Intralocus Sexual Conflict and the Tragedy of the Commons in Seed Beetles.
The evolution of male traits that inflict direct harm on females during mating interactions can result in a so-called tragedy of the commons, where selfish male strategies depress population viability. This tragedy of the commons can be magnified by intralocus sexual conflict (IaSC) whenever alleles that reduce fecundity when expressed in females spread in the population because of their benefits in males. We evaluated this prediction by detailed phenotyping of 73 isofemale lines of the seed beetle Callosobruchus maculatus. We quantified genetic variation in life history and morphology, as well as associated covariance in male and female adult reproductive success. In parallel, we created replicated artificial populations of each line and measured their productivity. Genetic constraints limited independent trait expression in the sexes, and we identified several instances of sexually antagonistic covariance between traits and fitness, signifying IaSC. Population productivity was strongly positively correlated to female adult reproductive success but uncorrelated with male reproductive success. Moreover, male (female) phenotypic optima for several traits under sexually antagonistic selection were exhibited by the genotypes with the lowest (highest) population productivity. Our study forms a direct link between individual-level sex-specific selection and population demography and places life-history traits at the epicenter of these dynamics.


Fingerprinting Brownian Motions of Polymers under Flow.
We present a quantitative approach to the self-dynamics of polymers under steady flow by employing a set of complementary reference frames and extending the spherical harmonic expansion technique to dynamic density correlations. Application of this method to nonequilibrium molecular dynamics simulations of polymer melts reveals a number of universal features. For both unentangled and entangled melts, the center-of-mass motions in the flow frame are described by superdiffusive, anisotropic Gaussian distributions, whereas the isotropic component of monomer self-dynamics in the center-of-mass frame is strongly suppressed. Spatial correlation analysis shows that the heterogeneity of monomer self-dynamics increases significantly under flow.


Mitochondria recycle nitrite back to the bioregulator nitric monoxide.
Nitric monoxide (NO) exerts a great variety of physiological functions. L-Arginine supplies amino groups which are transformed to NO in various NO-synthase-active isoenzyme complexes. NO-synthesis is stimulated under various conditions increasing the tissue of stable NO-metabolites. The major oxidation product found is nitrite. Elevated nitrite levels were reported to exist in a variety of diseases including HIV, reperfusion injury and hypovolemic shock. Denitrifying bacteria such as Paracoccus denitrificans have a membrane bound set of cytochromes (cyt cd1, cyt bc) which were shown to be involved in nitrite reduction activities. Mammalian mitochondria have similar cytochromes which form part of the respiratory chain. Like in bacteria quinols are used as reductants of these types of cytochromes. The observation of one-e- divergence from this redox-couple to external dioxygen made us to study whether this site of the respiratory chain may also recycle nitrite back to its bioactive form NO. Thus, the aim of the present study was therefore to confirm the existence of a reductive pathway which reestablishes the existence of the bioregulator NO from its main metabolite NO2-. Our results show that respiring mitochondria readily reduce added nitrite to NO which was made visible by nitrosylation of deoxyhemoglobin. The adduct gives characteristic triplet-ESR-signals. Using inhibitors of the respiratory chain for chemical sequestration of respiratory segments we were able to identify the site where nitrite is reduced. The results confirm the ubiquinone/cyt be1 couple as the reductant site where nitrite is recycled. The high affinity of NO to the heme-iron of cytochrome oxidase will result in an impairment of mitochondrial energy-production. "Nitrite tolerance" of angina pectoris patients using NO-donors may be explained in that way.


Urological procedures in Central Europe and the current reality based on the national registries of Czech Republic, Hungary, and Poland (2012 status).
In recent years, the laparoscopic approach in oncologic urology seems more attractable to the surgeons. It is considered to have the same oncologic quality as open surgery, but is less invasive in patients. It is used widely in all of Europe, but with various frequency. The aim of the study was to present a various amount of oncourological procedures from three neighbouring countries - Poland, Czech Republic and Hungary. Prostatectomy, cystectomy, nephrectomy and tumorectomy (Nephron Sparing Procedures - NSS) were presented as a list of procedures prepared from the national registry. The total amount of procedures was presented, as well as the LO (Lap to Open procedures) index, P/P (procedures/population) index, ratio of cystectomy/population, and cystectomy/TURBT. In the Czech Republic, the most complex procedures are performed (laparoscopic/robotic prostatectomy, NSS LAP, LAP nephrectomy) in the majority when analysing the country's population. In Hungary and Czech Republic, there are more laparoscopic/robotic radical prostatectomies performed, than open ones. In Poland the largest number of cystectomies is performed when analysing the country's population, but it is difficult to explain the much higher ratio of 6.57 TUR/one cystectomy. In the Czech Republic this procedure is performed in almost one quarter of the patients (23.36%). Interestingly, in Hungary the cystectomy with pouch creation is performed in about 67.65% cases. The highest reimbursement for surgical procedure is present in the Czech Republic with approximately 20-40% more than when compared to Poland or Hungary. The definitive leader in Central Europe (based on the national registry) is the Czech Republic, where the most complex procedures are performed (laparoscopic/robotic prostatectomy, NSS LAP, LAP nephrectomy) in biggest amounts when analysing the country's population. Explanation of such circumstances, can be the higher reimbursement rate for surgical procedure in this country.


The effectiveness of a structured educational intervention on disease-related misconception and quality of life in patients with irritable bowel syndrome.
A significant number of patients with irritable bowel syndrome hold misconceptions about their disease and experience more impaired quality of life compared with the general population and people suffering from other chronic diseases. This study was designed to explore the effectiveness of a structured educational intervention on disease-related misconceptions and quality of life in patients with irritable bowel syndrome in Wuhan, China. A convenience sample of 23 patients with irritable bowel syndrome participated in an educational program that consisted of 4 weekly sessions in a group setting. Instruments, including an irritable bowel syndrome-related misconception scale and irritable bowel syndrome quality-of-life scale, were used for evaluation at baseline and 3 months after the sessions. Three months after the structured educational intervention, the score for irritable bowel syndrome-related misconception was significantly decreased (p < .001), and the score for irritable bowel syndrome quality of life was significantly improved (p < .001). We conclude that the structured educational intervention seems to be a proper method to reduce the disease-related misconceptions and improve the quality of life in patients with irritable bowel syndrome. Planning and implementing such clinical education programs will be helpful in decreasing disease-related misconceptions and promoting quality of life in patients with irritable bowel syndrome.


Extracellular vesicles derived from bone marrow mesenchymal stem cells enhance myelin maintenance after cortical injury in aged rhesus monkeys.
Cortical injury, such as stroke, causes neurotoxic cascades that lead to rapid death and/or damage to neurons and glia. Axonal and myelin damage in particular, are critical factors that lead to neuronal dysfunction and impair recovery of function after injury. These factors can be exacerbated in the aged brain where white matter damage is prevalent. Therapies that can ameliorate myelin damage and promote repair by targeting oligodendroglia, the cells that produce and maintain myelin, may facilitate recovery after injury, especially in the aged brain where these processes are already compromised. We previously reported that a novel therapeutic, Mesenchymal Stem Cell derived extracellular vesicles (MSC-EVs), administered intravenously at both 24 h and 14 days after cortical injury, reduced microgliosis (Go et al. 2019), reduced neuronal pathology (Medalla et al. 2020), and improved motor recovery (Moore et al. 2019) in aged female rhesus monkeys. Here, we evaluated the effect of MSC-EV treatment on changes in oligodendrocyte maturation and associated myelin markers in the sublesional white matter using immunohistochemistry, confocal microscopy, stereology, qRT-PCR, and ELISA. Compared to vehicle control monkeys, EV-treated monkeys showed a reduction in the density of damaged oligodendrocytes. Further, EV-treatment was associated with enhanced myelin maintenance, evidenced by upregulation of myelin-related genes and increases in actively myelinating oligodendrocytes in sublesional white matter. These changes in myelination correlate with the rate of motor recovery, suggesting that improved myelin maintenance facilitates this recovery. Overall, our results suggest that EVs act on oligodendrocytes to support myelination and improves functional recovery after injury in the aged brain. SIGNIFICANCE: We previously reported that EVs facilitate recovery of function after cortical injury in the aged monkey brain, while also reducing neuronal pathology (Medalla et al. 2020) and microgliosis (Go et al. 2019). However, the effect of injury and EVs on oligodendrocytes and myelination has not been characterized in the primate brain (Dewar et al. 1999; Sozmen et al. 2012; Zhang et al. 2013). In the present study, we assessed changes in myelination after cortical injury in aged monkeys. Our results show, for the first time, that MSC-EVs support recovery of function after cortical injury by enhancing myelin maintenance in the aged primate brain.


