A study on quantitative structure-activity relationship and molecular docking of metalloproteinase inhibitors based on L-tyrosine scaffold.
MMP-2 enzyme is a kind of matrix metalloproteinases that digests the denatured collagens and gelatins. It is highly involved in the process of tumor invasion and has been considered as a promising target for cancer therapy. The structural requirements of an MMP-2 inhibitor are: (1) a functional group that binds the zinc ion, and (2) a functional group which interacts with the enzyme backbone and the side chains which undergo effective interactions with the enzyme subsites. In the present study, a QSAR model was generated to screen new inhibitors of MMP-2 based on L-hydroxy tyrosine scaffold. Descriptors generation were done by Hyperchem 8, DRAGON and Gaussian98W programs. SPSS and MATLAB programs have been used for multiple linear regression (MLR) and genetic algorithm partial least squares (GA-PLS) analyses and for theoretical validation. Applicability domain of the model was performed to screen new compounds. The binding site potential of all inhibitors was verified by structure-based docking according to their binding energy and then the best inhibitors were selected. The best QSAR models in MLR and GA-PLS were reported, with the square correlation coefficient for leave-one-out cross-validation (Q(2) LOO) larger than 0.921 and 0.900 respectively. The created MLR and GA-PLS models indicated the importance of molecular size, degree of branching, flexibility, shape, three-dimensional coordination of different atoms in a molecule in inhibitory activities against MMP-2. The docking study indicated that lipophilic and hydrogen bonding interactions among the inhibitors and the receptor are involved in a ligand-receptor interaction. The oxygen of carbonyl and sulfonyl groups is important for hydrogen bonds of ligand with Leu82 and Ala83. R2 and R3 substituents play a main role in hydrogen bonding interactions. R1 is sited in the hydrophobic pocket. Methylene group can help a ligand to be fitted in the lipophilic pocket, so two methylene groups are better than one. The Phenyl group can create a π-π interaction with Phe86. The QSAR and docking analyses demonstrated to be helpful tools in the prediction of anti-cancer activities and a guide to the synthesis of new metalloproteinase inhibitors based on L-tyrosine scaffold.


Magnetic resonance spectroscopy imaging-directed transrectal ultrasound biopsy increases prostate cancer detection in men with prostate-specific antigen between 4-10 ng/mL and normal digital rectal examination.
To evaluate the ability of magnetic resonance spectroscopic imaging to improve prostate cancer detection rate. A retrospective analysis was carried out of 278 men with prostate-specific antigen in the range of 4-10 ng/mL and normal digital rectal examination who underwent transrectal ultrasound-guided prostate biopsy. Outcomes were compared between men who had a standard biopsy versus those who also underwent a prebiopsy magnetic resonance spectroscopic imaging. Men with an abnormal voxel on magnetic resonance spectroscopic imaging had standard transrectal ultrasound biopsies plus biopsies directed to the abnormal voxels. The study group (n = 140) and control group (n = 138) were similar in baseline parameters, such as mean age, prostate size and mean prostate-specific antigen. The overall cancer detection in the magnetic resonance spectroscopic imaging positive group (24.4%) was more than double that of the control group (10.1%). On comparing the magnetic resonance spectroscopic imaging results with the transrectal ultrasound biopsy findings, magnetic resonance spectroscopic imaging had 95.6% sensitivity, 41.9% specificity, a positive predictive value of 24.4%, a negative predictive value of 98% and an accuracy of 51.4%. Magnetic resonance spectroscopic imaging-directed transrectal ultrasound biopsy increases the cancer detection rate compared with standard transrectal ultrasound biopsy in patients with normal digital rectal examination and elevated prostate-specific antigen in the range of 4-10 ng/mL.


Simultaneous 31P NMR spectroscopy and EMG in exercising and recovering human skeletal muscle: technical aspects.
The bioenergetics of human skeletal muscle can be studied by 31P NMR spectroscopy (31P-MRS) and by surface electromyography (SEMG). Simultaneous 31P-MRS and SEMG permit accurate and noninvasive studies of the correlation between metabolic and electrical changes in exercising and recovering human skeletal muscle, a relationship that is still poorly understood. This study describes the optimization of skeletal muscle 31P-MRS in a whole-body magnet, involving surface coil design, utilization of adiabatic radio frequency pulses and advanced time-domain fitting, to the technical design of SEMG. A nonmagnetic ergometer was used for ankle dorsiflexions that activated only the anterior tibial muscle as verified by post exercise imaging. The coil design and the adiabatic sech/tanh pulse improved sensitivity by 45% and 56% respectively, compared with standard techniques. Simultaneous electromyographic recordings did not deteriorate the NMR spectra. The VARPRO time domain fitting routine was very suitable for estimating 31P muscle spectra. With these methods it was possible to accurately estimate parameters describing metabolic and electrical changes during rest, exercise and the entire recovery period with a 20-s time resolution on a standard 1.5 T whole-body NMR scanner.


Effects of ondansetron on gastrointestinal symptoms in carcinoid syndrome.
The effect of short-term treatment with the highly selective serotonin receptor antagonist ondansetron on symptoms and gastric emptying in 11 carcinoid patients was studied. Diarrhoea improved in 6 of 6 patients, nausea in 3 of 4 patients. Flushing was not affected. The rate of gastric emptying increased during ondansetron treatment (P = 0.08). No changes in serotonin in platelets and urinary excretion of 5-hydroxyindoleacetic acid were found. It is concluded that ondansetron can improve gastrointestinal symptoms in carcinoid patients and possibly slows gastric emptying.


[Mucolipidosis type II (I-cell disease) with unusually severe heart involvement].
Mucolipidosis II (I-cell disease), an autosomal recessive inborn error of mucolipid metabolism with defective transport of lysosomal enzymes is described in a young infant. Besides the typical findings as a result of the "lysosomopathy", this case presented an unusual and distinct cardiac involvement: a cardiomyopathy with dilatation of the left ventricle and signs of an endocardfibroelastosis.


Humoral immune response after post-chemotherapy booster diphtheria-tetanus-pertussis vaccine in pediatric oncology patients.
The role of post-chemotherapy booster vaccination in pediatric oncology children remains to be established. In this randomized controlled study, we studied the effect of immune responses to diphtheria-tetanus-pertussis (DTP) booster vaccination in children 6 months after completing chemotherapy. Children 1-18 years old with chemotherapy completed for 6 months (baseline) were eligible. Subjects were randomized into vaccine and control group. In the former, three doses of DTP vaccine (Aventis Pasteur Inc., Lyon, France) were administered. IgG antibody titers against diphtheria, tetanus, pertussis, hepatitis B, measles, mumps, and rubella antibodies were measured serially in vaccine and control groups. Subsets of circulating lymphocytes (CD3(+), CD4(+), CD8(+), CD19(+), and CD16/56(+)) were quantified by flow cytometry using fluorescence-labeled monoclonal antibodies. Fifty-six children (28 vaccinees; 28 controls) were enrolled. Protective antibody levels against diphtheria, tetanus, pertussis were found at baseline in 83.6%, 96.5%, 96.1% of them respectively. After three doses of DTP, all vaccinees demonstrated a sustain rise in antibody levels and the antibody titers were significantly higher than control group. 35.8% of subjects were susceptible to measles mumps and rubella infection and 69% showed anti-HBs antibody titer less than protective level up to 18 months after stopping chemotherapy. Post-chemotherapy booster vaccinations produced a strong and sustained effect in humoral immunity against vaccine-preventable infectious diseases.


Defining phenotypes of long-term lithium and valproate response, including combination therapy: a modified application of the Alda scale in patients with bipolar disorders.
When evaluating the long-term treatment response to mood stabilizers using the Alda scale, mood stabilizer combination therapy is typically considered a confounding factor, and patients receiving combination therapy are excluded from the analysis. However, this may result in bias if those under combination therapy are worse treatment responders. This study aims to explore whether the Alda scale is applicable to patients taking lithium and valproate combination therapy. We compared long-term treatment response in patients receiving monotherapy and combination therapy of the two drugs, and investigated clinical correlates of the responses to each drug. The study subjects consisted of 102 patients with bipolar I (BD-I) or bipolar II (BD-II) disorder who had been undergoing maintenance treatment with lithium and/or valproate for more than 2 years at a single specialized bipolar disorder clinic. Long-term treatment response was measured using the Alda scale and compared among the lithium monotherapy group, the valproate monotherapy group, and the mood stabilizer combination group. Clinical correlates of long-term treatment response were evaluated in lithium users and valproate users separately. There were no significant differences in terms of baseline illness characteristics among groups. The combination group showed the worst treatment response for all the response measurements applied. This group also had the higher rate of 'poor responder' with a statistically significant difference compared to valproate group. Older age at onset and (hypo)manic episode at onset showed significant positive associations with total Alda score in lithium users, while comorbid anxiety disorders, obsessive-compulsive disorder and mixed episode showed significant negative associations in valproate users. The combination group had poorer long-term treatment response but did not show distinct clinical characteristics compared to the monotherapy groups. When exploring the long-term effects of mood stabilizers, excluding patients undergoing combination treatment could result in bias because they may represent a poor response group. The long-term treatment responses of lithium and valproate had different clinical correlates.


Implantable pulse generators (pacemakers) and electrodes: safety in the magnetic resonance imaging scanner environment.
Static magnetic fields, time-varying electric and magnetic fields, and electromagnetic interference within the magnetic resonance imaging scanner environment can cause the implantable pulse generator (pacemaker) to malfunction and render the electrodes hazardous to the patient. This article provides a review of the literature and of international regulatory guidance concerning safety considerations when these implantable devices are exposed to magnetic resonance imaging.


Antibiotic resistance of vibrio cholerae: special considerations of R-plasmids.
Studies on the transmission of R plasmid by conjugation between enterobacteria and vibrio or related bacteria were reviewed. The majority of the reports confirmed successful transmission from enterobacteria to Vibrio cholerae and related species, although the transmission frequencies were extremely low and the transmitted R plasmid was very unstable except for thermosensitive kanamycin plasmid and usual R plasmid coexisting with P plasmid. Strains of V. cholerae and Aeromonas liquefaciens as well as A. salmonicida bearing R plasmid were detected in nature. R plasmid was relatively unstable in V. cholerae strains with which transmission of R plasmid to enterobacteria was confirmed. At present, only 3 R plasmids have been obtained from naturally occurring strains of V. cholerae. Although the 2 European plasmids belong to the C incompatibility group with 98 megadalton closed covalent circular DNA molecule, one plasmid belongs to the J group with more than 25 megadalton molecular weight, and no CCC of satelite DNA was detected in bacteria harboring this plasmid.


