined the effect of intracarotid infusions of protamine sulfate on the blood-brain barrier of the rabbit. Evans blue, which binds tightly to serum albumin, served as the marker for blood-brain barrier disruption. Brains from 12 of 14 rabbits receiving 30-50 mg of protamine sulfate in an intracarotid infusion over 3 min demonstrated intense Evans blue-albumin staining in the distribution of the infused internal carotid artery. In contrast, brains from 5 animals receiving 0.9% saline and from 5 animals receiving 50 mg of protamine sulfate by the intravenous route showed no evidence of blood-brain barrier disruption. Premixing protamine sulfate with heparin prior to intracarotid administration greatly reduced or abolished Evans blue staining of the brain as did delayed administration of the marker dye. Thus, the interaction of the positively charged protamine molecule with the vascular endothelium of cerebral capillaries transiently alters the permeability of the blood-brain barrier in the rabbit.


Sulfamethoxazole/trimethoprim versus fluoroquinolones for the treatment of Stenotrophomonas maltophilia bloodstream infections.
Stenotrophomonas maltophilia causes high mortality rates, especially in bloodstream infections (BSIs) where there is a lack of comparative data with fluoroquinolones (FQs) and sulfamethoxazole/trimethoprim (SXT). The objective of this study was to evaluate outcomes in patients with S. maltophilia BSI who were treated with FQs versus SXT. A retrospective study was conducted to compare FQs (levofloxacin, ciprofloxacin and moxifloxacin) versus SXT for the treatment of S. maltophilia BSI. A total of 54 patients were included in this retrospective study, including 32 treated with SXT and 22 treated with FQs (11 ciprofloxacin, 5 levofloxacin and 6 moxifloxacin). There were 3 deaths (13.6%) in the FQ group versus 10 (31.3%) in the SXT group (P=0.20). Modified Acute Physiology and Chronic Health Evaluation (APACHE) II score [odds ratio (OR)=1.4, 95% confidence interval (CI) 1.1-1.8] and broad-spectrum antibiotics prior to culture (OR=8, 95% CI 1.3-49.8) were significant predictors of mortality. Ciprofloxacin, moxifloxacin and levofloxacin are possible alternatives to SXT for S. maltophilia BSI; however, further investigation is needed to confirm these findings.


First-line nivolumab plus ipilimumab in metastatic non-small cell lung cancer: 5-year outcomes in Japanese patients from CheckMate 227 Part 1.
In CheckMate 227 Part 1 (NCT02477826), first-line nivolumab plus ipilimumab demonstrated long-term durable overall survival (OS) benefit versus chemotherapy in patients with metastatic non-small cell lung cancer (NSCLC), regardless of tumor programmed death ligand 1 (PD-L1) expression. We report results in Japanese patients with ≥ 5-year follow-up. Adults with stage IV/recurrent NSCLC without EGFR/ALK aberrations were randomized 1:1:1 to nivolumab plus ipilimumab, nivolumab alone, or chemotherapy (patients with tumor PD-L1 ≥ 1%), or nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (patients with tumor PD-L1 < 1%). Five-year efficacy and safety were assessed in Japanese patients. At 62.1 months' minimum follow-up, 143 Japanese patients with PD-L1 ≥ 1% or < 1% were randomized to nivolumab plus ipilimumab (n = 66) or chemotherapy (n = 77). Five-year OS rates were 46% with nivolumab plus ipilimumab versus 34% with chemotherapy (PD-L1 ≥ 1%) and 36% versus 19% (PD-L1 < 1%). Median duration of response was 59.1 versus 7.1 months (PD-L1 ≥ 1%) and 17.3 versus 3.0 months (PD-L1 < 1%). Among 5-year survivors treated with nivolumab plus ipilimumab (PD-L1 ≥ 1% and < 1%; n = 27), 59% (95% CI, 39%-75%) were off treatment for ≥ 3 years without receiving subsequent therapy. No new safety signals were observed. At 5-year follow-up, nivolumab plus ipilimumab continued to show long-term durable clinical benefit versus chemotherapy, regardless of tumor PD-L1 expression. Consistent with findings for the global population, these data support the use of nivolumab plus ipilimumab as first-line treatment in Japanese patients with metastatic NSCLC.


