IGF-I but not insulin inhibits apoptosis at a low concentration in vascular smooth muscle cells.
Apoptosis of vascular smooth muscle cells (VSMCs) is of importance in the development of diabetic angiopathy. Our aim was to evaluate the effect of insulin and IGF-I on apoptosis in VSMCs. Rat aortic VSMCs were used and apoptosis was induced by serum starvation. As apoptotic markers we measured caspase-3 activity, histone-associated DNA fragments by ELISA and nuclear morphology by DAPI (4',6-diamidino-2-phenylindole) staining. Phosphorylation of IGF-I receptors was evaluated by Western blot. Serum starvation had increased caspase-3 activity even after 3 h. The highest activity was found after 3-12 h. IGF-I 10(-9 )M inhibited serum starvation-induced caspase-3 activity with a maximal effect after 12 h. When studied after starvation for 12 h, significant inhibitory effects on caspase-3 were found at IGF-I concentrations of 10(-8)-10(-7) M (P<0.01) and at an insulin concentration of 10(-6 )M (P<0.01). DNA fragmentation was detected by ELISA after 24 h and chromatin condensation and nuclear fragmentation by DAPI staining after 24 and 48 h respectively. IGF-I dose-dependently reduced apoptosis evaluated by ELISA, reaching a maximal effect at 10(-9) M. Insulin reduced apoptosis but the effect was weaker and a higher concentration was needed. IGF-I (10(-8 )M) and insulin at a very high concentration (10(-6) M) phosphorylated IGF-I receptors. Taken together, IGF-I and insulin have antiapoptotic effects on VSMCs but the effect of insulin is only found at high unphysiological concentration.


Beneficial effect of pancreas and kidney transplantation on advanced diabetic retinopathy.
In pancreas recipients with advanced diabetic eye disease, conflicting ophthalmologic results over different follow-up periods have been reported. In the present prospective study we performed ophthalmologic evaluation groups of type I diabetic patients: 1) normoglycemic recipients of pancreas and kidney grafts (group SPK, n = 43, follow-up 44.9 +/- 35.1 months), 2) pancreas and kidney graft recipients with nonfunctioning pancreatic graft, and recipients of isolated kidney graft (group K, n = 45, follow-up 60.3 +/- 34.2 months). The examinations were performed before transplantation, at the end of follow-up (at least 1 year), and in 63 recipients also at 3 years posttransplant. Visual acuity results at baseline and at the end of follow-up were 0.48 +/- 0.39 vs. 0.50 +/- 0.39 in the SPK group, and 0.46 +/- 0.38 vs. 0.40 +/- 0.39 in the K group. While intragroup changes were not significant, the changes were significantly different between the groups (p < 0.05). Fundoscopic findings at the end of follow-up were improved, stabilized, or deteriorated in the SPK group in 21.3%, 61.7%, and 17.0%, respectively. The respective figures for the K group were 6.1%, 48.8%, and 45.1% (p < 0.001). Similar results were obtained when evaluating findings at 3 years posttransplant. Before transplantation, 78% of the SPK group and 81% of the K group had been treated by laser. The need for additional posttransplant laser therapy was significantly lower in the SPK (31%) than in the K group (58%; p < 0.001). In conclusion, pancreas transplant exerts a beneficial effect on the course of diabetic retinopathy even in its late stage.


DLSSAffinity: protein-ligand binding affinity prediction via a deep learning model.
Evaluating the protein-ligand binding affinity is a substantial part of the computer-aided drug discovery process. Most of the proposed computational methods predict protein-ligand binding affinity using either limited full-length protein 3D structures or simple full-length protein sequences as the input features. Thus, protein-ligand binding affinity prediction remains a fundamental challenge in drug discovery. In this study, we proposed a novel deep learning-based approach, DLSSAffinity, to accurately predict the protein-ligand binding affinity. Unlike the existing methods, DLSSAffinity uses the pocket-ligand structural pairs as the local information to predict short-range direct interactions. Besides, DLSSAffinity also uses the full-length protein sequence and ligand SMILES as the global information to predict long-range indirect interactions. We tested DLSSAffinity on the PDBbind benchmark. The results showed that DLSSAffinity achieves Pearson's R = 0.79, RMSE = 1.40, and SD = 1.35 on the test set. Comparing DLSSAffinity with the existing state-of-the-art deep learning-based binding affinity prediction methods, the DLSSAffinity model outperforms other models. These results demonstrate that combining global sequence and local structure information as the input features of a deep learning model can improve the accuracy of protein-ligand binding affinity prediction.


[Effect of heliomycin on the respiration and oxidative phosphorylation of the liver mitochondria of the rat].
The effect of heliomycin and known uncouplers of oxidative phosphorylation on respiration and oxidative phosphorylation was studied comparatively. Heliomycin, as well as 2,4-dinitrophenol, valinomycin and gramicidin S inhibited the mitochondrial synthesis of ATP. This process was inhibited completely by heliomycin at a concentration of 1.5 x 10(-5) M. The synthesis of inorganic pyrophosphate, the other macroergic compound, was also inhibited by heliomycin, ATPase and pyrophosphatase of uncoupled mitochondria being not inhibited by the antibiotic. Like 2,4-dinitrophenol, heliomycin stimulated the synthesis of ATPase and respiration in intact mitochondria. Probably, heliomycin inhibited the synthesis of ATP and pyrophosphate by uncoupling the processes of respiration and oxidative phosphorylation. It was shown earlier that heliomycin, a specific inhibitor of bacterial RNA synthesis, also affected energy metabolism of bacterial cells by inhibiting the synthesis of ATP and active transport.


[Emergency treatment of cerebral infarction by the family physician].
The emergency treatment chain of procedures for an acute stroke begins and ends with the family physician who assumes important duties and responsibilities. The physician should be already familiar with the local treatment possibilities and suitable hospitals for cerebral infarction. High risk patients and their family members should know the symptoms of a stroke and the necessity of swift action. In an emergency, the first attending physician stabilizes the vital functions of the patient and documents the chronological appearance of the symptoms and concomitant diseases. The physician organizes the transport of the patient to an appropriate hospital, ideally one with a stroke unit, where further therapy and diagnostics are performed. Finally, the family physician controls and monitors the secondary prophylaxis.


Review: Dairy foods, red meat and processed meat in the diet: implications for health at key life stages.
Social and health care provision have led to substantial increases in life expectancy. In the UK this has become higher than 80 years with an even greater proportional increase in those aged 85 years and over. The different life stages give rise to important nutritional challenges and recent reductions in milk consumption have led to sub-optimal intakes of calcium by teenage females in particular when bone growth is at its maximum and of iodine during pregnancy needed to ensure that supply/production of thyroid hormones to the foetus is adequate. Many young and pre-menopausal women have considerably sub-optimal intakes of iron which are likely to be associated with reduced consumption of red meat. A clear concern is the low intakes of calcium especially as a high proportion of the population is of sub-optimal vitamin D status. This may already have had serious consequences in terms of bone development which may not be apparent until later life, particularly in post-menopausal women. This review aims to examine the role of dairy foods and red meat at key life stages in terms of their ability to reduce or increase chronic disease risk. It is clear that milk and dairy foods are key sources of important nutrients such as calcium and iodine and the concentration of some key nutrients, notably iodine can be influenced by the method of primary milk production, in particular, the iodine intake of the dairy cow. Recent meta-analyses show no evidence of increased risk of cardiovascular diseases from high consumption of milk and dairy foods but increasing evidence of a reduction in the risk of type 2 diabetes associated with fermented dairy foods, yoghurt in particular. The recently updated reports from the World Cancer Research Fund International/American Institute for Cancer Research on the associations between dairy foods, red meat and processed meat and various cancers provide further confidence that total dairy products and milk, are associated with a reduced risk of colorectal cancer and high intakes of milk/dairy are not associated with increased risk of breast cancer. Earlier evidence of a significant increase in the risk of colorectal cancer from consumption of red and particularly processed meat has been reinforced by the inclusion of more recent studies. It is essential that nutrition and health-related functionality of foods are included in evaluations of sustainable food production.


Resuscitation at the limit of viability: trapped between a rock and a hard place.
Current professional guidelines, such as the Neonatal Resuscitation Program, specify significant roles for parents in decision-making at periviability. However, current federal regulations and some legal precedents indicate that resuscitation decisions should be made by the physician at the time of delivery, based on physical assessment of the infant. The enforcement of such approach would potentially increase the resuscitation of infants with poor prognoses. To characterize the resuscitation practices of neonatologists attending deliveries of premature infants at the borderline of viability, in the context of current federal legislation. A questionnaire was administered to directors of all level III neonatal intensive care units in the state of New Jersey, eliciting resuscitation decisions for hypothetical birth scenarios as well as knowledge of legal statutes. Resuscitation decisions for infants born at 24 weeks of gestational age were not associated with parental wishes. In contrast, parental requests were significantly associated with decisions whether to treat infants born at 22 and 23 weeks gestation. Most neonatologists believed they were knowledgeable about federal legislation, but that knowledge did not change the way they practiced. Our findings suggest that resuscitation of premature infants at 24 weeks gestation is the standard of care in New Jersey, a socioeconomically and ethnically diverse state that may represent broader national trends. The high compliance with parental wishes at 22 or 23 weeks is probably related to physicians' expectation of poor outcomes at these gestational ages. This approach is consistent with current recommendations of the Neonatal Resuscitation Program but may not be compatible with existing federal statutes and legal precedent.


[Effects of isoprenaline on apoptosis related gene expression in rat myocardium cells].
To study the relationship between acute myocardial ischemia rat induced by isoprenaline (Iso) and expression of some apoptosis related genes in myocardium. Acute myocardial ischemic rat model was induced by subcutaneous injection of large doses of Iso. The myocardial expression of apoptosis related genes, Fas, CPP32, Bcl-2 and Bax, were detected with RT-PCR method. The influences of aloperine (Alo, 20 mg.kg-1) and propranolol (Prop, 2 mg.kg-1) on apoptosis related genes were also investigated by the same method. Myocardial expression of Fas, CPP32 and Bcl-2 were increased in acute myocardial ischemic rats, but no significance was detected in Bax expression. Both Alo and Prop were shown to decrease the expression of Fas and CPP32, and increase expression of Bcl-2. Prop also showed down regulated effect on expression of Bax. Subcutaneous injection of large doses of Iso was shown to induce expressions of apoptosis related genes in rat myocardium, which were also influences by Alo and Prop.