Altered conditioned taste aversion and glucose utilization in related brain nuclei of diabetic GK rats.
The impact of diabetes and especially hyperglycemia on brain glucose utilization and insulin binding are still not clear. This is probably due to the fact that most studies have been performed in streptozotocin treated rats that are highly hyperglycemia and that could have an effect per se on the brain. The aim of the present work was to measure, in vivo, glucose utilization and insulin binding in different areas of the brain of the spontaneously diabetic GK rats that present a moderate hyperglycemia. Brain insulin receptors number was not changed in the brain of GK rats. By contrast, an increased glucose utilization was present in the external plexiform and the intergranular layers of the olfactory bulbs, as well as in the amygdaloid of the GK rats. These structures are involved in conditioned taste aversion, which was found to be greatly altered in the diabetic rats. These results sustain the hypothesis of impaired neuropsychological functions in diabetic patients particularly in term of learning and memory.


The antiinflammatory mechanism of Igongsan in mouse peritoneal macrophages via suppression of NF-κB/Caspase-1 activation.
Igongsan (IGS), which is an herbal prescription composed of five different herbs, Ginseng Radix (root of Panax ginseng, Araliaceae), Atractylodis Rhizoma Alba (rhizome of Atractylodes Macrocephala, Compositae), Poria Sclerotium (sclerotium of Poria cocos, Polyporaceae), Glycyrrhizae Radix et Rhizoma (root and rhizome of Glycyrrhiza uralensis, Leguminosae), and Citri Unshius Pericarpium (Peel of Citrus unshiu, Rutaceae), has been traditionally used in Korea to treat a variety of inflammatory diseases. In this study, we investigated to elucidate the mechanism responsible for IGS's antiinflammatory effect in mouse peritoneal macrophages. The findings demonstrate that IGS inhibited the production of inflammatory cytokine and prostaglandins E2 . IGS inhibited the enhanced levels of cyclooxygenase-2 and inducible NO synthase caused by lipopolysaccharide (LPS). Additionally, it was shown that the antiinflammatory effect of IGS is through regulating the activation of nuclear factor-kappa B and caspase-1 in LPS-stimulated mouse peritoneal macrophages. These results provide novel insights into the pharmacological actions of IGS as a potential candidate for development of new drugs to treat inflammatory diseases. These results provide novel insights into the pharmacological actions of IGS as a potential candidate for development of new drugs to treat inflammatory diseases.


The CTGF gene -945 G/C polymorphism is associated with target lesion revascularization for in-stent restenosis.
Previous studies have shown that transforming growth factor β (TGF-β) and vascular endothelial growth factor A (VEGF-A) pathways are involved in the in-stent restenosis (ISR) process. The present study aimed to assess the relationship between single-nucleotide polymorphisms (SNPs) in genes encoding downstream proteins of TGF-β and VEGF-A pathways and the risk of target lesion revascularization (TLR) for in-stent restenosis. A total of 657 patients (with 781 treated lesions) who underwent percutaneous coronary intervention (PCI) with stent implantation at our center between 2007 and 2012 and completed a 4-year follow-up for clinically-driven TLR, were included. SNPs in CTGF (rs6918698), TGFBR2 (rs2228048), SMAD3 (rs17293632), KDR (rs2071559), CCL2 (rs1024610) were genotyped using TaqMan assay. Major allele carriers of CTGF gene -945 G/C polymorphism (rs6918698) were significantly less likely to underwent clinically-driven TLR during follow-up than minor allele carriers. After adjustment for clinical, angiographic, and procedural covariates, CTGF polymorphism was significantly associated with TLR, and minor allele (C) carriers had nearly two times higher risk of developing ISR requiring TLR (HR of 1.93, 95%CI 1.15-3.24) compared to patients with major (GG) genotype. No significant relationship was found between other analyzed polymorphisms and cumulative incidence of TLR at 4-years. Our results suggest that functional -945 G/C polymorphism in the gene encoding connective tissue growth factor is associated with the need for TLR in patients who underwent PCI for stable coronary artery disease.


Preparation and properties of soil conditioner microspheres based on self-assembled potassium alginate and chitosan.
Fulvic acid (FA), as one type of soil conditioner, can enhance drought tolerance, improve nutrient ingestion, stabilize pH values of soil, and reduce fertilizer extracting behaviors. Moreover, it shows a good effect on increasing the permissiveness of plants to various environments, and the stress of salinity and drought is included. Therefore, it can be used as an ideal soil conditioner. In order to extend its effect, it may be loaded into the core-shell polymer microspheres. In this study, FA was added to calcium carbonate (CaCO3) microspheres, potassium alginate (PAL) and chitosan (CS) were assembled outside. Thus, PAL/CS/FA-CaCO3 microspheres were prepared using layer-by-layer self-assembly methods. The surface morphology, encapsulation efficiency and in vitro drug release characteristics were investigated. It was revealed that PAL/CS/FA-CaCO3 microspheres were formed with a particle size distribution between 2 and 6 μm due to self-assembly between PAL and CS. Drug release behavior analysis exhibited the sustained release processes were delayed to varying degrees due to different degradation degrees of CaCO3 microspheres at different pH values. Results also illustrated that these microspheres had a high loading capacity for FA, and possessed good biodegradability. Thus, PAL/CS/FA-CaCO3 microspheres exhibited promise for future applications compared with that of traditional soil conditioners.


Structural and functional studies on the transformation of the intestinal mucosa in rats with experimental diabetes.
Twenty days after the onset of alloxan-induced diabetes, a villous hyperplasia has developed in the intestines of rats having free access to food. The transformation is characterised by a considerable increase in the area of the villous surface, caused by an enhanced mitotic activity in the crypts. The absorption of glucose or methionine by jejunal loops, whether expressed in terms of serosal area or villous area, is unchanged at this stage. On the other hand, the specific activity of certain disaccharidases and dipeptidases in crude mucosal homogenates is greater in diabetic animals, but quantitative histochemistry revealed no changes in the activities of alkaline phosphatase, leucine amino-peptidase and non-specific esterase in the individual enterocytes. Thus the biochemical changes may simply reflect the hyperplasia of the mucosa. The blood sugar level does not appear to be directly responsible for the mucosal transformation; however, the positive correlation between the daily food intake and the villus height suggests a role of hyperphagia and consequent increased luminal nutrition in the development of the hyperplasia.


Rural versus urban colorectal and lung cancer patients: differences in stage at presentation.
Rural surgeons are often uneasy when their outcomes are compared with those of urban surgeons because they perceive that rural patients typically present with worse disease. Rural patients with cancer are commonly thought to present at a later stage of disease, although this is based largely on anecdotal evidence. Retrospective, descriptive analysis of cancer stage at presentation of rural versus urban patients with two common cancers (lung, colorectal) using the Surveillance, Epidemiology, and End Results database from the National Cancer Institute. Rural versus urban designations were based on rural-urban continuum codes from the US Department of Agriculture. We constructed an ordinal logistic regression model to compare stage at presentation between rural and urban colorectal and lung cancer patients, while controlling for other factors that might be associated with late stage at presentation, including age, race, gender, marital status, income level, and level of education. In univariate and multivariate analyses, patients with colorectal and lung cancer from rural areas were not more likely to present at later stage. The ordinal logistic regression model indicated that urban patients are more likely to present with late-stage colorectal and lung cancer, compared with rural patients (p < 0.001). For colon cancer, other factors notably associated with stage IV disease were low-income, African-American race, age younger than 65 years, divorce, male gender, and language isolation. For lung cancer, factors notably associated with stage IV disease were African-American race, divorce, male gender, and language isolation. Urban rather than rural residence appears to be associated with later stages of lung and colorectal cancer at presentation. This finding is contrary to the common assumption that rural patients present at later stages of disease.


The blood concentration and organ distribution of haloperidol at therapeutic and toxic doses in severe fatty liver disease.
The aim of this study was to investigate the difference between the pharmacokinetics of haloperidol in normal rats and in rats with fatty liver disease. A therapeutic dosage (0.1 mg/kg) and a toxic dose (15 mg/kg) of haloperidol were administrated to normal 9-week-old male rats or those with severe fatty liver disease, and the blood concentration of haloperidol was determined 15 min, 1, 2, and 3 h following haloperidol administration. The concentration of haloperidol in the organs was determined 1, 2, and 3 h after the haloperidol administration. Additionally, the volume of the portal vein blood flow was measured 3 h after haloperidol administration. When given at the therapeutic dosage, the concentrations of haloperidol in both the blood and organs of the rats with fatty liver disease were significantly higher than those in the normal rats. However, when given at the toxic level, the blood and organ haloperidol concentrations 1 h after administration tended to be lower in the rats with fatty liver disease than those in the normal rats; these lower haloperidol levels returned to be the levels in the normal rats 3 h after the administration of haloperidol. The volume of the portal vein blood flow significantly increased following the toxic haloperidol dose as compared with the volume pre-administration and following the therapeutic haloperidol dose in the normal rats. However, the volume did not change after the toxic or the therapeutic dose of haloperidol compared with pre-administration in rats with severe fatty liver disease, although it was significantly higher than in the normal rats. The pathway for haloperidol metabolism might have been saturated before the administration of haloperidol in rats with fatty liver disease; thus, it is possible that the blood concentration of haloperidol tends to be much higher in individuals with severe fatty liver disease than in those with normal livers in an inverse proportion to the dosage of haloperidol.


Arenimonas aquatica [corrected] sp. nov., a member of the gammaproteobacterium, isolated from a freshwater reservoir.
A novel bacterial strain, designated NA-09(T), was isolated from a freshwater sample collected from the Cheonho reservoir, Republic of Korea. Colonies were creamy-white pigmented, translucent, and circular with convex shape. The isolate was Gram-staining negative, strictly aerobic, motile, and rod-shaped. The 16S rRNA gene sequence analysis revealed that strain NA-09(T) belonged to the genus Arenimonas and showed the highest sequence similarities with Arenimonas malthae CC-JY-1(T) (95.4%), A. oryziterrae YC6267(T) (94.9%), A. composti P2-12-1(T) (94.8%), and A. donghaensis H03-R19(T) (94.1%). The major fatty acids were iso-C(16:0) (20.8%), iso-C(15:0) (16.9%), summed feature 1 (13.2%), and iso-C(16:1) ω7c alcohol (10.2%). The major isoprenoid quinone of the isolate was ubiquionone-8. On the basis of the data from the polyphasic characterization, the strain NA-09(T) represents a novel species, for which the name Arenimonas aquatica [corrected] sp. nov. is proposed (type strain NA-09(T) =KACC 14663(T) =NBRC 106550(T)).


