The elusive role of the potential factor X cation-binding exosite-1 in substrate and inhibitor interactions.
A number of studies suggest that blood-clotting factor X (FX) uses secondary site(s) to interact (as a substrate) with its activators. Numerous pieces of evidence also imply that, within prothrombinase (as an enzyme), activated FX (FXa) uses exosite(s) for cofactor Va and/or prothrombin recognition. Similarly, FXa exosite(s) seem to govern interaction with inhibitors. An obvious difference between FXa and thrombin resides within a region called exosite-1: positively charged in thrombin and clearly of opposite polarity in FXa. To investigate the role of this potential cation-binding exosite, we prepared a series of mutants within loops 34-40 and 70-80 of FX. Overall, the mutations induced relatively subtle, non-synergistic modulation. The potential exosite was dispensable for FX activation and is unlikely to constitute a critical region for factor Va binding, albeit it is clearly important for prothrombin activation. Our data also implicate loop 34-40 of FXa in the interaction with the tissue factor pathway inhibitor, in prevention of plasminogen activator inhibitor-1 binding, and in tempering inhibition by heparin-activated antithrombin. Compared with FX, mutants with reduced electrostatic potential potentiated thrombin production in FX-depleted plasma, whereas mutants with inverted electrostatic potential impeded clotting. Despite the definite consequences observed, disruption of the potential cation-binding exosite of FX had rather weak effects, far from what would be expected if this region was as crucial as in thrombin.


Disruption of the Ang II type 1 receptor promotes longevity in mice.
The renin-angiotensin system plays a role in the etiology of hypertension and the pathophysiology of cardiac and renal diseases in humans. Ang II is the central product of this system and is involved in regulating immune responses, inflammation, cell growth, and proliferation by acting through Ang II type 1 receptors (AT1 and AT2). Here, we show that targeted disruption of the Agtr1a gene that encodes AT1A results in marked prolongation of life span in mice. Agtr1a-/- mice developed less cardiac and vascular injury, and multiple organs from these mice displayed less oxidative damage than wild-type mice. The longevity phenotype was associated with an increased number of mitochondria and upregulation of the prosurvival genes nicotinamide phosphoribosyltransferase (Nampt) and sirtuin 3 (Sirt3) in the kidney. In cultured tubular epithelial cells, Ang II downregulated Sirt3 mRNA, and this effect was inhibited by an AT1 antagonist. These results demonstrate that disruption of AT1 promotes longevity in mice, possibly through the attenuation of oxidative stress and overexpression of prosurvival genes, and suggests that the Ang II/AT1 pathway may be targeted to influence life span in mammals.


Large-scale production of hierarchical TiO2 nanorod spheres for photocatalytic elimination of contaminants and killing bacteria.
We report a facile non-hydrothermal method for the large-scale production of hierarchical TiO(2) nanorod spheres for the photocatalytic elimination of contaminants and killing bacteria. Crescent Ti/RF spheres were prepared by deliberately adding titanium trichloride (TiCl(3)) to the reaction of resorcinol (R) and formaldehyde (F) in an open reactor under heating and stirring. The hierarchical TiO(2) nanorod spheres were obtained by calcining the crescent Ti/RF spheres in a furnace in air to burn off the RF spheres. This method has many merits, such as large-scale production, good crystallisation of TiO(2), and good reproducibility, all of which are difficult to realise by conventional hydrothermal methods. The calcination temperature plays a significant role in influencing the morphology, crystallisation, porosity, Brunauer-Emmett-Teller (BET) specific surface area, and hierarchy of the TiO(2) nanorod spheres, thus resulting in different photocatalytic performances under UV light and solar light irradiation. The experimental results have demonstrated that the hierarchical TiO(2) nanorod spheres obtained after calcination of the crescent Ti/RF spheres at different temperatures displayed similar photocatalytic activities under irradiation with UV light. We attribute this to a balance of opposing effects of the investigated factors. A higher calcination temperature leads to greater light absorption capability of the TiO(2) nanorod spheres, thus resulting in higher photocatalytic antibacterial activity under solar light irradiation. It is also interesting to note that the hierarchical TiO(2) nanorod spheres displayed intrinsic antibacterial activity in the absence of light irradiation, apparently because their sharp outward spikes can easily pierce and penetrate the walls of bacteria. In this study, the sharpest hierarchical TiO(2) nanorod spheres were obtained after calcination at 500°C, and these exhibited the highest antibacterial activity without light irradiation. A higher calcination temperature proved detrimental to the sharpness of the TiO(2) nanorods, thus reducing their intrinsic antibacterial activity.


[Silent enemy in acute rheumatic fever: subclinical carditis].
Routine use of Doppler echocardiography for the initial diagnosis of acute rheumatic fever (ARF) might allow early detection and, hence, prevention of rheumatic recurrences. This study sought to determine the incidence of subclinical carditis in ARF patients. The study included 80 patients (64 migratory polyarthritis, 16 rheumatic chorea) who were diagnosed with ARF according to the Jones criteria, 1992 update. Rheumatic carditis was defined as the presence of the following findings on Doppler echocardiography: mitral and aortic regurgitant jets in at least two planes, the length of the jets >1 cm, and peak flow velocities of >2.5 m/sec for both mitral and aortic regurgitations persisting throughout systole and diastole, respectively. The patients diagnosed with subclinical carditis were re-evaluated at 1, 3, 6, and 12 months. Echocardiography revealed subclinical carditis in 25 patients (31.3%; 13 girls, 12 boys; mean age 11.4±2.5 years) with ARF. Of 64 patients with migratory polyarthritis, 34 (53.1%) had clinical carditis and 17 (26.6%) had subclinical carditis. The incidences of clinical and subclinical carditis among 16 patients with rheumatic chorea were 31.3% (n=5) and 50% (n=8), respectively. Of 20 patients who completed one-year follow-up, persistence of subclinical carditis was observed in 11 cases (55%). Clinicians should be attentive to the presence of cardiac involvement among patients with suspected ARF. Considering the high incidence of subclinical carditis, echocardiographic evidence of carditis should be used as a diagnostic criterion.


Growth temperatures and temperature characteristics of Aeromonas.
Six of the 13 Aeromonas hydrophila, 1 of 10 A. shigelloides, and none of 10 A. salmonicida were found to be psychrophiles. All of the rest of the strains were mesophiles. The mu values (temperature characteristics) could not be used to distinguish psychrophiles from mesophiles.


Impact on Breast Cancer Survival by Surgical Facility Type Secondary to the ACOSOG Z0011 Trial.
Studies have reported differences between age, socioeconomic status, treatment facility, and tumor burden based on survival outcomes for breast cancer (BC). The goal of this study is to evaluate BC survival and mortality outcomes by facility type. To examine likely influence of evidence-based practices, these groups were then sub stratified by pre- and post-Z0011 trial. This is a population-based study using the National Cancer Database of Commission on Cancer (CoC) designated centers. Intergroup comparisons of demographics were performed using chi-square test. Kaplan-Meier curve and Cox Hazard Ratios were used to evaluate survival differences. Multivariable regression methods were used to evaluate risk-adjusted 30- and 90-day mortality among BC patients. A difference-in-difference (DiD) analysis was used to evaluate the change of treatment over time pre- and post-Z0011 trial. Median survival was highest among comprehensive community facilities at 63.2 months and integrated community facilities at 62.7 months, while the lowest for community and academic facilities at 60.6 months and 61 months. Academic facilities had the lowest 30- and 90-day mortality. Community centers saw the largest improvement in overall mortality post-Z0011 trial. The benefit after the Z0011 trial was evident among community centers at the 90-day mortality period as their decrease in mortality (-1.7%) was significantly lower than the decrease of mortality among academic centers (-1.3%), P-value = .01. While the Z0011 trial had a positive influence in both community and academic facilities, community programs benefited the most. Z0011 trial showed the most change in practice for the community centers.


Creating a Culture of Mindfulness in Medicine.
Well-documented challenges faced by primary care clinicians have brought growing awareness to the issues of physician wellness and burnout and the potential subsequent impact on patients. Research has identified mindfulness as a tool to increase clinician well-being and enhance clinician characteristics associated with a more patient-centered orientation to clinical care. The overall goal of our intervention was to promote the cultivation of mindful awareness throughout our health system, creating a culture of mindfulness in medicine. We developed a systems-level strategy to promote health and resilience for clinicians and patients by preparing a group of clinician leaders to serve as catalysts to practice and teach mindfulness. The strategy involved 3 steps: (1) select 5 primary care leaders to help foster mindfulness within both health care delivery and education; (2) provide funds for these leaders to attend advanced mindfulness training designed specifically for clinicians; and (3) foster mindfulness within our health system and beyond via collaborative planning meetings and seed money for implementation of projects. All 5 leaders endorsed the personal value of the mindfulness training, with some describing it as life-changing. Within 8 months, 4 of the leaders fostered a wide variety of mindfulness activities benefitting colleagues, medical students, and patients across our state and beyond. We found that the value received from our investment in mindfulness far exceeded our relatively low cost, although further evaluation is needed to prove this.


Dietary Habits of Saharawi Type II Diabetic Women Living in Algerian Refugee Camps: Relationship with Nutritional Status and Glycemic Profile.
Diabetes is one of the main health problems among Saharawi refugees living in Algerian camps, especially for women. As is known, diet plays an important role in the management of diabetes. However, the dietary habits of Saharawi diabetic women are unknown. Therefore, we investigated the dietary habits and established their relationship with the nutritional status and glycemic profile of such women. We recruited 65 Saharawi type II diabetic women taking orally glucose-lowering drugs only. Dietary habits were investigated using qualitative 24 h recall carried out over three non-consecutive days. Anthropometric measurements were taken and blood parameters were measured. About 80% of the women were overweight and about three out of four women had uncompensated diabetes and were insulin resistant. The Saharawi diet was found to mainly include cereals, oils, sugars, vegetables (especially onions, tomatoes, and carrots), tea, and meat. Principal component analysis identified two major dietary patterns, the first one "healthy" and the second one "unhealthy". Women in the higher tertile of adherence to the unhealthy dietary pattern had a higher homeostatic model assessment for insulin resistance (HOMA) index (b = 2.49; 95% CI: 0.41-4.57; p = 0.02) and circulating insulin (b = 4.52; 95% CI: 0.44-8.60; p = 0.03) than the women in the lowest tertile. Food policies should be oriented to improve the quality of diet of Saharawi diabetic women.