Upper wisconsinan till recovered on the continental shelf southeast of new England.
Basal till was identified in two sediment cores collected about 69 kilometers southeast of Nantucket Island on the east and west sides of Great South Channel. These are the first samples of till collected on the outer continental shelf off the northeastern United States. The carbon-14 age of the total organic carbon in the tills provides a "no older than" age of about 20,000 years before present and suggests that the tills were deposited during the late Wisconsinan glaciation. This conclusion is in support of the hypothesis of an extensive Laurentide ice sheet that extended to the northern side of Georges Bank.


TCR-alpha CDR3 loop audition regulates positive selection.
How positive selection molds the T cell repertoire has been difficult to examine. In this study, we use TCR-beta-transgenic mice in which MHC shapes TCR-alpha use. Differential AV segment use is directly related to the constraints placed on the composition of the CDR3 loops. Where these constraints are low, efficient selection of alphabeta pairs follows. This mode of selection preferentially uses favored AV-AJ rearrangements and promotes diversity. Increased constraint on the alpha CDR3 loops leads to inefficient selection associated with uncommon recombination events and limited diversity. Further, the two modes of selection favor alternate sets of AJ segments. We discuss the relevance of these findings to the imprint of self-MHC restriction and peripheral T cell activation.


Relationship between anthropometric measurements and hamstring autograft diameter in anterior cruciate ligament reconstruction.
The role of anthropometric measurements in the prediction of hamstring autograft size remains unclear. In this internal review board - approved study, we evaluated medical records for patients receiving anterior cruciate ligament (ACL) reconstruction with hamstring autograft at our institution between 2006 and 2008. One hundred and thirty-two patients received hamstring autografts. Correlation coefficients and step-wise multiple linear regression analysis were used to determine the relationships between sex, age, height, body mass index (BMI), and hamstring graft diameter. Women had significantly smaller grafts than men (P < .00001). Twenty-four patients had grafts less than 7 mm in diameter and 18 of those patients were female. Age and BMI did not correlate with graft diameter in women. Height correlated to graft diameter in women (P = .002, R(2) = 0.14). Women shorter than 65 in had significantly smaller graft diameters (mean [SD], 6.94 [0.45] mm), than those women 65 in and taller (mean [SD], 7.20 0.49] mm; (P = .03). Age and height did not correlate with graft size in men. BMI greater than 25 kg/m(2) correlated with larger graft diameter, but BMI less than 18 kg/m(2) did not predict graft sizes less than 7 mm. Therefore, alternative graft options should be considered in women less than 65 in tall.


Serum amyloid A is a marker for pulmonary involvement in systemic sclerosis.
Inflammation in systemic sclerosis (SSc) is a prominent, but incompletely characterized feature in early stages of the disease. The goal of these studies was to determine the circulating levels, clinical correlates and biological effects of the acute phase protein serum amyloid A (SAA), a marker of inflammation, in patients with SSc. Circulating levels of SAA were determined by multiplex assays in serum from 129 SSc patients and 98 healthy controls. Correlations between SAA levels and clinical and laboratory features of disease were analyzed. The effects of SAA on human pulmonary fibroblasts were studied ex vivo. Elevated levels of SAA were found in 25% of SSc patients, with the highest levels in those with early-stage disease and diffuse cutaneous involvement. Significant negative correlations of SAA were found with forced vital capacity and diffusion capacity for carbon monoxide. Patients with elevated SAA had greater dyspnea and more frequent interstitial lung disease, and had worse scores on patient-reported outcome measures. Incubation with recombinant SAA induced dose-dependent stimulation of IL-6 and IL-8 in normal lung fibroblasts in culture. Serum levels of the inflammatory marker SAA are elevated in patients with early diffuse cutaneous SSc, and correlate with pulmonary involvement. In lung fibroblasts, SAA acts as a direct stimulus for increased cytokine production. These findings suggest that systemic inflammation in SSc may be linked to lung involvement and SAA could serve as a potential biomarker for this complication.


Toward design of synergistically active carbon-based catalysts for electrocatalytic hydrogen evolution.
Replacement of precious Pt catalyst with cost-effective alternatives would be significantly beneficial for hydrogen production via electrocatalytic hydrogen evolution reaction (HER). All candidates thus far are exclusively metallic catalysts, which suffer inherent corrosion and oxidation susceptibility during acidic proton-exchange membrane electrolysis. Herein, based on theoretical predictions, we designed and synthesized nitrogen (N) and phosphorus (P) dual-doped graphene as a nonmetallic electrocatalyst for sustainable and efficient hydrogen production. The N and P heteroatoms could coactivate the adjacent C atom in the graphene matrix by affecting its valence orbital energy levels to induce a synergistically enhanced reactivity toward HER. As a result, the dual-doped graphene showed higher electrocatalytic HER activity than single-doped ones and comparable performance to some of the traditional metallic catalysts.


A comparison of reported and unreported noncrash events.
Two sources of data for the investigation of noncrash-related injuries are compared: police accident reports and a hospital emergency room monitoring system. Two main issues are considered: the extent to which these sources provide similar descriptions of the noncrash event, and an assessment of these data sources for investigation of noncrash events. Several critical features between the two types of data collection systems can be summarized from the analysis. First, reliance solely on police reports would indicate that there are very few cases of injuries as a result of noncrash events. Second, a narrow view of causes of injuries in noncrash events are found in the police report cases: most were ejections, while interior impacts were more common in the hospital cases. Third, noncrash events appear to be similar to other "household" accidents, with the injured child transported by the parent/guardian to the hospital. In summary, the police report investigations provide a limited view of the extent of noncrash events. Data sources such as hospital monitoring systems are more productive than police reports in studies directed at nonstandard traffic accident events, such as the noncrash.


Social media and medical professionalism: rethinking the debate and the way forward.
This Perspective addresses the growing literature about online medical professionalism. Whereas some studies point to the positive potential of social media to enhance and extend medical practice, the dominant emphasis is on the risks and abuses of social media. Overall evidence regarding online medical professionalism is (as with any new area of practice) limited; however, simply accumulating more evidence, without critically checking the assumptions that frame the debate, risks reinforcing negativity toward social media. In this Perspective, the author argues that the medical community should step back and reconsider its assumptions regarding both professionalism and the digital world of social media. Toward this aim, she outlines three areas for critical rethinking by educators and students, administrators, professional associations, and researchers. First she raises some cautions regarding the current literature on using social media in medical practice, which sometimes leaps too quickly from description to prescription. Second, she discusses professionalism. Current debates about the changing nature and contexts of professionalism generally might be helpful in reconsidering notions of online medical professionalism specifically. Third, the author argues that the virtual world itself and its built-in codes deserve more critical scrutiny. She briefly summarizes new research from digital studies both to situate the wider trends more critically and to appreciate the evolving implications for medical practice. Next, the author revisits the potential benefits of social media, including their possibilities to signal new forms of professionalism. Finally, the Perspective ends with specific suggestions for further research that may help move the debate forward.


The dominant white spotting oncogene allele Kit(W-42J) exacerbates XY(DOM) sex reversal.
The Y chromosome from certain populations of M. m. domesticus is incapable of normal testis determination in the B6 inbred strain resulting in XY hermaphrodites or XY females (XY(DOM) sex reversal). B6 consomic strains have been developed with either transient (B6-Y(AKR)) or severe (B6-Y(TIR)) XY(DOM) sex reversal. We report that a point mutation, the dominant white spotting oncogene allele, Kit(W-42J), exacerbates XY(DOM) sex reversal. In B6-Y(AKR), penetrance of the trait is low; however, in B6-Y(TIR), Kit(W-42J) exacerbated sex reversal to such an extent that almost all XY progeny developed into females. The exacerbation of sex reversal was not linked to retardation of early fetal growth or reduction of testis size. Furthermore, semiquantitative RT-PCR for the testis-determining gene, Sry, suggests that exacerbation of sex reversal in B6-Y(TIR) is not due to blockade of Sry expression, a substantial delay in initiation of Sry expression, or exceptionally low levels of Sry mRNAs. We propose that Kit(W-42J) enhances sex reversal by adversely affecting a critical step in testis differentiation that is downstream of Sry.


Chronic intractable headache in a patient with Marfan's syndrome.
A 30-year-old woman with Marfan's syndrome had chronic intractable headaches and spontaneous intracranial hypotension. The pain was concentrated over the occipitonuchal region, had elements of both migraine and tension headache, and was often aggravated by postural change. Myelography showed multiple, large, lumbosacral arachnoid diverticula. Radioisotope cisternography revealed a halolike accumulation in the lumbosacral region and rapid uptake of isotope in the urinary bladder, indicating cerebrospinal fluid leakage. Epidural blood patching brought immediate relief from the positional headaches. We concluded that patients with Marfan's syndrome and undifferentiated chronic headaches should be radiologically evaluated for spinal meningeal defects.


Heavy arv exposure and exhausted/limited arv options: predictors and clinical outcomes.
People with HIV and extensive antiretroviral exposure may have limited/exhausted treatment options (LExTO) due to resistance, comorbidities, or antiretroviral-related toxicity. Predictors of LExTO were investigated in the RESPOND cohort. Participants on ART for at least 5 years were defined as having LExTO when switched to at least two anchor agents and one-third antiretroviral (any class), a two-drug regimen of two anchor agents (excluding rilpivirine with dolutegravir/cabotegravir), or at least three nucleoside reverse transcriptase inhibitors. Baseline was the latest of January 1, 2012, cohort enrolment or 5 years after starting antiretrovirals. Poisson regression modeled LExTO rates and clinical events (all-cause mortality, non-AIDS malignancy, cardiovascular disease [CVD], and chronic kidney disease [CKD]). Of 23 827 participants, 2164 progressed to LExTO (9.1%) during 130 061 person-years follow-up (PYFU); incidence 1.66/100 PYFU (95% CI 1.59-1.73). Predictors of LExTO were HIV duration more than 15 years (vs. 7.5-15; adjusted incidence rate ratio [aIRR] 1.32; 95% CI 1.19-1.46), development of CKD (1.84; 1.59-2.13), CVD (1.64; 1.38-1.94), AIDS (1.18; 1.07-1.30), and current CD4+ cell count of 350 cells/μl or less (vs. 351-500 cells/μl, 1.51; 1.32-1.74). Those followed between 2018 and 2021 had lower rates of LExTO (vs. 2015-2017; 0.52; 0.47-0.59), as did those with baseline viral load of 200 cp/ml or less (0.46; 0.40-0.53) and individuals under 40. Development of LExTO was not significantly associated with clinical events after adjustment for age and current CD4, except CKD (1.74; 1.48-2.05). Despite an aging and increasingly comorbid population, we found declining LExTO rates by 2018-2021, reflecting recent developments in contemporary ART options and clinical management. Reassuringly, LExTO was not associated with a significantly increased incidence of serious clinical events apart from CKD.