The association between weather and the number of daily shootings in Chicago (2012-2016).
Previous studies have linked weather to crime and aggression but have not considered the causal structure of the variables included in the model(s). This cross-sectional study used data from 2012 to 2016 to measure the association between weather and the number of shootings in Chicago. The number of shootings per day was obtained via the Chicago Tribune (2012-2016). Daily high temperature, humidity, wind speed, difference in temperature from historical average, precipitation type and amount, were extracted via The Weather Underground. Weekend, holidays, and other non-school days were also included as possible effect measure modifiers. Causally-adjusted negative binomial regressions were used to evaluate the associations between the exposures of interest and daily number of shootings. A 10-degree (°C) higher temperature was significantly associated with 34% more shootings on weekdays, and 42% more shootings on weekends or holidays. A 10-degree higher temperature than average was also associated with 33.8% higher rate of shootings. In recent years, shootings in Chicago were more likely to happen on warm days and especially during the weekend or holidays. This finding is in-line with studies that have linked crime to higher temperature and also suggests that shootings may be related to when individuals are outside and more likely to encounter violence. Interventions that keep people inside, such as air-conditioning and summer programs for students, might be effective in reducing the number of shootings in Chicago. We believe using a causal structure is useful for understanding the link between weather and shootings.


Choledochal fungal ball. An unusual cause of biliary obstruction.
A 31-year-old patient with sickle-cell disease who had previous cholecystectomy developed acute onset of jaundice and abdominal pain. An endoscopic retrograde cholangiography demonstrated multiple filling defects within the bile ducts. Microscopic examination of "calculi" removed at surgery revealed that a fungal ball composed of Candida was the cause of biliary obstruction in this case. The patient eventually recovered after removal of the fungal masses and intrabiliary instillation of amphotericin.


Comprehensive host-pathogen protein-protein interaction network analysis.
Infectious diseases are a cruel assassin with millions of victims around the world each year. Understanding infectious mechanism of viruses is indispensable for their inhibition. One of the best ways of unveiling this mechanism is to investigate the host-pathogen protein-protein interaction network. In this paper we try to disclose many properties of this network. We focus on human as host and integrate experimentally 32,859 interaction between human proteins and virus proteins from several databases. We investigate different properties of human proteins targeted by virus proteins and find that most of them have a considerable high centrality scores in human intra protein-protein interaction network. Investigating human proteins network properties which are targeted by different virus proteins can help us to design multipurpose drugs. As host-pathogen protein-protein interaction network is a bipartite network and centrality measures for this type of networks are scarce, we proposed seven new centrality measures for analyzing bipartite networks. Applying them to different virus strains reveals unrandomness of attack strategies of virus proteins which could help us in drug design hence elevating the quality of life. They could also be used in detecting host essential proteins. Essential proteins are those whose functions are critical for survival of its host. One of the proposed centralities named diversity of predators, outperforms the other existing centralities in terms of detecting essential proteins and could be used as an optimal essential proteins' marker. Different centralities were applied to analyze human protein-protein interaction network and to detect characteristics of human proteins targeted by virus proteins. Moreover, seven new centralities were proposed to analyze host-pathogen protein-protein interaction network and to detect pathogens' favorite host protein victims. Comparing different centralities in detecting essential proteins reveals that diversity of predator (one of the proposed centralities) is the best essential protein marker.


Specific Associations between Anxiety Sensitivity Dimensions and Fear and Distress Dimensions of Emotional Distress Disorders.
Anxiety sensitivity (AS) comprises three lower-order dimensions, physical concerns, cognitive concerns, and social concerns, all of which are related to unipolar mood and anxiety disorders (emotional distress disorders). The pattern of these relations suggests that AS cognitive concerns might be best classified as associated with emotional distress disorders clustered together as distress disorders whereas AS physical concerns might be best classified as associated with emotional distress disorders clustered together as fear disorders. In contrast, AS social concerns appears to be generally associated with both fear and distress disorders. To test the specificity of lower-order AS dimensions, structural equation modeling was employed in a sample of 579 individuals (M age = 36.87 years, SD = 13.47; 51.6% male) constituting a sample at risk for psychopathology as these individuals were seeking smoking cessation treatment. AS physical concerns was associated with the fear disorders dimension, even when controlling for negative affect (NA). AS cognitive concerns was associated with the distress disorder dimension, only when the effects of NA were not included. Finally, AS social concerns demonstrated non-specific relations with both the distress and fear disorders dimensions. Given that measures of AS and psychopathology were collected concurrently, these findings cannot address the role of lower-order AS dimensions as risk factors for specific psychopathology clusters. These results provide further support for the hierarchical model of emotional distress disorders as well as implicate AS cognitive and physical concerns as important variables at the intermediate level of this model.


Does neighbourhood walkability moderate the effects of mass media communication strategies to promote regular physical activity?
Mass media campaigns are widely used in Australia and elsewhere to promote physical activity among adults. Neighbourhood walkability is consistently shown to be associated with walking and total activity. Campaigns may have different effects on individuals living in high and low walkable neighbourhoods. The purpose of this study is to compare pre- and post-campaign cognitive and behavioural impacts of the Heart Foundation's Find Thirty every day® campaign, in respondents living in high and lower walkable neighbourhoods. Pre- and post-campaign cross-sectional survey data were linked with objectively measured neighbourhood walkability. Cognitive and behavioural impacts were assessed using logistic regression stratified by walkability. Cognitive impacts were significantly higher post-campaign and consistently higher in respondents in high compared with lower walkable neighbourhoods. Post campaign sufficient activity was significantly higher and transport walking significantly lower, but only in residents of lower walkable areas. Cognitive impacts of mass media physical activity campaigns may be enhanced by living in a more walkable neighbourhood.


pHAPE: a plasmid for production of DNA size marker ladders for gel electrophoresis.
DNA size markers (also known as 'molecular weight markers' or 'DNA ladders') are an essential tool when using gel electrophoresis to identify and purify nucleic acids. However, the cost of these DNA ladders is not insignificant and, over time, impinges on the funds available for research and training in molecular biology. Here, we describe a method for the generation of 'pHAPE', a plasmid from which a variety of DNA ladders can be generated via simple restriction enzyme digestions. The pHAPE plasmid can be generated by mutagenesis of the commonly used pBluescript II SK+ phagemid followed by insertion of a 7141 bp sequence (comprised of three smaller, synthetic fragments). Our use of pHAPE allows us some small relief from the ever-rising costs of performing molecular biology experiments ('Don't worry, pHAPE').


Sinonasal squamous cell carcinomas: clinical outcomes and predictive factors.
This was a retrospective study of 33 patients treated for sinonasal squamous cell carcinoma between 1995 and 2008. Epidemiological, clinical, histological, and therapeutic aspects of this series of patients were analysed, and their impacts on overall survival and disease-free survival established using the Kaplan-Meier method. A search for prognostic factors was made using a log-rank test. There were 27 men. The average age at diagnosis was 64.7 years. Tobacco-smoking was found to be a risk factor in 24 patients (72.7%). The median follow-up was 66 months (range 0-99 months). Tumours were classified as T1 in 18.3%, T2 in 27.3%, T3 in 6%, and T4 in 48.5% of cases. Disease-free survival rates at 1 and 5 years were 58.5% and 46.1%, respectively, and overall survival rates were 70.3% and 40%, respectively. Overall survival was correlated to tumour status (TNM, American Joint Committee on Cancer) (P = 0.010) and involvement of key structures (skull base, dura mater, brain, orbit, cavernous sinus, infratemporal fossa, skin) (P = 0.049). Surgery followed by radiotherapy improved overall survival (P = 0.005) and disease-free survival (P = 0.028) when compared to other treatment modalities. When compared to surgery alone, it improved disease-free survival (P = 0.049) regardless of tumour stage.


Fasting serum concentration of short-chain fatty acids in subjects with microscopic colitis and celiac disease: no difference compared with controls, but between genders.
Short-chain fatty acids (SCFAs), particularly propionic and butyric acids, have been shown to have many positive health effects. The amount and type of SCFAs formed from dietary fibre by the colonic microbiota depends on the substrate available and is reflected in blood. The total intake and type of dietary fibre in people with gastrointestinal diseases differs considerably from healthy subjects. To compare fasting SCFA concentrations in subjects with microscopic colitis (MC), celiac disease and controls without these diseases. SCFAs were also analysed over 6.5 h in young healthy subjects, who had eaten a fibre-rich breakfast, to identify a possible peak concentration of SCFAs after a meal. SCFAs in serum were pre-concentrated using hollow fibre-supported liquid membrane extraction and gas chromatography. The MC group had a higher concentration of valeric acid than the control group (p < 0.01). No significant differences in other SCFA concentrations were seen between groups, but the control group tended to have higher concentration of acetic acid (p = 0.1). Furthermore, males had higher concentrations of SCFAs (with the exception of valeric acid) than females (p < 0.05), which were independent of groups. The peaks for acetic, propionic and butyric acids came approximately 5 h, 6.5 h and 2-3 h, respectively, after breakfast. The fasting concentrations of SCFAs were quite similar, although the fibre intake had probably been quite different for a long time. The results might have been different if SCFAs had been recorded over a longer period.