Prognostic value of aldehyde dehydrogenase 1 (ALDH1) in invasive breast carcinomas.
Aldehyde dehydrogenase 1 (ALDH1) has been identified as a marker of cancer stem cells in breast cancer (BC). Recent studies showed that ALDH1 expression is correlated with poor prognostic parameters and worse clinical outcome in BC. We evaluated ALDH1 expression by immunohistochemistry in a series of 217 invasive BCs and investigated the correlation between ALDH1 expression and clinicopathological parameters, molecular subtypes (luminal A, luminal B, human epidermal growth factor receptor 2 [HER2] type, and triple-negative BC [TNBC]), and patient survival. There was a significant association between ALDH1 expression and tumor grade (p < 0.001), i.e., the expression of ALDH1 was higher in high-grade tumors. ALDH1 expression was significantly associated with estrogen and progesterone receptor (ER and PR) negativity (p < 0.001) and HER2 positivity (p = 0.001). ALDH1 expression ratios were higher in HER2 type and TNBC. There was a statistically significant correlation between ALDH1 negativity and luminal A subtype (p < 0.001). The overall and disease free survival were shorter in ALDH1+ tumors, although without statistical significance. We confirm that ALDH1 is a potentially important, poor prognostic factor in BC, associated with high histological grade, ER/PR negativity and HER2 positivity. For more accurate results, ALDH1 expression should be evaluated in larger case series including various types/subtypes of BC.


An integrated rehabilitation system for the upper limb spasticity assessment and treatment: the Rehabotics passive exoskeletal system.
Limb spasticity is caused by stroke, multiple sclerosis, traumatic brain injury and various central nervous system pathologies such as brain tumors resulting in joint stiffness, loss of hand function and severe pain. This paper presents with the Rehabotics integrated rehabilitation system aiming to provide highly individualized assessment and treatment of the function of the upper limbs for patients with spasticity after stroke, focusing on the developed passive exoskeletal system. The proposed system can: (i) measure various motor and kinematic parameters of the upper limb in order to evaluate the patient's condition and progress, as well as (ii) offer a specialized rehabilitation program (therapeutic exercises, retraining of functional movements and support of daily activities) through an interactive virtual environment. The outmost aim of this multidisciplinary research work is to create new tools for providing high-level treatment and support services to patients with spasticity after stroke.Clinical Relevance- This paper presents a new passive exoskeletal system aiming to provide enhanced treatment and assessment of patients with upper limb spasticity after stroke.


Metabolic crisis in maple syrup urine disease: an unusual complication of a rare disease: a case report.
A 19-year-old woman with known maple syrup urine disease presented to hospital with metabolic crisis in the setting of influenza type A infection and intractable vomiting, rapidly progressing to acute cerebral oedema manifesting as refractory seizures and decreased level of consciousness needing emergency intubation and mechanical ventilation, continuous veno-venous haemodiafiltration and thiopentone coma. A computed tomography scan and magnetic resonance imaging of the brain demonstrated classic signs of cerebral oedema secondary to a metabolic crisis from the metabolic disorder. Her management posed multiple challenges to all teams involved due to lack of familiarity and experience in managing this clinical scenario in the adult intensive care setting.


Multi-walled carbon nanotube-physicochemical properties predict the systemic acute phase response following pulmonary exposure in mice.
Pulmonary exposure to multi-walled carbon nanotubes (MWCNTs) has been linked to an increased risk of developing cardiovascular disease in addition to the well-documented physicochemical-dependent adverse lung effects. A proposed mechanism is through a strong and sustained pulmonary secretion of acute phase proteins to the blood. We identified physicochemical determinants of MWCNT-induced systemic acute phase response by analyzing effects of pulmonary exposure to 14 commercial, well-characterized MWCNTs in female C57BL/6J mice pulmonary exposed to 0, 6, 18 or 54 μg MWCNT/mouse. Plasma levels of acute phase response proteins serum amyloid A1/2 (SAA1/2) and SAA3 were determined on day 1, 28 or 92. Expression levels of hepatic Saa1 and pulmonary Saa3 mRNA levels were assessed to determine the origin of the acute phase response proteins. Pulmonary Saa3 mRNA expression levels were greater and lasted longer than hepatic Saa1 mRNA expression. Plasma SAA1/2 and SAA3 protein levels were related to time and physicochemical properties using adjusted, multiple regression analyses. SAA3 and SAA1/2 plasma protein levels were increased after exposure to almost all of the MWCNTs on day 1, whereas limited changes were observed on day 28 and 92. SAA1/2 and SAA3 protein levels did not correlate and only SAA3 protein levels correlated with neutrophil influx. The multiple regression analyses revealed a protective effect of MWCNT length on SAA1/2 protein level on day 1, such that a longer length resulted in lowered SAA1/2 plasma levels. Increased SAA3 protein levels were positively related to dose and content of Mn, Mg and Co on day 1, whereas oxidation and diameter of the MWCNTs were protective on day 28 and 92, respectively. The results of this study reveal very differently controlled pulmonary and hepatic acute phase responses after MWCNT exposure. As the responses were influenced by the physicochemical properties of the MWCNTs, this study provides the first step towards designing MWCNT that induce less SAA.


Impact of visit copayments on outpatient mental health utilization by members of a health maintenance organization.
The authors examined the impact of increasing cost sharing on use of outpatient mental health services. A quasi-experimental design was used to study outpatient utilization by members of a health maintenance organization (HMO) who were subject to increasing copayments for mental health visits (state government employees and dependents). Their outpatient mental health utilization was compared with that of similar HMO members who were not subject to cost sharing (federal government employees and dependents). Analyses compared both likelihood of any service use and number of visits per year among service users. Institution of $20/visit copayments was associated with a 16% decrease in likelihood of service use but no change in visit rate among service users. A subsequent copayment increase to $30/visit resulted in no significant change in likelihood of use but was associated with a 9% decrease in visits per year among those using services. The impact of the first copayment change on likelihood of using services did not vary according to level of clinical need (as measured by prior service use and psychotropic drug use). In this staff-model HMO, modest visit copayments significantly reduced initial access to mental health treatment and had a smaller effect on treatment intensity. Copayments restricted access regardless of clinical need. Designers of mental health benefits must consider the impact of copayments on those with the greatest need for treatment.


Perioperative Endocarditis Management in a Patient with Homozygous Sickle Cell Disease.
Background Homozygous sickle cell disease (SCD) compounded with bacterial endocarditis makes open-heart surgery a multidisciplinary challenge. Case description A 45-year-old African male patient with homozygous SCD presented with right heart decompensation, tricuspid regurgitation, and endocarditis of the aortic valve. Blood coulters were positive for coagulase-negative staphylococci. An emergent double valve replacement was successfully performed involving a multidisciplinary team. Conclusion Homozygous SCD is associated with an increased risk of preoperative vaso-occlusive complications. Surgery with cardiopulmonary bypass can be performed, if hypothermia, hypoxia, acidosis, or low-flows are being avoided. Due to the lack of data, the adequate approach is still intuitive and requires standardization.


The impact of clinical trial monitoring approaches on data integrity and cost--a review of current literature.
Monitoring is a costly requirement when conducting clinical trials. New regulatory guidance encourages the industry to consider alternative monitoring methods to the traditional 100 % source data verification (SDV) approach. The purpose of this literature review is to provide an overview of publications on different monitoring methods and their impact on subject safety data, data integrity, and monitoring cost. The literature search was performed by keyword searches in MEDLINE and hand search of key journals. All publications were reviewed for details on how a monitoring approach impacted subject safety data, data integrity, or monitoring costs. Twenty-two publications were identified. Three publications showed that SDV has some value for detection of not initially reported adverse events and centralized statistical monitoring (CSM) captures atypical trends. Fourteen publications showed little objective evidence of improved data integrity with traditional monitoring such as 100 % SDV and sponsor queries as compared to reduced SDV, CSM, and remote monitoring. Eight publications proposed a potential for significant cost reductions of monitoring by reducing SDV without compromising the validity of the trial results. One hundred percent SDV is not a rational method of ensuring data integrity and subject safety based on the high cost, and this literature review indicates that reduced SDV is a viable monitoring method. Alternative methods of monitoring such as centralized monitoring utilizing statistical tests are promising alternatives but have limitations as stand-alone tools. Reduced SDV combined with a centralized, risk-based approach may be the ideal solution to reduce monitoring costs while improving essential data quality.


Surface Hopping Dynamics with DFT Excited States.
Nonadiabatic dynamics simulation of electronically-excited states has been a research area of fundamental importance, providing support for spectroscopy, explaining photoinduced processes, and predicting new phenomena in a variety of specialties, from basic physical-chemistry, through molecular biology, to materials engineering. The demands in the field, however, are quickly growing, and the development of surface hopping based on density functional theory (SH/DFT) has been a major advance in the field. In this contribution, the surface hopping approach, the methods for computation of excited states based on DFT, the connection between these methodologies, and their diverse implementations are reviewed. The shortcomings of the methods are critically addressed and a number of case studies from diverse fields are surveyed.


Impact of Cannabis Use on Least Pain Scores Among African American and White Patients with Cancer Pain: A Moderation Analysis.
Based on many published reports, African American patients with cancer experience higher pain severity scores and lower pain relief than White patients. This disparity results from undertreatment of pain and is compounded by low adherence to prescribed non-opioid and opioid analgesics among African American patients with cancer. While nearly one in four patients use cannabis to manage cancer-related symptoms, less is known about how cannabis use influences pain relief in this patient population. This study is based on preliminary data from an ongoing study of longitudinal outcomes of opioid therapy among African American and White patients with cancer. Linear mixed-effects models were utilized to assess the interaction of race and cannabis use on pain relief using "least pain" item scores from the Brief Pain Inventory (BPI) averaged across three time points. Models were adjusted for sociodemographic and clinical variables. This analysis included 136 patients (49 African American, 87 White). Overall, 30.1% of the sample reported cannabis use for cancer pain. The mean "least pain" score on BPI was 3.3 (SD=2.42) on a scale of 0-10. African American patients had a mean "least pain" score 1.32±0.48 units higher (indicating lower pain relief) than White patients (p=0.006). Cannabis use did not have a significant main effect (p=0.28). However, cannabis use was a significant moderator of the relationship between race and "least pain" (p=0.03). In the absence of cannabis use, African Americans reported higher "least pain" scores compared to Whites (mean difference=1.631±0.5, p=0.001). However, this disparity was no longer observed in African American patients reporting cannabis use (mean "least pain" difference=0.587±0.59, p=0.32). These findings point to the possible role of cannabis in cancer pain management and its potential to reduce racial disparities. These findings are preliminary and further research into the role of cannabis in cancer pain outcomes is needed.