Relationship Between Preoperative Extrusion of the Medial Meniscus and Surgical Outcomes After Partial Meniscectomy.
No previous study has examined arthritic change after meniscectomy with regard to extrusion of the medial meniscus. (1) To determine the factors related to preoperative meniscal extrusion; (2) to investigate the relationship between medial meniscal extrusion and postoperative outcomes of partial meniscectomy, and to identify a cutoff point of meniscal extrusion that contributes to arthritic change after partial meniscectomy in nonosteoarthritic knees. Cohort study; Level of evidence, 3. A total of 208 patients who underwent partial meniscectomy of the medial meniscus between January 2000 and September 2006 were retrospectively reviewed. The extent of extrusion and severity of degeneration of the medial meniscus as shown on preoperative MRI were evaluated. The minimum follow-up duration was 7 years. Clinical function was assessed with the Lysholm knee scoring scale, the International Knee Documentation Committee (IKDC) subjective knee evaluation form, and the Tapper and Hoover grading system. Radiological evaluation was conducted by use of the IKDC radiographic assessment scale. Regression analysis was performed to identify factors affecting preoperative extrusion of the medial meniscus and factors influencing follow-up results after partial meniscectomy. Receiver operating characteristic curve was used to identify a cutoff point for the extent of meniscal extrusion that was associated with arthritic change. The mean ± SD preoperative Lysholm knee score was 65.0 ± 6.3 and the mean IKDC subjective score was 60.1 ± 7.5. The mean follow-up functional scores were 93.2 ± 5.1 ( P < .001) for the Lysholm knee score and 89.0 ± 6.2 for the IKDC subjective score ( P < .001). Preoperative extent of meniscal degeneration ( P < .001) and preoperative pattern of meniscal tear ( P < .001) were related to preoperative meniscal extrusion. Preoperative extrusion of the meniscus showed a tendency to increase as the extent of intrameniscal degeneration increased, and the medial meniscus was extruded more in patients with horizontal, horizontal flap, and complex tears. The preoperative extent of meniscal extrusion had a statistically significant correlation with follow-up Lysholm knee score (coefficient = -0.10, P = .002), IKDC subjective score (coefficient = -0.09, P = .007), Tapper and Hoover grade (odds ratio = 1.05, P < .001), and IKDC radiographic grade (odds ratio = 1.13, P < .001) at the mean follow-up period of 88.6 months. The cutoff point for the relative value of preoperative meniscal extrusion associated with arthritic change was 34.6% (sensitivity = 69.3%; specificity = 82.7%; accuracy = 77.9%). The preoperative extent of intrameniscal degeneration and the preoperative patterns of meniscal tear including horizontal, horizontal flap, and complex tears were associated with preoperative extrusion of the medial meniscus. The preoperative extrusion of the medial meniscus was negatively correlated with outcomes of partial meniscectomy. The preoperative extent of meniscal extrusion can be used as a predictive factor for osteoarthritis in partial meniscectomy.


Regulation of the immune response. 3. Kinetic differences between thymus- and bone marrow- derived lymphocytes in the proliferative response to heterologous erythrocytes.
The kinetics of the in vivo response to SRBC was studied in mouse spleen at both the B cell and T cell levels. The B cell response was assayed by following the appearance of antibody-secreting cells in the spleen using the hemolytic plaque assay. The T cell response was monitored by following the increase in or "priming" of helper activity in the spleen using a quantitative in vitro assay. The role of cellular proliferation in both responses was established with the inhibitor of mitosis, vinblastine. The results show that, although the development of T cell activity precedes that of anti-SRBC PFC by as much as 1 day, T cells lag at least 1 day behind B cells in the onset of cellular proliferation. The evidence suggests either that the helper T cell which proliferates in response to SRBC does so after helping in the initiation of the primary B cell response or that the proliferative T cell response and the initiation of the primary B cell response involve two different subpopulations of T cells.


Vascular remodeling and media calcification increases arterial stiffness in chronic kidney disease.
Cardiovascular disease is the most common cause of death in patients with chronic kidney disease (CKD). Arterial stiffness and calcification are non-traditional risk factors of cardiovascular disease in CKD. In CKD rats, we investigated the involvement of smooth muscle cells differentiation to osteoblast-like cells and blood vessel wall remodeling, associated with media calcification, in arterial stiffness. CKD with vascular calcification was induced by subtotal nephrectomy followed by treatment with a high calcium and phosphate diet, and vitamin D supplementation (Ca/P/VitD). At week 3-6, hemodynamic parameters and pulse wave velocity (PWV) were assessed. Vascular media calcification and remodeling were determined by histological von Kossa staining and confocal immunofluorescence analysis of osteocalcin, elastin, α-smooth muscle actin (α-SMA) and collagen-1. Treatment of CKD rats with Ca/P/VitD, but not normal animals, induced a significant increase in pulse pressure and PWV (p < 0.05) and marked calcification in the media. In calcification areas, de novo expression of osteocalcin was observed, whereas α-SMA immunofluorescence levels were reduced (p < 0.01). The immunofluorescence levels of elastin were also reduced, which was related to disruption of elastic lamella. In contrast, collagen-1 immunofluorescence levels in areas of calcification were increased (p < 0.01). Changes in both α-SMA and elastin inversely correlated with the PWV. This study indicate that smooth muscle cells differentiation to osteoblast-like cells and the associated media remodeling, which includes disruption of elastic lamellas and deposition of collagen are, at least in part, associated with the increased arterial stiffness observed in CKD rats with vascular calcification.


Delta-aminolaevulinate dehydratase, the regulatory enzyme of the haem-biosynthetic pathway in Neurospora crassa.
The activity of delta-aminolaevulinate dehydratase is very low in the mould Neurospora crassa compared with the activities detected in bacterial and animal systems. The enzyme is inducible in iron-deficient cultures by addition of iron and is repressed by protoporphyrin. The properties of the purified enzyme indicate its allosteric nature and susceptibility to feedback inhibition by coproporphyrinogen III. Neurospora extracts also contain a protein inhibitor of the enzyme and a small-molecule activator, which appears to be associated with the enzyme. The regulatory function of this enzyme in vivo is correlated with the accumulation of delta-aminolaevulinic acid in normal cultures of N. crassa. The decay curve of the iron-induced enzyme in vivo shows a biphasic pattern, with one of the components showing a half-life of 4-5 min.


Recent Advances and Perspective on Electrochemical Ammonia Synthesis under Ambient Conditions.
Ammonia is an essential chemical for agriculture and industry. To date, NH3 is mainly supplied by the traditional Haber-Bosch process, which is operated under high-temperature and high-pressure in a centralized way. To achieve ammonia production in an environmentally benign way, electrochemical NH3 synthesis under ambient conditions has become the frontier of energy and chemical conversion schemes, as it can be powered by renewable energy and operates in a decentralized way. The recent progress on developing different strategies for NH3 production, including 1) classic NH3 synthesis pathways over nanomaterials; 2) the Mars-van Krevelen (MvK) mechanism over metal nitrides (MNx ); 3) reducing the nitrate into NH3 over Cu-based nanomaterial; and 4) metal-N2 battery release of NH3 from Lix M. Moreover, the most recent advances in engineering strategies for developing highly active materials and the design of the reaction systems for NH3 synthesis are covered.


(+)Amphetamine-stimulus generalization to an herbal ephedrine product.
We have previously demonstrated that a (+)amphetamine stimulus generalizes both to (-)ephedrine and caffeine. Using rats trained to discriminate intraperitoneal (IP) administration of 1.0 mg/kg of (+)amphetamine (ED(50) = 0.4 mg/kg) from saline vehicle in a standard two-lever drug discrimination procedure, the present investigation shows that the (+)amphetamine stimulus generalizes to (+)amphetamine (ED(50) = 1.0 mg/kg) when administered via the intragastric (IG) route, and that (+)amphetamine appears about 2. 5-fold less potent when administered via the IG route compared to the IP route. Likewise, (-)ephedrine (ED(50) = 10.8 mg/kg) and caffeine (ED(50) = 32.9 mg/kg) are also 2.5-fold less potent when administered via the IG route compared to their potency when administered via the IP route. The (+)amphetamine stimulus also generalizes to an IG-administered herbal preparation (i.e., Herbal XTC; the herbal preparation possesses an approximate potency roughly comparable to what might have been expected on the basis of its reported ephedrine and/or caffeine content. These results demonstrate, for the first time, that an ephedrine-containing herbal preparation can produce a (+)amphetamine-like effect in animals.


From body scale ontogeny to species ontogeny: Histological and morphological assessment of the Late Devonian acanthodian Triazeugacanthus affinis from Miguasha, Canada.
Growth series of Palaeozoic fishes are rare because of the fragility of larval and juvenile specimens owing to their weak mineralisation and the scarcity of articulated specimens. This rarity makes it difficult to describe early vertebrate growth patterns and processes in extinct taxa. Indeed, only a few growth series of complete Palaeozoic fishes are available; however, they allow the growth of isolated elements to be described and individual growth from these isolated elements to be inferred. In addition, isolated and in situ scales are generally abundant and well-preserved, and bring information on (1) their morphology and structure relevant to phylogenetic relationships and (2) individual growth patterns and processes relative to species ontogeny. The Late Devonian acanthodian Triazeugacanthus affinis from the Miguasha Fossil-Lagerstätte preserves one of the best known fossilised ontogenies of early vertebrates because of the exceptional preservation, the large size range, and the abundance of complete specimens. Here, we present morphological, histological, and chemical data on scales from juvenile and adult specimens (scales not being formed in larvae). Histologically, Triazeugacanthus scales are composed of a basal layer of acellular bone housing Sharpey's fibers, a mid-layer of mesodentine, and a superficial layer of ganoine. Developmentally, scales grow first through concentric addition of mesodentine and bone around a central primordium and then through superposition of ganoine layers. Ontogenetically, scales form first in the region below the dorsal fin spine, then squamation spreads anteriorly and posteriorly, and on fin webs. Phylogenetically, Triazeugacanthus scales show similarities with acanthodians (e.g. "box-in-box" growth), chondrichthyans (e.g. squamation pattern), and actinopterygians (e.g. ganoine). Scale histology and growth are interpreted in the light of a new phylogenetic analysis of gnathostomes supporting acanthodians as stem chondrichthyans.