Separation of functional subpopulations of murine and human lymphoid cells on colloidal silica density gradients. I. Preparation of the Ludox AM gradient material and characterization of separation capacities.
This report describes a unique modification of an isopycnic density gradient system utilizing as a separating menstrum colloidal silica (Ludox AM). The primary advantages of this preparation are: (1) It is chemically defined, allowing extremely reproducible cell separation employing different lots of material; (2) the physical parameters (pH, density, salt concentration) of the final gradient suspension can be manipulated over a wide range of values, allowing for the separation of many different biological materials; (3) it allows separation of very large numbers of lymphoid cells with greater than 95% recovery of applied cells; (4) separated cellular subpopulations can be easily washed free of silica and cellular function is retained. This paper is a report of the preparation and functional characteristics of the gradient material as it relates to the separation of very large numbers of lymphoid cell subpopulations in both mouse and man. Subpopulations of murine and human lymphocytes separated by this gradient material were assayed for IgM synthesis, T-cell mediated cytotoxicity, and lymphokine production.


Do urocortins have a role in treating cardiovascular disease?
Corticotropin-releasing factor (CRF) and the three homolog neuropeptides, urocortin (UCN) 1, 2 and 3, are the major neuroendocrine factors implicated in the response of the body to stress. Recent evidence suggests that UCNs have a significant role in the pathogenesis and management of cardiovascular disease, such as congestive heart failure, ischemic heart disease, and hypertension. These data led to the initiation of clinical trials testing a possible role of UCNs in the diagnosis and therapy of cardiovascular disease, with encouraging results. Here, we summarize the available literature concerning the role of UCNs in the cardiovascular system, focusing on the emerging data creating a potential for clinical applications.


Management of coronary artery disease: therapeutic options in patients with diabetes.
The aim of this review is to discuss the particularities of coronary artery disease (CAD), the effect of intensive medical management and the outcome of percutaneous and surgical revascularization in patients with diabetes mellitus (DM). CAD represents the leading cause of death in patients with DM. Numerous clinical, biological and angiographic risk factors have been shown to be associated with CAD in diabetic patients. Metabolic abnormalities in patients with DM including insulin resistance, hyperglycemia and dyslipidemia are briefly discussed. Then the potential roles of medical management and of percutaneous and surgical coronary revascularization are more extensively reviewed. More vigorous control of hyperglycemia, hyperlipidemia, hypertension and other risk factors may be of crucial importance for risk reduction. Despite remarkable progress in recent years, the choice of a coronary revascularization strategy remains a challenge in these patients. Diabetic patients with CAD are predisposed to higher cardiovascular events after balloon angioplasty. Whether stenting and new antiplatelet drugs improve the results of percutaneous revascularization in this population needs further evaluation. The superiority of the surgical approach is also not definitely established. Therefore, many aspects of coronary revascularization are still unclear in these patients. The results of ongoing randomized trials comparing multiple coronary stents to bypass surgery will likely provide some answers to our questions and additional randomized trials evaluating intensive diabetic control with or without coronary revascularization are needed to determine the best therapeutic approach in these patients.


Divergences of soil carbon turnover and regulation in alpine steppes and meadows on the Tibetan Plateau.
The grasslands of the Tibetan Plateau store approximately 2.5% of global soil organic carbon (SOC) and considerable soil inorganic carbon (SIC) and have the potential to become a vast carbon source or sink as climate change progresses. However, the soil carbon (C) sequestration mechanisms that occur across large-scale natural gradients remain unclear. Here, humic substances (HS) were utilized to trace soil C turnover at 0-20 cm, and we compared divergences among three main grassland types (alpine meadow, alpine steppe, and artificial plantation) using structural equation modeling (SEM). The results showed that the alpine meadows sequestered the most soil C (63.99 ± 4.41 g kg-1 SOC and 4.11 ± 0.63 g kg-1 SIC), sequestering 2-3 times more than the alpine steppe ecosystems (19.78 ± 1.98 g kg-1 SOC and 9.21 ± 0.66 g kg-1 SIC). The alpine steppe and artificial plantation regions have strong C sink potential due to their low C/N ratios (P < 0.05). Importantly, SIC played an important role in the alpine steppes, accounting for nearly 26-37% of soil C. The ratios of recalcitrant HS to SOC were estimated as 46.50%, 65.09%, and 78.17% in the alpine meadow, alpine steppe, and artificial plantation ecosystems, respectively, indicating that SOC in the alpine meadow was the most sensitive to climate change. Fulvic acid (FA) accounted for 50.86% of SOC in the 0-20-cm interval, contributing most to the formation of SOC in all vegetation types. In addition, in contrast to climatic controls on soil C turnover in the alpine meadow, climate conditions rarely controlled C turnover in the alpine steppe. Moreover, sand and silt were the main soil minerals involved in C turnover in alpine meadow and alpine steppe ecosystems, respectively. Our study improves understanding of the mechanism by which soil C sinks form on the Tibetan Plateau under warming and wetting conditions.