Cerebellar ataxia as a possible organ-specific autoimmune disease.
The purpose of this study was to investigate the possibility that autoimmunity is responsible for some cases of sporadic idiopathic ataxia. We prospectively investigated 400 patients with progressive ataxia and identified a group of patients with idiopathic sporadic ataxia. A comparison of the prevalence of autoimmune diseases, the autoimmunity linked HLA DQ2, and serum anticerebellar antibodies was made between patients with idiopathic sporadic and those with genetically characterized ataxia. Ninety-one of 400 (23%) patients with progressive ataxia had idiopathic sporadic ataxia. The prevalence of autoimmune diseases in this group was 47% as compared with 6% in the group of patients with genetic ataxias (P < 0.0001). The HLA DQ2 was found in 71% of patients with sporadic ataxia, in 34% in patients with genetic ataxia, and in 36% of healthy local population (P = 0.0005 by Chi squared test). Anticerebellar antibodies were detected in 12 out of 20 patients with idiopathic sporadic as opposed to one of 20 patients with genetic ataxia. The significantly higher prevalence of autoimmune diseases, HLA DQ2 and anti-cerebellar antibodies in patients with idiopathic sporadic ataxia compared to genetic ataxia supports the notion that autoimmunity may account for some cases of idiopathic sporadic cerebellar ataxia.


Long-term results after bronchial sleeve resection.
In bronchial sleeve resections part of the bronchial wall is removed followed by the creation of a bronchial end-to-end anastomosis. The cylindrical part that is removed is called a "sleeve". In this way functional lung parenchyma can be saved in centrally located bronchogenic carcinomas while performing an oncologically valid operation. However, controversial results were reported in literature regarding long-term survival after bronchial sleeve resection especially in relation to nodal status. In a series of 145 patients undergoing bronchial sleeve resection for a bronchogenic tumor in the Antonius Hospital, Nieuwegein, the Netherlands, long-term results were studied. A univariate and multivariate analysis were performed to determine significant factors related to survival. Follow-up was updated until 1999, so a minimum follow-up of 10 years was obtained for surviving patients. For the entire group 5, 10 and 15-year survival rates were 45, 35 and 23%, respectively. Median survival time was 52 +/- 10 months. Five- and 10-year survival rates for the 71 patients with N0 disease were 62% and 53%, respectively; for the 58 patients with N1 disease, 29% and 21%; and for the 16 patients with N2 disease, 31% and 6%. There was a highly significant difference in survival between patients with N0 and N1 (p = 0.001) or N2 (p < 0.001) disease. The difference between N1 and N2 disease reached statistical significance (p = 0.047). A Cox multivariate regression analysis showed only nodal stage and patient age to be significant factors in relation to survival. To improve long-term survival adjuvant treatment should be considered in case of N1 or N2 disease as most of these patients die of distant metastases.


Particlelike Phonon Propagation Dominates Ultralow Lattice Thermal Conductivity in Crystalline Tl_{3}VSe_{4}.
We investigate the microscopic mechanisms of ultralow lattice thermal conductivity (κ_{l}) in Tl_{3}VSe_{4} by combining a first principles density functional theory based framework of anharmonic lattice dynamics with the Peierls-Boltzmann transport equation for phonons. We include contributions of the three- and four-phonon scattering processes to the phonon lifetimes as well as the temperature dependent anharmonic renormalization of phonon energies arising from an unusually strong quartic anharmonicity in Tl_{3}VSe_{4}. In contrast to a recent report by Mukhopadhyay et al. [Science 360, 1455 (2018)SCIEAS0036-807510.1126/science.aar8072] which suggested that a significant contribution to κ_{l} arises from random walks among uncorrelated oscillators, we show that particlelike propagation of phonon excitations can successfully explain the experimentally observed ultralow κ_{l}. Our findings are further supported by explicit calculations of the off-diagonal terms of the heat current operator, which are found to be small and indicate that wavelike tunneling of heat carrying vibrations is of minor importance. Our results (i) resolve the discrepancy between the theoretical and experimental κ_{l}, (ii) offer new insights into the minimum κ_{l} achievable in Tl_{3}VSe_{4}, and (iii) highlight the importance of high order anharmonicity in low-κ_{l} systems. The methodology demonstrated here may be used to resolve the discrepancies between the experimentally measured and the theoretically calculated κ_{l} in skutterides and perovskites, as well as to understand the glasslike κ_{l} in complex crystals with strong anharmonicity, leading towards the goal of rational design of new materials.


Breast diseases during pregnancy and lactation.
Breast is a typical female sexual physiologic organ that is influenced by steroid hormone from menarche until menopause. Therefore various diseases can be developed by continuous action of estrogen and progesterone. Breast diseases are mainly categorized as benign and malignant. It is very important to distinguish the malignancy from breast diseases. However, it is very difficult to diagnose malignancy in pregnant and lactating women even though the same breast diseases took place. Therefore, we will review breast diseases such as breast carcinoma during pregnancy and lactation.


Nuclear TAZ activity distinctly associates with subtypes of non-small cell lung cancer.
The transcription co-factor TAZ plays critical roles in the regulation of human carcinogenesis. However, the pathological role for TAZ in lung cancer has remained incompletely understood. TAZ expression was examined by immunohistochemistry for 163 NSCLC tissues. TAZ expression was also examined by western blotting for 20 frozen paired NSCLC and adjacent normal lung tissues. We report that TAZ is overexpressed in non-small cell lung cancer (NSCLC) tissues and correlates with shorter patient survival. Intriguingly, we find that TAZ is overexpressed primarily in lung squamous cell carcinomas (LUSC) but not lung adenocarcinomas (LUAD) compared to normal lung tissues, and that the expression levels of TAZ are significantly higher in LUSC than LUAD. The nuclear localization of TAZ correlates worse clinical outcomes in LUSC, but not LUAD, further suggesting a prognostic value for activated TAZ in LUSC. A meta-analysis of the public datasets from TCGA, Broad institute, and Oncomine shows that the TAZ gene (WWTR1) copy numbers are significantly increased in LUSC and correlate with the increase of TAZ mRNA expression, suggesting that TAZ is overexpressed in LUSC at least partly through gene amplifications. Collectively, our results suggest that TAZ expression distinctly associates with subtypes of NSCLC and may be useful for developing novel therapeutics treating LUSC.


Defining Outcome Measures for Psoriatic Arthritis: A Report from the GRAPPA-OMERACT Working Group.
The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)-Outcome Measures in Rheumatology (OMERACT) Psoriatic Arthritis (PsA) Core Set working group recently published the updated 2016 psoriatic arthritis (PsA) core domain set, a set of disease features that should be measured in all clinical trials. At the GRAPPA annual meeting in July 2016, the PsA working group presented the updated PsA core domain set endorsed by 90% of participants at OMERACT in May 2016 and drafted a roadmap for the development of the PsA core outcome measurement set. In this manuscript, we review the development process of the PsA core domain set and the ongoing and proposed work streams for development of a PsA core measurement set.


Closely related, yet unique: Distinct homo- and heterodimerization patterns of G protein coupled chemokine receptors and their fine-tuning by cholesterol.
Chemokine receptors, a subclass of G protein coupled receptors (GPCRs), play essential roles in the human immune system, they are involved in cancer metastasis as well as in HIV-infection. A plethora of studies show that homo- and heterodimers or even higher order oligomers of the chemokine receptors CXCR4, CCR5, and CCR2 modulate receptor function. In addition, membrane cholesterol affects chemokine receptor activity. However, structural information about homo- and heterodimers formed by chemokine receptors and their interplay with cholesterol is limited. Here, we report homo- and heterodimer configurations of the chemokine receptors CXCR4, CCR5, and CCR2 at atomistic detail, as obtained from thousands of molecular dynamics simulations. The observed homodimerization patterns were similar for the closely related CC chemokine receptors, yet they differed significantly between the CC receptors and CXCR4. Despite their high sequence identity, cholesterol modulated the CC homodimer interfaces in a subtype-specific manner. Chemokine receptor heterodimers display distinct dimerization patterns for CXCR4/CCR5 and CXCR4/CCR2. Furthermore, associations between CXCR4 and CCR5 reveal an increased cholesterol-sensitivity as compared to CXCR4/CCR2 heterodimerization patterns. This work provides a first comprehensive structural overview over the complex interaction network between chemokine receptors and indicates how heterodimerization and the interaction with the membrane environment diversifies the function of closely related GPCRs.


Mechanism of myo-inositol hexakisphosphate sorption on amorphous aluminum hydroxide: spectroscopic evidence for rapid surface precipitation.
Inositol hexakisphosphates are the most abundant organic phosphates (OPs) in most soils and sediments. Adsorption, desorption, and precipitation reactions at environmental interfaces govern the reactivity, speciation, mobility, and bioavailability of inositol hexakisphosphates in terrestrial and aquatic environments. However, surface complexation and precipitation reactions of inositol hexakisphosphates on soil minerals have not been well understood. Here we investigate the surface complexation-precipitation process and mechanism of myo-inositol hexakisphosphate (IHP, phytate) on amorphous aluminum hydroxide (AAH) using macroscopic sorption experiments and multiple spectroscopic tools. The AAH (16.01 μmol m(-2)) exhibits much higher sorption density than boehmite (0.73 μmol m(-2)) and α-Al2O3 (1.13 μmol m(-2)). Kinetics of IHP sorption and accompanying OH(-) release, as well as zeta potential measurements, indicate that IHP is initially adsorbed on AAH through inner-sphere complexation via ligand exchange, followed by AAH dissolution and ternary complex formation; last, the ternary complexes rapidly transform to surface precipitates and bulk phase analogous to aluminum phytate (Al-IHP). The pH level, reaction time, and initial IHP loading evidently affect the interaction of IHP on AAH. In situ ATR-FTIR and solid-state NMR spectra further demonstrate that IHP sorbs on AAH and transforms to surface precipitates analogous to Al-IHP, consistent with the results of XRD analysis. This study indicates that active metal oxides such as AAH strongly mediate the speciation and behavior of IHP via rapid surface complexation-precipitation reactions, thus controlling the mobility and bioavailability of inositol phosphates in the environment.