Unrecognized viral infections and chromosome abnormalities as a cause of fetal death - examination with fluorescence in situ hybridization, immunohistochemistry and polymerase chain reaction.
Fifteen to 50% of fetal deaths remain unexplained after post-mortem examination depending on inclusion criteria and classification systems. Our aim was to examine a selection of unexplained fetal deaths in order to investigate whether any common chromosome aberrations or viral infections were present. Reports from 351 fetal autopsies performed at the Department of Pathology and Medical Genetics at St. Olavs University Hospital from 2001 through 2010 were reviewed. Of these, 105 fetal deaths were classified as unexplained. Tissue samples from 30 cases were further examined with fluorescence in situ hybridization (FISH) to detect abnormalities in chromosomes 13, 18, and 21. The samples were also examined with immunohistochemistry (IHC) and polymerase chain reaction (PCR) to detect infections with cytomegalovirus, parvovirus B19, herpes simplex virus 1 and 2, enterovirus, and parechovirus. In two cases, a possible trisomy 13 mosaicism was found. No viruses were detected. In our selection of 30 unexplained cases, possible trisomy 13 mosaicism was found in two cases, and no viruses were detected. High degree of maceration and missing placental examination often complicate the investigation of fetal death, and extensive ancillary examinations do not necessarily contribute to a more specific diagnosis.


Ampullary Cancer: Histological Subtypes, Markers, and Clinical Behaviour-State of the Art and Perspectives.
There are different cancers in the peri-ampullary region, including pancreatic ductal adenocarcinoma (PDAC), duodenum cancers (DCs), and ampullary adenocarcinoma (AAC). Here, significant morphological-molecular characterizations should be necessary for the distinction of primary tumours and classifications of their subtypes of cancers. The sub classification of AACs might include up to five different variants, according to different points of view, concerning the prevalence of the two more-cellular components found in the ampulla. In particular, regarding the AACs, the most important subtypes are represented by the intestinal (INT) and the pancreato-biliary (PB) ones. The subtyping of AACs is essential for diagnosis, and their identifications have been impacting clinical management responses to treatments and overall survival (os) after surgery. Pb is associated with a worse clinical outcome. Otherwise, the criteria, through which are possible to attribute its subtype classification, are not well established. A triage of immune markers represented by CK7, CK20, and CDX-2 seem to represent the best compromise in order to split the cohort of AAC patients in the INT and PB groups. The test of choice for the sub-classification of AACs is represented by the immuno-histochemical approach, in which its molecular classification acquires its diagnostic, predictive, and prognostic value for both the INT and PB patients.


Thermodynamic evidence for K(+)-SO4(2-) ion pair formation on Pt(111). New insight into cation specific adsorption.
This work contributes to the understanding of cation specific effects on platinum electrochemistry by means of a thorough thermodynamic analysis of potassium adsorption on Pt(111) in sulfuric acid solutions. It is concluded that potassium specific adsorption is better described as the adsorption of the K(+)-SO ion pair. From the evaluation of the potassium sulfate concentration, it is found that potassium specific adsorption only takes place in the presence of coadsorbed sulfate species. Within the main sulfate adsorption state, for ∼0.3 V < E < ∼0.4 V (vs. SHE), the extent of potassium specific adsorption is small, reaching ∼0.1 × 10(14) species per cm(2) for c(K(+)) > 0.1 M. Then, at higher potentials, E > 0.55 V (vs. SHE), a second potassium adsorption process takes place, concomitant with the second sulfate adsorption process (associated to the small voltammetric feature called "the hump"). This last process involves the adsorption of an equal amount of potassium and sulfate species, leading to the adsorption of ∼0.5 × 10(14) ion pair species per cm(2) (∼0.03 ion pair species per platinum surface atom). Furthermore, the results of the formal partial charge numbers corroborate that potassium adsorption involves sulfate cooperative coadsorption, in such a way that the effective adsorbing species is anionic, rather than cationic. In conclusion, this work evidences that cation specific effects may originate from the formation of surface ion pairs, which is probably related to the presence of ion pairs in solution.


In vivo volumetric imaging of subcutaneous microvasculature by photoacoustic microscopy.
Photoacoustic microscopy was developed to achieve volumetric imaging of the anatomy and functions of the subcutaneous microvasculature in both small animals and humans in vivo with high spatial resolution and high signal-to-background ratio. By following the skin contour in raster scanning, the ultrasonic transducer maintains focusing in the region of interest. Furthermore, off-focus lateral resolution is improved by using a synthetic-aperture focusing technique based on the virtual point detector concept. Structural images are acquired in both rats and humans, whereas functional images representing hemoglobin oxygen saturation are acquired in rats. After multiscale vesselness filtering, arterioles and venules in the image are separated based on the imaged oxygen saturation levels. Detailed structural information, such as vessel depth and spatial orientation, are revealed by volume rendering.


Chlorine Dioxide Spray Washes for Reducing Fecal Contamination on Beef †.
The ability of chlorine dioxide (ClO2) to reduce bacterial populations (i.e., aerobic plate count, APC) on fecally contaminated beef carcass tissue (BCT) was examined in two separate experiments. In the first study, individual pieces of BCT were inoculated with fresh bovine feces to obtain approximately 6.60 log APC/cm2 and spray treated (10 s; 520 kPa; 16°C) with ClO2 at tank concentrations ranging from 0 to 20 ppm. Bacterial populations were reduced by no more than 0.93 log CFU/cm2, regardless of ClO2 concentration, and were not statistically different (P ≥ 0.05) from water-treated BCT. In the second study, tap water (16°C) and ClO2 at a tank concentration of 20 ppm (16°C) were sprayed (690 kPa) for 15, 30, and 60 s onto BCT inoculated with fresh bovine feces to obtain approximately 5.80 log APC/cm2 and the remaining bacterial populations compared. While spray treatments with ClO2 or water reduced APC by 1.53 to 2.07 log CFU/cm2, spray treatments with either water or ClO2 at 15, 30 or 60 s were not statistically different (P ≥ 0.05). Similar reductions (1.61 log CFU/cm2) were observed when BCT was spray treated for 60 s with tap water followed by a 60 s spray wash with ClO2. These results demonstrate that spray treatments with ClO2 are no more effective than water for reducing fecal contamination on beef.


[Validation of the Temporal Experience of Pleasure Scale (TEPS) in a French-speaking environment].
Anhedonia is defined as a diminished capacity to experience pleasant emotion and is commonly included among the negative symptoms of schizophrenia. However, if patients report experiencing a lower level of pleasure than controls, they report experiencing as much pleasure as controls with online measurements of emotion. The Temporal Experience of Pleasure Scale (TEPS) measures pleasure experienced in the moment and in anticipation of future activities. The TEPS is an 18-item self-report measurement of anticipatory (10 items) and consummatory (eight items) pleasure. The goal of this paper is to assess the psychometric characteristics of the French translation of this scale. A control sample was composed of 60 women and 22 men, with a mean age of 38.1 years (S.D.: 10.8). Thirty-six were without qualification and 46 with qualified professional diploma. A sample of 21 patients meeting DSM IV-TR criteria for schizophrenia was recruited among the community psychiatry service of the department of psychiatry in Lausanne. They were five women and 16 men; mean age was of 34.1 years (S.D.: 7.5). Ten obtained a professional qualification and 11 were without qualification. None worked in competitive employment. Their mean dose of chlorpromazine equivalent was 431 mg (S.D.: 259). All patients were on atypical antipsychotics. The control sample fulfilled the TEPS and the Physical Anhedonia Scale (PAS). The patient sample fulfilled the TEPS and was independently rated on the Calgary Depression Scale and the Scale for Assessment of Negative Symptoms. For comparison with controls, patients were matched on age, sex and professional qualification. This required the supplementary recruitment of two control subjects. Results with the control sample indicate that the TEPS presents an acceptable internal validity with Crombach alphas of 0.84 for the total scale, 0.74 for the anticipatory pleasure scale and 0.79 for the consummatory pleasure scale. The confirmatory factor analysis indicated that the model is well adapted to our data (chi(2)/dl=1.333; df=134; p<0.0006; root mean square residual, RMSEA=0.064). External validity measured with the PAS showed R=-0.27 (p<0.05) for the consummatory scale and R=-0.26 for the total score. Comparisons between patients and matched controls indicated that patients were significantly lower than control on anticipatory pleasure (t=2.7, df(40), 2-tailed p=0.01; cohen's d=0.83) and on total score of the TEPS (t=2.8, df (40), 2-tailed p=0.01; cohen's d=0.87). The two samples did not differ on consummatory pleasure. The anticipatory pleasure factor and the total TEPS showed significant negative correlation with the SANS anhedonia, respectively R=-0.78 (p<0.01) for the anticipatory factor and R=-0.61 (p<0.01) for the total TEPS. There was also a negative correlation between the anticipatory factor and the SANS avolition of R=-0.50 (p<0.05). These correlations were maintained, with partial correlations controlling for depression and chlorpromazine equivalents. The results of this validation show that the French version of the TEPS has psychometric characteristics similar to the original version. These results highlight the discrepancy between results of direct or indirect report of experienced pleasure in patients with schizophrenia. Patients may have difficulties in anticipating the pleasure of future enjoyable activities, but not in experiencing pleasure once in an enjoyable activity. Medication and depression do not seems to modify our results, but this should be better controlled in a longitudinal study. The anticipatory versus consummatory pleasure distinction appears to be useful for the development of new psychosocial interventions, tailored to improve desire in patients suffering from schizophrenia. Major limitations of the study are the small size of patient sample and the under representation of men in the control sample.


"Together at school"--a school-based intervention program to promote socio-emotional skills and mental health in children: study protocol for a cluster randomized controlled trial.
Schools provide a natural context to promote children's mental health. However, there is a need for more evidence-based, high quality school intervention programs combined with an accurate evaluation of their general effectiveness and effectiveness of specific intervention methods. The aim of this paper is to present a study protocol of a cluster randomized controlled trial evaluating the "Together at School" intervention program. The intervention program is designed to promote social-emotional skills and mental health by utilizing whole-school approach and focuses on classroom curriculum, work environment of school staff, and parent-teacher collaboration methods. The evaluation study examines the effects of the intervention on children's socio-emotional skills and mental health in a cluster randomized controlled trial design with 1) an intervention group and 2) an active control group. Altogether 79 primary school participated at baseline. A multi-informant setting involves the children themselves, their parents, and teachers. The primary outcomes are measured using parent and teacher ratings of children's socio-emotional skills and psychological problems measured by the Strengths and Difficulties Questionnaire and the Multisource Assessment of Social Competence Scale. Secondary outcomes for the children include emotional understanding, altruistic behavior, and executive functions (e.g. working memory, planning, and inhibition). Secondary outcomes for the teachers include ratings of e.g. school environment, teaching style and well-being. Secondary outcomes for both teachers and parents include e.g. emotional self-efficacy, child rearing practices, and teacher-parent collaboration. The data was collected at baseline (autumn 2013), 6 months after baseline, and will be collected also 18 months after baseline from the same participants. This study protocol outlines a trial which aims to add to the current state of intervention programs by presenting and studying a contextually developed and carefully tested intervention program which is tailored to fit a national school system. Identification of effective intervention elements to promote children's mental health in early school years is crucial for optimal later development. ClinicalTrials.gov register: NCT02178332.