An unusual presentation of chordoma as a pyloric ring submucosal tumor: The first case report of a primary gastrointestinal lesion in humans.
Chordomas are rare malignant bone neoplasms that are presumed to arise from chordal remnants in the fetal stage and typically occur along the axial skeleton. The extra-skeletal chordomas reported to date include soft tissue of the extremities and nasopharynx. Chordoma arising from the gastrointestinal wall has not been previously described. We report on a 42-year-old man with primary chordoma presenting as a gastroduodenal submucosal tumor centered on the pyloric ring. The patient was consistently asymptomatic, and the tumor was an incidental finding. However, during a follow-up at approximately 1.6 years, an increase in tumor size was identified on computed tomography (CT), and surgical resection was performed without a definite pathologic diagnosis. The patient was successfully treated with distal gastrectomy, and the histological diagnosis was a conventional chordoma. The diagnosis was confirmed via immunohistochemical staining for brachyury, pan-cytokeratin, S-100, and SOX9. Postoperative CT and magnetic resonance imaging revealed no recurrence or metastasis during the 1.5-year follow-up period. Primary chordomas of the digestive tract are rare. Embryologic development of the notochord does not explain the existence of remnants in the gastrointestinal wall. Moreover, notochordal remnants, as precursors of chordoma, were not identified in the current case. The gastroduodenal chordoma may not have originated from embryonic notochordal remnants but through aberrant brachyury activation without a notochordal precursor. We report the first case of primary gastrointestinal chordoma in humans. The tumor was completely removed surgically, without postoperative recurrence.


AMD1 is required for the maintenance of leukemic stem cells and promotes chronic myeloid leukemic growth.
Polyamines are critical elements in mammals, but it remains unknown whether adenosyl methionine decarboxylase (AMD1), a rate-limiting enzyme in polyamine synthesis, is required for myeloid leukemia. Here, we found that leukemic stem cells (LSCs) were highly differentiated, and leukemia progression was severely impaired in the absence of AMD1 in vivo. AMD1 was highly upregulated as chronic myeloid leukemia (CML) progressed from the chronic phase to the blast crisis phase, and was associated with the poor prognosis of CML patients. In addition, the pharmacological inhibition of AMD1 by AO476 treatment resulted in a robust reduction of the progression of leukemic cells both in vitro and in vivo. Mechanistically, AMD1 depletion induced loss of mitochondrial membrane potential and accumulation of reactive oxygen species (ROS), resulting in the differentiation of LSCs via oxidative stress and aberrant activation of unfolded protein response (UPR) pathway, which was partially rescued by the addition of polyamine. These results indicate that AMD1 is an essential element in the progression of myeloid leukemia and could be an attractive target for the treatment of the disease.


Application of zirconium dioxide nanoparticle sorbent for the clean-up step in post-harvest pesticide residue analysis.
The use of yttria-stabilized zirconium dioxide nanoparticles as d-SPE clean-up sorbent for a rapid and sensitive liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) method for the determination of post-harvest fungicides (carbaryl, carbendazim, chlorpropham, diphenylamine, ethoxyquin, flutriafol, imazalil, iprodione, methomyl, myclobutanil, pirimiphos-methyl, prochloraz, pyrimethanil, thiabendazole, thiophanate-methyl and tolclofos-methyl) in orange and pear samples has been evaluated and validated. The sample preparation was a modification of the QuEChERS extraction method using yttria-stabilized zirconium dioxide and multi-walled carbon nanotubes (MWCNTs) nanoparticles as the solid phase extraction (d-SPE) clean-up sorbents prior to injecting the ten-fold diluted extracts into the LC system. By using the yttria-stabilized zirconium dioxide extraction method, more recoveries in the 70-120% range were obtained - thus this method was used for the validation. Quantification was carried out using a matrix-matched calibration curve which was linear in the 1-500 µg kg(-1) range for almost all the pesticides studied. The validated limit of quantification was 10 µg kg(-1) for most of the studied compounds, except chlorpropham, ethoxyquin and thiophanate-methyl. Pesticide recoveries at the 10 and 100 µg kg(-1) concentration levels were satisfactory, with values between 77% and 120% and relative standard deviations (RSD) lower than 10% (n=5). The developed method was applied for the determination of selected fungicides in 20 real orange and pear samples. Four different pesticide residues were detected in 10 of these commodities; 20% of the samples contained pesticide residues at a quantifiable level (equal to or above the LOQs) for at least one pesticide residue. The most frequently-detected pesticide residues were: carbendazim, thiabendazole and imazalil-all were below the MRL. The highest concentration found was imazalil at 1175 µg kg(-1) in a pear sample.