Esophageal Radiography Interpretation: a Primer for the Gastroenterologist.
Radiological studies can be helpful when evaluating patients with suspect esophageal disorders. From benign strictures to malignancy and motility disorders such as achalasia, imaging modalities play a significant role in diagnosis. This review explores the role of different imaging modalities in the most frequently encountered esophageal pathologies. Conventional barium esophagram has long been considered the primary imaging modality of the esophagus. In the same fashion, a timed barium esophagram is a valuable tool in the evaluation of achalasia and esophagogastric junction outlet obstruction. Over the last few decades there has been an increase in CT and MRI studies, which also play a role in the evaluation of esophageal pathologies. However, not infrequently, these newer imaging techniques can result in incidental esophageal findings. It is important that gastroenterologists appreciate the value of different modalities and recognize key imaging features. The diagnosis and management of esophageal disorders is evolving. A basic understanding of esophageal radiology is essential to any gastroenterologist caring for patients with esophageal complaints.


Stability and generalization in seed dispersal networks: a case study of frugivorous fish in Neotropical wetlands.
When species within guilds perform similar ecological roles, functional redundancy can buffer ecosystems against species loss. Using data on the frequency of interactions between fish and fruit, we assessed whether co-occurring frugivores provide redundant seed dispersal services in three species-rich Neotropical wetlands. Our study revealed that frugivorous fishes have generalized diets; however, large-bodied fishes had greater seed dispersal breadth than small species, in some cases, providing seed dispersal services not achieved by smaller fish species. As overfishing disproportionately affects big fishes, the extirpation of these species could cause larger secondary extinctions of plant species than the loss of small specialist frugivores. To evaluate the consequences of frugivore specialization for network stability, we extracted data from 39 published seed dispersal networks of frugivorous birds, mammals and fish (our networks) across ecosystems. Our analysis of interaction frequencies revealed low frugivore specialization and lower nestedness than analyses based on binary data (presence-absence of interactions). In that case, ecosystems may be resilient to loss of any given frugivore. However, robustness to frugivore extinction declines with specialization, such that networks composed primarily of specialist frugivores are highly susceptible to the loss of generalists. In contrast with analyses of binary data, recently developed algorithms capable of modelling interaction strengths provide opportunities to enhance our understanding of complex ecological networks by accounting for heterogeneity of frugivore-fruit interactions.


A hard day's night: time use in shift workers.
Differences in how shift workers accumulate physical activity (PA) while at work and in leisure time, on days when they are working at night, during the day, or on non-work days, are largely unexplored. The aim of this study was to improve understanding of physical activity patterns in two groups of shift workers, and to measure variations according to their shift schedules. This pragmatic pilot study was conducted in two workplaces. Employees in Workplace 1 (n = 10) were required to drive for most of their shift. Workplace 2 was a manufacturing company where most of the employees' (n = 30) occupational tasks were completed while standing. Use of time was assessed using the adult version of the Multimedia Activity Recall for Children and Adults (MARCA) administered by telephone interview. Three MARCA interviews were conducted with each participant, in order to capture a typical profile of a day-shift day, a night-shift day and a non-work day, using a two-day recall for each interview. Participants were asked to wear the activPAL3™ activity monitor, for 7 consecutive days. Paired and independent t-tests were used to compute significant differences between day-shift, night-shift and non-work days within and between workplaces. The total number of days quantified for the MARCA data was 192 days (64 day-shift, 60 night-shift and 68 non-work days). Workplace 2 participants reported more physical activity and less sedentary behaviour on day-shift and night shift days than on non-work days. Time spent in sedentary behaviour was similar on day-shift, night-shift and non-work days in Workplace 1. Workplace 1 participants were more sedentary (p = 0.003) and engaged in more light intensity PA (p = 0.031) on day-shift and night-shift workdays, than those from Workplace 2. Sleep times were lowest on day-shift days. As the occupational tasks for participants in Workplace 2 involved physical activities, the findings do not support the conventional view that shift workers are more sedentary than those who only work during the day. Rather occupational tasks appear to be a more important determinant of physical activity patterns both on work and non-work days than varying shift patterns.


[The effect of the amplitude and frequency of blood pulsations on the peripheral vascular tonus].
In acute experiments on cats, hindlimbs' skeletal muscles, small intestine, a lung's lobe or a kidney were perfused. The mean value of the perfusion pressure was constant. The increase in frequency of the perfusion pressure oscillations from 0.75 to 10 Hz, at a constant amplitude, entailed a weak increase in the resistance to blood flow in skeletal muscles. The increase in amplitude of the oscillations from 30-40 to 100-120 mm Hg induced an obvious vasodilation. Intestinal vessels revealed a biphasic shift in the resistance to blood flow whereas no changes occurred in lungs. The dynamic mechanical deformation of the blood vessels' walls seems to exert a different effect upon the circulation in different areas.


Inhibition of PARP prevents angiotensin II-induced aortic fibrosis in rats.
Fibrosis is one of the major pathological features of hypertensive vascular disease. In this study, we aim to explore the possible protective effects of poly(ADP-ribose) polymerase (PARP) inhibitor on angiotensin II (AngII)-induced aortic fibrosis. Sprague-Dawley rats were infused subcutaneously with AngII. PARP inhibitor was intraperitoneally injected once a day. Collagen deposition in thoracic aorta was assayed by Masson tricrome staining. The mRNA and protein expression of TGF-β target genes involved in extracellular matrix (ECM) remodeling in aorta was measured. Plasma level and aortic expression of TGF-β1 was assayed. Correlation of systolic blood pressure (SBP) with plasma level of TGF-β1 was analyzed. In cultured rat vascular smooth muscle cells (VSMCs), effects of PARP inhibition on TGF-β1 expression, Smad3 transactivity, and TGF-β/Smad3 target gene expression were investigated. Infusion of AngII promoted aortic PARP activation. Treatment with PARP inhibitor alleviated AngII-induced collagen deposition and expression of TGF-β target genes involved in ECM remodeling in aorta of rat. AngII increased plasma level and aortic expression of TGF-β1. A positive correlation between SBP and plasma level of TGF-β1 was revealed. Treatment with PARP inhibitor prevented AngII-induced elevation of SBP. Further experiments uncovered that AngII treatment increased TGF-β dependent gene expression through Smad3 pathway in cultured VSMCs. Inhibition of PARP prevented AngII-induced increases in TGF-β1 expression, Smad3 transactivity and its target gene expression. These data indicate that inhibition of PARP prevents aortic fibrosis in AngII-induced hypertension in rats. This beneficial effect is mediated by inhibiting TGF-β/Smad3 pathway.


Influence of clinical usage of GT and GTX files on cyclic fatigue resistance.
To compare static cyclic fatigue resistance of unused, unused and sterilized and clinically used conventional NiTi GT and M-Wire GTX files. One hundred and sixty new files (80 GT and 80 GT series X) were divided into four control groups and four experimental groups (n = 20 each). Control groups were new unused files and new sterilized files. In the experimental groups, instruments were used in three (GT1 and GTX1 groups) or four molars (GT2 and GTX2 groups). Cyclic fatigue resistance was tested in stainless steel curved canals (60°, r = 3 mm). Each file was rotated until fracture (300 rpm, 2 N cm torque). Time-to-fracture (s) was registered. Mean life, eta and beta parameters of their Weibull distributions were calculated. Unused and sterilized GTX files will last significantly longer than GT files with a probability of 75% and 65%, respectively; whilst mean life was significantly longer for GT than for GTX in used files with a probability of 68%. Sterilized GT files will last longer than unused files with a probability of 66%. In both brands, unused and sterilized files will last significantly longer than files used clinically with a probability higher than 98%. The probability that GT will last longer after being used in three rather than four molars was 62% (statistically significant) and 52% (not statistically significant) for GTX. GTX files had an extended cyclic fatigue life when compared with GT when they were unused or unused and sterilized, but GT were significantly more resistant to cyclic fatigue after clinical usage than GT series X files 3 mm from the tip. Sterilization of files enhanced the cyclic fatigue resistance of GT instruments. Clinical use of files diminished cyclic fatigue resistance.


The treatment of moderate to severe hypertension with ACE inhibitors.
Quinapril, when given as initial monotherapy or in addition to diuretics, was extensively evaluated in patients with moderate to severe hypertension, defined as sitting diastolic blood pressure (DBP) greater than or equal to 105 mm Hg with concomitant diuretic therapy or greater than or equal to 110 mm Hg during placebo baseline. In four double-blind, comparative trials and a subset analysis from a placebo-controlled study, 368 patients were treated with quinapril, and 338 patients were treated with comparative therapies (i.e., captopril, enalapril, or placebo). In three studies, quinapril was given in addition to diuretics, and in one study nonresponders received optional atenolol. Two studies assessed quinapril as first-line monotherapy, with nonresponders receiving hydrochlorothiazide in one study. Quinapril dosages ranged from 10 to 40 mg/day, with some patients receiving up to 80 mg/day. Quinapril effectively reduced blood pressure in patients with moderate to severe hypertension either as first-line monotherapy or when given concomitantly with a diuretic or a beta-blocker. Quinapril was comparable in efficacy to enalapril, and in several analyses quinapril was significantly more efficacious than captopril (p less than 0.05). Quinapril was well tolerated, and the incidence of adverse events was comparable with or less than that of captopril or enalapril.


Mycobacterium avium subsp. paratuberculosis and M. avium subsp. avium are independently evolved pathogenic clones of a much broader group of M. avium organisms.
Mycobacterium avium comprises organisms that share the same species designation despite considerable genomic and phenotypic variability. To determine the degree and nature of variability between subspecies and strains of M. avium, we used multilocus sequencing analysis, studying 56 genetically diverse strains of M. avium that included all described subspecies. In total, 8,064 bp of sequence from 10 gene loci were studied, with 205 (2.5%) representing variable positions. The majority (149/205) of these variations were found among M. avium subsp. hominissuis organisms. Recombination was also evident in this subspecies. In contrast, there was comparatively little variability and no evidence of recombination within the pathogenic subspecies, M. avium subsp. paratuberculosis, M. avium subsp. avium, and M. avium subsp. silvaticum. Phylogenetic analysis showed that M. avium subsp. avium and M. avium subsp. silvaticum strains clustered together on one branch, while a distinct branch defined M. avium subsp. paratuberculosis organisms. Despite the independent origin of these pathogenic subspecies, an analysis of their rates of nonsynonymous (dN) to synonymous (dS) substitutions showed increased dN/dS ratios for both: 0.67 for M. avium subsp. paratuberculosis and 0.50 for M. avium subsp. avium/M. avium subsp. silvaticum, while the value was 0.08 for M. avium subsp. hominissuis organisms. In conclusion, M. avium subsp. hominissuis represents a diverse group of organisms from which two pathogenic clones (M. avium subsp. paratuberculosis and M. avium subsp. avium/M. avium subsp. silvaticum) have evolved independently.