Coherence of acoustic modes propagating through shallow water internal waves.
The 1995 Shallow Water Acoustics in a Random Medium (SWARM) experiment [Apel et al., IEEE J. Ocean. Eng. 22, 445-464 (1997)] was conducted off the New Jersey coast. The experiment featured two well-populated vertical receiving arrays, which permitted the measured acoustic field to be decomposed into its normal modes. The decomposition was repeated for successive transmissions allowing the amplitude of each mode to be tracked. The modal amplitudes were observed to decorrelate with time scales on the order of 100 s [Headrick et al., J. Acoust. Soc. Am. 107(1), 201-220 (2000)]. In the present work, a theoretical model is proposed to explain the observed decorrelation. Packets of intense internal waves are modeled as coherent structures moving along the acoustic propagation path without changing shape. The packets cause mode coupling and their motion results in a changing acoustic interference pattern. The model is consistent with the rapid decorrelation observed in SWARM. The model also predicts the observed partial recorrelation of the field at longer time scales. The model is first tested in simple continuous-wave simulations using canonical representations for the internal waves. More detailed time-domain simulations are presented mimicking the situation in SWARM. Modeling results are compared to experimental data.


Presynaptic inhibition in restless legs syndrome.
Introduction: Restless legs syndrome (RLS) is a condition that particularly urges at night in resting and causes the need to move the legs. Although the pathophysiology has not yet been clarified, dopamine and iron metabolism and spinal cord pathologies are blamed for causing the condition. There are few studies on spinal reflex mechanisms on RLS. In the present study, we aimed to investigate the role of presynaptic inhibition (PreI) in the spinal cord in RLS.Methods: Fourteen patients with RLS and 14 controls with similar demographic characteristics were included in the study. Soleus muscle H-reflex (Ht) investigation was performed for subjects whose electrophysiologic investigation was normal. The Ht response was conditioned to the stimulation of the common peroneal nerve (CPN) (Hc). The test and conditioned stimulation intervals were kept between 10 ms, 20 ms, 30 ms, 40 ms, 50 ms, 75 ms, 100 ms, 150 ms and 200 ms. In each inter-stimulus interval, nonparametric repeat measurement evaluations were conducted with the percentage value of Hc/Ht. The Hc/Ht values of the study and control groups in the same intervals were compared separately.Results: A significant decrease was detected in Hc values in the control group in the repeat measurement values at 20 ms and 100 ms inter-stimulus intervals; however, there was not decrease in any intervals in the patient's group.Conclusion: The absence of any decrease in Hc reflexes for 20-100 ms intervals revealed that discernible PreI was vanished in RLS patients.


Indomethacin has a potent antiviral activity against SARS coronavirus.
Severe acute respiratory syndrome (SARS) is a newly emerging, highly transmissible and fatal disease caused by a previously unknown coronavirus (SARS-CoV). Existing in non-identified animal reservoirs, SARS-CoV continues to represent a threat to humans because there is no effective specific antiviral therapy for coronavirus infections. Starting from the observation that cyclopentenone cyclooxygenase (COX) metabolites are active against several RNA viruses, we investigated the effect of the COX inhibitor indomethacin on coronavirus replication. Work involving infectious SARS-CoV was performed in biosafety level 3 facilities. SARS-CoV was grown in monkey VERO cells and human lung epithelial A549 cells, while canine coronavirus (CCoV) was grown in A72 canine cells. Antiviral activity was analysed by determining infective virus titres by TCID50, viral RNA synthesis by Northern blot analysis and real-time RT-PCR, and viral protein synthesis by SDS-PAGE analysis after 35S-methionine-labelling. Antiviral efficacy in vivo was determined by evaluating virus titres in CCoV-infected dogs treated orally with 1 mg/kg body weight indomethacin (INDO). Unexpectedly, we found that INDO has a potent direct antiviral activity against the coronaviruses SARS-CoV and CCoV. INDO does not affect coronavirus binding or entry into host cells, but acts by blocking viral RNA synthesis at cytoprotective doses. This effect is independent of cyclooxygenase inhibition. INDO's potent antiviral activity (>1,000-fold reduction in virus yield) was confirmed in vivo in CCoV-infected dogs. The results identify INDO as a potent inhibitor of coronavirus replication and suggest that, having both anti-inflammatory and antiviral activity, INDO could be beneficial in SARS therapy.


EPR and Mössbauer studies of protocatechuate 4,5-dioxygenase. Characterization of a new Fe2+ environment.
Protocatechuate 4,5-dioxygenase from Pseudomonas testosteroni has been purified to homogeneity and crystallized. The iron containing, extradiol dioxygenase is shown to be composed of two subunit types (alpha, Mr = 17,700 and beta, Mr = 33,800) in a 1:1 ratio; such a composition has not been observed for other extradiol dioxygenases. The 4.2 K Mössbauer spectrum of native protocatechuate 4,5-dioxygenase prepared from cells grown in 57Fe-enriched media consists of a doublet with quadrupole splitting, delta EQ = 2.22 mm/s, and isomer shift delta Fe = 1.28 mm/s, demonstrating a high spin Fe2+ site. These parameters, and the temperature dependence of delta EQ, are unique among enzymes but are strikingly similar to those reported for the reaction center of the photosynthetic bacterium Rhodopseudomonas sphaeroides R-26, suggesting very similar ligand environments. The Fe2+ of protocatechuate 4,5-dioxygenase can be oxidized, for instance by H2O2, to yield high spin Fe3+ with EPR g values around g = 6 (and g = 4.3). In the oxidized state, protocatechuate 4,5-dioxygenase is inactive; the iron, however, can be rereduced by ascorbate to yield active enzyme. Our data suggest that protocatechuate binds to Fe2+; the spectra indicate that the ligand binding is heterogenous. The Mössbauer spectra observed here are fundamentally different from those reported earlier (Zabinski, R., Münck, E., Champion, P., and Wood, J. M. (1972) Biochemistry 11, 3212-3219). The spectra of the earlier (reconstituted) preparations, which had substantially lower specific activities, probably reflect adventitiously bound Fe3+. We discuss here how adventitiously bound iron can be identified and removed. The Fe2+ which is present in native protocatechuate 4,5-dioxygenase and its complexes with substrates and inhibitors reacts quantitatively with nitric oxide to produce a species with electronic spin S = 3/2. The EPR and Mössbauer spectra of these complexes compare favorably with EDTA . Fe(II) . NO. We have studied the latter complex extensively and have analyzed the Mössbauer spectra with an S = 3/2 spin Hamiltonian. EPR spectra show that protocatechuate 4,5-dioxygenase-NO complexes with substrates or inhibitors are heterogeneous and consist of several well defined subspecies. The data show that NO, and presumably also O2, has access to the active site Fe2+ in the enzyme-substrate complex. The use of EPR-detectable NO complexes as a rapid and sensitive tool for the study of the EPR silent active site iron of extradiol dioxygenases is discussed.


Development of QSARs for the toxicity of chlorobenzenes to the soil dwelling springtail Folsomia candida.
To meet the goals of Registration, Evaluation, Authorisation, and Restriction of Chemicals (REACH) as formulated by the European Commission, fast and resource-effective tools are needed to predict the toxicity of compounds in the environment. We developed quantitative structure-activity relationships (QSARs) for the toxicity of nine chlorinated benzenes to the soil-dwelling collembolan Folsomia candida in natural LUFA2.2 (Landwirtschaftliche Untersuchungs und Forschungsanstalt [LUFA]) standard soil and in Organisation for Economic Co-operation and Development artificial soil. Toxicity endpoints used were the effect concentrations causing 10% (EC10) and 50% (EC50) reduction in the reproduction of the test organism over 28 d, while lethal effects on survival (LC50) were used for comparisons with earlier studies. Chlorobenzene toxicity was based on concentrations in interstitial water as estimated using nominal concentrations in soil and literature soil-water partition coefficients. Additionally, for LUFA2.2 soil the estimated concentrations in interstitial water were experimentally determined by solid-phase microextraction measurements. Measured and estimated concentrations showed the same general trend, but significant differences were observed. With the exception of hexachlorobenzene, estimated EC10 and EC50 values were all negatively correlated with their logK(ow) and QSARs were developed. However, no correlation for the LC50 could be derived and 1,2,4,5-tetrachlorobenzene and hexachlorobenzene had no effect on adult survival at all. The derived QSARs may contribute to the development of better ecotoxicity-based models serving the REACH program.


Effects of energy balance on cancer in genetically altered mice.
Evidence has accumulated from laboratory-based animal experiments and population-based human epidemiological studies that lifestyle factors that affect energy balance, such as caloric intake, nutritional status, and exercise, act in concert with genetic susceptibility to influence cancer development and progression. The use of animal models with specific genetic alterations, in combination with lifestyle modifications that alter overall energy balance, has contributed to a greater understanding of the mechanistic changes occurring during carcinogenesis and to the identification of points of intervention. Studies in our laboratory focusing on the role of energy balance and genetic susceptibility in mice deficient in one (+/-) or both (-/-) alleles of the p53 tumor suppressor gene and mice with a mutant APC allele (APC(Min)) showed that calorie restriction decreases tumor burden, increases tumor latency, and decreases serum insulin-like growth factor (IGF)-1 and leptin levels. Data from our studies, combined with results from other animal and human studies, have established a role for IGF-1 in carcinogenesis. Studies using genetic models of cancer that have been interbred with mice with abnormal levels of IGF-1 will enable the examination of combined effects of energy balance and genetic alterations on the cancer process. Models that integrate lifestyle and genetic effects in a single system provide a physiologically intact system in which combination interventions and therapies for cancer prevention can be tested and validated, thus building a strong preclinical foundation that will inform the development of clinical trials and add perspective to epidemiological studies.