Immunohistochemistry identifies carriers of mismatch repair gene defects causing hereditary nonpolyposis colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) may be caused by mutations in mismatch repair (MMR) genes. The aim of this study was to validate immunohistochemistry and family history as prescreening tools to predict germline mutations in MLH1, MSH2, and MSH6. Pedigrees from 250 families were extended, cancer diagnoses were verified, and families were classified according to the Amsterdam and the Bethesda criteria. Tumor specimens were examined with immunohistochemistry for the presence of MLH1, MSH2, and MSH6 proteins. Mutation analyses were performed in blood samples from the same patients. Blood samples from affected index persons in 181 families and tumor specimens from 127 of the affected index persons were obtained. Thirty tumors lacked one or more gene products. Sensitivity of immunohistochemistry to detect mutation carriers was 100%, specificity was 82%, and positive predictive value was 85%. Sensitivities, specificities, and positive predictive values for the Amsterdam criteria were 82%, 8%, and 45%, respectively, and for the Bethesda criteria were 100%, 0%, and 48%, respectively. Distribution of mutations was MLH1 = 4, MSH2 = 11, and MSH6 = 4. Wide clinical criteria to select HNPCC kindreds, followed by immunohistochemistry of tumor material from one affected person in each family, had high sensitivity and specificity to predict MMR mutations.


Six new Salmonella sub-genus III serotypes isolated from snakes in Israel.
Six new Salmonella sub-genus III serotypes (Arizona) were isolated from snakes in Israel. Their antigenic structure was established as follows: S. arizonae 16:Z52:Z35 (Ar.25:26-21); S. arizonae 18:1,v:e,n,x,z15 (Ar.7a,7b:23-28); S. arizonae 21:i:1,5(7) (Ar.22:33-30); S. arizonae 41:c:e,n,x,z15 (Ar.13:32-28); S. arizonae 51:k:z35 (Ar.1,2:29-21); and S. arizonae 53:1,v:z35 (Ar.1,4:23-21).


An analysis of the climate change effects on pesticide vapor drift from ground-based pesticide applications to cotton.
Vapor drift of applied pesticides is an increasing concern. Among the major crops cultivated in the Lower Mississippi Delta (LMD), cotton receives most of the pesticides. An investigation was carried out to determine the likely changes in pesticide vapor drift (PVD) as a result of climate change that occurred during the cotton growing season in LMD. This will help to better understand the consequences and prepare for the future climate. Pesticide vapor drift is a two-step process: (a) volatilization of the applied pesticide to vapors and (b) mixing of the vapors with the atmosphere and their transport in the downwind direction. This study dealt with the volatilization part alone. Daily values of maximum and minimum air temperature, averages of relative humidity, wind speed, wet bulb depression and vapor pressure deficit for 56 years from 1959 to 2014 were used for the trend analysis. Wet bulb depression (WBD), indicative of evaporation potential, and vapor pressure deficit (VPD), indicative of the capacity of atmospheric air to accept vapors, were estimated using air temperature and relative humidity (RH). The calendar year weather dataset was trimmed to the cotton growing season based on the results of a precalibrated RZWQM for LMD. The modified Mann Kendall test, Pettitt test and Sen's slope were included in the trend analysis suite using 'R'. The likely changes in volatilization/PVD under climate change were estimated as (a) average qualitative change in PVD for the entire growing season and (b) quantitative changes in PVD at different pesticide application periods during the cotton growing season. Our analysis showed marginal to moderate increases in PVD during most parts of the cotton growing season as a result of climate change patterns of air temperature and RH during the cotton growing season in LMD. Estimated increased volatilization of the postemergent herbicide S-metolachlor application during the middle of July appears to be a concern in the last 20 years that exhibits climate alteration.