Pneumomediastinum, subcutaneous emphysema, and pneumothorax after a pulmonary function testing in a patient with bleomycin-induced interstitial pneumonitis.
Spontaneous pneumomediastinum is an uncommon event, the clinical picture of which includes retrosternal chest pain, subcutaneous emphysema, dyspnea, and dysphonia. The pathophysiological mechanism involved is the emergence of a pressure gradient between the alveoli and surrounding structures, causing alveolar rupture with subsequent dissection of the peribronchovascular sheath and infiltration of the mediastinum and subcutaneous tissue with air. Known triggers include acute exacerbations of asthma and situations that require the Valsalva maneuver. We described and documented with HRCT scans the occurrence of pneumomediastinum after a patient with bleomycin-induced interstitial lung disease underwent pulmonary function testing. Although uncommon, the association between pulmonary function testing and air leak syndromes has been increasingly reported in the literature, and lung diseases, such as interstitial lung diseases, include structural changes that facilitate the occurrence of this complication.


Soluble CD200 in secretory phase endometriosis endometrial venules may explain endometriosis pathophysiology and provide a novel treatment target.
Retrograde menstruation is common and in about 10% of women, endometrial tissues implant at ectopic sites and grow as endometriosis (EM) deposits. To date, there has been no marker to identify which patients have an endometrium that will generate deposits. Both endometrial regulatory T cells (Tregs) and increased stromal cell indoleamine 2,3-dioxygenase (IDO) have been implicated, and may suppress rejection by peritoneal NK cells, neutrophils, and cytotoxic macrophages. CD200 is a tolerance signaling molecule which promotes Tregs, IDO-producing macrophages, and can directly inhibit cytolytic natural killer (NK) cells and neutrophils. To determine if CD200 might be overexpressed in the endometrium of women with endometriosis, a pilot study using quantitative immunohistochemistry was done using uterine sections and EM deposits from hysterectomy patients. Both CD200 and CD200R proteins were detectable in endometriosis (EM) deposits and in endometrial epithelium and stroma. CD200 increased slightly in secretory phase whole endometrium of EM patients, but strikingly increased soluble CD200 (sCD200) absent sCD200R within venules typified both endometriosis deposits and secretory phase endometrial stromal venules and lymphatics in EM endometria compared to secretory phase NE endometria (P = 0.000006). In our opinion, accumulation of sCD200 in secretory phase endometrial blood vessels may explain development of ectopic deposits and quantifying sCD200 in menstrual blood may cases and identify predisposition to EM. Animal model studies are required to determine if antagonizing CD200 could be therapeutic.


[Effect of hypothyroidism on glial fibrillary acid protein in the structures of the rat brain].
The content and polypeptide composition of the glial fibrillary acid protein (GFAP) in the hemispheres' cortex, hippocamp, thalamus and brain stem in the condition of thyroid gland hypofunction in Wistar rats of different age (preadolescent rats five weeks old, pubertal rats five months old and old rats 18 - 20 months old) were investigated. Hypothyroidism was created by adding mercasolil (10 mg/kg) to the standard diet. At the end of experiment the level of thyrotropin and thyroxin in serum was defined with immunoenzyme method. It was established that experimental hypothyroidism caused significant increase 14-72% of the filament fraction GFAP content in the thalamus and brain stem (preadolescent rats) and in the thalamus and hemispheres' cortex (adult rats), Defragmented polypeptides with molecular weight 47 -37 kDa were revealed by immunoblotting. It is connected with the activation of cytosceletal changes of astroglia. There were changes in the group of old rats that is possibly a reason of reduced the flexibility of CNS.


The influence of admixture and consanguinity on population genetic diversity in Middle East.
The Middle East (ME) is an important crossroad where modern humans migrated 'out of Africa' and spread into Europe and Asia. After the initial peopling and long-term isolation leading to well-differentiated populations, the ME also had a crucial role in subsequent human migrations among Africa, Europe and Asia; thus, recent population admixture has been common in the ME. On the other hand, consanguinity, a well-known practice in the ME, often reduces genetic diversity and works in opposition to admixture. Here, we explored the degree to which admixture and consanguinity jointly affected genetic diversity in ME populations. Genome-wide single-nucleotide polymorphism data were generated in two representative ME populations (Arabian and Iranian), with comparisons made with populations worldwide. Our results revealed an overall higher genetic diversity in both ME populations relative to other non-African populations. We identified a much larger number of long runs of homozygosity in ME populations than in any other populations, which was most likely attributed to high levels of consanguineous marriages that significantly decreased both individual and population heterozygosity. Additionally, we were able to distinguish African, European and Asian ancestries in ME populations and quantify the impact of admixture and consanguinity with statistical approaches. Interestingly, genomic regions with significantly excessive ancestry from individual source populations are functionally enriched in olfactory pathways, which were suspected to be under natural selection. Our findings suggest that genetic admixture, consanguinity and natural selection have collectively shaped the genetic diversity of ME populations, which has important implications in both evolutionary studies and medical practices.


Genotoxicity evaluation of Moringa oleifera seed extract and lectin.
This article reports the genotoxicity assessment of an extract of M. oleifera seed powder and the water-soluble Moringa oleifera lectin (WSMoL) isolated from seeds. The lectin isolated by chitin chromatography showed hemagglutinating activity with different erythrocytes, activity in a broad pH range (4.5 to 9.5), and retention of hemagglutinating activity after being heated to 100 °C. Genotoxicity of the seed extract and WSMoL were assessed using the cell-free plasmid DNA as well as the Salmonella typhimurium (Ames and Kado) assays with TA97, TA98, TA100, and TA102 in the presence or absence of hepatic metabolization. Seed extract at concentration (0.2 μg/μL) recommended to treat water was not genotoxic by Ames, Kado, and cell-free plasmid DNA assays. S. typhimurium strains showed to be sensitive to M. oleifera extract revealing a mutagenic effect at doses higher than 0.6 μg/μL with hepatic metabolization. The extract at doses higher than 0.4 μg/μL, without hepatic metabolization, was mutagenic for TA100 and TA102. WSMoL was nonmutagenic by used assays. The use of high concentrations of the extract may pose a risk to human health and the safe use of M. oleifera seed powder to treat water for human consumption requires more study; however, the purified lectin could be an alternative for water treatment. The concentration 0.2 μg/μL of M. oleifera seed extract recommended to treat water for humans did not pose a risk to human health. The mutagenicity detected at concentrations higher than 0.4 μg/μL was not due to WSMoL, lectin isolated from extract.


Effects of matrix viscoelasticity on cell-matrix interaction, actin cytoskeleton organization, and apoptosis of osteosarcoma MG-63 cells.
Many recent reports have shown the effects of viscoelasticity of the extracellular matrix on the spreading, migration, proliferation, survival and cell-matrix interaction of mesenchymal stem cells and normal cells. However, the effect of matrix viscoelasticity on the behavior of tumor cells is still in the state of preliminary exploration. To this aim, we prepared a viscoelastic hydrogel matrix with a storage modulus of about 2 kPa and a loss modulus adjustable from 0 to 600 Pa, through adding linear alginate and regulating the compactness of a polyacrylamide covalent network. Overall, the addition of viscous components inhibited the apoptosis of osteosarcoma MG-63 cells, while it promoted their spreading and proliferation and in particular led to a well-developed cytoskeleton organization. However, with the increase of the viscous fraction, this trend was reversed, and the apoptosis of MG-63 cells gradually increased with gradually decreased spreading and proliferation, accompanied by a surprising manner change of the cytoskeleton from fusiform cells dominated by focal adhesion to dendritic cells dominated by pseudopodia. Besides the upregulation of MAPK, Ras, Rap1 and PI3K-Akt pathways commonly involved in mechanotransduction, the upregulation of the Wnt pathway and inhibited endoplasmic reticulum stress-mediated apoptosis were observed for the viscous matrix with a low loss modulus. The high viscosity matrix showed additional involvement of Hippo and NF-kappa B signaling pathways related to the cell-matrix interaction, with downregulation of the endoplasmic reticulum stress pathway and upregulation related to mitochondrial organization. Our study would provide insight into the effect of viscosity on fundamental behaviors of tumor cells and might have important implications in designing antitumor materials.


Near-Infrared Light Responsive Folate Targeted Gold Nanorods for Combined Photothermal-Chemotherapy of Osteosarcoma.
Folate-targeted gold nanorods (GNRs) are proposed as selective theranostic agents for osteosarcoma treatment. An amphiphilic polysaccharide based graft-copolymer (INU-LA-PEG-FA) and an amino derivative of the α,β-poly(N-2-hydroxyethyl)-d,l-aspartamide functionalized with folic acid (PHEA-EDA-FA), have been synthesized to act as coating agents for GNRs. The obtained polymer-coated GNRs were characterized in terms of size, shape, zeta potential, chemical composition, and aqueous stability. They protected the anticancer drug nutlin-3 and were able to deliver it efficiently in different physiological media. The ability of the proposed systems to selectively kill tumor cells was tested on U2OS cancer cells expressing high levels of FRs and compared with human bronchial epithelial cells (16HBE) and human dermal fibroblasts (HDFa). The property of the nanosystems of efficiently controlling drug release upon NIR laser irradiation and of acting as an excellent hyperthermia agent as well as Two Photon Luminescence imaging contrast agents was demonstrated. The proposed folate-targeted GNRs have also been tested in terms of chemoterapeutic and thermoablation efficacy on tridimensional (3-D) osteosarcoma models.


False-negative serology in patients with neuroborreliosis and the value of employing of different borrelial strains in serological assays.
The risk of obtaining false-negative results in serological assays in serum and CSF specimens with only one strain of Borrelia burgdorferi sensu lato as antigen was investigated in 79 patients with neuroborreliosis with specimens obtained at initial presentation. Serum antibodies were assessed by immunoblotting; the criteria of Hauser et al. were used to evaluate the test. The intrathecal synthesis of borrelial-specific IgM and IgG antibodies was examined by enzyme immunoassay (EIA). Strains of B. burgdorferi sensu stricto (BbZ160), B. garinii (Bbii50) and B. afzelii (PKO) served as sources of antigen in both assays. All patients produced either a positive IgM or IgG test in serum with at least one strain of B. burgdorferi sensu lato. Reactivity of IgM or IgG antibodies, or both, with antigens of all three strains was demonstrated in 67 (85%) of 79 sera. The correlation of results of immunoblotting with different strains was significantly better for IgG (85%) than for IgM antibodies (54%). The variability of positive IgM reactions in 18 specimens was mainly due to the fact that the antibodies were directed to the relevant variable outer-surface protein C (p23). Intrathecal synthesis of IgG antibodies was demonstrated in 58 patients (81%) of 72 and of IgM antibodies in 25 of 58 patients. No patient had isolated intrathecal synthesis of IgM antibodies. The majority of CSF samples (56 of 58) were assessed as IgG antibody-positive, independent of the borrelial strain used as antigen in EIA, whereas only 10 of 25 IgM antibody-positive CSF specimens reacted with all three strains. All patients in the study had intrathecal antibody synthesis demonstrable at 6-week follow-up. From this study it is concluded that there is a small, but real, risk of false-negative serological findings at the time of initial clinical presentation in patients with typical symptoms of neuroborreliosis. In these patients a negative serological result with one strain should prompt the repetition of the test with other strains of B. burgdorferi sensu lato.