Prehospital sepsis recognition and outcomes for patients with sepsis by race and ethnicity.
Background First medical contact for patients with sepsis often initiates in the prehospital setting, yet limited studies have explored the EMS sepsis recognition-mortality relationship. Racial and ethnic minority patients often have worse sepsis outcomes, yet the role of prehospital recognition in this inequity has not been explored. Our objective was to describe prehospital sepsis recognition and hospital mortality, with analysis by patient race and ethnicity.Methods Using linked EMS and hospital records from the 2021 ESO Data Collaborative, we retrospectively analyzed 9-1-1 EMS transports for adult patients with emergency department ICD-10 sepsis diagnosis codes. EMS sepsis recognition was defined as a primary or secondary sepsis impression, use of an electronic health record specialty sepsis form, or a prehospital sepsis alert. We used multivariable logistic regression to assess the association between EMS sepsis recognition and hospital mortality, adjusting for age, sex, race and ethnicity, scene socioeconomic status, and documented clinical characteristics: altered mental status, hypotension, tachypnea, tachycardia, fever. We conducted a secondary analysis of patients who were positive for the quick sequential organ failure assessment (qSOFA) using first prehospital vital signs.Results We analyzed 20,172 records for EMS-transported patients with diagnosed sepsis. Overall, 8% of patients were Black, 8% were Hispanic, and 72% were White. Prehospital sepsis recognition was 18%. Prehospital sepsis recognition was similar across racial and ethnic groups (Black: 17.2%, Hispanic: 17.4%, White: 18.1%) and adjusted odds of sepsis recognition did not differ between racial and ethnic groups. Overall mortality was 11% (2,186). Prehospital sepsis recognition was associated with a 18% reduction in odds of mortality (OR: 0.82, 95% CI: 0.70-0.94) after adjustment. Of patients who were qSOFA positive in the field (n = 2,168), EMS sepsis recognition was 32% and was similar across race and ethnicities. Adjusted odds of mortality were 0.68 (95% CI: 0.53-0.88) when sepsis was recognized in the prehospital setting.Conclusion EMS identified sepsis in fewer than one in three patients even after limiting to those positive for qSOFA, without differences by race and ethnicity. EMS sepsis recognition was associated with reduced odds of mortality; however, Black patients remained at greater odds of death suggesting additional factors that warrant investigation.


The Effect of Replacing Fish Meal in the Diet with Enzyme-Treated Soybean Meal (HP310) on Growth and Body Composition of Rainbow Trout Fry.
The potential of enzyme-treated soybean meal powder (HP310) as fish meal alternative in diets for rainbow trout weighing 1.17 ± 0.3 g was evaluated for 60 days. Fish meal was replaced with HP310 at 25%, 50%, 75% and 100% of experimental diets. A control group was also considered. The results showed that diets containing 75% and 100% HP310 had significantly higher feed conversion ratio and lower feed intake, weight gain and specific growth rate compared to fish feed diets containing higher levels of fish protein ingredients (p < 0.05). Results suggested use of 50% HP310 in trout diet had a positive effect on growth performance (p < 0.05). All fish feed diets with HP310 had lower hematocrit, hemoglobin and red blood cells compared to the control group, but the differences between the control and the other treatments up to 75% HP310 replacement levels of diet (p > 0.05). However increasing in level of HP310 in the diet caused a significant increase of the white blood cells (p < 0.05). The fish fed with a diet totally replaced by HP310 showed the highest values of ash and moisture content among the diets and showed significantly different levels when compared with the control and other feeding treatments (p < 0.05).


Depletion of lamina-associated polypeptide 1 from cardiomyocytes causes cardiac dysfunction in mice.
We previously showed that striated muscle-selective depletion of lamina-associated polypeptide 1 (LAP1), an integral inner nuclear membrane protein, leads to profound muscular dystrophy with premature death in mice. As LAP1 is also depleted in hearts of these mice, we examined their cardiac phenotype. Striated muscle-selective LAP1 knockout mice display ventricular systolic dysfunction with abnormal induction of genes encoding cardiomyopathy related proteins. To eliminate possible confounding effects due to skeletal muscle pathology, we generated a new mouse line in which LAP1 is deleted in a cardiomyocyte-selective manner. These mice had no skeletal muscle pathology and appeared overtly normal at 20 weeks of age. However, cardiac echocardiography revealed that they developed left ventricular systolic dysfunction and cardiac gene expression analysis revealed abnormal induction of cardiomyopathy-related genes. Our results demonstrate that LAP1 expression in cardiomyocytes is required for normal left ventricular function, consistent with a report of cardiomyopathy in a human subject with mutation in the gene encoding LAP1.


How other countries can improve Canada's maternal mortality statistics.
Maternal mortality is the death of a woman while pregnant or within 42 days of the end of pregnancy. Late maternal deaths are from 42 to 365 days thereafter. Maternal mortality is an important surrogate indicator of a woman's overall health, social and economic status, and the provision of antenatal and emergency obstetric care at regional and national levels. Canada does not have a national system to report on maternal mortality; rather, maternal death investigations fall under the legal purview of coroners and medical examiners within each individual province or territory. Furthermore, the Canadian Perinatal Surveillance System is limited by its access to a comprehensive dataset. Hence, there is no accurate national picture of mortality prevalence or trends. The implementation of a national confidential enquiry system is a crucial step toward detailing pregnancy and post-pregnancy maternal mortality in Canada and should be organized in accordance with existing successful international systems.


Pathological laughter in a patient with multiple sclerosis.
Pseudobulbar affect-such as pathological laughter or crying-is associated with several different neurologic diseases and is most frequently seen in patients with Alzheimer disease. However, many physicians do not recognize it as a symptom associated with multiple sclerosis. The present report describes a case of pathological laughter in a 56-year-old man who was diagnosed as having multiple sclerosis 20 years earlier.


Determination of mineral contents of Turkish herbal tea (Salvia aucheri var. canescens) at different infusion periods.
Inductively coupled plasma atomic emission spectrometry has been used for the determination of contents of major and minor elements in Salvia aucheri var. canescens (sage) and its infusions for different intervals. Twenty-five elements (Al, B, Ba, Bi, Ca, Cd, Co, Cr, Cu, Fe, Ga, Ln, K, Li, Mg, Mn, Na, Ni, P, Pb, S, Sr, Ti,V, and Zn) were detected in both S. aucheri and its infusions. The ranges of mineral levels varied from Cd (1.6668 mg/kg) to K (13,570 mg/kg) and Ni (0.05273 mg/kg) to K (196.25 mg/kg) in the herb and its infusions, respectively. The levels of K, Ca, Na, Mg, and S in all infusions in this work were higher than those of the other elements. However, Al, Ba, Ca, Cd, Co, Cu, Fe, Li, K, Mg, Na, Ni, P, Pb, Sr, Ti, and Zn contents were high in the first period of infusion. As a result, the first period of infusion may be proposed as the optimum infusion time because of nutritional properties. These results may be useful for the evaluation of dietary information.


Spatial distribution and source apportionment of surface soil's polycyclic aromatic hydrocarbons in the Yangtze River Delta.
Soil acts as a crucial reservoir of polycyclic aromatic hydrocarbons (PAHs) in the environment, and its PAH content serves as a significant indicator of regional PAH pollution. Monitoring PAH levels in soil is important for assessing the potential risks to human and environmental health. In this study, 53 surface soil samples were collected from the Yangtze River Delta. These samples were monitored for 16 priority PAHs. Pollution levels, compositional profiles, and source differences of soil PAHs were analyzed among different regions, urban and rural areas, and functional zones. The total PAH content (Σ16PAHs) in the surface soil of the Yangtze River Delta was 2326.01 ± 2901.53 ng/g. High-ring PAHs (4-6 rings) accounted for the predominant portion (85.50%) of total PAHs. The average pollution level of soil PAHs in Jiangsu Province (2651.92 ± 3242.87 ng/g) was significantly higher than that of Zhejiang Province (2001.44 ± 2621.71 ng/g) and Shanghai (1669.13 ± 1758.34 ng/g), and high-ring PAHs constituted a predominant portion in these three regions. There was no significant difference in the PAH content between urban and rural areas. In different functional areas, automobile stations exhibited the highest PAH levels among the functional zones analyzed, with traffic emissions identified as a major source of soil PAH in this area. The primary factors influencing the distribution of soil PAHs in the study area were the duration of urbanization exposure (r = 0.753, p < 0.01) and soil organic carbon content (r = 0.452, p < 0.01). This provides novel evidence for the cumulative build-up of PAHs during urbanization. The positive matrix factorization model was used to analyze the sources of PAHs in the surface soil of the Yangtze River Delta, revealing that biomass and coal combustion (60.19%) and traffic emissions and coal combustion (31.82%) were the primary sources of PAHs in the region.