Conjugation of catechins with cysteine generates antioxidant compounds with enhanced neuroprotective activity.
Antioxidant compounds derived from the conjugation of (-)-epicatechin and (-)-epicatechin 3-O-gallate with cysteine and cysteine derivatives protected HT-22 nerve cells (EC50 between 36 and 65 microM) from death triggered by glutamate while underivatized (-)-epicatechin was almost inactive (EC50=610 microM). Differences in free radical scavenging capacity (DPPH assay) could not account for the improvement in neuroprotective activity upon derivatization of (-)-epicatechin with thiols. Moreover, while the gallate-containing compounds are more efficient radical scavengers than their non-galloylated counterparts, they are only equally or less potent as neuroprotective agents. Although all of the conjugates were able to scavenge mitochondrially generated reactive oxygen species (ROS) inside the cells, the majority of their neuroprotective activity appeared to be dependent upon their ability to maintain glutathione levels. These results suggest that a mechanism other than ROS scavenging is involved in the neuroprotective action exerted by the epicatechin conjugates.


Agonism of GPR39 displays protective effects against advanced glycation end-product (AGE)-induced degradation of extracellular matrix in human SW1353 cells.
Excessive degradation of the cartilage articular extracellular matrix (ECM) in chondrocytes has been considered as an important pathological characteristics of OA. In the present study, we demonstrate that the G protein-coupled receptor GPR39 is expressed on SW1353 chondrocytes and is significantly downregulated in response to advanced glycation end products (AGEs). Our findings show that agonism of GPR39 exerts significant protective effects against AGE-induced degradation of articular extracellular matrix. Agonism of GPR39 rescued degradation of type II collagen by decreasing expression of the collagen-degrading enzymes matrix metalloproteinase (MMP)-3 and MMP-13. Additionally, agonism of GPR39 rescued AGE-induced suppression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Agonism of GPR39 prevented degradation of aggrecan by downregulating AGE-induced expression of a disintegrin and metalloproteinase with type I thrombospondin motif (ADAMTS)-4 and ADAMTS-5. Finally, we demonstrate that the effects of GPR39 are mediated through the p38 mitogen activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) cellular signaling pathway. Taken together, our findings show for the first time that targeted therapies involving GPR39 may provide a novel approach for the prevention and treatment of osteoarthritis.


Value of diffusion-weighted MR imaging in the diagnosis of lymph node metastases in patients with cholangiocarcinoma.
To evaluate diffusion-weighted MR imaging (DWI) in the diagnosis of lymph node metastases in patients with cholangiocarcinoma. In 24 patients with cholangiocarcinoma, MR imaging of the upper abdomen was performed prior to surgery at 1.5 T using a respiratory-triggered single-shot echo-planar imaging (SSEPI) sequence (b values: 50, 300, and 600 s/mm(2)). ADC (apparent diffusion coefficient) values and diameters of regional lymph nodes (LN) were determined. Subsequently, in all patients, surgical exploration and/or resection of the primary tumor and regional LN dissection were performed. Imaging results were correlated with results of histopathologic analysis. ADC values and diameters of benign and malignant LN were compared using the Mann-Whitney U test. In addition, a ROC (receiver operating characteristic curve) analysis was performed. The mean ADC value (×10(-3) mm(2)/s) of metastatic LN (1.21 ± 0.15) was significantly lower than that of benign LN (1.62 ± 0.33, p < 0.001) while there was no significant difference in the mean diameter of malignant (16.8 ± 5.4 mm) and benign LN (14.1 ± 4.0 mm; p = 0.09). Using an ADC value of 1.25 × 10(-3) mm(2)/s as threshold, 91.4% of LN were correctly classified as benign or malignant with a sensitivity/specificity of 83.3%/92.8% and a positive/negative predictive value of 66.7%/96.7%. The area under the ROC curve was 0.93. DWI using a respiratory-triggered SSEPI sequence, according to our preliminary experience, is a promising imaging modality in the differentiation of benign and malignant LN in patients with cholangiocarcinoma.