Patient Safety Culture in Handling Prescriptions and Interprofessional Collaboration Practices Amongst Community Pharmacists: An Investigative Simulated Patient Study from the United Arab Emirates.
Community pharmacists are in a unique position to identify drug therapy-related problems (DTRPs) in prescriptions and mitigate them by communicating with prescriber. This study assessed the ability of community pharmacists (CPs) to identify DTRPs in prescriptions, the level of interprofessional collaboration among physician and CPs in mitigating the identified DTRPs, and the existing safety culture practices among CPs. Trained simulated patients (SPs), five final-year BSc Pharm female students, visited conveniently selected community pharmacies (n = 50) in Ajman emirate of the United Arab Emirates, with dummy prescriptions containing DTRPs (total 50 prescriptions with five different types of DTRPs categorized per the Pharmaceutical Care Network Europe Version 8) and assessed the DTRP-identifying ability of the CPs. SPs also observed the steps taken by the CPs to mitigate identified DTRPs and existing (if any) collaborative practices between CPs and physician. SPs documented their observations in a checklist immediately after leaving the pharmacy premises, which served as the data source. Statistical analyses were performed with chi-square at alpha = 0.05. Of the 50 respondents, 44% (n = 22) were able to identify the DTRPs. DTRP identification by pharmacists was associated with labeling [chi-square = 7.879, p value = 0.019], reconciliation [chi-square = 10.359, p value = 0.001], counseling standard [chi-square = 19.09, p = 0.000] and physician visit suggestion [chi-square = 31.15, p = 0.000]. The labeling standards for prescriptions with DTRPs were "low" in five (50%), "average" in three (30%) and "good" in two (20%) of the cases with wrong dose. Average counseling time of the CPs was 80.38 ± 71.61 seconds. The counseling standard had no significant association with counseling time [chi-square = 34.79, p = 0.250] and use of drug information sources [chi-square = 2.86, p = 0.243]. Average time spent in dispensing is 74.4 ± 73.05 seconds. None (n = 0) of the CPs communicated with the physician, and only five out of 50 (10%) of CPs checked any DI sources. However, in 19 (38%) cases, the CPs recommended the SPs to consult their physician prior to taking the medications. CPs were generally able to identify DTRPs and mitigate DTRPs by recommending physician consultation. Nevertheless, there were no professional collaborations between the SPs and physicians. The dispensing and counseling standards were not appreciable.


[Enzymes of cyclic nucleotide degradation in eye tissues during experimental ocular herpes].
Activity of phosphodiesterases disintegrating cAMP and cGMP in the cornea, sclera and ciliary body was investigated in health and in different stages of experimental herpetic keratitis. The problems concerning the role of the cyclase system in the pathogenesis of herpetic keratitis and the possibility of applying some of the drugs to the disease treatment are discussed.


Isothermal calorimetry: a predictive tool to model drug-propellant interactions in pressurized metered dose systems.
The purpose of this work was to evaluate gas perfusion isothermal calorimetry (ITC) as a method to characterize the physicochemical changes of active pharmaceutical ingredients (APIs) intended to be formulated in pressurized metered dose inhalers (pMDIs) after exposure to a model propellant. Spray dried samples of beclomethasone dipropionate (BDP) and salbutamol sulphate (SS) were exposed to controlled quantities of 2H,3H-decafluoropentane (HPFP) to determine whether ITC could be used as a suitable analytical method for gathering data on the behavioural properties of the powders in real time. The crystallization kinetics of BDP and the physiochemical properties of SS were successfully characterized using ITC and supported by a variety of other analytical techniques. Correlations between real and model propellant systems were also established using hydrofluoroalkane (HFA-227) propellant. In summary, ITC was found to be suitable for gathering data on the crystallization kinetics of BDP and SS. In a wider context, this work will have implications on the use of ITC for stability testing of APIs in HFA-based pMDIs.


History, Passion, and Performance.
History, Passion, and Performance was chosen as the theme for the 75th anniversary of the American Association of Occupational Health Nurses (AAOHN) kickoff. The American Association of Occupational Health Nurses has a long history created by passionate, dedicated members. This article highlights historical foundations of the Association, describes the occupational health nurse's passion to drive quality care for workers and discusses future professional and organizational challenges.


[The value of aimed biopsy in gastroscopy].
The introduction of the fiberscops with the possibility of the aimed biopsy has considerably improved the diagnostic evidence of gastroscopy, though there exists a whole series of technical problems in the histological ascertainment. Though all regions of the stomach are accessible to the biopsy forceps, the histological findings cannot always be ascertained clearly histologically. Of 105 carcinomata of the stomach and the oesophagus only 84 were verified clearly histologically. Of 101 ulcers appearing benign five proved to be malignant in histological respect. In 14 scars in two cases a carcinoma could be proved. Altogether from 27 polyps appearing benign bioptic material was taken, which in all cases confirmed the primary diagnosis, nevertheless at the operation one polyp proved to be malignant. In 105 cases endoscopically the diagnosis of a carcinoma was made, but in seven cases it was a benign ulcer clearly confirmed by the operation. It is reported on some own experiences concerning the improvement of the result of the aimed biopsy.


[PERCUTANEOUS CYSTOLITHOTRIPSY: THE FIRST CLINICAL EXPERIENCE].
This paper reviews results of examination and treatment for benign prostatic hyperplasia (BPH) and infravesical obstruction in 16 patients observed in Department of Urology of Zhukovsky CCH in 2013-2014. Most operated patients required particularly careful approach to the surgery planning due to advanced age and multiple comorbidities. Treatment of all patients was carried out in a single therapeutic session performed in two stages. Percutaneous cystolithotripsy was performed on the first stage and subsequently transurethral resection of the prostate (TURP) was carried out. It was found, that combination of minimally invasive percutaneous approach and TURP is the most sparing way to restore lower urinary tract urodynamics and eliminate bladder stones in all operated patients. With appropriate patient selection and a clear definition of indications, proposed treatment combination is a promising and effective strategy in management of patient with urolithiasis with infravesical obstruction and BPH.


Magnetic resonance imaging in the evaluation of cognitive function.
Image quality of magnetic resonance imaging (MRI) scans of the brain currently approximate gross anatomy as would be viewed at autopsy. During the first decade of the 21st Century incredible advances in image processing and quantification have occurred permitting more refined methods for studying brain-behavior-cognitive functioning. The current presentation overviews the current status of MRI methods for routine clinical assessment of brain pathology, how these techniques identify neuropathology and how pathological findings are quantified. Diffusion tensor imaging (DTI), functional MRI (fMRI), and resting state fMRI are all reviewed, emphasizing how these techniques permit an examination of brain function and connectivity. General regional relationships of brain function associated with cognitive control will be highlighted.


[Influence of sport practice and physical exercise on anthropometric indicators and weight satisfaction in men university students: a pilot study].
University students generally have low levels of physical activity, which could affect the body weight and composition and the knowledge and acceptance of their own body. To assess weight status and body composition, as well as self-perception and satisfaction with body weight in university students, and to analyze the influence of sport practice and physical exercise on these variables. A sample of 62 male students with a mean age of 20.7+/-1.7 years was evaluated. Sport practice and physical exercise in leisure time were analyzed by questionnaire. Weight status and body composition were assessed by anthropometry. Data about self-reported and desired weight and self-reported height were also registered. Measurements of actual, self-reported and desired weight were used to estimate self- perception and satisfaction with weight. Statistical analysis was performed using SPSS version 22.0. Overall 17.7% of participants had overweight and 6.5% underweight. The energy consumption due to sport practice and/or physical exercise was ≤ 3,000 kcal/ week in the 45.2% of the students and > 3,000 kcal/week in the 32.3%. Self-perception and satisfaction with weight was better in the group who practiced sport and/or physical exercise at the rate of ≤ 3.000 kcal/week than in those who did not practice any sport or exercise (P < 0.05). Regular practice of sport or physical exercise is associated with a better self-perception and satisfaction with body weight compared with a sedentary lifestyle. The university studies period should be used to promote sport practice and physical exercise, using the resources or assets of the University.


Association of cause of injury and traumatic axonal injury: a clinical MRI study of moderate and severe traumatic brain injury.
The authors investigated the association between the cause of injury and the occurrence and grade of traumatic axonal injury (TAI) on clinical MRI in patients with moderate or severe traumatic brain injury (TBI). Data for a total of 396 consecutive patients, aged 7-70 years, with moderate or severe TBI admitted to a level 1 trauma center were prospectively registered. Data were included for analysis from the 219 patients who had MRI performed within 35 days (median 8, IQR 4-17 days) and for whom cause of injury was known. Cause of injury was registered as road traffic accident (RTA) or fall (both with respective subcategories), alpine skiing or snowboarding accident, or violence. The MRI protocol consisted of T2*-weighted gradient echo, FLAIR, and diffusion-weighted imaging scans. TAI lesions were evaluated in a blinded manner and categorized into 3 grades, hemispheric/cerebellar white matter (grade 1), corpus callosum (grade 2), and brainstem (grade 3). The absence of TAI was analyzed as grade 0. Contusions and mass lesions on CT were also registered. Cause of injury did not differ between included and nonincluded patients. TAI was found in 83% of patients in the included group after RTAs and 62% after falls (p < 0.001). Observed TAI grades differed between the subcategories of both RTAs (p = 0.004) and falls (p = 0.006). Pedestrians in RTAs, car drivers/passengers in RTAs, and alpine skiers had the highest prevalence of TAI (89%-100%) and the highest TAI grades (70%-82% TAI grades 2-3). TAI was found in 76% of patients after falls from > own height (45% TAI grade 2-3), 63% after falls down the stairs (26% TAI grade 2-3), and 31% after falls from ≤ own height (12% TAI grade 2-3). Moreover, 53% of patients with TAI after RTAs and 68% with TAI after falls had cortical contusions or mass lesions on CT. This prospective study of moderate and severe TBI is to the authors' knowledge the first clinical MRI study to demonstrate both the high prevalence and grade of TAI after most of the different types of RTAs, alpine skiing accidents, and falls from a height. Importantly, TAI was also common following more low-energy trauma such as falls down the stairs or from own height. Physicians managing TBI patients in the acute phase should be aware of the possibility of TAI no matter the cause of injury and also when the CT scan shows cortical contusions or mass lesions.