Ukrainian Dietary Bread with Selenium-Enriched Soya Malt.
The production of bread with addition of selenium-enriched soya malt was studied. Processing of this soya malt included soaking of the soya beans in the solution of hydroselenite with concentration 1.5 mg Se/L (20 μg of Se per 1 g of soya beans), then 4 days of beans germination at 20 °C, drying at 50 °C until moisture content 8%, separation from the sprouts and grinding. The soya malt was a powder containing 15-18 μg of Se in 1 g. The accumulated selenium was mainly in the protein fraction of soya malt. Addition of selenium-enriched soya malt to leaven intensified activity of yeasts and lactic acid bacteria. The quality of the wheat bread with selenium-enriched soya malt was better than that of the bread in control. The enriched bread had specific pleasant smell and soft texture. The daily intake of 277 g of bread with the selenium-enriched soya malt, which is added in quantity of 1.0-1.75% to mass of plain flour, ensures the consumption of 30-50% of selenium recommended daily allowance for 17 million population of the northern and northwestern Ukraine.


Preliminary validation and principal components analysis of the Control of Eating Questionnaire (CoEQ) for the experience of food craving.
The Control of Eating Questionnaire (CoEQ) comprises 21-items that are designed to assess the severity and type of food cravings an individual experiences over the previous 7 days. The CoEQ has been used in clinical trials as a multi-dimensional measure of appetite, craving and mood regulation however its underlying component structure has yet to be determined. The current paper has two aims; (1) to examine the psychometric properties, and internal consistency of the CoEQ; and (2) to provide a preliminary examination of the underlying components by exploring their construct and predictive validity. Data were pooled from four studies in which a total 215 adults (80% women; Age=29.7 ± 10.3; BMI=26.5 ± 5.2) had completed the CoEQ alongside measures of psychometric eating behaviour traits, ad libitum food intake, and body composition. A principal components analysis (PCA) and parallel analysis was conducted to examine the underlying structure of the questionnaire. The resulting subscales were tested for internal consistency (Cronbach's α=0.66-0.88). PCA revealed four components that explained 54.5% of the variance. The components were identified as: Craving Control, Positive Mood, Craving for Sweet, and Craving for Savoury. Associations between the underlying CoEQ subscales and measures of body composition and eating behaviour traits confirmed construct validity of the subscales. The associations between the subscales and snack food selection and intake of palatable snack foods supported the CoEQ's predictive validity. The CoEQ has good psychometric properties with a clear component structure and acceptable internal consistency. This preliminary validation supports the CoEQ as a measure of the experience of food cravings.


Reproducibility and accuracy of echocardiographic measurements of left ventricular parameters using real-time three-dimensional echocardiography.
We sought to determine whether assessment of left ventricular (LV) function with real-time (RT) three-dimensional echocardiography (3DE) could reduce the variation of sequential LV measurements and provide greater accuracy than two-dimensional echocardiography (2DE). Real-time 3DE has become feasible as a standard clinical tool, but its accuracy for LV assessment has not been validated. Unselected patients (n = 50; 41 men; age, 64 +/- 8 years) presenting for evaluation of LV function were studied with 2DE and RT-3DE. Test-retest variation was performed by a complete restudy by a separate sonographer within 1 h without alteration of hemodynamics or therapy. Magnetic resonance imaging (MRI) images were obtained during a breath-hold, and measurements were made off-line. The test-retest variation showed similar measurements for volumes but wider scatter of LV mass measurements with M-mode and 2DE than 3DE. The average MRI end-diastolic volume was 172 +/- 53 ml; LV volumes were underestimated by 2DE (mean difference, -54 +/- 33; p < 0.01) but only slightly by RT-3DE (-4 +/- 29; p = 0.31). Similarly, end-systolic volume by MRI (91 +/- 53 ml) was underestimated by 2DE (mean difference, -28 +/- 28; p < 0.01) and by RT-3DE (mean difference, -3 +/- 18; p = 0.23). Ejection fraction by MRI was similar by 2DE (p = 0.76) and RT-3DE (p = 0.74). Left ventricular mass (183 +/- 50 g) was overestimated by M-mode (mean difference, 68 +/- 86 g; p < 0.01) and 2DE (16 +/- 57; p = 0.04) but not RT-3DE (0 +/- 38 g; p = 0.94). There was good inter- and intra-observer correlation between RT-3DE by two sonographers for volumes, ejection fraction, and mass. Real-time 3DE is a feasible approach to reduce test-retest variation of LV volume, ejection fraction, and mass measurements in follow-up LV assessment in daily practice.


Clinical ergotism with lingual ischemia induced by clarithromycin-ergotamine interaction.
The macrolide class of antibiotics, including erythromycin and troleandomycin, is associated with clinically significant adverse drug interactions. This results from macrolide inhibition of cytochrome P-450 metabolism of numerous xenobiotics, resulting in elevated serum drug levels and clinical intoxication. Animal studies, however, suggest that clarithromycin, the newest approved macrolide antibiotic, has has less potential for adverse drug reactions. We describe a patient who, on her fifth day of clarithromycin therapy, developed clinical ergotism (i.e., hypertension, lingual ischemia, and peripheral cyanosis) several hours after administration of her usual 2-mg dose of ergotamine tartrate. To our knowledge, this is the first report of clinical ergotism precipitated by clarithromycin-ergotamine interaction and suggests that, like other macrolide antibiotics, ergot preparations should be avoided in patients who are taking clarithromycin.


Characteristics Associated With Antihypertensive Treatment and Blood Pressure Control: A Population-Based Follow-Up Study in Peru.
Over one-quarter of the world's adult population has hypertension, yet achieving adequate treatment or control targets remains a challenge. This study sought to identify, longitudinally, characteristics associated with antihypertensive treatment and blood pressure (BP) control among individuals with hypertension. Data from individuals enrolled in the population-based CRONICAS Cohort Study (adults ≥35 years, living in 4 different rural/urban and coastal/high-altitude Peruvian settings) with hypertension at baseline were used. Antihypertensive treatment and BP control were assessed at baseline and at 15 months. Multinomial logistic regressions were used to estimate relative risk ratios (RRR) and 95% confidence intervals (95% CI) of factors associated with antihypertensive treatment and BP control at follow-up. At baseline, among 717 individuals with hypertension (53% women, mean age 61.5 ± 12.4 years), 28% were unaware of their hypertension status, 30% were aware but untreated, 16% were treated but uncontrolled, and 26% were treated and controlled. At follow-up, 89% of unaware and 82% of untreated individuals persisted untreated, and only 58% of controlled individuals remained controlled. Positive predictors of receiving treatment and being controlled at follow-up included age (RRR: 0.81; 95% CI: 0.73 to 0.91 for every 5 years) and family history of a chronic disease (RRR: 0.53; 95% CI: 0.31 to 0.92 vs. no history); whereas Puno rural site (RRR: 16.51; 95% CI: 1.90 to 143.56 vs. Lima) and male sex (RRR: 2.59; 95% CI: 1.54 to 4.36) were risk factors. Systolic BP at baseline (RRR: 1.27; 95% CI: 1.16 to 1.39 for every 5 mm Hg) and male sex (RRR: 1.75, 95% CI: 1.02 to 2.98) were risk factors for being treated but uncontrolled at follow-up. Large gaps in treatment of hypertension were observed. Targeting specific populations such as men, younger individuals, or those without family history of disease may increase coverage of antihypertensive treatment. Also, targeting male individuals or those with higher systolic BP could yield better rates of BP control in the short term.


Multiple pathways to the same end: mechanisms of myonuclear apoptosis in sarcopenia of aging.
Sarcopenia, the age-related decline in muscle mass and function, represents a significant health issue due to the high prevalence of frailty and disability associated with this condition. Nevertheless, the cellular mechanisms responsible for the loss of muscle mass in old age are still largely unknown. An altered regulation of myocyte apoptosis has recently emerged as a possible contributor to the pathogenesis of sarcopenia. Studies in animal models have shown that the severity of skeletal muscle apoptosis increases over the course of aging and correlates with the degree of muscle mass and strength decline. Several apoptotic pathways are operative in aged muscles, with the mitochondria- and TNF-alpha-mediated pathways likely being the most relevant to sarcopenia. However, despite the growing number of studies on the subject, a definite mechanistic link between myocyte apoptosis and age-related muscle atrophy has not yet been established. Furthermore, the evidence on the role played by apoptosis in human sarcopenia is still sparse. Clearly, further research is required to better define the involvement of myocyte apoptosis in the pathogenesis of muscle loss at advanced age. This knowledge will likely help in the design of more effective therapeutic strategies to preserve muscle mass into old age, thus fostering independence of the elderly population and reducing the socioeconomic burden associated with sarcopenia.


Alaska air carrier operator and pilot safety practices and attitudes: a statewide survey.
Aviation crashes are a leading cause of occupational fatalities in Alaska, with Alaskan pilots having nearly 100 times the fatality rate of U.S. workers overall. A survey was designed to study pilot and company practices and attitudes in order to develop intervention strategies that would reduce aviation fatalities. Two surveys were administered: one of air carrier operators and one of active commercial pilots. Surveys from 153 air taxi and public-use operators were received at a 79% response rate. There are almost 2000 pilots employed in Alaska during peak season by air taxi operators and public agencies. Surveyed operators and pilots generally agreed that improved weather information and regional hazards training would be effective ways to prevent crashes. Operators were more in favor of operator financial incentives (p < 0.05) and better pre-employment hiring checks on pilots (p < 0.05) compared with pilots' survey responses. There were 48% of pilots of large operators and 73% of pilots of small operators who considered their jobs to be at least as safe as other jobs. The results of operator-pilot comparisons suggest that financial pressures on operators may influence their views on what measures would be effective in preventing crashes, and that Alaskan pilots underestimate their occupational fatality risk.


Tyrosine411 and Arginine410 of Human Serum Albumin Play an Important Role in the Binding of Sodium 4-Phenylbutyrate to Site II.
Sodium 4-phenylbutyrate (PB) has many pharmacological activities; therefore extending its clinical use to the treatment of a wider variety of diseases would be desirable. However, our knowledge of the binding of PB to plasma proteins is not extensive. To address this issue in more detail, we characterized the protein binding of PB. Binding experiments showed that PB mainly binds to human serum albumin (HSA) in plasma. PB was also found to bind to a single site on HSA, which was identified as site II by fluorescent probe displacement experiment. Furthermore, an appropriate alkyl chain length and a carboxylic group in the PB structure were required for PB binding to HSA, suggesting that hydrophobic (and van der Waals) and electrostatic interactions are involved as binding modes. The contributions of hydrogen bonding and/or van der Waals interactions were also indicated by thermodynamic analyses. Tyrosine411 and arginine410 were identified as being involved in the binding of PB to site II, based on binding experiments using chemically modified- and mutant-HSA preparations. In conclusion, the available evidence indicates that PB binds to site II of HSA with assistance by multiple forces and that tyrosine411 and arginine410 both play important roles in this phenomenon.