Sleep benefit in Parkinson's disease is associated with short sleep times.
Sleep benefit in Parkinson's disease is characterized by restoration of mobility upon awakening from sleep and prior to drug intake. With this study, we aimed at assessing clinical and nocturnal sleep correlates of this phenomenon. We recorded motor and non-motor symptoms in 131 Parkinson patients with and without sleep benefit, as assessed by questionnaires. Polysomnography recordings were performed in 60 of these patients. Thirty-nine Parkinson patients (30%) reported sleep benefit. Motor symptoms, measures of sleepiness, fatigue, depression, anxiety, sleep-wake disorders, and dopaminergic treatment were not associated with sleep benefit, and most polysomnography measures were similar between both groups. However, Parkinson patients with sleep benefit had shorter total sleep times and longer sleep latencies at nocturnal polysomnography. The link between the occurrence of sleep benefit and shorter nocturnal sleep in Parkinson's disease remains unclear.


Chemical Profiling, Antiproliferative and Antimigratory Capacity of Haberlea rhodopensis Extracts in an In Vitro Platform of Various Human Cancer Cell Lines.
Haberlea rhodopensis is a Balkan endemic plant that belongs to the Gesneriaceae family, and is believed to have medicinal use and health-promoting properties. This study aimed to (i) prepare aqueous (HAE) and ethanolic (HEE) extracts from the leaves of H. rhodopensis from in vitro propagated plants, (ii) screen for their potential antiproliferative and antimigratory activities, and (iii) chemically characterize both HAE and HEE by identifying compounds which may contribute to their observed bioactivity thereby further supporting their potential use in biomedical applications. The antiproliferative activity of both extracts was assessed against six human cancer cell lines by employing the sulforhodamine-B (SRB) assay. HEE was found to be more potent in inhibiting cancer cell growth as compared to HAE. Therefore, HEE's antimigratory effects were further studied in hepatocellular carcinoma (HepG2) and non-small cell lung adenocarcinoma (A459) cell lines as they were among the most sensitive ones to its antiproliferative activity. HEE was found to exert significant antimigratory concentration-dependent effects in both cell lines assessed with the wound healing assay. Chemical characterization by UPLC-MS/MS analysis identified that HEE contains higher levels of flavonoids, phenolic compounds, pigments (chlorophyll-/-b, lycopene, and β-carotene), monoterpenoids, and condensed tannins compared to HAE, while HAE, contains higher levels of soluble protein and sugars. Furthermore, HEE demonstrated remarkable antioxidant activity evaluated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH●), 2,2-azinobis (3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS●+) and ferric reducing/antioxidant power (FRAP) assays. We have obtained comprehensive results highlighting the potential of HEE as a source of bioactive compounds with anticancer properties. Future studies should aim at identifying the chemical constituents responsible for the bioactivities observed, and focus on investigating HEE's effects, in in vivo preclinical cancer models.


A model for the time-dependent thermal distribution within an iceball surrounding a cryoprobe.
The optimal cooling parameters to maximize cell necrosis in different types of tissue have yet to be determined. However, a critical isotherm is commonly adopted by cryosurgeons as a boundary of lethality for tissue. Locating this isotherm within an iceball is problematic due to the limitations of MRI, ultrasound and CT imaging modalities. This paper describes a time-dependent two-dimensional axisymmetric model of iceball formation about a single cryoprobe and extensively compares it with experimental data. Thermal histories for several points around a CRYOprobe are predicted to high accuracy (5 degrees C maximum discrepancy). A realistic three-dimensional probe geometry is specified and cryoprobe temperature may be arbitrarily set as a function of time in the model. Three-dimensional temperature distributions within the iceball, predicted by the model at different times, are presented. Isotherm locations, as calculated with the infinite cylinder approximation, are compared with those of the model in the most appropriate region of the iceball. Infinite cylinder approximations are shown to be inaccurate when applied to this commercial probe. Adopting the infinite cylinder approximation to locate the critical isotherm is shown to lead the user to an overestimate of the volume of target tissue enclosed by this isotherm which may lead to incomplete tumour ablation.


Traditional beliefs and willingness to pay for improving a mining-polluted river in Ghana.
Pollution of water resources is a widespread challenge across the globe which requires effective policy measures. However, in many instances, state institutions are weak in addressing these problems. One then wonders what alternative management regimes can be used in place of public policies. This study examined the willingness to pay (WTP) for the improvement of the Ankobra River, a mining-polluted river in the Western Region of Ghana, using the contingent valuation method. Primary data was collected from 611 respondents from 8 communities in the Prestea-Huni Valley Municipality and were analysed using probit and interval regression models. The findings suggest that respondents were concerned about the current polluted state of the Ankobra River and traditional beliefs regarding the spiritual value of the river were still very relevant to them. Consequently, respondents with the belief that the river is an abode of gods as well as natives who believe that Ankobra River is a god were more likely to pay for the improvement of its water quality. Surprisingly, respondents who believed that the river is a god had a lower WTP. Income, natives, existence value, secondary and tertiary education also had positive significant association with WTP, older respondents were less likely to pay while respondents with bigger household sizes, and the divorced had lower WTP. The estimated mean WTP for water quality improvement of the Ankobra River is GHC 51.52 ($6.62) per annum. Local community involvement in policy decision-making regarding water resources is key.


Patterns of Social Connectedness and Psychosocial Wellbeing among African American and Caribbean Black Adolescents.
Adolescents are connected to multiple and interrelated settings (e.g., family, school), which interact to influence their development. Using the National Survey of American Life-Adolescent (NSAL-A), a nationally representative cross-sectional survey, this study examined patterns of social connection and Black adolescents' wellbeing and whether social connection-wellbeing links differed by ethnicity and gender. The sample included 1170 Black adolescents ages 13-17 (69% African American, 31% Caribbean Black, 52% female, mean age 15). Latent profile analysis was used to identify profiles of adolescent connections across family, peer, school, religion, and neighborhood settings. Four profiles of social connection emerged: unconnected, minimal connection, high family connection, and well-connected. The profiles differed in life satisfaction, self-esteem, mastery, coping, perceived stress, and depressive symptoms. The well-connected profile, characterized by connection to all five settings, had significantly higher life satisfaction, self-esteem, mastery, and coping, and lower perceived stress compared to the unconnected and minimal connection profiles and lower depressive symptoms than the unconnected profile. The well-connected profile also had better self-esteem and coping compared to the high family connection profile. The youth in the unconnected profile had significantly lower self-esteem and mastery and significantly higher depressive symptoms than the minimally connected youth. Moderation analyses showed no differences by ethnicity. However, differences by gender were observed for the association between connectedness and life satisfaction. The results support the critical need to examine connectedness across multiple settings and within group heterogeneity among Black youth to develop strategies to promote their psychosocial wellbeing.


Apple ethanol extract promotes proliferation of human adult stem cells, which involves the regenerative potential of stem cells.
Tissue regeneration using adult stem cells (ASCs) has significant potential as a novel treatment for many degenerative diseases. Previous studies have established that age negatively affects the proliferation status and differentiation potential of ASCs, suggesting a possible limitation in their potential therapeutic use. Therefore, we hypothesized that apple extract might exert beneficial effects on ASCs. The specific objectives were to investigate the proliferative effect of apple ethanol extract on human adipose tissue-derived mesenchymal stem cells (ADSCs) and human cord blood-derived mesenchymal stem cells (CB-MSCs), and identify the possible molecular mechanisms. Apple extract promoted proliferation of ADSCs and CB-MSCs as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Click-iT 5-ethynyl-2'-deoxyuridine flow cytometry assays. In addition, phosphorylation of p44/42 MAPK (ERK), mammalian target of rapamycin (mTOR), p70 S6 kinase (p70S6K), S6 ribosomal protein (S6RP), eukaryotic initiation factor (eIF) 4B and eIF4E was induced stepwise in ADSCs. Furthermore, apple extract significantly induced the production of vascular endothelial growth factor and interleukin-6 in both ADSCs and CB-MSCs. Similarly, apple extract-induced phosphorylation of the mTOR/p70S6K/S6RP/eIF4B/eIF4E pathway was blocked by pretreatment with PD98059, a specific ERK inhibitor. These results indicate that apple extract-induced proliferation of ADSCs under serum-free conditions is mediated by ERK-dependent cytokine production. Moreover, the beneficial effect of apple extract on proliferation of ASCs may overcome the limitation in therapeutic use of stem cells in tissue regeneration and maintenance of stem cell homeostasis.