Identification of Happyhour/MAP4K as Alternative Hpo/Mst-like Kinases in the Hippo Kinase Cascade.
In Drosophila and mammals, the canonical Hippo kinase cascade is mediated by Hpo/Mst acting through the intermediary kinase Wts/Lats to phosphorylate the transcriptional coactivator Yki/YAP/TAZ. Despite recent reports linking Yki/YAP/TAZ activity to the actin cytoskeleton, the underlying mechanisms are poorly understood and/or controversial. Using Drosophila imaginal discs as an in vivo model, we show that Wts, but not Hpo, is genetically indispensable for cytoskeleton-mediated subcellular localization of Yki. Through a systematic screen, we identify the Ste-20 kinase Happyhour (Hppy) and its mammalian counterpart MAP4K1/2/3/5 as an alternative kinase that phosphorylates the hydrophobic motif of Wts/Lats in a similar manner as Hpo/Mst. Consistent with their redundant function as activating kinases of Wts/Lats, combined loss of Hpo/Mst and Hppy/MAP4K abolishes cytoskeleton-mediated regulation of Yki/YAP subcellular localization, as well as YAP cytoplasmic translocation induced by contact inhibition. These Hpo/Mst-like kinases provide an expanded view of the Hippo kinase cascade in development and physiology.


Selection of patients for heart transplantation in the current era of heart failure therapy.
We sought to assess the relationship between survival, peak exercise oxygen consumption (VO(2)), and heart failure survival score (HFSS) in the current era of heart failure (HF) therapy. Based on predicted survival, HF patients with peak VO(2) <14 ml/min/kg or medium- to high-risk HFSS are currently considered eligible for heart transplantation. However, these criteria were developed before the widespread use of beta-blockers, spironolactone, and defibrillators-interventions known to improve the survival of HF patients. Peak VO(2) and HFSS were assessed in 320 patients followed from 1994 to 1997 (past era) and in 187 patients followed from 1999 to 2001 (current era). Outcomes were compared between these two groups of patients and those who underwent heart transplantation from 1993 to 2000. Survival in the past era was 78% at one year and 67% at two years, as compared with 88% and 79%, respectively, in the current era (both p < 0.01). One-year event-free survival (without urgent transplantation or left ventricular assist device) was improved in the current era, regardless of initial peak VO(2): 64% vs. 48% for peak VO(2) <10 ml/min/kg (p = 0.09), 81% vs. 70% for 10 to 14 ml/min/kg (p = 0.05), and 93% vs. 82% for >14 ml/min/kg (p = 0.04). Of the patients with peak VO(2) of 10 to 14 ml/min/kg, 55% had low-risk HFSS and exhibited 88% one-year event-free survival. One-year survival after transplantation was 88%, which is similar to the 85% rate reported by the United Network for Organ Sharing for 1999 to 2000. Survival for HF patients in the current era has improved significantly, necessitating re-evaluation of the listing criteria for heart transplantation.


Assessment of COVID-19 lung involvement on computed tomography by deep-learning-, threshold-, and human reader-based approaches-an international, multi-center comparative study.
The extent of lung involvement in coronavirus disease 2019 (COVID-19) pneumonia, quantified on computed tomography (CT), is an established biomarker for prognosis and guides clinical decision-making. The clinical standard is semi-quantitative scoring of lung involvement by an experienced reader. We aim to compare the performance of automated deep-learning- and threshold-based methods to the manual semi-quantitative lung scoring. Further, we aim to investigate an optimal threshold for quantification of involved lung in COVID pneumonia chest CT, using a multi-center dataset. In total 250 patients were included, 50 consecutive patients with RT-PCR confirmed COVID-19 from our local institutional database, and another 200 patients from four international datasets (n=50 each). Lung involvement was scored semi-quantitatively by three experienced radiologists according to the established chest CT score (CCS) ranging from 0-25. Inter-rater reliability was reported by the intraclass correlation coefficient (ICC). Deep-learning-based segmentation of ground-glass and consolidation was obtained by CT Pulmo Auto Results prototype plugin on IntelliSpace Discovery (Philips Healthcare, The Netherlands). Threshold-based segmentation of involved lung was implemented using an open-source tool for whole-lung segmentation under the presence of severe pathologies (R231CovidWeb, Hofmanninger et al., 2020) and consecutive quantitative assessment of lung attenuation. The best threshold was investigated by training and testing a linear regression of deep-learning and threshold-based results in a five-fold cross validation strategy. Median CCS among 250 evaluated patients was 10 [6-15]. Inter-rater reliability of the CCS was excellent [ICC 0.97 (0.97-0.98)]. Best attenuation threshold for identification of involved lung was -522 HU. While the relationship of deep-learning- and threshold-based quantification was linear and strong (r2 deep-learning vs. threshold=0.84), both automated quantification methods translated to the semi-quantitative CCS in a non-linear fashion, with an increasing slope towards higher CCS (r2 deep-learning vs. CCS= 0.80, r2 threshold vs. CCS=0.63). The manual semi-quantitative CCS underestimates the extent of COVID pneumonia in higher score ranges, which limits its clinical usefulness in cases of severe disease. Clinical implementation of fully automated methods, such as deep-learning or threshold-based approaches (best threshold in our multi-center dataset: -522 HU), might save time of trained personnel, abolish inter-reader variability, and allow for truly quantitative, linear assessment of COVID lung involvement.


Influence of Ionic Liquids on an Iron(III) Catalyzed Three-Component Coupling/Hydroarylation/Dehydrogenation Tandem Reaction.
A three-component oxidative dehydrogenation tandem reaction via the coupling and hydroarylation of benzaldehyde, aniline and phenylacetylene to a quinoline derivate was catalyzed by an iron-containing ionic liquid. The reaction was air mediated and could be performed under neat conditions. The iron(III) of the ionic liquid was the oxidizing species.


Resistance pattern and assessment of phenicol agents' minimum inhibitory concentration in multiple drug resistant Chryseobacterium isolates from fish and aquatic habitats.
To assess the susceptibility of Chryseobacterium isolates of fish and aquatic habitats to antimicrobial compounds. Special attention was paid to the resistance to chloramphenicol and florfenicol, a phenicol derivative recently licensed for use in veterinary medicine and fish farming. Sixty-seven Chryseobacterium spp. isolates and reference strains, originating mainly from different aquatic habitats, were tested using the disk-diffusion method. In addition, agar dilution was used for assessing minimum inhibitory concentration of chloramphenicol and florfenicol. In spite of (i) conditions that hampered properly standardized experiments and (ii) the heterogeneity of the isolates resulting in some aberrant values in diffusion, correlation between the two methods was confirmed. Most of the isolates exhibited considerable multiresistance to most antimicrobial drug families, and many were clearly resistant to phenicols. Molecular investigations conducted on 10 strains selected for high resistance to florfenicol did not establish the existence of floR or cmlA genes currently reported in the literature as responsible for florfenicol resistance. Nevertheless, when an efflux pump inhibitor, phenyl-arginin-beta-naphthylamide, was combined with diffusion tests, drug susceptibility to florfenicol was restored, suggesting that Chryseobacterium's resistance to this molecule is under the control of efflux mechanisms. Constitutive multiresistance to antibiotics is common in chryseobacteria isolated from the aquatic environment. Although no gene related to the floR family could be detected, efflux mechanisms could partly support the resistance to phenicols. These results explain the difficulty of treatment and clearly reflect the properties previously reported in Chryseobacterium isolates of human origin. Because several species have been involved in opportunistic infections in humans, the possible role of aquatic organisms as a source of infection should be considered.


Novel and prevalent CYP11B1 gene mutations in Turkish patients with 11-β hydroxylase deficiency.
11β-Hydroxylase deficiency is the second most frequent type of congenital adrenal hyperplasia and is more common in those of Turkish descent than in other populations. The purpose of this study is to examine the spectrum of CYP11B1 gene mutations in Turkish patients with 11β-hydroxylase deficiency. Twenty-eight patients from 24 families, ages ranging from 0.1 to 7 years, were included in the study. Clinical diagnosis was based on virilization and high levels of 11-deoxycortisol. Twenty-six cases exhibited the classical and 2 cases the non-classical form. Mutation screening of 9 CYP11B1 exons was performed by direct DNA sequence analysis, specifically amplifying CYP11B1 gene fragments while avoiding simultaneous amplification of homologous CYP11B2 gene sequences. Seventeen different mutations were detected, 6 of which are novel (p.Gln189Hisfs*70, p.Glu198Gly, p.Thr318Lys, p.Gly446Ser, IVS8+5G>C and exon 3-5 del). All of the identified mutations resulted in the classical form with severe virilization, except for the p.Gly446Ser mutation, which caused a late-onset type of 11β-hydroxylase deficiency. The c.954G>A;p.Thr318Thr mutation was the most common in our cohort, with an allele frequency of 14.6%.Of the CYP11B1 gene mutations detected, 75% were found in exons 3, 5 and 7 and the half of the mutations were nonsense, splice site, deletion or insertion mutations, causing severe virilization in female patients. The findings are important for genetic counseling and the prenatal diagnosis of Turkish patients with 11β-hydroxylase deficiency.


Fatigue failure of cortical bone screws.
An experimental study of the fatigue life of cortical bone screws under conditions which stimulated in vivo usage was performed. The two most important factors influencing fatigue life were axial screw tension (the force normal of the plate to bone) and the cyclic shearing load. All screws failed at the root of the thread in the interface between the plate and the bone. A modified screw design effectively resisted fatigue under the described experimental conditions.


Late screw-related complications in locking plating of proximal humerus fractures: A systematic review.
Locking plating is a common surgical treatment of proximal humeral fractures with satisfactory clinical results. Implant-related complications, especially screw-related, have been reported, however, the lack of information regarding their onset, used surgical technique, complexity of the fracture, bone quality etc., prevents from understanding the causes for them. The aim of this systematic review is to identify the potential risk factors for late screw complications by gathering information about the patient characteristics, comorbidities, fracture types, surgical approaches and implant types. A PubMed search was performed using humerus, fractures, bone and locking as keywords in clinical papers written in English. All abstracts and manuscripts on distal or humerus shaft fractures, and those on proximal humerus fractures without any or with only iatrogenic complications were excluded. One hundred studies met the inclusion criteria, resulting in 33% of the reported cases having at least one complication, with 11% of all complications being screw-related. Most of the latter were secondary screw perforations and screw cut-outs, being predominantly linked to poor bone quality, while screw loosening and retraction were found less frequently as a result of locking mechanism failure. Overall, the amount of information for complications was limited and screw perforation was the most frequent screw-related complication, mostly reported in female patients older than 50 years, following four-part or AO/OTA type C fractures and detected four weeks postoperatively. The sparse information in the literature could be an indicator that the late screw complications might have been under-reported and under-described, making the understanding of the screw-related complications even more challenging.