Reactive oxygen species in colorectal cancer adjuvant therapies.
Colorectal cancer (CRC), a prevalent global malignancy, often necessitates adjuvant therapies such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy to mitigate tumor burden in advanced stages. The efficacy of these therapies is significantly influenced by reactive oxygen species (ROS). Previous research underscores the pivotal role of ROS in gut pathology, targeted therapy, and drug resistance. ROS-mediated CRC adjuvant therapies encompass a myriad of mechanisms, including cell death and proliferation, survival and cell cycle, DNA damage, metabolic reprogramming, and angiogenesis. Preliminary clinical trials have begun to unveil the potential of ROS-manipulating therapy in enhancing CRC adjuvant therapies. This review aims to provide a comprehensive synthesis of studies exploring the role of ROS in CRC adjuvant therapies.


Involvement of hyperpolarization-activated cation channels in synaptic modulation.
The frequency of miniature excitatory postsynaptic currents (mEPSCs) in cultured hippocampal neurons increases under the action of drugs that trigger a rise in the intracellular concentration of cyclicAMP. It is generally believed that this type of effect is mediated by protein kinase A. Here, we show that it largely depends on the activation of hyperpolarization-activated cation channels (Ih) by cyclicAMP. In mammals, Ih channels control membrane excitability, thanks to their function as ionic channels. Here, we show that the effect of Ih channels on glutamate release is not mediated by the depolarization induced by their activation and thus is not linked to the ionic channel aspect of Ih channels. This suggests that the Ih channel could be a bifunctional protein.


Acquired immune deficiency syndrome in children. Current problems and therapeutic considerations.
Acquired immune deficiency syndrome (AIDS) in children has until recently been under-reported, since the initial Centers for Disease Control definition of AIDS was restrictive. The case definition has now been revised. Most children with AIDS acquired their infection perinatally and have a parent with established AIDS-related complex or AIDS or belong to a high-risk group. Prior to March 1985, children also acquired human immunodeficiency virus from a contaminated blood product transfusion or from factor replacement for hemophilia. In the United States, AIDS in children occurs predominantly in cities with large populations of intravenous drug users. There are a number of differences between the clinical manifestations of human immunodeficiency virus infection in children compared with adults. For example, recurrent bacterial infection is more common in children, perhaps reflecting the abnormal B cell function that occurs relatively early in the disease course. Certain opportunistic infections (e.g., toxoplasmosis, cryptococcal meningitis) are less common in children than adults. Lymphocytic interstitial pneumonia does not occur in adults but is found in 30 to 50 percent of children. On the other hand, Kaposi's sarcoma and other malignancies are less common in children. Treatment has consisted largely of general supportive care in hospital or at home; this is dependent on the availability and utilization of resources and financial support. However, as anti-retroviral therapy becomes available, studies in children have been initiated. It is hoped that in the future it may be possible to prevent the disease; in the meantime, earlier diagnosis and better therapy are important goals.


Failure Rates After Revision Arthroscopic Stabilization for Recurrent Anterior Shoulder Instability Based on Anterior Capsulolabral Complex Conditions.
A labral retear is an important contributing factor to surgical failure after arthroscopic soft tissue stabilization for recurrent anterior shoulder instability. However, surgeons frequently encounter poor tissue conditions in the anterior capsule, such as capsular tears, during revision surgery. To analyze the clinical outcomes and failure rates of revision arthroscopic stabilization after failed Bankart repair based on the tissue conditions of the anterior capsule and the labrum. Outcomes were compared for revision after failed Bankart repair because of a labral retear versus a healed labrum but with capsular tears. Cohort study; Level of evidence, 3. A total of 55 patients who underwent revision arthroscopic stabilization after failed Bankart repair were included. Revision surgery was indicated if patients had a history of recurrent instability with positive apprehension test results, regardless of magnetic resonance imaging (MRI) findings of a labral retear. Patients were allocated into 2 groups based on arthroscopic findings at the time of revision surgery: group 1 consisted of patients who had a healed labrum with definite anterior capsular tears, and group 2 comprised patients who had labral retears without capsular tears. Clinical outcomes were assessed using the American Shoulder and Elbow Surgeons score, Rowe score, and surgical failure rate. Overall, 10 patients were included in group 1, and 45 patients were included in group 2. No capsular tears were detected on preoperative MRI or magnetic resonance arthrography scans in either group, whereas all patients in group 2 had evidence of anterior labral retears on imaging scans. After revision surgery, 9 patients (16.4%) showed surgical failure by 25.6 months postoperatively. Patients in group 1 had a significantly higher surgical failure rate than did those in group 2 (4 patients [40.0%] vs 5 patients [11.1%], respectively; P = .04). The incidence of capsular tears was significantly higher in patients with surgical failure versus those without surgical failure (44.4% vs 13.0%, respectively; P = .04). A capsular tear of the anterior capsulolabral complex was an important indicator for surgical failure after revision arthroscopic stabilization. If patients demonstrate symptomatic instability after arthroscopic soft tissue stabilization without evidence of labral retears on imaging scans, an anterior capsular tear should be considered as a possible factor for recurrence.


Periodontal conditions, low birth weight and preterm birth among postpartum mothers in two tertiary health facilities in Uganda.
Literature reports have indicated an increase in research evidence suggesting association between periodontal disease and the risk of pre-term birth (PTB) and low birth weight (LBW). Periodontal diseases in Uganda have been documented as a public health problem, but their association to adverse pregnancy outcomes is unknown. This study was conducted to assess the association between periodontital diseases in postpartum mothers and PTB and LBW of babies in Mulago and Mbarara referral hospitals. This was a cross sectional study using medical records, clinical examination and oral interview of mothers at the two tertiary health facilities. Mothers with singleton babies from Mulago (n = 300) and Mbarara Hospital (n = 100) were recruited for the study. The women were clinically examined for periodontal disease by 2 trained and calibrated dentists. Data on PTB and LBW were retrieved from medical records. The data were analyzed to determine the relationship between the four parameters for periodontal disease (bleeding gingiva, periodontal pockets, gingival recession and calculus with plaque deposits) and the adverse pregnancy outcomes. Frequency distribution was used to describe the data. Bivariate and multivariate analyses were used to study the association between the periodontal diseases and adverse pregnancy outcomes. Approximately 26% and 29% of the postpartum mothers examined had bleeding gingiva and periodontal pockets of 4 mm or more deep, respectively. Advanced periodontitis i.e. pocket depth ≥ 6 mm was recorded in 13 (3.6%) of the mothers. Calculus with plaque deposits were recorded in 86% (n = 343) of the mothers. Gingival recession was recorded in 9.0% of the mothers and significantly and directly related to birth weight (p < 0.05). Periodontal conditions of postpartum mothers in this study were found to be better than previously reported amongst the Ugandan population. Bivariate analysis showed a significant association only between gingival recession and low birth weight. However, this finding should be interpreted with caution as it could have occurred by chance.


Cardiometabolic and reproductive benefits of early dietary energy restriction and voluntary exercise in an obese PCOS-prone rodent model.
Polycystic ovary syndrome (PCOS) is one of the most common endocrine-metabolic disorders in women of reproductive age characterized by ovulatory dysfunction, hyperandrogenism and cardiometabolic risk. The overweight-obese PCOS phenotype appears to have exacerbated reproductive dysfunction and cardiometabolic risk. In overweight-obese adult women with PCOS, exercise and energy restricted diets have shown limited and inconsistent effects on both cardiometabolic indices and reproductive outcomes. We hypothesized that an early lifestyle intervention involving exercise and dietary energy restriction to prevent or reduce the propensity for adiposity would modulate reproductive indices and cardiometabolic risk in an obese PCOS-prone rodent model. Weanling obese PCOS-prone and Lean-Control JCR:LA-cp rodents were given a chow diet ad libitum or an energy-restricted diet combined with or without voluntary exercise (4 h/day) for 8 weeks. Dietary energy restriction and exercise lowered total body weight gain and body fat mass by 30% compared to free-fed sedentary or exercising obese PCOS-prone animals (P<0.01). Energy restriction induced an increase in exercise intensity compared to free-feeding plus exercise conditions. Energy restriction and exercise decreased fasting plasma triglycerides and apoB48 concentrations in obese PCOS-prone animals compared to free-fed and exercise or sedentary groups. The energy restriction and exercise combination in obese PCOS-prone animals significantly increased plasma sex-hormone binding globulin, hypothalamic cocaine-and amphetamine-regulated transcript (CART) and Kisspeptin mRNA expression to levels of the Lean-Control group, and this was further associated with improvements in estrous cyclicity. The combination of exercise and dietary energy restriction when initiated in early life exerts beneficial effects on cardiometabolic and reproductive indices in an obese PCOS-prone rodent model, and this may be associated with normalization of the hypothalamic neuropeptides, Kisspeptin and CART.


Noradrenaline, by activation of alpha-1-adrenoceptors in the region of the supraoptic nucleus, causes secretion of vasopressin in the unanaesthetized rat.
In unanaesthetized rats chronically prepared with venous and intracerebral cannulae, noradrenaline injected into the region of the supraoptic nuclei caused a dose-dependent increase in plasma vasopressin, measured by radioimmunoassay. A similar response was obtained with phenylephrine, but not with either clonidine or isoprenaline. The secretion of vasopressin was not secondary to change in arterial pressure, since similar injections of noradrenaline resulted in a small increase in arterial pressure, measured in the anaesthetized rat. These results suggest that noradrenaline stimulates alpha-1-adrenoceptors, presumably located on vasopressin-secreting neurones, thereby causing these cells to secrete vasopressin into the circulation. Tyramine injections also resulted in a prompt elevation in plasma vasopressin, indicating that endogenous noradrenaline is capable of releasing vasopressin.