Diversity, Inclusion, and Health Equity in Academic Family Medicine.
Diversity, inclusion, and health equity (DIHE) are integral to the practice of family medicine. Academic family medicine has been grappling with these issues in recent years, particularly with a focus on racism and health inequity. We studied the current state of DIHE activities in academic family medicine departments and suggest a framework for departments to become more diverse, inclusive, antiracist, and focused on health equity and racial justice. As part of a larger annual membership survey, family medicine department chairs were asked for their assessment of departmental DIHE and antioppression activities, and infrastructure and resources committed to increasing DIHE. More than 60% of family medicine department chairs participating in this study rate their departments highly in promoting DIHE and antioppression, and 66% of chairs report an institutional infrastructure that is working well. Just over half of departments or institutions have had a climate survey in the past 3 years, 47.3% of departments have a diversity officer, and 26% of departments provide protected time or resources for a diversity officer. The majority of family medicine department chairs rate their departments highly on DIHE. However, only 50% of departments have formally assessed climate in the past 3 years, fewer have diversity officers, and even fewer invest resources in their diversity officers. This disconnect should motivate academic family medicine departments to undertake formal self-assessment and implement a strategic plan that includes resource investment in DIHE, measurable outcomes, and sustainability.


Systematic reviews of chemotherapy and endocrine therapy in metastatic breast cancer.
Metastatic breast cancer is incurable but often responsive to treatment. There is little evidence-based consenus on when to use which treatments, in what combination and for how long. Systematic reviews were performed on 12 prospectively defined, clinically relevant research questions to support the development of evidence-based clinical practice guidelines. A comprehensive search of Medline from 1966 to 1996 identified over 1800 controlled trials. Eligibility and data extraction were performed independently by two blinded reviewers. Trial results were summarised by ratios of median survivals (RMS) and P -values for survival curve comparisons with meta-analysis by weighted combination of these statistics. Sixty-five publications reporting 97 treatment comparisons were included. There was moderate evidence that more rather than fewer cycles of chemotherapy improved survival (RMS:1.23, P -0.01). The evidence did not support: higher rather than lower doses of chemotherapy (or of endocrine therapy); any one class of endocrine agent over all others; multiple endocrine agents over a single agent; or, combined chemotherapy and endocrine therapy over either single modality. Only six trials assessed quality of life revealing better quality of life with more rather than fewer cycles of chemotherapy and with standard rather than lower doses of chemotherapy. These systematic reviews reveal counterintuitive evidence useful to everyday practice, in particular that more rather than fewer cycles of chemotherapy lead to better quality of life and longer survival.


Educating patients about lifestyle modifications for prostate health.
Benign prostatic hyperplasia (BPH) and other prostatic diseases share many observational and mechanistic features with cardiovascular disease. Both BPH and cardiovascular disease increase significantly with age and affect a disproportionate number of men from racial/ethnic minority populations. Pharmacotherapy and surgical options are the treatments most often discussed in the medical literature for the 2 conditions, and these treatments have demonstrated remarkable effectiveness, regardless of the severity of the condition. Obesity, lack of physical activity, dyslipidemia, diabetes mellitus, higher blood pressure, a heart-unhealthy diet, and other factors that increase the risk for cardiovascular disease also appear to be associated with increased risk for BPH. However, the potential for lifestyle changes to prevent or reduce the severity of BPH, especially as an adjunct to conventional treatments, has not received significant attention, even in recent specialty treatment guidelines. Because lifestyle changes may affect the risk for developing BPH or its progression, clinicians are in need of guidelines they can use to educate patients about the potential links between increased risk of cardiovascular disease and increased risk or greater severity of BPH. Patients need to know that a heart-healthy lifestyle is also a prostate-healthy lifestyle. This article provides educational and lifestyle recommendations that may favorably affect BPH and improve overall health in men.


Gamete adhesion molecules.
Despite the importance of fertilization for animal production, species preservation and controlling reproduction, the molecular basis underlying fertilization is not well understood. More progress has been made in mice than in other mammals, but targeted deletion of specific genes in the mouse has often yielded unexpected results. The pig is also a useful animal to study, as large numbers of pig gametes can be acquired easily. However, it appears that the pig zona pellucida proteins that bind to spermatozoa may not be homologues of ZP3, the mouse zona pellucida protein that spermatozoa bind to. Therefore, a zona pellucida receptor on spermatozoa that is important for mouse fertilization may be redundant, along with other receptors, in pig fertilization. In this review, the important steps of fertilization in pigs are discussed and the binding of pig gametes is compared with that of mouse gametes. In addition, the molecules that may be important for gamete adhesion are considered. New technical advances and creative ideas offer the opportunity to make important advances in this crucial area.


K+ transport across the lamprey erythrocyte membrane: characteristics of a Ba(2+)- and amiloride-sensitive pathway.
The characteristics of K+ transport in erythrocytes from the river lamprey (Lampetra fluviatilis) were investigated using standard radioisotope flux techniques. The cells were shown to have a ouabain-sensitive transport pathway that carried 43K+ and 86Rb+ into the cell at similar rates. Most of the ouabain-resistant 43K+ and 86Rb+ influx was via a pathway that was insensitive to cotransport inhibitors and to the replacement of extracellular Cl- or Na+. This pathway showed a strong selectivity for 43K+ over 86Rb+. It was inhibited fully by Ba2+ (I50 approximately 2.8 mumol l-1), amiloride (I50 approximately 150 mumol l-1) and ethylisopropylamiloride (I50 approximately 3.3 mumol l-1) and less effectively by quinine and by the tetraethylammonium ion. Inhibition by Ba2+ took full effect within a few minutes whereas the full inhibitory effect of amiloride took more than 1 h to develop. Experiments with the membrane potential probe [14C]tetraphenylphosphonium ion gave results consistent with the lamprey erythrocyte membrane having a Ba(2+)-sensitive K+ conductance that was significantly greater than the membrane Na+ conductance and which gave rise to a marked dependence of the membrane potential on the extracellular K+ concentration. The rate constants for Ba(2+)-sensitive 43K+ and 86Rb+ influx decreased (proportionally) with increasing extracellular K+ concentration in a manner that was consistent with the transport being via a conductive pathway. The decrease was attributed to a depolarisation of the membrane (in response to the increasing extracellular K+ concentration) and a consequent decrease in the driving force for the conductive movement of 43K+ and 86Rb+ into the cells. Ba(2+)-sensitive 86Rb+ influx increased significantly with decreasing cell volume and with increasing intracellular pH (at a constant extracellular pH) but increased only slightly with increasing extracellular pH. The pathway operated normally in the complete absence of extracellular Ca2+ but its activity decreased in cells pretreated with ionomycin and EGTA; this suggests a role for intracellular Ca2+ in the operation of the pathway.


Scanning-electron microscopy studies of 'ground substance' in the cement lines, resting lines, hypercalcified rings and reversal lines of human cortical bone.
Adult human cortical bone was decalcified and stained with Harris's hematoxylin, which has a strong affinity for cement lines, resting lines, hypercalcified rings and reversal lines. Small pieces of bone tissue containing these morphological entities were then dissected and manipulated mechanically so as to disrupt them partially. Scanning electron microscopy of these regions of interest revealed the presence of relatively large concentrations of amorphous 'ground substance' which was morphologically distinguishable from the fibrous collagen fiber bundles located in the adjoining collagen-rich lamellae. The methodology used in this study confirms the existence of the above-mentioned regions as true morphological entities and also makes possible enzymatic studies designed to identify the major biochemical components constituting the observed 'ground substance'.


Turk Talk: human-machine hybrid virtual scenarios for professional education.
This article was migrated. The article was marked as recommended. Virtual scenarios provide a means for creating rich and complex online cases for health professional students to explore. However, the response options available to the learner are usually predefined, which limits the utility of virtual patients. Using artificial intelligence or natural language processing to accommodate such flexibility is expensive and hard to design. This project description lays out an alternative approach to making virtual scenarios more adaptable and interactive. Using OpenLabyrinth, an open-source educational research platform, we modified the interface and functionality to provide a human-computer hybrid interface, where a human facilitator can interact with learners from within the online case scenario. Using a design-based research approach, we have iteratively improved our cases, workflows and scripts and interface designs. The next step is testing this new functionality in a variety of situations. This report describes the pilot implementation of this pilot project. It includes the background, rationale, objectives, learning and educational designs, and implications for software development. The costs and time required to modify the software were much lower than anticipated. Facilitators managed text input from multiple concurrent learners. Learners noted a delay while waiting for the facilitator's response, but denied becoming frustrated. The implementation and use of this new technique seems promising for training and assessment purposes related to developing effective communication skills. This report also explores the provisional implications arising from the study so far.