Baclofen promotes alcohol abstinence in alcohol dependent cirrhotic patients with hepatitis C virus (HCV) infection.
Hepatitis C virus (HCV) and alcoholic liver disease (ALD), either alone or in combination, count for more than two thirds of all liver diseases in the Western world. There is no safe level of drinking in HCV-infected patients and the most effective goal for these patients is total abstinence. Baclofen, a GABA(B) receptor agonist, represents a promising pharmacotherapy for alcohol dependence (AD). Previously, we performed a randomized clinical trial (RCT), which demonstrated the safety and efficacy of baclofen in patients affected by AD and cirrhosis. The goal of this post-hoc analysis was to explore baclofen's effect in a subgroup of alcohol-dependent HCV-infected cirrhotic patients. Any patient with HCV infection was selected for this analysis. Among the 84 subjects randomized in the main trial, 24 alcohol-dependent cirrhotic patients had a HCV infection; 12 received baclofen 10mg t.i.d. and 12 received placebo for 12-weeks. With respect to the placebo group (3/12, 25.0%), a significantly higher number of patients who achieved and maintained total alcohol abstinence was found in the baclofen group (10/12, 83.3%; p=0.0123). Furthermore, in the baclofen group, compared to placebo, there was a significantly higher increase in albumin values from baseline (p=0.0132) and a trend toward a significant reduction in INR levels from baseline (p=0.0716). In conclusion, baclofen was safe and significantly more effective than placebo in promoting alcohol abstinence, and improving some Liver Function Tests (LFTs) (i.e. albumin, INR) in alcohol-dependent HCV-infected cirrhotic patients. Baclofen may represent a clinically relevant alcohol pharmacotherapy for these patients.


Vertigo: Incidences, Diagnosis and Its Relations with Hearing Loss.
Vertigo is one of the most common complaints in our regular practice. Vertigo is of peripheral or central cause. The association of vertigo with or without hearing loss helps to narrow the differential diagnosis. The aim of the study is to evaluate the various causes of vertigo based on the vertigo attacks and hearing loss.


Antioxidant, antimicrobial, 15-LOX, and AGEs inhibitions by pineapple stem waste.
Pineapple stem has been extensively used for bromelain extraction; however, almost no attention has been given to the waste obtained during bromelain manufacturing. In this regard, antioxidant, antimicrobial, and inhibitions against 15-lipoxygenase and advanced glycation end product formations by pineapple stem waste (PSW) obtained during bromelain manufacturing process were studied. The PSW had moderate bioactivities in all the performed assays. It also showed a considerable inhibition against fungal growth, probably due to high amounts of the benzoic acid present in the sample. These results indicate that PSW could be utilized as an economic source of preventive or therapeutic agent in disease and in different functional food industries. A large amount of wastes are generated during bromelain manufacturing from pineapple stem. So far, these wastes are not utilized and are often considered as a burden while disposing them. However, we found some important phytochemicals with considerable bioactivities in these wastes. We believe that these wastes may have a promising usage as a cheap source of one of the ingredients in functional food based industries.


Frontotemporal dementia: from Mendelian genetics towards genome wide association studies.
Frontotemporal lobar degeneration is the most common cause of dementia of non-Alzheimer's type worldwide. It manifests, clinically, with behavioural changes and language impairment and is pathologically associated with tau- or ubiquitin-positive inclusions detected in neurons and glial cells of the frontal and temporal lobes in the brain. Genetic variations in the microtubule-associated protein tau and progranulin genes explain almost 50% of familial cases, whilst variations in TAR DNA-binding protein, charged multivescicular body protein 2B, valosin-containing protein and fused in sarcoma genes contribute to <5% of cases. The rapidly developing investigative techniques available to geneticists such as genome-wide association studies, whole-exome sequencing and, soon, whole-genome sequencing promise to contribute to the unravelling of the genetic architecture of this complex disease and, in the future, to the development of more sensitive, accurate and effective diagnostic and treatment measures.


Blackouts and hangover experiences among Hispanic and Non-Hispanic White college students.
Blackouts and hangovers may negatively impact college students' health and productivity. However, few studies have considered the impact of cultural differences on students' individual experiences with blackouts and hangovers. To address this issue, the current study explored the potential relationships of shame and resilience with Hispanic (n = 381) and non-Hispanic White (NHW, n = 332) students' self-reported blackouts and hangover experiences. Students completed an online survey measuring shame, resilience, presence of lifetime blackout experiences preceding a hangover, and past-year hangover severity. Analyses included separate path models examining shame and resilience, and the interaction between shame and resilience with Hispanic ethnicity in relation to blackouts and hangover experiences. Significant pathways emerged between resilience, but not shame, and blackouts and hangover experiences. A subscale of resilience reflecting personal competence and tenacity was related to greater likelihood of reporting blackouts and greater hangover severity for Hispanics but not NHW students. Conversely, a dimension of resilience characterized by trusting one's instincts and tolerance of negative affect was related to a lower likelihood of reporting a blackout preceding a hangover for Hispanics but not NHW students. Finally, a resilience subscale associated with spiritual influences was positively related to blackouts in the participant population as a whole. These results reinforce the notion that resilience is an important target for intervention and prevention of hazardous drinking, but reveal that it may have both positive and negative effects in college students, which may differ by ethnicity.


Immunoelectron microscopic localization of nitric oxide synthase III in the guinea pig organ of Corti.
Nitric oxide synthase III (NOS III) was identified in the guinea pig cochlea on an ultrastructural level using a post-embedding immunolabeling procedure. Ultrathin sections of London Resin (LR) White-embedded specimens were incubated with various concentrations of a commercially available antibody to NOS III and the immunoreactivity visualized by a gold-labeled secondary antibody. Analysis of ultrathin sections of the organ of Corti in the second turn of the cochlea showed that NOS III could be localized in the endothelial cells of the blood vessels under the basilar membrane, which was comparable to its location in similar cells types in various biological systems. Besides this, NOS III was also found in the cytoplasm and in the nuclei of inner and outer hair cells. Immunoreactivity was not distributed homogeneously within receptor cells. Numerous gold particles could be identified at the border of the cuticular plates, in the middle parts of the stereocilia and in the cytoplasm. Gold-labeled anti-NOS III antibodies in these sites were seen mostly on the cytoplasmic side of the submembranous cisterns in the vicinity of mitochondria and in the central parts of the hair cells, whereas the cisterns were nearly free from any immunoreactivity. NOS III was also detected in the efferent and afferent nerve endings that were located at the basal and basolateral side of the outer hair cells. Some immunoreactivity was visible in different nerve fibers of the inner and outer spiral tunnels. Besides this, gold-labeled antibodies were also present in the cuticular plate of inner and outer pillar cells, in the cytoskeletal elements located in the apical parts of Deiters cells, forming the lamina reticularis, and in the cytoskeletal-containing region of the cytoplasm of those Deiters cells located at the basal side of the outer hair cells. The role of the NOS III immunoreactivity identified in the organ of Corti was consistent with respect to hair cell and tissue modulation.


Influences of different surface oxygen species on oxidation of toluene and/or benzene and their reaction pathways over Cu-Mn metal oxides.
Catalytic oxidation is considered as the most effective and economical method to remove low concentration volatile organic compounds (VOCs). Activation of oxygen to form active oxygen species on metal oxides catalyst plays a key role in the process. Three copper-manganese oxide catalysts with cubic Cu1.5Mn1.5O4 phases were prepared by microwave heating (CM-MW), sol-gel (CM-SG) and co-precipitation (CM-CP) methods, and applied for the elimination of toluene and benzene as representative aromatic VOCs. These catalysts exhibit different catalytic oxidation performance due to their different physicochemical properties. Various characterizations were used to clarify the role of different oxygen species in the oxidation of VOCs, and the reaction pathway. In situ DRIFTS were carried out to explore the function of surface adsorbed oxygen, oxygen vacancy, and surface lattice oxygen in the catalytic oxidation of VOCs over three catalysts. Various types of intermediate species and detailed reaction pathways are also explored by combining in situ DRIFTS and mass spectrometry. Among these catalysts, CM-MW with nanosheet morphology shows the best catalytic oxidation performance of toluene and/or benzene with/without H2O due to the most abundant active oxygen species, and the highest oxygen vacancy concentration which is beneficial to activate oxygen. Meanwhile, toluene and benzene do not interfere with each other during the mixture oxidation. This study can provide new inspiration for rational design of metal oxide catalysts to remove VOCs.


Polyheterocyclic peptidomimetics: Parallel solid phase synthesis of oligo cyclic guanidines and their inhibition activity against Mycobacterium tuberculosis DNA gyrase.
Polyheterocycles are one of the most desired synthetic targets due to their numerous and valuable applications in various fields. We report the design and the parallel synthesis of novel linear oligocyclic guanidine peptidomimetics from predesigned reduced polyamides. A screening of these compounds identified active Mycobacterium tuberculosis DNA gyrase inhibitors which do not inhibit human DNA topoisomerase IIα and topoisomerase I.


A head-to-head comparison of the degradation rate of resorbable bioceramics.
Resorbable bioceramics offer advantages in healing bone defects due to their degradation capability. Degradation rates differ significantly from one bioceramic to another; nevertheless, the degradation rate should match the growth rate of new bone. In the present study, a head-to-head comparison of the degradation rate of calcium sulfate and tricalcium phosphate is conducted. First, the degradation behaviors of calcium sulfate and tricalcium phosphate are evaluated separately. The comparison indicates that the degradation rate of calcium sulfate is one order of magnitude faster than that of tricalcium phosphate. Along with a fast degradation rate, the formation of calcium phosphate on the surface of calcium sulfate pellets is also faster. A core-shell roll composed of a calcium sulfate core and a tricalcium phosphate shell is also prepared. After soaking the core-shell roll in phosphate buffered saline solution for 24 h, calcium phosphate precipitates form only on the surface of core, the part containing calcium sulfate anhydrite.


Erratum to prophylaxis of breast cancer chemotherapy for bone marrow toxicity: more individualized and safer.
[This corrects the article DOI: 10.21037/atm.2019.12.50.].