Subaortic membrane and aorto-septal angle: an echocardiographic assessment and surgical outcome.
Development of a subaortic membrane is not fully understood. Recurrence after surgical removal continues to be high. We sought to assess the differences in aorto-septal angles (AoSA) to possibly explain alterations within the left ventricular outflow tract, hence in subaortic membrane formation. A total of 113 patients who underwent subaortic membrane resection were matched by age and sex with 113 controls. The subaortic membrane resection group included isolated subaortic membranes (n = 34, group I), associated with ventricular septal defect (n = 29, group II), or patent ductus arteriosus (n = 50, group III). Mean (± standard deviation) AoSA (in degrees) were not different between subaortic membrane groups I, II, and III but were steeper than their control groups (126.2 ± 9.2 vs 138.6 ± 7.0, 129.2 ± 9.9 vs 137.7 ± 10.0, and 126.2 ± 8.1 vs 135 ± 8.5, respectively; all Ps < .05). Additionally, group II had lower preoperative gradients (28.8 ± 20.7 mm Hg) compared to groups I and III (67.0 ± 32.9 and 66.2 ± 33.1 mm Hg, respectively, P < .001). Follow-up ranged from 3 to 132 months. In 22 (32%) patients, a subaortic membrane recurred. Early postoperative residual gradients and development of aortic regurgutation were associated with the need for reoperation (P < .05). These findings suggest a contributing role of the AoSA in the development of subaortic membrane. Further rheological experiments are warranted. Whether the steeper the angle the higher the risk of recurrence may be revealed by longer follow-up periods.


NF-kappaB promotes survival during mitotic cell cycle arrest.
By activating the mitotic checkpoint, anti-microtubule drugs such as nocodazole cause mammalian cells to arrest in mitosis and then undergo apoptosis. Microtubule depolymerization is rapid and results in the activation of the transcription factor NF-kappaB and induction of NF-kappaB-dependent gene expression. However, the functional consequence of NF-kappaB activation has remained unclear. Evidence has accumulated to suggest that NF-kappaB transcriptional activity is required to suppress apoptosis. In the present study, we confirm and extend previous findings that microtubule depolymerization leads to the rapid activation of NF-kappaB and test the hypothesis that the induction of NF-kappaB regulates cell survival during mitotic cell cycle arrest in order to define its role. Using a range of functional assays, we have shown that microtubule depolymerization correlates with the activation of IKKalpha and IKKbeta; the phosphorylation, ubiquitination, and degradation of IkappaBalpha; the translocation of native p65 (RelA) into the nucleus; and increased NF-kappaB transcriptional activity. By inhibiting either the activation of the IKKs or the degradation of IkappaBalpha, we find that the level of apoptosis is significantly increased in the mitotically arrested cells. Inhibition of NF-kappaB signaling in the nonmitotic cells did not affect their survival. We establish that although NF-kappaB is activated rapidly in response to microtubule depolymerization, its cell survival function is not required until mitotic cell cycle arrest, when the mitotic checkpoint is activated and apoptosis is triggered. We conclude that NF-kappaB may regulate the transcription of one or more antiapoptotic proteins that may regulate cell survival during mitotic cell cycle arrest.


Substrate-independent activation pathways of the CRISPR-Cas9 HNH nuclease.
A hallmark of tightly regulated high-fidelity enzymes is that they become activated only after encountering cognate substrates, often by an induced-fit mechanism rather than conformational selection. Upon analysis of molecular dynamics trajectories, we recently discovered that the Cas9 HNH domain exists in three conformations: 1) Y836 (which is two residues away from the catalytic D839 and H840 residues) is hydrogen bonded to the D829 backbone amide, 2) Y836 is hydrogen bonded to the backbone amide of D861 (which is one residue away from the third catalytic residue N863), and 3) Y836 is not hydrogen bonded to either residue. Each of the three conformers differs from the active state of HNH. The conversion between the inactive and active states involves a local unfolding-refolding process that displaces the Cα and side chain of the catalytic N863 residue by ∼5 Å and ∼10 Å, respectively. In this study, we report the two largest principal components of coordinate variance of the HNH domain throughout molecular dynamics trajectories to establish the interconversion pathways of these conformations. We show that conformation 2 is an obligate step between conformations 1 and 3, which are not directly interconvertible without conformation 2. The loss of hydrogen bonding of the Y836 side chain in conformation 3 likely plays an essential role in activation during local unfolding-refolding of an α-helix containing the catalytic N863. Three single Lys-to-Ala mutants appear to eliminate this substrate-independent activation pathway of the wild-type HNH nuclease, thereby enhancing the fidelity of HNH cleavage.


Listeria meningoencephalitis in an immunocompetent person.
Listeria monocytogenes is a small, aerobic or facultative anaerobic, non-sporulating gram positive bacillus that can be isolated from soil, vegetation or animal reservoirs. There are six species of Listeria, and only L. monocytogenes is pathogenic for humans. Human disease occurs mainly in immunocompromised people, neonates and in pregnancy, while the cases in immunocompetent people are rare. CNS manifestations of the disease can be in form of meningitis, encephalitis, and also cerebritis and abscess since L. monocytogenes shows tropism for brain and brain stem as well for the meninges. In this case we presented 55 year old male patient with etiologically confirmed listerial meningoencephalitis, transferred from regional hospital tothe Clinic for Infectious Diseases with diagnosis of acute meningoencephalitis. Disease started 4 days before the admission. Prior to this the patient was completely healthy. In his history he denied any preexisting disease. At admittance he was febrile, with altered consciousness, disoriented, showing ocular deviation, dystaxia, and with completely positive meningeal signs. Neurologist diagnosis was rhombencephalitis. CSF analysis showed mildly opalescent liquor with pleocytosis 546/mm3 and polymorphonuclear cell predominance >70%. CSF culture showed positive isolate of L. monocytogenes. Initial therapy was: Penicillin G and Chloramphenicol, together with all other supportive and symptomatic therapy. After initial therapy and based on antibiogram, ampicillin was administered for4 weeks, followed by imipenemum for 10 days. Control CSF analysis showed pleocytosis and increased protein level and the patient was discharged as recovered with diagnosis of acute meningoencephalitis


Measurement of Dynamic Hyperinflation During the 6-Minute Walk Test Using a Mobile Device.
Dynamic hyperinflation is a major cause of dyspnea in patients with COPD. Dynamic hyperinflation is usually measured with cardiopulmonary exercise testing, but this test requires maximal effort from the patient, and inspiratory capacity (IC) measurements may influence test results. This study investigated another approach by measuring dynamic hyperinflation during the more natural and better-tolerated 6-min walk test (6MWT), using a mobile system for IC measurements. Twenty subjects were studied, including 10 healthy subjects and 10 subjects with COPD. Each subject performed a pair of 6MWTs. The study showed that test-retest reliability in healthy subjects was excellent (intraclass correlation coefficient 0.995). In addition, mean resting IC in healthy subjects (3.27 ± 0.77 L) was not affected at the end of the 6MWT, whereas mean resting IC in subjects with COPD (2.45 ± 0.90 L) decreased to 1.93 L ± 0.68 L at the end of the 6MWT (P = .004). The tolerability of the device for subjects with COPD appeared to be only slightly hampered by an increased sense of dyspnea attributed to wearing a mask. This study provides a proof of principle for mobile IC measurements during the 6MWT, demonstrating good test performance, reasonable tolerability, and a power to differentiate normal from pathologic conditions.


The effect of transition from traditional to urban life-style on the insulin secretory response in Australian Aborigines.
Recent epidemiologic studies have revealed a high prevalence of maturity-onset diabetes in certain populations that have undergone comparatively rapid urbanization. There is evidence suggesting that Australian Aborigines may respond to urbanization in this way. Thirteen full-blood Aborigines from the Mowanjum Community, Derby, Western Australia, cooperated in the present study. They spent 3 mo living in their traditional hunter-gatherer life-style, after which their insulin response to glucose was measured in a starch tolerance test. The findings were compared in follow-up studies conducted 3 mo after returning to their urban environment. Similar studies were conducted in Caucasians of comparable age and weight. Fasting glucose concentrations were lower in Aborigines than in Caucasians and were unaffected by life-style changes. Although basal insulin levels were similar in the three groups, there were striking intergroup differences in the insulin responses to glucose. The areas under the insulin curves in the first hour after starch ingestion were: urban Aborigines 4478 +/- 465 microU/ml-1/min, traditional Aborigines 2959 +/- 301 microU/ml-1/min, and Caucasians 2097 +/- 224 microU/ml-1/min. This appeared to reflect differences in the early rates of change of glucose concentrations. The data suggest that these Aborigines have an abnormally high insulin response to glucose, which is ameliorated, but not normalized, by reverting to their traditional life-style.


Impacts of a farmers' market incentive programme on fruit and vegetable access, purchase and consumption.
The present study examines the impact of Health Bucks, a farmers' market incentive programme, on awareness of and access to farmers' markets, and fruit and vegetable purchase and consumption in low-income New York City neighbourhoods. The evaluation used two primary data collection methods: (i) an on-site point-of-purchase survey of farmers' market shoppers; and (ii) a random-digit-dial telephone survey of residents in neighbourhoods where the programme operates. Additionally, we conducted a quasi-experimental analysis examining differential time trends in consumption before and after programme introduction using secondary Community Health Survey (CHS) data. New York City farmers' markets and communities. Farmers' market shoppers (n 2287) completing point-of-purchase surveys in a representative sample of New York City farmers' markets in 2010; residents (n 1025) completing random-digit-dial telephone survey interviews in 2010; and respondents (n 35 606) completing CHS interviews in 2002, 2004, 2008 and 2009. Greater Health Bucks exposure was associated with: (i) greater awareness of farmers' markets; (ii) increased frequency and amount of farmers' market purchases; and (iii) greater likelihood of a self-reported year-over-year increase in fruit and vegetable consumption. However, our CHS analysis did not detect impacts on consumption. While our study provides promising evidence that use of farmers' market incentives is associated with increased awareness and use of farmers' markets, additional research is needed to better understand impacts on fruit and vegetable consumption.