Comparison of the effects of synthesis methods of B, N, S, and P-doped carbon dots with high photoluminescence properties on HeLa tumor cells.
Although heteroatom doping is widely used to promote the optical properties of carbon dots for biological applications, the synthesis process still has problems such as multi-step process, complicating the setting of instrument along with uncontrolled products. In the present study, some elements such as boron, nitrogen, sulfur, and phosphor were intentionally doped into citric acid-based carbon dots by furnace- and microwave-assisted direct and simple carbonization processes. The process produced nanoparticles with an average diameter of 5-9 nm with heteroatoms (B, N, S, and P) placed on the core and surface of carbon dots. Among the doped carbon dots prepared, boron-doped carbon dots obtained by the microwave-assisted (B-CDs2) process showed the highest photoluminescence intensity with a quantum yield (QY) of about 32.96%. All obtained carbon dots exhibit good stability (at pH 6-12 and high ionic strength concentrations up to 0.5 M), whereas cytotoxicity analysis showed that all doped carbon dots are low-toxic with an average cell viability percentage above 80% up to 500 μg mL-1. It can be observed from the CLSM image of all doped carbon dots that the doping process not only increases the QY percentage, but also might accelerate the HeLa uptake on it and produce strong carbon dot emission at the cytoplasm of the cell. Thus, the proposed synthesis process is promising for high-potency bioimaging of HeLa cancer cells.


Linear Hydrocarbon Chain Growth from a Molecular Diruthenium Carbide Platform.
The formation of linear hydrocarbon chains by sequential coupling of C1 units on the metal surface is the central part of the Fischer-Tropsch (F-T) synthesis. Organometallic complexes have provided numerous models of relevant individual C-C coupling events but have failed to reproduce the complete chain lengthening sequence that transforms a linear Cn hydrocarbon chain into its Cn+1 homologue in an iterative fashion. In this work, we demonstrate stepwise growth of linear Cn hydrocarbon chains and their conversion to their Cn+1 homologues via consecutive addition of CH2 units on a molecular diruthenium carbide platform. The chain growth sequence is initiated by the formation of a μ-η1:η1-C═CH2 ligand from a C + CH2 coupling between the μ-carbido complex [(Cp*Ru)2(η-NPh)(μ-C)] (1; Cp* = η5-C5Me5) and Ph2SCH2. Then, the chain propagates via a general C═CHR + CH2 coupling and subsequent hydrogen-assisted isomerization of the resulting allene ligand μ-η1:η3-H2C═C═CHR to a higher vinylidene homologue μ-η1:η1-C═CH(CH2)R. By repeating this reaction sequence, up to C6 chains have been synthesized in a stepwise fashion. The key step of this chain homologation sequence is the selective hydrogenation of the μ-η1:η3-allene unit to the corresponding μ-alkylidene ligand. Isotope labeling and computational studies indicate that this transformation proceeds via the hydrogenation of the allene ligand to a terminal alkene form and its isomerization to the μ-alkylidene ligand facilitated by the coordinatively unsaturated diruthenium platform.


Think Big: A multinational collaboration to promote children's role as coresearchers in participatory research.
The field of participatory research with children developed largely thanks to shared learning between different cultures, places, and disciplines. However, grand narratives and power relationships in academia inherited from colonialism and imperialism can threaten to obstruct the transformative value of this approach. In this article, we present the case of Think Big, a multinational collaboration for participatory research with children that involved adult and child coresearchers from Australia, Chile, Colombia, and the United Kingdom. Our aim was to explore how this project helped build solidarities between adult researchers from different countries and disciplines. We applied a methodology of diffraction to explore the processes and outcomes of this collaboration and presented our insights using the metaphor of a tree to explain the roots (knowledges and frameworks), trunk (ongoing collaboration and communication between the teams from different countries), branches (local projects), and fruits (research outcomes) of our work. Based on our experience, we proposed that multinational collaborations for participatory research offer important opportunities for adult researchers to collaborate with children to generate more democratic knowledge about their lives and to generate more egalitarian relationships between adult researchers from different places and backgrounds. However, it is important to anticipate that multinational collaborations are more likely to be affected by social and political upheavals, and language barriers must be overcome to decentralize academia. Also, the organizations involved in these collaborations need to develop strategies that facilitate funding, ethics clearance, and international research agreements.


Increased OPG expression and impaired OPG/TRAIL ratio in the aorta of diabetic rats.
Despite accumulating evidence showing that TNF-related apoptosis inducing ligand (TRAIL) plays a role in vascular biology and that its decoy receptor osteoprotegerin (OPG) is expressed in the vessel wall, modulation of these TNF and TNF-R family members in the early phases of diabetes mellitus has not been investigated. The expression of TRAIL and of OPG was examined both at the mRNA and protein levels in control and streptozotocin (SZT)-induced diabetic rats at early time points after the induction of diabetes mellitus. No differences in the steady-state mRNA levels of TRAIL were noticed by quantitative RT-PCR among the two groups of animals. On the other hand, diabetic rats showed a rapid and significant increase of the steady-state mRNA levels of OPG in the aortic wall of diabetic animals with respect to vehicle-treated (control) animals. These findings were confirmed at the protein level by analysing the amount of TRAIL and OPG proteins in aortic lysates by either Western blot or immunohistochemistry. Thus, an abnormal elevation of the OPG/TRAIL ratio in the vessel wall characterizes the early onset of diabetes mellitus and might represent a molecular mechanism involved in the vascular dysfunction characterizing diabetes mellitus.


[Human Papilloma virus. Epidemiologic, carcinogenic, diagnostic and therapeutic aspects].
Human Papillomavirus (HPV) is the most common infection among women. Natural History of HPV infection has changed as well as diagnosis and treatment. Clinical picture is variable even with spontaneous remission. Molecular Biology for diagnosis and typification of HPV has changed its treatment. The disease can be treated according to clinical experience. Sometimes can not eradicated since just it is impossible make to disappear it from genital tract.


First description and morphology of haemal nodes in piglets (Sus scrofa domestica).
In this study, the presence of haemal nodes, previously recognised especially in ruminants, was determined for the first time in piglets. The morphology of haemal nodes located in the abdominal cavity of seven piglets was studied by gross inspection and by histological methods. Haemal nodes reddish in colour and oval or round in shape were observed on the thin branches originating from the caudal and cranial mesenteric arteries. These nodes, having connection only with blood vessels, were covered with a thin connective tissue capsule. The haemal nodes had a hilus at the entrance of which large blood vessels were seen. These blood vessels extended into the inside of the nodes through trabeculae. Afferent and efferent lymph vessels were not observed in the haemal nodes. The nodes contained many sinuses formed by reticular fibres and reticular cells and filled by red blood cells. In the haemal nodes, lymphocytic infiltration was more commonly seen than lymph follicles.


Identification of a de novo, Novel Pathogenic Variant in the Splice Region of the SOX10 Gene in an Iranian Azeri Turkish Family with Waardenburg Syndrome.
Waardenburg syndrome (WS) is an inherited heterogeneous auditory pigmentary syndrome, divided into at least four types and characterized by iris heterochromia, white forelock, prominent nasal root, dystopia canthorum, middle eyebrow hypertrichosis, and deafness. Pathogenic variants in the SOX10 gene have been reported to be involved in WS disease. Whole exome sequencing (WES) was conducted on a 24-year-old male, who originated from Iranian Azeri Turkish ethnic group, with symptoms of deafness and blue eyes from brown-eyed parents. Web-based tools including Mutation Taster, VarSome, SIFT, Human Splicing Finder (HSF), and I-TASSER, were used for bioinformatics analysis. To verify the WES findings, DNAs taken from the blood samples of all family members were subjected to PCR-Sanger sequencing. A novel heterozygous pathogenic variant, NC_000022.11 (NM_006941):c.428+1G>T, located in the second intron of the SOX10 gene and disrupting the splicing site, was identified in the proband. Sanger sequencing was applied on the proband and his parents. The results showed that the variant was a de novo pathogenic variant with an autosomal dominant inheritance pattern. Identification of a novel de novo pathogenic variant, NC_000022.11 (NM_006941):c.428+1G>T, in the second intron of the SOX10 gene with autosomal dominant inheritance pattern.