B cell antigen receptors of the IgM and IgD classes are clustered in different protein islands that are altered during B cell activation.
The B cell antigen receptors (BCRs) play an important role in the clonal selection of B cells and their differentiation into antibody-secreting plasma cells. Mature B cells have both immunoglobulin M (IgM) and IgD types of BCRs, which have identical antigen-binding sites and are both associated with the signaling subunits Igα and Igβ, but differ in their membrane-bound heavy chain isoforms. By two-color direct stochastic optical reconstruction microscopy (dSTORM), we showed that IgM-BCRs and IgD-BCRs reside in the plasma membrane in different protein islands with average sizes of 150 and 240 nm, respectively. Upon B cell activation, the BCR protein islands became smaller and more dispersed such that the IgM-BCRs and IgD-BCRs were found in close proximity to each other. Moreover, specific stimulation of one class of BCR had minimal effects on the organization of the other. These conclusions were supported by the findings from two-marker transmission electron microscopy and proximity ligation assays. Together, these data provide evidence for a preformed multimeric organization of BCRs on the plasma membrane that is remodeled after B cell activation.


Neurocognitive Outcomes in Multiethnic Pediatric Brain Tumor Patients Treated With Proton Versus Photon Radiation.
We analyzed post-radiation (RT) neurocognitive outcomes in an ethnically diverse pediatric brain tumor population undergoing photon radiotherapy (XRT) and proton radiotherapy (PRT). Post-RT neurocognitive outcomes from 49 pediatric patients (37% Hispanic/Latino) with primary brain tumors were analyzed. Tests included cognitive outcomes, behavioral outcomes, and overall intelligence. For each outcome, proportion of patients with cognitive impairment (scores <1.5 SD) was calculated. The Fisher exact tests compared proportion of patients with impairment and t tests compared T-scores between XRT (n=32) and PRT (n=17) groups. Linear regression assessed associations between radiation modality and outcomes. Median follow-up was 3.2 and 1.8 years in the XRT and PRT groups, respectively. The median RT dose was 54.0 Gy. We found impairment in 16% to 42% of patients across most neurocognitive domains except executive function. There was no difference in scores between XRT and PRT groups. Regression analyses revealed no association of neurocognitive outcomes with radiation modality. Non-Hispanic patients had better Verbal Comprehension Index and General Ability Index scores than Hispanic patients ( P <0.05). Among pediatric patients with brain tumors receiving RT, all cognitive domains were affected except executive function. Radiation modality was not associated with neurocognitive outcomes. Hispanic patients may be more vulnerable to posttreatment cognitive effects that warrant further study.


History of malaria control in Tajikistan and rapid malaria appraisal in an agro-ecological setting.
Reported malaria cases in rice growing areas in western Tajikistan were at the root of a rapid appraisal of the local malaria situation in a selected agro-ecological setting where only scarce information was available. The rapid appraisal was complemented by a review of the epidemiology and control of malaria in Tajikistan and Central Asia from 1920 until today. Following a resurgence in the 1990s, malaria transmission has been reduced considerably in Tajikistan as a result of concerted efforts by the government and international agencies. The goal for 2015 is transmission interruption, with control interventions and surveillance currently concentrated in the South, where foci of Plasmodium vivax and Plasmodium falciparum persist. The rapid malaria appraisal was carried out in six communities of irrigated rice cultivation during the peak of malaria transmission (August/September 2007) in western Tajikistan. In a cross-sectional survey, blood samples were taken from 363 schoolchildren and examined for Plasmodium under a light microscope. A total of 56 farmers were interviewed about agricultural activities and malaria. Potential Anopheles breeding sites were characterized using standardized procedures. A literature review on the epidemiology and control of malaria in Tajikistan was conducted. One case of P. vivax was detected among the 363 schoolchildren examined (0.28%). The interviewees reported to protect themselves against mosquito bites and used their own concepts on fever conditions, which do not distinguish between malaria and other diseases. Three potential malaria vectors were identified, i.e. Anopheles superpictus, Anopheles pulcherrimus and Anopheles hyrcanus in 58 of the 73 breeding sites examined (79.5%). Rice paddies, natural creeks and man-made ponds were the most important Anopheles habitats. The presence of malaria vectors and parasite reservoirs, low awareness of, and protection against malaria in the face of population movements and inadequate surveillance may render local communities vulnerable to potential epidemics. To attain malaria transmission interruption in Tajikistan by 2015, there is a need for rigorous surveillance along with strengthening of primary health care facilities for effective case management, and possibly a more differentiated vector control strategy based on additional local evidence.


HIV rumbles on in the south of the USA.
Poverty within the USA seems to be the defining characteristic for regional HIV risk, and entrenched political positions are hampering progress. Talha Burki reports.


Localization of multidomain adaptor proteins, p140Cap and vinexin, in the pancreatic islet of a spontaneous diabetes mellitus model, Otsuka Long-Evans Tokushima Fatty rats.
We have shown that two multidomain adaptor proteins, p140Cap and vinexin, interact with each other and are likely to be involved in neurotransmitter release. Because the basic molecular mechanism governing neurotransmitter and insulin secretion is conserved, these two proteins may also to play pivotal roles in insulin secretion. We therefore performed some characterization of p140Cap and vinexin in pancreas of a wild-type rat or a spontaneous type 2 diabetes mellitus (DM) model, the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. These two proteins were detected in Wistar rat pancreas by Western blotting. Immunohistochemistry revealed that p140Cap and vinexin are enriched in β and α cells, respectively, in the rat pancreas. We then found that pancreatic islet structure was disorganized in the OLETF rat with hyperinsulinemia or with hyperglycemia, based on immunohistochemical analyses of vinexin. In β cells of these model rats, p140Cap was distributed in a cytoplasmic granular pattern as in the control rats, although its expression was reduced to various extents from cell to cell. These results may suggest possible involvement of p140Cap in insulin secretion, and reduction of p140Cap might be related to abnormal insulin secretion in DM.


A Review on Recent Technologies and Patents on Silica Nanoparticles for Cancer Treatment and Diagnosis.
Cancer is a condition in which some cells in the body grow uncontrollably and can also spread in other parts of the body. Among males, oral and lung cancers account for 25 % cancer deaths, while in females, breast and oral cancers cause 25% death. Breast and cervical cancers are the underlying cause of the high mortality rate among women. Owing to limitations of conventional cancer therapy like low drug specificity, less solubility, multidrug resistance, poor access to tumor cells and low bioavailability development of environmentally sensitive and target specific nanocarriers are imperative. The objective of this study is to review advancements made in techniques to synthesize Mesoporous Silica Nanoparticles (MSN's) as well as strategies to functionalize its silanol group for site-specific drug release in the tumor environment and to review recent patents published regarding it. To describe rationale for selection of MSN's for cancer theranostics amidst other nanocarriers developed. In the first section of this review, the physical and chemical properties of MSNs making it an ideal delivery system for cancer therapy and diagnostics are discussed. In the next section, various techniques involved in synthesizing and loading MSNs, including the influence of basic components of MSNs and reaction conditions on its properties are reviewed. Then the wide application of MSNs and various exogenous and endogenous stimuli harnessed for site-specific delivery of cargo and recent patents on modifying environmental conditions for large scale synthesis of MSNs and its active targeting for cancer treatment and bioimaging are discussed. Physico-chemical properties and synthetic protocols of MSNs justifying them to be a promising nanovector to overcome the ill effects of traditional chemotherapy. The superlative attributes of MSNs including, tunable size, morphology, high load volume, stability, ease of modifying external and internal surface leverage applications in various dimensions of therapeutics, diagnostics, and combinatorial drug delivery. MSNs surface functionalization can be harnessed for passive and active targeting by either coating the surface with polymers or attaching various ligands. An ideal nano-carrier must have high loading efficiency, easily detectable, and must have stimuli's sensitive, site-specific drug release. The patent study explores new dimensions on MSNs synthesis by claiming new cost-effective templates and silica source, a more safe environment for synthesis, reducing synthesis steps, duration of reaction, effective loading of low solubility drugs by magnetized nanocarriers, pathogen-specific release and development of novel photoluminescent rechargeable MSNs under mild conditions. It's a challenging task for researchers to successfully translate their prototypes to industries and make it feasible for commercialization. We can further work on excellent targeting concepts and architecture of MSNs for the increased opportunity in cancer theranostics.


Strain-specificity in nicotine attenuation of phencyclidine-induced disruption of prepulse inhibition in mice: relevance to smoking in schizophrenia patients.
Schizophrenia patients may exhibit high tobacco smoking rates in part to self-medicate sensory gating deficits with nicotine contained in tobacco. To test this hypothesis, we induced sensori-motor gating deficits in four mouse strains with phencyclidine, a noncompetitive antagonist of glutamatergic N -methyl-d-aspartate receptors. Nicotine attenuated the disruption in prepulse inhibition induced by phencyclidine in DBA/2J and C3H/HeJ but not in C57BL/6J or 129T2/SvEmsJ mice. These results highlight genetic variations in the regulation by nicotinic cholinergic systems of the dysfunction in glutamatergic transmission contributing to gating deficits in schizophrenia. Further, these findings support the hypothesis of self-medication of gating deficits in schizophrenia through tobacco smoking, and suggest that treatments targeting genetic dysfunctions in nicotinic-glutamatergic interactions that would treat cognitive deficits will assist schizophrenia patients in minimizing tobacco smoking.


Aggregation of activated platelets with Walker 256 carcinoma cells.
Walker 256 carcinoma cells form irreversible aggregates with rat platelets activated by ADP or serotonin. Since serotonin induces platelet shape change but not platelet aggregation the degree of activation indicated by the disc-sphere transformation is sufficient for platelets to interact with these tumor cells. This is confirmed by experiments with spheroid washed platelets which form irreversible mixed aggregates with Walker 256 carcinoma cells without a stimulus being required. This type of tumor cells could react with platelets in vivo, provided the platelets are activated by disturbed blood flow or contact with subendothelium. Our observations can explain why other authors found no interaction between Walker 256 carcinoma cells and non-activated platelets in vitro even though platelets contributed to the formation of bloodborne metastases of this tumor.