Extensive heterogeneity of the protein composition of Chlamydia trachomatis following serial passage in two different cell lines.
To determine if the host-modulated adherence characteristics of the intracellular bacterial pathogen Chlamydia trachomatis were due to the acquisition of altered surface-exposed proteins, highly purified chlamydiae grown in two different host cells were analysed. Two serovars, L1 and E, were grown for multiple passages in both HeLa and McCoy host cells. Numerous protein differences in the chlamydial elementary bodies (EB) of each serovar grown in the two different hosts were detected by two-dimensional (2-D) gel electrophoresis and fluorography of radioactively labelled proteins. At least four to six serial passages in the alternative host were necessary before the changes were apparent. Iodination of suspensions of purified chlamydiae and 2-D electrophoresis revealed several surface proteins that were determined by the host cells in which the bacteria had replicated. These iodinated chlamydial proteins were removed by treatment of the iodinated EB with trypsin, indicating their location at the bacterial surface. Two of the major constituents of the outer-membrane complex, the cysteine- and methionine-rich 60 kDa and 40 kDa proteins, remained unchanged in both molecular mass and charge during the host adaptation. Several chlamydial proteins capable of binding iodinated host membrane preparations also exhibited host-dependent alterations. Immunoblotting experiments with a rabbit and a human polyclonal sera indicated that distinct host-specified chlamydial proteins were reactive with the two sera.


Approaches to the treatment of seasonal allergic rhinitis.
Between 15 and 30 million Americans have allergic rhinitis. Costs of diminished job and school performance extend beyond the financial burden of treatment, taking their toll in worker productivity and school absences. Therapeutic approaches include allergen avoidance, pharmaceuticals, and allergy immunotherapy. Among the pharmaceutical agents, decongestants, anti-inflammatory drugs, and antihistamines relieve allergic rhinitis symptoms. Often, decongestants are prescribed along with antihistamines to provide maximum relief. Anti-inflammatory agents such as cromolyn sodium and topical corticosteroids are efficacious despite their delayed effect. However, allergic rhinitis is most frequently treated with antihistamines. Today's antihistamines have minimal sedative effects and cholinergic actions, are safe to use, and do not impair performance.


[Comparative study of salivary gland polytene chromosome asynapsis in larvae of Drosophila melanogaster, Drosophila simulans and their hybrids].
Quantitative comparative study of larvae salivary gland chromosome asynapsis has been performed on 3L arm for sibling species of Drosophila melanogaster, D. simulans and their hybrids (D. melanogaster female X D. simulans hermaphrodite). A frequency of asynapsis occurence, an asynapsis localization and distributions of asynapsis terminal points and asynapsis lengths were determined. It is revealed that parent species are very similar as regards to quantitative characteristics studied. For hybrids there are some essential differences with either of parent species. These are: 1) reliably larger frequency of asynapsis, 2) different character of asynapsis localization, and 3) two new "peaks" of distal terminal points of asynapsis and three new "peaks" of proximal terminal points of asynapsis are revealed, main parents "peaks" being kept.


Treatment of erectile dysfunction in the obese type 2 diabetic ZDF rat with adipose tissue-derived stem cells.
Erectile dysfunction (ED) is a major complication of type 2 diabetes, and many diabetic men with ED are refractory to common ED therapies. To determine whether autologous adipose tissue-derived stem cells (ADSCs) injected into the penis of impotent type 2 diabetic rats improve erectile function. Blood glucose levels, intracavernous pressure (ICP) increase upon cavernous nerve (CN) electrostimulation, and immunohistochemistry. Twenty-two male Zucker diabetic fatty (ZDF) rats were used. At 22 weeks of age, all the animals underwent unilateral CN electrostimulation and ICP measurement to confirm impotence. Paragonadal adipose tissue was harvested to procure ADSCs. The impotent animals were randomized to ADSC treatment and sham control groups. At 23 weeks of age, the treatment group animals underwent a penile injection of 1 million ADSCs; the control group animals received vehicle only. Erectile function studies were repeated at 26 weeks of age, followed by tissue harvest. The rats developed diabetes within the first 10 weeks of age. At 22 weeks of age, 20 out of the 22 rats presented with ED. The post-treatment ICP increase during CN stimulation and ICP increase/mean arterial pressure were significantly higher in the treatment group compared with controls. Three weeks after injection into the corpus cavernosum, only a small number of BrdU-labeled ADSCs was detectable within corporal tissue of the treatment group. There was a significant increase in neuronal nitric oxide synthase (nNOS) in the penile dorsal nerve and in the number of endothelial cells in the corpora cavernosa of the rats in the treatment group. Autologous ADSCs injected into the penis were effective to improve erectile function and to alter the microarchitecture of the corpus cavernosum. Since the number of ADSCs retained in the corpus cavernosum is very small, we postulate that their paracrine function, not trans-differentiation to smooth muscle or endothelial cells, is responsible for the improvement in penile function.


Minimizing Negative Transfer of Knowledge in Multivariate Gaussian Processes: A Scalable and Regularized Approach.
Recently there has been an increasing interest in the multivariate Gaussian process (MGP) which extends the Gaussian process (GP) to deal with multiple outputs. One approach to construct the MGP and account for non-trivial commonalities amongst outputs employs a convolution process (CP). The CP is based on the idea of sharing latent functions across several convolutions. Despite the elegance of the CP construction, it provides new challenges that need yet to be tackled. First, even with a moderate number of outputs, model building is extremely prohibitive due to the huge increase in computational demands and number of parameters to be estimated. Second, the negative transfer of knowledge may occur when some outputs do not share commonalities. In this paper we address these issues. We propose a regularized pairwise modeling approach for the MGP established using CP. The key feature of our approach is to distribute the estimation of the full multivariate model into a group of bivariate GPs which are individually built. Interestingly pairwise modeling turns out to possess unique characteristics, which allows us to tackle the challenge of negative transfer through penalizing the latent function that facilitates information sharing in each bivariate model. Predictions are then made through combining predictions from the bivariate models within a Bayesian framework. The proposed method has excellent scalability when the number of outputs is large and minimizes the negative transfer of knowledge between uncorrelated outputs. Statistical guarantees for the proposed method are studied and its advantageous features are demonstrated through numerical studies.


Impact of obesity on outcomes after open surgical and endovascular abdominal aortic aneurysm repair.
This study examined impact of obesity on outcomes after abdominal aortic aneurysm repair. Data were obtained from the Veterans Affairs National Surgical Quality Improvement Program. Body mass index (BMI) was categorized according to National Institutes of Health guidelines. Multivariate regression adjusted for 40 other risk factors to analyze trends in complications and death within 30 days. We identified 2,201 patients undergoing 1,185 open and 1,016 endovascular aneurysm repairs (EVAR) for abdominal aortic aneurysms from January 2004 through December 2005. BMI distribution was identical in both groups and reflected national population statistics: approximately 30% were normal (BMI 18.5 to 24.9), 40% were overweight (25.0 to 29.9), and 30% were obese class I (30.0 to 34.9), II (35.0 to 39.9), or III (>/=40.0). After open repair, obesity of any class was independently predictive of wound complications (adjusted odds ratio = 2.4; 95% CI, 1.5 to 5.3; p = 0.002). Class III obesity was also an independent predictor or renal complications (adjusted odds rato = 6.3; 95% CI, 2.2 to 18.0; p < 0.0001) and cardiac complications (adjusted odds ratio = 4.5; 95% CI, 1.1 to 22.9; p = 0.045. After EVAR, obesity (any class) was predictive of wound complications (adjusted odds ratio = 3.1; 95% CI, 1.1 to 8.1; p = 0.026), but not predictive of other complications or death. Between the two types of operation, there were fewer complications and deaths after EVAR compared with open repair across all BMI categories, but outcomes were most disparate among the obese. Obesity is an independent risk factor that surgeons should consider during patient selection and operative planning for abdominal aortic aneurysm repair. Obese patients appear to particularly benefit from successful EVAR over open repair, but if open repair is required, special attention should be paid to cardiac risk, perioperative renal protection, and aggresive wound infection prevention measures.


Identification of palmitoylated mitochondrial proteins using a bio-orthogonal azido-palmitate analogue.
Increased levels of circulating saturated free fatty acids, such as palmitate, have been implicated in the etiology of type II diabetes and cancer. In addition to being a constituent of glycerolipids and a source of energy, palmitate also covalently attaches to numerous cellular proteins via a process named palmitoylation. Recognized for its roles in membrane tethering, cellular signaling, and protein trafficking, palmitoylation is also emerging as a potential regulator of metabolism. Indeed, we showed previously that the acylation of two mitochondrial proteins at their active site cysteine residues result in their inhibition. Herein, we sought to identify other palmitoylated proteins in mitochondria using a nonradioactive bio-orthogonal azido-palmitate analog that can be selectively derivatized with various tagged triarylphosphines. Our results show that, like palmitate, incorporation of azido-palmitate occurred on mitochondrial proteins via thioester bonds at sites that could be competed out by palmitoyl-CoA. Using this method, we identified 21 putative palmitoylated proteins in the rat liver mitochondrial matrix, a compartment not recognized for its content in palmitoylated proteins, and confirmed the palmitoylation of newly identified mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase. We postulate that covalent modification and perhaps inhibition of various mitochondrial enzymes by palmitoyl-CoA could lead to the metabolic impairments found in obesity-related diseases.


[Decreased transfusion requirements in acquired severe bleeding with recombinant activated factor VII].
Patients with severe and persistent bleeding have high mortality rates despite standard therapy, including blood transfusion support. The aim of the study was to evaluate the role of rFVIIa in the management of severe bleeding, refractory to other treatments. All cases with severe bleeding and failure of previous treatments who received rFVIIa (n = 21) at one single center were retrospectively included in the study. A response after the administration of rFVIIa was reported in 16 of 21 patients (76.2%). Hemorrhage was completely halted in 14 cases, and 12 patients (57.1%) were alive 30 days after treatment. The use of rFVIIa was associated with a normalization of coagulation tests, especially the prothrombin time (p = 0.001). A marked reduction in blood requirements, red cell units (p = 0.003), fresh frozen plasma (p = 0.009) and platelets (p = 0.017) was also observed. rFVIIa may have an important role in the achievement of an adequate hemostasis and reduces blood requirements in patients with severe bleeding, emerging as an alternative to blood transfusion.