Amelioration of collagen-induced arthritis and immune-associated bone loss through signaling via estrogen receptor alpha, and not estrogen receptor beta or G protein-coupled receptor 30.
The effects of estrogen may be exerted via the nuclear estrogen receptors (ERs) ERalpha or ERbeta or via the recently proposed transmembrane estrogen receptor G protein-coupled receptor 30 (GPR-30). The purpose of this study was to elucidate the ER specificity for the ameliorating effects of estrogen on arthritis and bone loss in a model of postmenopausal rheumatoid arthritis (RA). Female DBA/1 mice underwent ovariectomy or sham operation, and type II collagen-induced arthritis was induced. Mice were treated subcutaneously 5 days/week with the specific agonists propylpyrazoletriol (PPT; for ERalpha), diarylpropionitrile (DPN; for ERbeta), G1 (for GPR-30), or with a physiologic dose of estradiol. Clinical arthritis scores were determined continuously. At termination of the study, bone mineral density (BMD) was analyzed, paws were collected for histologic assessment, serum was analyzed for cytokines and markers of bone and cartilage turnover, and bone marrow was subjected to fluorescence-activated cell sorting. Treatment with PPT as well as estradiol dramatically decreased the frequency and severity of arthritis. Furthermore, estradiol and PPT treatment resulted in preservation of bone and cartilage, as demonstrated by increased BMD and decreased serum levels of bone resorption markers and cartilage degradation markers, whereas no effect was seen after DPN or G1 treatment. In a well-established model of postmenopausal RA, ERalpha, but not ERbeta or GPR-30 signaling, was shown to ameliorate the disease and the associated development of osteoporosis. Since long-term treatment with estrogen has been associated with significant side effects, increased knowledge about the mechanisms behind the beneficial effects of estrogen is useful in the search for novel treatments of postmenopausal RA.


Snowmobile-related deaths in Ontario: a 5-year review.
To investigate the demographic characteristics and circumstances surrounding fatal snowmobile accidents in Ontario, to examine the risk factors and to observe any fatality trends over the study period. Case series. All 131 people who died accidentally while operating a snowmobile in Ontario from 1985-86 to 1989-90. Records were obtained from the chief coroner's office; registration data were obtained from the Ministry of Transportation. Although the absolute number of deaths increased each year, owing to a rapid increase in the number of registered snowmobiles, the risk of death from snowmobile accidents remained relatively constant. Deaths occurred most frequently in northeastern Ontario. Youths and men predominated among the victims. Fatal accidents occurred more often on lakes (in 66% of the cases in which this information was known) than on roads (in 26%) or trails (in 8%). Weekend fatalities predominated, and deaths occurred most often during times of suboptimal lighting (from 4 pm to 8 am). The driver was killed in 84% of the cases in which the person's role was known. Alcohol use before death was implicated in 69% of the cases, the level exceeding the Ontario legal limit in 59%. Snowmobile-related deaths result from factors that are generally avoidable. Strategies need to be instituted to reduce the rate of these events.


Functional microstates within human REM sleep: first evidence from fMRI of a thalamocortical network specific for phasic REM periods.
High thalamocortical neuronal activity characterizes both, wakefulness and rapid eye movement (REM) sleep, but apparently this network fulfills other roles than processing external information during REM sleep. To investigate thalamic and cortical reactivity during human REM sleep, we used functional magnetic resonance imaging with simultaneous polysomnographic recordings while applying acoustic stimulation. Our observations indicate two distinct functional substates within general REM sleep. Acoustic stimulation elicited a residual activation of the auditory cortex during tonic REM sleep background without rapid eye movements. By contrast, periods containing bursts of phasic activity such as rapid eye movements appear characterized by a lack of reactivity to sensory stimuli. We report a thalamocortical network including limbic and parahippocampal areas specifically active during phasic REM periods. Thus, REM sleep has to be subdivided into tonic REM sleep with residual alertness, and phasic REM sleep with the brain acting as a functionally isolated and closed intrinsic loop.


Royleanumioside--a new phytotoxic triterpenoid from Teucrium royleanum.
Royleanumioside (1), a new lupane type triterpenoid, was secluded from the CHCl3 soluble fraction of Teucrium royleanum. The structure of royleanumioside (1) was ascertained by spectral studies including 1D and 2D NMR spectroscopy and by the assessment with the reported data in literature. This new identified compound 1 was further tested for its phytotoxic activity against lettuce seedlings. Interestingly royleanumioside (1) had shown moderate phytotoxic activity.


Ordered activation of the Ig lambda locus in Abelson B cell lines.
Derivatives of the mu-producing Abelson line P8 have been analyzed for L chain gene rearrangements. Two of seven clones studied assembled their V lambda genes while growing in culture. V lambda gene rearrangements occurred only in those Abelson subclones that either were rearranging or had rearranged their recombining sequence (RS) element on both Ig kappa alleles. Our data suggest that (a) RS rearrangements are preferentially initiated in kappa- pre-B cells; and (b) the deletion or inactivation of sequences lying between J kappa and RS is a requirement for the activation of the Ig lambda locus.


A Procarcinogenic Colon Microbe Promotes Breast Tumorigenesis and Metastatic Progression and Concomitantly Activates Notch and β-Catenin Axes.
The existence of distinct breast microbiota has been recently established, but their biological impact in breast cancer remains elusive. Focusing on the shift in microbial community composition in diseased breast compared with normal breast, we identified the presence of Bacteroides fragilis in cancerous breast. Mammary gland as well as gut colonization with enterotoxigenic Bacteroides fragilis (ETBF), which secretes B. fragilis toxin (BFT), rapidly induces epithelial hyperplasia in the mammary gland. Breast cancer cells exposed to BFT exhibit "BFT memory" from the initial exposure. Intriguingly, gut or breast duct colonization with ETBF strongly induces growth and metastatic progression of tumor cells implanted in mammary ducts, in contrast to nontoxigenic Bacteroides fragilis. This work sheds light on the oncogenic impact of a procarcinogenic colon bacterium ETBF on breast cancer progression, implicates the β-catenin and Notch1 axis as its functional mediators, and proposes the concept of "BFT memory" that can have far-reaching biological implications after initial exposure to ETBF. SIGNIFICANCE: B. fragilis is an inhabitant of breast tissue, and gut or mammary duct colonization with ETBF triggers epithelial hyperplasia and augments breast cancer growth and metastasis. Short-term exposure to BFT elicits a "BFT memory" with long-term implications, functionally mediated by the β-catenin and Notch1 pathways.This article is highlighted in the In This Issue feature, p. 995.


Prognosis of bronchial artery embolization in the management of hemoptysis.
Bronchial artery embolization (BAE) is a well-accepted and widely used treatment modality for the management of massive and recurrent hemoptysis. However, few reports have previously investigated the long-term results. To investigate the prognosis of patients with hemoptysis who had undergone BAE. Twenty-two patients with hemoptysis underwent BAE. The underlying diseases included bronchiectasis in 9, aspergillosis in 3, chronic bronchitis in 2, idiopathic bronchial bleeding in 4, and other diseases in 4. The follow-up period ranged from 25 to 88 months (median 47 months). After the initial BAE, 11 of 22 (50%) patients had re-bleeding (5 patients with hemoptysis and 6 patients with minor hemosputa). Among them, 1 patient suffered from recurrent massive hemoptysis and died from airway obstruction within 1 month after BAE. In addition, 10 of these 11 (90.9%) patients experienced recurrent airway bleeding within 3 years after BAE. Recurrent cases of hemoptysis were seen in 6 of 22 patients (27.3%) within 3 years and no case recurred later than 3 years after BAE. A recurrence of hemoptysis was frequently seen in patients with either bronchiectasis or pulmonary-bronchial artery (P-B) shunt. Although BAE is an effective treatment for the immediate control of hemoptysis, 5 of the patients experienced recurrent bleeding in the long-term follow-up. It is important to follow-up such patients until 3 years after initial BAE, especially when either ectatic changes of the bronchi on a CT scan or a P-B shunt on angiographic findings are detected.


An existential function of enemyship: evidence that people attribute influence to personal and political enemies to compensate for threats to control.
Perceiving oneself as having powerful enemies, although superficially disagreeable, may serve an important psychological function. On the basis of E. Becker's (1969) existential theorizing, the authors argue that people attribute exaggerated influence to enemies as a means of compensating for perceptions of reduced control over their environment. In Study 1, individuals dispositionally low in perceived control responded to a reminder of external hazards by attributing more influence to a personal enemy. In Study 2, a situational threat to control over external hazard strengthened participants' belief in the conspiratorial power of a political enemy. Examining moderators and outcomes of this process, Study 3 showed that participants were especially likely to attribute influence over life events to an enemy when the broader social system appeared disordered, and Study 4 showed that perceiving an ambiguously powerful enemy under conditions of control threat decreased perceptions of external risk and bolstered feelings of personal control.