DNA replication-associated inborn errors of immunity.
Inborn errors of immunity are a heterogeneous group of monogenic immunologic disorders caused by mutations in genes with critical roles in the development, maintenance, or function of the immune system. The genetic basis is frequently a mutation in a gene with restricted expression and/or function in immune cells, leading to an immune disorder. Several classes of inborn errors of immunity, however, result from mutation in genes that are ubiquitously expressed. Despite the genes participating in cellular processes conserved between cell types, immune cells are disproportionally affected, leading to inborn errors of immunity. Mutations in DNA replication, DNA repair, or DNA damage response factors can result in monogenic human disease, some of which are classified as inborn errors of immunity. Genetic defects in the DNA repair machinery are a well-known cause of T-B-NK+ severe combined immunodeficiency. An emerging class of inborn errors of immunity is those caused by mutations in DNA replication factors. Considerable heterogeneity exists within the DNA replication-associated inborn errors of immunity, with diverse immunologic defects and clinical manifestations observed. These differences are suggestive for differential sensitivity of certain leukocyte subsets to deficiencies in specific DNA replication factors. Here, we provide an overview of DNA replication-associated inborn errors of immunity and discuss the emerging mechanistic insights that can explain the observed immunologic heterogeneity.


The urethral plate--does it grow into the genital tubercle or within it?
To determine whether the urethral plate grows into the genital tubercle or develops within it. Sprague-Dawley rat embryos were examined at 11-21 days of gestation and compared with available human embryo sections. Rat embryos were examined by a combination of light microscopy, dissection, serial histological section and immunohistochemistry. In rat embryos the urethral plate extended to the tip of the genital tubercle from the earliest stages of genital tubercle development. The plate formed from adherence in the sagittal plane of the inner walls of the primitive cloacal cavity. The urethral plate continued to extend to the tip of the genital tubercle throughout penile development in the male and developed a lumen ahead of the advancing perineal mesenchyme. In the female the perineal side of the urethral plate disintegrated by massive apoptosis. This loss of perineal substance allowed the genital tubercle to collapse on itself and left the urogenital opening at the base of the genital tubercle. Human embryos also showed the presence of the urethral plate at the tip of the genital tubercle throughout genital tubercle development. The urethral plate forms ab initio within the genital tubercle and extends to the tip; it does not grow into the genital tubercle as is often described. The contribution of ectodermal ingrowth to urethral development at the tip of the penis is minimal.


DIP2C expression in breast cancer and its clinical significance.
The aim of this study was to investigate DIP2C expression in different subtypes of breast cancer tissues and cell lines and its correlation with clinicopathologic and histopathological features, in an effort to elucidate the DIP2C expression profile in breast cancer and its clinical significance. Hereby, we investigated the DIP2C expression in breast cancer tissues using TMA-IHC method and the DIP2C expression in breast cell lines using quantitative RT-PCR. DIP2C displayed universal expression, being present in all the breast cancer subtypes. There were more cases that staining weakly in breast cancer tissues (n=79/150, 52.7%) than that in fibroadenomas tissues (n=2/18, 11.1%) and normal tissues (n=2/20, 10.0%) (χ2=21.84, P <0.001). Within different intrinsic subtypes of breast cancer assayed by IHC expression profiles, there were less cases of the strongly staining group in basal-like subtype (n=38/86, 44.2%) and HER-2 subtype (n=6/24, 25.0%) than that in luminal A (14/20, 70%) and luminal B (13/20, 65%) subtypes (χ2=11.77, p=0.008). Furthermore, DIP2C expression was positive correlated with ER (χ2=8.90, p=0.003) and PR expression (χ2=10.94, p=0.001), while negative correlated with EGFR expression (χ2=9.27, p=0.002), in accordance with the results of cell lines with different subtypes. Oncomine database also confirmed that, DIP2C was expressed lower in breast cancer tissues, and could indicate prognosis. our data revealed DIP2C expression level decreased in breast cancer, especially in basal-like and HER-2 subtypes, and could be a valuable target for diagnosis on specific subtype of breast cancer.


Streptokinase Is Still the Agent of Choice for Most Patients with Myocardial Infarction.
I believe streptokinase is still the trombolytic of choice for the majority of patients with acute myocardial infarction for the following reasons: 1. The superiority of alteplase over streptokinase rests on insecure grounds, statistically (when net clinical benefit is computed for the SK/subcutaneous heparin arm versus the accelerated t-PA arm, the P value is only 0.04). 2. The excess of cerebral haemorrhage with t-PA is statistically highly significant and consistent over all trials. 3. Patients at greater risk of cerebral hemorrhage are those with raised systolic arterial pressure above about 130 to 140 on admission and those aged over about 55 years. These comprise the majority of patients admitted to ordinary Coronary Care Units. If t-PA is given to patients at low risk of cerebral hemorrhage, the extra cost per life saved will be very high, since such patients are at relatively low risk in any case. 4. The open design of the GUSTO-2 trial (the only trial showing a small mortality benefit for accelerated t-PA versus SK) introduces the possibility of bias. For example, unfamiliarity with SK in North American centers may have given risk to premature stopping of treatment because of hypotension; this might have resulted in a more favorable experience for accelerated t-PA in North American centers compared with the rest of the world. (The mortality benefit for accelerated t-PA in the GUSTO trial was seen only in North American centers.)


Structural transphobia is associated with psychological distress and suicidality in a large national sample of transgender adults.
Transgender adults face increasingly discriminatory laws/policies and prejudicial attitudes in many regions of the United States (US), yet research has neither quantified state-level transphobia using indicators of both, nor considered their collective association with transgender adults' psychological wellbeing, hindering the identification of this potential social determinant of transgender mental health inequity. We therefore used factor analysis to develop a more comprehensive structural transphobia measure encompassing 29 indicators of transphobic laws/policies and attitudes at the state level, which we linked to individual-level mental health data from a large national sample of 27,279 transgender adults (ages 18-100) residing in 45 US states and the District of Columbia (DC). Controlling for individual- (i.e., demographics), interpersonal- (i.e., perceived discrimination), and state- (i.e., income inequality, religiosity) level covariates, transgender adults from US states with higher (vs. lower) levels of structural transphobia reported more severe past-month psychological distress and were more likely to endorse past-year and lifetime suicidal thoughts, plans, and attempts. Findings provide novel evidence that state-level transphobic laws/policies and attitudes collectively shape a range of important mental health outcomes among transgender adults in the US. Multilevel intervention strategies, such as affirming mental health treatments, provider-training interventions, and supportive legislation, are needed to address structural transphobia's multifaceted nature and negative mental health consequences.


Relationship between mono-hydroxy-carbazepine serum concentrations and adverse effects in patients on oxcarbazepine monotherapy.
To evaluate the relationship between serum concentrations of mono-hydroxy-carbazepine (MHD), the main metabolite of oxcarbazepine (OXC), and the occurrence of adverse effects (AE) in a large group of patients on OXC monotherapy. An antiepileptic drug (AED) therapeutic drug monitoring (TDM) database was analyzed especially with regard to OXC dosage, MHD serum concentration, and the occurrence of AE. In total, 893 blood samples of 442 patients were included in this retrospective study. The statistical evaluation was performed by means of Kaplan-Meier estimates, log-rank tests and generalized estimating equations (GEE). At least one AE was reported in 78 (17.6%) of the 442 patients. At MHD serum concentrations of 30.0 μg/ml and 43.7 μg/ml and OXC dosages of 33.1 mg/kg and 62.3 mg/kg, 25% and 75% of patients, respectively, experienced at least one AE. Log-rank tests indicated that younger patients (<18 years) may be able to tolerate higher MHD serum levels (p = 0.006) and higher OXC dosages per body weight (p < 0.001) compared to adult patients (≥ 18 years). Furthermore, AEs occurred at higher body-weight adjusted OXC dosages of extended release formulations compared to immediate-release formulations (p = 0.010), whereas MHD serum levels at which AEs occurred did not differ significantly between formulations (p = 0.125). Multivariate GEE confirmed the results. The occurrence of AEs is significantly (and non-linearly) dependent on MHD serum level, whereas the dependence of OXC dosage is less distinctive. But, tolerability of OXC seems to depend on age of the patients as well as on pharmaceutical formulation of OXC.


Reducing cytogenetic testing in the era of next generation sequencing: Are we choosing wisely?
In most laboratories, next generation sequencing (NGS) has been added without consideration for redundancy compared to conventional cytogenetics (CG). We tested a streamlined approach to genomic testing in patients with suspected myeloid and plasma cell neoplasms using next generation sequencing ("NGS first") as the primary testing modality and limiting cytogenetics (CG) to samples with morphologic abnormalities in the marrow aspirate. Based on morphologic interpretation of bone marrow aspirate and flow cytometry, samples were triaged into four groups: (a) Samples with dysplasia or excess blasts had both NGS and karyotyping; (b) Samples without excess blasts or dysplasia had NGS only; (c) Repeat samples with previous NGS and/or CG studies were not retested; (d) Samples for suspected myeloma with less than 5% plasma cell had CG testing cancelled. Seven hundred eleven adult bone marrow (BM) samples met the study criteria. The NGS first algorithm eliminated CG testing in 229/303 (75.6%) of patients, primarily by reducing repeat testing. Potential cost avoided was approximately $124 000 per annum. Hematologists overruled the triage comment in only 11/303 (3.6%) cases requesting CG testing for a specific indication. Utilizing NGS as the primary genomic testing modality NGS was feasible and well accepted, reducing over three quarters of all CG requests and improving the financial case for adoption of NGS. Key factors for the success of this study were collaboration of clinical and genomic diagnostic teams in developing the algorithm, rapid turnaround time for BM interpretation for triage, and communication between laboratories.


Effects on Lignin Structure of Coumarate 3-Hydroxylase Downregulation in Poplar.
The lignin structural ramifications of coumarate 3-hydroxylase (C3H) downregulation have not been addressed in hardwoods. Such information is required to accompany an assessment of the digestibility and bioenergy performance characteristics of poplar, in particular. Structurally rich 2D NMR methods were applied to the entire lignin fraction to delineate lignin p-hydroxyphenyl:guaiacyl:syringyl (H:G:S) levels and linkage distribution changes (and to compare with traditional degradative analyses). C3H downregulation reduced lignin levels by half and markedly increased the proportion of H units relative to the normally dominant G and S units. Relative stem H unit levels were up by ∼ 100-fold to ∼ 31 %, almost totally at the expense of G units; differences in the lignin interunit linkage distributions were more subtle. The H level in the most drastically C3H-downregulated transgenic poplar falls well beyond the H:G:S compositional bounds of normal angiosperms. The response observed here, in poplar, differs markedly from that reported for alfalfa where the S:G ratio remained almost constant even at substantial H levels, highlighting the often differing responses among plant species.