Agent-based modeling of oxygen-responsive transcription factors in Escherichia coli.
In the presence of oxygen (O2) the model bacterium Escherichia coli is able to conserve energy by aerobic respiration. Two major terminal oxidases are involved in this process - Cyo has a relatively low affinity for O2 but is able to pump protons and hence is energetically efficient; Cyd has a high affinity for O2 but does not pump protons. When E. coli encounters environments with different O2 availabilities, the expression of the genes encoding the alternative terminal oxidases, the cydAB and cyoABCDE operons, are regulated by two O2-responsive transcription factors, ArcA (an indirect O2 sensor) and FNR (a direct O2 sensor). It has been suggested that O2-consumption by the terminal oxidases located at the cytoplasmic membrane significantly affects the activities of ArcA and FNR in the bacterial nucleoid. In this study, an agent-based modeling approach has been taken to spatially simulate the uptake and consumption of O2 by E. coli and the consequent modulation of ArcA and FNR activities based on experimental data obtained from highly controlled chemostat cultures. The molecules of O2, transcription factors and terminal oxidases are treated as individual agents and their behaviors and interactions are imitated in a simulated 3-D E. coli cell. The model implies that there are two barriers that dampen the response of FNR to O2, i.e. consumption of O2 at the membrane by the terminal oxidases and reaction of O2 with cytoplasmic FNR. Analysis of FNR variants suggested that the monomer-dimer transition is the key step in FNR-mediated repression of gene expression.


Triple Therapy Versus Dual Antiplatelet Therapy for Patients with Atrial Fibrillation and Acute Coronary Syndromes: A Systematic Literature Review.
Patients with acute coronary syndromes (ACS) and a history of atrial fibrillation (AF) have indications for both dual antiplatelet therapy (DAPT) and oral anticoagulation (OAC). Triple therapy (TT), the combination of DAPT and OAC, is recommended in guidelines. We examined studies comparing clinical outcomes on DAPT versus TT for patients with AF and ACS. We searched Medline, Medline pending, EMBASE and Evidence-Based Medicine Reviews databases for studies published between January 2000 to December 2016 in AF patients with ACS that compared DAPT and TT that reported ischaemic and/or bleeding outcomes. Studies that were not purely an AF population were excluded. Ten studies were included in the review, all of which were observational, 8 of which were retrospective. None of the studies detailed the specifics of treatment allocation. All but one were of AF patients with a mix of stable coronary disease and ACS patients. TT was associated with increased bleeding when compared to DAPT, with adjusted odds ratios ranging from 1.25 to 6.84. While the largest study reported a reduction in stroke associated with TT (odds ratio 0.67), two other studies reported non-significant increases in stroke with TT. Variable composite ischaemic endpoints were reported, none showing a statistical significant difference between DAPT and TT. In patients with ACS and AF, TT is likely to be associated with increased risk of bleeding, without a clear reduction in ischaemic endpoints. The quality of the evidence to support current guidelines for this patient group was generally poor.


Novel Anthranilic Diamide Scaffolds Containing N-Substituted Phenylpyrazole as Potential Ryanodine Receptor Activators.
To discover potent insecticides targeting ryanodine receptors (RyRs), a series of novel anthranilic diamides analogues (12a-12u) containing N-substituted phenylpyrazole were designed and synthesized. These compounds were characterized by (1)H NMR, (13)C NMR, and HRMS, and the structure of compound 12u was confirmed by X-ray diffraction. Their insecticidal activities indicated that these compounds displayed moderate to excellent activities. In particular, 12i showed 100 and 37% larvicidal activities against oriental armyworm (Mythimna separata) at 0.25 and 0.05 mg L(-1), equivalent to that of chlorantraniliprole (100%, 0.25 mg L(-1); and 33%, 0.05 mg L(-1)). The activity of 12i against diamondback moth (Plutella xylostella) was 95% at 0.05 mg L(-1), whereas the control was 100% at 0.05 mg L(-1). The calcium-imaging technique experiment results showed that the effects of 12i on the intracellular calcium ion concentration ([Ca(2+)]i) in neurons were concentration-dependent. After the central neurons of Helicoverpa armigera were dyed by loading with fluo-5N and treated with 12i, the free calcium released in endoplasmic reticulum indicated the target of compound 12i is RyRs or IP3Rs. The activation of RyRs by natural ryanodine completely blocked the calcium release induced by 12i, which indicated that RyRs in the central neurons of H. armigera third-instar larvae is the possible target of compound 12i.


Detection and Characterization of Leptospira Infection and Exposure in Rats on the Caribbean Island of Saint Kitts.
In this study, we detected and characterized Leptospira infection and exposure in rats on the Caribbean island of Saint Kitts for the first time. We detected Leptospira infection in 17/29 (59%), 14/29 (48)%, and 11/29 (38)% of rats by RT-PCR, culture, and immunofluorescence assay, respectively. Whole genome sequencing (WGS) and analysis and serogrouping of 17 Leptospira strains isolated from rats revealed their close relationship with L. interrogans serogroup Icterohaemorrhagiae (n = 10) and L. borgpetersenii serogroup Ballum (n = 7). WGS, serogrouping, and additional PCR tests on rat kidneys confirmed mixed infections with L. interrogans and L. borgpetersenii in the kidneys of three rats. Microscopic agglutination test (MAT) was positive for 25/29 (87%) of the rats tested, and the response was restricted to serovars Icterohaemorrhagiae {24/29(83%)}, Mankarso {4/29(14%)}, Copenhageni {4/29(14%)}, Grippotyphosa {2/29(7%)}, and Wolffi {1/29(3%)}. Interestingly, there was no agglutinating antibody response to serovar Ballum. We observed a similar pattern in the serologic response using Leptospira isolates obtained from this study with each of the rat sera, with strong response to L. interrogans isolates but minimal reactivity to L. borgpetersenii isolates. Our findings suggest the use of multiple complementary diagnostic tests for Leptospira surveillance and diagnosis to improve the accuracy of the data.


Integrated assessment of urban drainage system under the framework of uncertainty analysis.
Due to a rapid urbanization as well as the presence of large number of aging urban infrastructures in China, the urban drainage system is facing a dual pressure of construction and renovation nationwide. This leads to the need for an integrated assessment when an urban drainage system is under planning or re-design. In this paper, an integrated assessment methodology is proposed based upon the approaches of analytic hierarchy process (AHP), uncertainty analysis, mathematical simulation of urban drainage system and fuzzy assessment. To illustrate this methodology, a case study in Shenzhen City of south China has been implemented to evaluate and compare two different urban drainage system renovation plans, i.e., the distributed plan and the centralized plan. By comparing their water quality impacts, ecological impacts, technological feasibility and economic costs, the integrated performance of the distributed plan is found to be both better and robust. The proposed methodology is also found to be both effective and practical.


Short-term impact of COVID-19 on quality of life, perceived stress, and serious psychological distress in an adult population in the midwest United States.
This study aimed to investigate changes over time in quality of life, perceived stress, and serious psychological distress for individuals diagnosed with COVID-19 in an urban academic health system. Phone-based surveys were completed with adult patients tested for COVID-19 during emergency department visits, hospitalizations, or outpatient visits at the Froedtert and Medical College of Wisconsin Health Network. Data were then matched to medical record data. Unadjusted and adjusted mixed effects linear models using random intercept were run for each outcome (physical health-related quality of life, mental health-related quality of life, perceived stress, and serious psychological distress) with time (baseline vs 3-month follow-up) as the primary independent variable. Individuals were treated as a random effect, with all covariates (age, sex, race/ethnicity, payor, comorbidity count, hospitalization, and intensive care unit (ICU) stay) treated as fixed effects. 264 adults tested positive for COVID-19 and completed baseline and 3-month follow-up assessments. Of that number, 31.8% were hospitalized due to COVID-19, and 10.2% were admitted for any reason to the ICU. After adjustment, patients reported higher physical health-related quality of life at 3 months compared to baseline (0.63, 95% CI 0.15, 1.11) and decreased stress at 3 months compared to baseline (- 0.85, 95% CI - 1.33, - 0.37). There were no associations between survey time and mental health-related quality of life or serious psychological distress. Results suggest the influence of COVID-19 on physical health-related quality of life and stress may resolve over time, however, the influence of mental health on daily activities, work, and social activities may not.


Dynamics of Pseudomonas aeruginosa genome evolution.
One of the hallmarks of the Gram-negative bacterium Pseudomonas aeruginosa is its ability to thrive in diverse environments that includes humans with a variety of debilitating diseases or immune deficiencies. Here we report the complete sequence and comparative analysis of the genomes of two representative P. aeruginosa strains isolated from cystic fibrosis (CF) patients whose genetic disorder predisposes them to infections by this pathogen. The comparison of the genomes of the two CF strains with those of other P. aeruginosa presents a picture of a mosaic genome, consisting of a conserved core component, interrupted in each strain by combinations of specific blocks of genes. These strain-specific segments of the genome are found in limited chromosomal locations, referred to as regions of genomic plasticity. The ability of P. aeruginosa to shape its genomic composition to favor survival in the widest range of environmental reservoirs, with corresponding enhancement of its metabolic capacity is supported by the identification of a genomic island in one of the sequenced CF isolates, encoding enzymes capable of degrading terpenoids produced by trees. This work suggests that niche adaptation is a major evolutionary force influencing the composition of bacterial genomes. Unlike genome reduction seen in host-adapted bacterial pathogens, the genetic capacity of P. aeruginosa is determined by the ability of individual strains to acquire or discard genomic segments, giving rise to strains with customized genomic repertoires. Consequently, this organism can survive in a wide range of environmental reservoirs that can serve as sources of the infecting organisms.


A longitudinal study of kidney structure and function in adults.
Although kidney size is commonly measured in patients with chronic kidney disease (CKD), its relationship with kidney function is poorly understood. We conducted this longitudinal study to better understand the relationship between kidney size and function. We retrospectively studied 178 kidneys measured by ultrasound in 93 patients with CKD who did not have autosomal polycystic kidney disease. Renal function was measured using estimated glomerular filtration rate (GFR). A mixed model that accounted for repeated measurements or nested observations was used for statistical analysis. In cross-sectional analyses, the following independent variables emerged as predictors of kidney size: estimated GFR along with its squared term, height, age and interactions of each of these two independent variables with aetiology of CKD. In longitudinal analyses over a median follow-up of 3.7 years, after accounting for predictors of baseline kidney size such as aetiology, height and estimated GFR, we found that kidney atrophy occurred at a rate of 0.072 cm/year (SD 0.016, P = 0.007). This atrophy was 'blunted' with declining GFR. Each 1 mL/min/1.73 m(2)/year greater decline in eGFR abrogated kidney atrophy by 0.015 cm/year (P = 0.024). Although in cross-sectional surveys kidney size is directly related to function, the longitudinal relationship between form and function is inverted. Since the rate of change in GFR determines kidney atrophy, we conclude that kidney size is a determinant of renal prognosis.