A mentor-protégé program for new faculty, part I: stories of protégés.
With the projected shortage of nursing faculty, formalized programs are needed to provide mentorship programs that will encourage and support faculty as they move from the role of novice to expert educator. The purpose of this qualitative study is to explore the experience of protégés participating in a mentorship program for novice faculty. An interpretive phenomenological research study was conducted to illuminate the meaning of the experiences of the protégés participating in the program. The study of the experience of protégés participating in a mentor-protégé program led to the emergence of three main themes: Creating a Meaningful Mentor-Protégé Relationship, Transitioning as a New Nurse Educator, and the Mentor-Protégé Program-Lessons Learned. Data from the study will provide insight into the meaning of receiving mentorship in the role of novice nurse educator.


[Changes in the cyclic nucleotide levels during the contraction of smooth muscles exposed to muscarinic cholinomimetics].
Intracellular levels of cyclic nucleotides AMP and GMP were measured in isolated preparations of the guinea pig ileum, taenia coli, bladder and vas deferens. The cAMP level was about ten-fold as high as the cGMP level. During cholinergic stimulation for 5-10 sec contractile response preceded the cGMP rise. Muscarinic cholinomimetics obviously increased the cGMP levels especially in vas deferens, whereas no significant changes occurred in the cAMP levels. Changes in the cGMP levels were only found during phasic tension of muscles.


Graph-distance distribution of the Boltzmann ensemble of RNA secondary structures.
Large RNA molecules are often composed of multiple functional domains whose spatial arrangement strongly influences their function. Pre-mRNA splicing, for instance, relies on the spatial proximity of the splice junctions that can be separated by very long introns. Similar effects appear in the processing of RNA virus genomes. Albeit a crude measure, the distribution of spatial distances in thermodynamic equilibrium harbors useful information on the shape of the molecule that in turn can give insights into the interplay of its functional domains. Spatial distance can be approximated by the graph-distance in RNA secondary structure. We show here that the equilibrium distribution of graph-distances between a fixed pair of nucleotides can be computed in polynomial time by means of dynamic programming. While a naïve implementation would yield recursions with a very high time complexity of O(n (6) D (5)) for sequence length n and D distinct distance values, it is possible to reduce this to O(n (4)) for practical applications in which predominantly small distances are of of interest. Further reductions, however, seem to be difficult. Therefore, we introduced sampling approaches that are much easier to implement. They are also theoretically favorable for several real-life applications, in particular since these primarily concern long-range interactions in very large RNA molecules. The graph-distance distribution can be computed using a dynamic programming approach. Although a crude approximation of reality, our initial results indicate that the graph-distance can be related to the smFRET data. The additional file and the software of our paper are available from http://www.rna.uni-jena.de/RNAgraphdist.html.


Habitat collapse due to overgrazing threatens turtle conservation in marine protected areas.
Marine protected areas (MPAs) are key tools for combatting the global overexploitation of endangered species. The prevailing paradigm is that MPAs are beneficial in helping to restore ecosystems to more 'natural' conditions. However, MPAs may have unintended negative effects when increasing densities of protected species exert destructive effects on their habitat. Here, we report on severe seagrass degradation in a decade-old MPA where hyper-abundant green turtles adopted a previously undescribed below-ground foraging strategy. By digging for and consuming rhizomes and roots, turtles create abundant bare gaps, thereby enhancing erosion and reducing seagrass regrowth. A fully parametrized model reveals that the ecosystem is approaching a tipping point, where consumption overwhelms regrowth, which could potentially lead to complete collapse of the seagrass habitat. Seagrass recovery will not ensue unless turtle density is reduced to nearly zero, eliminating the MPA's value as a turtle reserve. Our results reveal an unrecognized, yet imminent threat to MPAs, as sea turtle densities are increasing at major nesting sites and the decline of seagrass habitat forces turtles to concentrate on the remaining meadows inside reserves. This emphasizes the need for policy and management approaches that consider the interactions of protected species with their habitat.


Candida albicans cell wall proteins.
The Candida albicans cell wall maintains the structural integrity of the organism in addition to providing a physical contact interface with the environment. The major components of the cell wall are fibrillar polysaccharides and proteins. The proteins of the cell wall are the focus of this review. Three classes of proteins are present in the candidal cell wall. One group of proteins attach to the cell wall via a glycophosphatidylinositol remnant or by an alkali-labile linkage. A second group of proteins with N-terminal signal sequences but no covalent attachment sequences are secreted by the classical secretory pathway. These proteins may end up in the cell wall or in the extracellular space. The third group of proteins lack a secretory signal, and the pathway(s) by which they become associated with the surface is unknown. Potential constituents of the first two classes have been predicted from analysis of genome sequences. Experimental analyses have identified members of all three classes. Some members of each class selected for consideration of confirmed or proposed function, phenotypic analysis of a mutant, and regulation by growth conditions and transcription factors are discussed in more detail.


Capture ELISA and flow cytometry methods for toxicologic assessment following immunization and cyclophosphamide challenges in beagles.
The purpose of this subacute 22-day study was to evaluate methods for canine circulating immunoglobulins (IgM, IgG, and IgE) and select B- and T-lymphocyte populations (CD4-helpers, CD8-suppressors, pan-T and pan-B) for immunotoxicity testing using an organ system (concordance) approach. The challenge substance for immunoglobulin testing was repeated immunization with six-way distemper vaccination (DHLAPP), while the challenge substance for leukocyte subpopulations was treatment with cyclophosphamide. Immunoglobulin measurements were made by capture enzyme-linked immunosorbent assay (ELISA), and leukocyte immunophenotyping by fluorescein isothiocyanate/phycoerythrin conjugation (flow cytometry). A battery of parameters that would be used in a typical regulatory study were taken to aid interpretation of the data generated by these methods. Body weights, food consumption, clinical observations, complete clinical chemistry and urinalysis measurements were taken. Gross pathology and micropathology of sternal bone marrow, spleen, mesenteric and retropharyngeal lymph nodes, thymus, liver and kidney were completed. The ELISA method demonstrated acceptable intra-assay reproducibility for IgM, IgG and IgE, with values in good agreement as reported for radial immunodiffusion. The immunologic challenge demonstrated a biological trend of an increase in IgM that preceded an increase in IgG with no discernible trend in IgE response, and no abnormalities in lymphocyte subpopulations. Principle flow cytometry findings related to cyclophosphamide were that the relative percent of B cells decreased dramatically and progressively after compound administration; being statistically decreased in males on day 22 compared with day -5. The relative percent CD4 and CD8 contribution increased, but the CD4/CD8 ratio remained relatively unchanged as total white blood cells decreased progressively. The increase in relative percent CD4 (males only) was statistically significant according to a two-sample t-test on days 17, 20 and 22 when compared with the pre-treatment day -5. There was a relative percent increase in CD5-panT, but absolute numbers were dramatically decreased. We conclude that an organ system approach to assessment of the immune system which incorporates humoral antibody, enumeration of lymphocyte populations and pathologic evaluation of the lymphoreticular organs assists in the interpretation of an adverse toxicological response. The ELISA method for measurement of Igs detected the expected levels of IgG, IgM and IgE due to repeated vaccinations and to cyclophosphamide treatment. The flow cytometry method was acceptable for measuring select canine lymphocyte populations and detecting the expected decrease in B cells due to cyclophosphamide treatment. Both methods may be added to a testing battery for assessing immunotoxicityl in canine regulatory studies.


Deciphering Off-Target Effects in CRISPR-Cas9 through Accelerated Molecular Dynamics.
CRISPR-Cas9 is the state-of-the-art technology for editing and manipulating nucleic acids. However, the occurrence of off-target mutations can limit its applicability. Here, all-atom enhanced molecular dynamics (MD) simulations-using Gaussian accelerated MD (GaMD)-are used to decipher the mechanism of off-target binding at the molecular level. GaMD reveals that base pair mismatches in the target DNA at distal sites with respect to the protospacer adjacent motif (PAM) can induce an extended opening of the RNA:DNA heteroduplex, which leads to newly formed interactions between the unwound DNA and the L2 loop of the catalytic HNH domain. These conserved interactions constitute a "lock" effectively decreasing the conformational freedom of the HNH domain and hampering its activation for cleavage. Remarkably, depending on their positions at PAM distal sites, DNA mismatches responsible for off-target cleavages are unable to "lock" the HNH domain, thereby leading to the unselective cleavage of DNA sequences. In consistency with the available experimental data, the ability to "lock" the catalytic HNH domain in an inactive "conformational checkpoint" is shown to be a key determinant in the onset of off-target effects. This mechanistic rationale contributes in clarifying a long lasting open issue in the CRISPR-Cas9 function and poses the foundation for designing novel and more specific Cas9 variants, which could be obtained by magnifying the "locking" interactions between HNH and the target DNA in the presence of any incorrect off-target sequence, thus preventing undesired cleavages.