Increased cerebral blood flow is correlated with neurocognitive impairment in long-term hemodialysis patients: an arterial spin labeling MRI study.
The purpose of this study was to investigate cerebral blood flow (CBF) changes in hemodialysis patients with arterial spin labeling (ASL) and to correlate these changes with clinical risk factors and neurocognitive function. Thirty-two hemodialysis patients and 35 age-, sex-, and education-matched healthy controls (HCs) were recruited in this prospective study. The Mini-Mental State Examination (MMSE) was performed to evaluate neurocognitive function. Pulsed ASL was performed to measure CBF. Two independent sample t-test was used to explore the CBF difference between the patients and HCs. Multiple stepwise regression was used to investigate the risk factors for CBF in patients. Correlation analysis was used to explore the relationship between the MMSE scores and CBF changes with and without adjusting for anemia status. Compared to HCs, the hemodialysis patients showed significantly increased CBF in some neurocognition-related cerebral regions (all P < 0.001, Bonferroni corrected). Increased CBF in the right opercular and triangular part of the inferior frontal gyrus correlated with the poorer MMSE scores (r = -0.502, P = 0.004; r = -0.423, P = 0.018, FDR corrected) and these correlations still remained after adjusting for anemia status (r = -0.516, P = 0.005; r = -0.439, P = 0.019, FDR corrected). The increased dialysis duration, and decreased hemoglobin, hematocrit, and serum phosphorus were predictive risk factors for increased CBF (P < 0.05). In conclusion, long-term hemodialysis patients had increased CBF, which correlated with neurocognitive impairment, and after adjusting for the effect of anemia, the correlation still remained.


Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast).
Morphine-induced glial proinflammatory responses have been documented to contribute to tolerance to opioid analgesia. Here, we examined whether drugs previously shown to suppress glial proinflammatory responses can alter other clinically relevant opioid effects; namely, withdrawal or acute analgesia. AV411 (ibudilast) and minocycline, drugs with distinct mechanisms of action that result in attenuation of glial proinflammatory responses, each reduced naloxone-precipitated withdrawal. Analysis of brain nuclei associated with opioid withdrawal revealed that morphine altered expression of glial activation markers, cytokines, chemokines, and a neurotrophic factor. AV411 attenuated many of these morphine-induced effects. AV411 also protected against spontaneous withdrawal-induced hyperactivity and weight loss recorded across a 12-day timecourse. Notably, in the spontaneous withdrawal study, AV411 treatment was delayed relative to the start of the morphine regimen so to also test whether AV411 could still be effective in the face of established morphine dependence, which it was. AV411 did not simply attenuate all opioid effects, as co-administering AV411 with morphine or oxycodone caused three-to-five-fold increases in acute analgesic potency, as revealed by leftward shifts in the analgesic dose response curves. Timecourse analyses revealed that plasma morphine levels were not altered by AV411, suggestive that potentiated analgesia was not simply due to prolongation of morphine exposure or increased plasma concentrations. These data support and extend similar potentiation of acute opioid analgesia by minocycline, again providing converging lines of evidence of glial involvement. Hence, suppression of glial proinflammatory responses can significantly reduce opioid withdrawal, while improving analgesia.


Tracking pollution from fur farms using forensic paleolimnology.
Eutrophication, which remains one of the greatest threats to water quality worldwide, is particularly acute in agricultural areas. Here we assessed long-term drivers of potential pollution inputs to lakes in southwest Nova Scotia (Canada), a region marked by fur farming (mainly mink) and other agricultural activities. We used a BACI (before-after-control-impact) study design with sediment cores collected from 14 lakes selected based on their proximity to mink farms. We combined economic data, mink faecal samples, and a series of geochemical markers in dated sediment cores, including sterols, δ15N, visible reflectance spectroscopy (VRS)-inferred chlorophyll-a, and heavy metals, to relate changes in sediment geochemistry to the growth of mink farms in the region. Sterol biomarkers (cholesterol and β-sitosterol) measured in a range of samples (i.e. mink faeces and feed, aquaculture feed), were elevated where mink farms were located close to each study lake. Mink-related sterols (cholesterol, β-sitoserol), δ15N measurements, VRS chlorophyll-a, and heavy metals As, Cu, Sr increased in the 1980s coeval with a ∼400% increase of mink farms in the region, especially near Nowlans Lake. Agricultural impacts were subtler in other lakes. Our study expands on prior applications of geochemical fingerprinting in forensic paleolimnology when direct monitoring data are incomplete. This multi-proxy approach has promising applications for environmental pollution assessments in other lake ecosystems experiencing water quality issues.


Evaluation of femoral approach to coronary sinus catheterisation in electrophysiological and ablation procedures: Single centre experience.
It has been reported that the cannulation of coronary sinus (CS) from the femoral approach is safer than the traditional subclavian approach but is associated with a lower rate of success. We aimed to test the validity of this claim. We evaluated retrospectively 1320 consecutive patients who underwent electrophysiological study (EPS) or ablation over a period of three years using a prospectively collected data. In cases requiring CS cannulation, it was attempted first from the femoral approach, switching if necessary to a subclavian approach when the femoral route failed. Out of 1320 patients, 1165 (88.3%) required CS cannulation. The CS was successfully cannulated from the femoral approach in 99.3% of the cases in which it was attempted. One patient (0.09%) developed transient first degree atrioventricular block during an ablation procedure for AV nodal re-entrant tachycardia during cannulation of the CS that resolved within 3 min. Femoral access failed in 8 patients. In 4 of these cases, the procedure was concluded using CS cannulation via subclavian or jugular venous access. In the other 4 cases, the procedure was concluded successfully without CS cannulation, including an AF ablation in which CS cannulation proved impossible by either subclavian or femoral approach. Femoral access can be used for CS cannulation with a high rate of procedural success in the vast majority of patients undergoing EPS and ablation. This approach is safe, and associated with a high rate of procedural success.


A biomimetic approach to the synthesis of an antiviral marine steroidal orthoester.
Orthoesterol B, a marine natural product exhibiting antiviral activities, contains a [3.2.1]-bicyclic orthobutyrate bridging the steroid side chain and ring D. A biosynthetic reaction was proposed by which rearrangement of an epoxy ester results in the formation of the orthoester moiety. Steroidal model compounds incorporating 16-butyroxy and 20,22-epoxy groups were synthesized from tigogenin and were shown to rearrange to orthoesters under mild acidic catalysis.


beta-Microseminoprotein in human spermatozoa and its potential role in male fertility.
beta-Microseminoprotein (MSMB) is one of the most abundant proteins in human seminal plasma. The objectives of this study were: (1) to purify MSMB from seminal plasma (SP) and generate antibodies against the pure protein; (2) to investigate the interaction of MSMB with ejaculated spermatozoa and its possible effect on the spontaneous acrosome reaction (AR); and (3) to quantify MSMB content in SP and examine its relationship with the clinical sperm parameters. MSMB was purified from SP and its presence on the sperm surface was examined by indirect immunofluorescence using a specific polyclonal antibody. The effect of MSMB on the AR was evaluated using guinea pig epididymal spermatozoa as a model. MSMB quantification assay was performed with a two-site binding ELISA using two polyclonal antibodies against MSMB. MSMB was assessed in semen samples from fertile donors (controls) and subfertile patients according to World Health Organization criteria. MSMB was detected on the sperm surface and mainly localized to the acrosomal region of the head and neck. A significant spontaneous AR inhibition was observed when guinea pig epididymal spermatozoa were preincubated with MSMB. Finally, MSMB was significantly increased in subfertile patients when compared with fertile controls (P<0.02). The association of MSMB to the sperm surface, the inhibitor effect on the spontaneous AR and the increased MSMB levels found in SP in subfertile men suggests a relationship between this protein and semen quality and a possible role in the process of fertilization.


Impedance plethysmography: its limitations as a substitute for phlebography.
Impedance plethysmography (IPG) was used to study 132 legs: 100 in normal volunteers not subjected to radiocontrast phlebography, seven in patients whose limbs were phlebographically normal, and 25 proven by phlebography to have deep venous thrombosis (DVT). There were no false positive IPG results when a maximum venous outflow of 0.2% was the discriminant. However, in the 25 legs with thrombosis in calf, popliteal, femoral, and iliac veins, clots were not detected by IPG in 44--51% of legs, depending upon the discriminant. These results, which are in agreement with data reported elsewhere, indicate that it is reasonable to use the IPG method as the sole diagnostic maneuver when the test result is clearly abnormal, but that if the result is not abnormal, a radiocontrast phlebogram is necessary.


Amplitude of low-frequency fluctuation (ALFF) alterations in adults with subthreshold depression after physical exercise: A resting-state fMRI study.
Physical exercise has been proved to reduce the risk of major depression in Subthreshold depression (StD) individuals effectively, yet little is known about the spontaneous brain activity changes associated with physical exercise. A total of 70 adult subjects, including 38 StD and 32 healthy control (HC) subjects, underwent a resting-state functional magnetic resonance imaging (rs-fMRI) before and after eight-week aerobic exercise respectively. Then, the amplitude of low-frequency fluctuation (ALFF) alterations between the two groups were quantitatively analyzed. Before exercise intervention, the rs-fMRI data showed increased ALFF of the right putamen in the StD group compared with HC group. After exercise intervention, there was no significant ALFF change observed between the StD and HC groups. The longitudinal ALFF differences from pre- to post- exercise intervention showed significantly decreased ALFF in the right middle and inferior occipital gyrus, right middle and inferior temporal gyrus, right fusiform gyrus (FG), while increased ALFF in the right middle cingulate, right superior parietal louble, right inferior parietal lobule (IPL) (inferior parietal gyrus and supramarginal gyrus), and bilateral precuneus in the StD group. As for HC group, the results showed that decreased ALFF in the right FG and right parahippocampus, while increased ALFF in the right precuneus, right middle cingulate, right supplementary motor area, right superior parietal lobule and right paracentral lobule in the HC group. No significant correlation between changes of ALFF and clinical scale scores in the StD group. The definitions of StD are varied in terms of different studies, the final sample size was relatively small, and the age range of the subjects in this study was narrow. Meanwhile, the exercise intervention trial was short-term. These results further support the standpoint that physical exercise has the potential to reshape the abnormal patterns of spontaneous brain activity in adults with StD.