Placement of tRNA primer on the primer-binding site requires pol gene expression in avian but not murine retroviruses.
In an early step in the retroviral infectious process, reverse transcriptase copies the genomic RNA of the virus into complementary minus-strand DNA. The primer for this synthetic event is a molecule of cellular tRNA, which is annealed by its 3' 18 nucleotides to a region of the genomic RNA termed the primer-binding site (PBS); the sequence of the PBS and hence the identity of the tRNA depend upon the retrovirus species. In addition to the primer tRNA, retrovirus particles contain a substantial number of other tRNA molecules. The latter tRNA population is enriched for the tRNA species which serves as primer for the virus. While there is considerable evidence that the enrichment for the primer species can be attributed to the pol gene product, nothing is known regarding mechanisms of annealing the primer to the PBS. We have analyzed pol- mutants of avian leukosis virus (ALV) and murine leukemia virus (MuLV) for the presence of primer at the PBS in virion genomic RNA. Remarkably, the results were different for the two viruses: the PBS was substantially occupied by primer in MuLV but not in ALV. Previous data indicates that the Pol-dependent enrichment of the primer within the virion is much greater in ALV than in MuLV. We therefore propose that the absence of primer at the PBS in pol- ALV is due to the deficiency of the primer species within the particle. The results suggest that, at least in MuLV, the tRNA is unwound by either the Gag protein or a cellular protein for annealing to the PBS. Further, the C-terminal 17 amino acids of Gag are unnecessary for this function in MuLV.


Stimulation of functional neuronal regeneration from Müller glia in adult mice.
Many retinal diseases lead to the loss of retinal neurons and cause visual impairment. The adult mammalian retina has little capacity for regeneration. By contrast, teleost fish functionally regenerate their retina following injury, and Müller glia (MG) are the source of regenerated neurons. The proneural transcription factor Ascl1 is upregulated in MG after retinal damage in zebrafish and is necessary for regeneration. Although Ascl1 is not expressed in mammalian MG after injury, forced expression of Ascl1 in mouse MG induces a neurogenic state in vitro and in vivo after NMDA (N-methyl-d-aspartate) damage in young mice. However, by postnatal day 16, mouse MG lose neurogenic capacity, despite Ascl1 overexpression. Loss of neurogenic capacity in mature MG is accompanied by reduced chromatin accessibility, suggesting that epigenetic factors limit regeneration. Here we show that MG-specific overexpression of Ascl1, together with a histone deacetylase inhibitor, enables adult mice to generate neurons from MG after retinal injury. The MG-derived neurons express markers of inner retinal neurons, synapse with host retinal neurons, and respond to light. Using an assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), we show that the histone deacetylase inhibitor promotes accessibility at key gene loci in the MG, and allows more effective reprogramming. Our results thus provide a new approach for the treatment of blinding retinal diseases.


Effectiveness and safety of procalcitonin-guided antibiotic therapy in lower respiratory tract infections in "real life": an international, multicenter poststudy survey (ProREAL).
In controlled studies, procalcitonin (PCT) has safely and effectively reduced antibiotic drug use for lower respiratory tract infections (LRTIs). However, controlled trial data may not reflect real life. We performed an observational quality surveillance in 14 centers in Switzerland, France, and the United States. Consecutive adults with LRTI presenting to emergency departments or outpatient offices were enrolled and registered on a website, which provided a previously published PCT algorithm for antibiotic guidance. The primary end point was duration of antibiotic therapy within 30 days. Of 1759 patients, 86.4% had a final diagnosis of LRTI (community-acquired pneumonia, 53.7%; acute exacerbation of chronic obstructive pulmonary disease, 17.1%; and bronchitis, 14.4%). Algorithm compliance overall was 68.2%, with differences between diagnoses (bronchitis, 81.0%; AECOPD, 70.1%; and community-acquired pneumonia, 63.7%; P < .001), outpatients (86.1%) and inpatients (65.9%) (P < .001), algorithm-experienced (82.5%) and algorithm-naive (60.1%) centers (P < .001), and countries (Switzerland, 75.8%; France, 73.5%; and the United States, 33.5%; P < .001). After multivariate adjustment, antibiotic therapy duration was significantly shorter if the PCT algorithm was followed compared with when it was overruled (5.9 vs 7.4 days; difference, -1.51 days; 95% CI, -2.04 to -0.98; P < .001). No increase was noted in the risk of the combined adverse outcome end point within 30 days of follow-up when the PCT algorithm was followed regarding withholding antibiotics on hospital admission (adjusted odds ratio, 0.83; 95% CI, 0.44 to 1.55; P = .56) and regarding early cessation of antibiotics (adjusted odds ratio, 0.61; 95% CI, 0.36 to 1.04; P = .07). This study validates previous results from controlled trials in real-life conditions and demonstrates that following a PCT algorithm effectively reduces antibiotic use without increasing the risk of complications. Preexisting differences in antibiotic prescribing affect compliance with antibiotic stewardship efforts. isrctn.org Identifier: ISRCTN40854211.


Differentiation of pyogenic from amebic hepatic abscesses.
Recent immigration trends have resulted in an increased prevalence of amebic hepatic abscesses in southern states and in many northern American cities. Because amebic hepatic abscesses generally do not require drainage, differentiation from pyogenic hepatic abscesses is important. We, therefore, reviewed the records of patients admitted to the UCLA Medical Center from 1968 through 1983 to compare the clinical manifestations and to access the results of treatment of pyogenic and amebic hepatic abscesses. During this 15 year period, 82 patients (42 pyogenic and 40 amebic) with hepatic abscesses were admitted. Factors which distinguished patients with pyogenic abscesses included: age greater than 50 years; jaundice; pruritus; sepsis and shock; a palpable mass; elevated bilirubin level; elevated alkaline phosphatase level, and abnormal abdominal roentgenograms. Patients with amebic abscesses of the liver were more likely to have Mexican ancestry, recently traveled to an endemic area, abdominal pain, diarrhea, abdominal tenderness, hepatomegaly and positive amebic serology. Hepatic scans and ultrasonography were excellent methods of detecting the presence of but not the type of hepatic abscess. Over-all, the mortality was 40 per cent for patients with pyogenic abscesses whereas all 40 of the patients with an amebic abscess survived. However, operative mortality was only 4.5 per cent for the 22 patients with pyogenic abscess who were managed with systemic antibiotics and surgical drainage. We conclude that many clinical and laboratory parameters can aid in the differentiation and, as a result, management of patients with pyogenic and amebic hepatic abscesses.


Therapeutic targeting of argininosuccinate synthase 1 (ASS1)-deficient pulmonary fibrosis.
Argininosuccinate synthase 1 (ASS1) serves as a critical enzyme in arginine biosynthesis; however, its role in interstitial lung diseases, particularly idiopathic pulmonary fibrosis (IPF), remains largely unknown. This study aims at characterization and targeting of ASS1 deficiency in pulmonary fibrosis. We find that ASS1 was significantly decreased and inversely correlated with fibrotic status. Transcriptional downregulation of ASS1 was noted in fibroblastic foci of primary lung fibroblasts isolated from IPF patients. Genetic manipulations of ASS1 studies confirm that ASS1 expression inhibited fibroblast cell proliferation, migration, and invasion. We further show that the hepatocyte growth factor receptor (Met) receptor was activated and acted upstream of the Src-STAT3 axis signaling in ASS1-knockdown fibroblasts. Interestingly, both arginine-free conditions and arginine deiminase treatment were demonstrated to kill fibrotic fibroblasts, attenuated bleomycin-induced pulmonary fibrosis in mice, as well as synergistically increased nintedanib efficacy. Our data suggest ASS1 deficiency as a druggable target and also provide a unique therapeutic strategy against pulmonary fibrosis.


GLC determination of 17 alpha-ethynylestriol 3-cyclopentyl ether.
A rapid, sensitive, and accurate GLC method of analysis of a new estrogenic drug, 17 alpha-ethynylestriol 3-cyclopentyl ether, was developed. The drug and the internal standard, tetratriacontane, are dissolved in chloroform, and an aliquot is heated with N-trimethylsilylimidazole at 80 degrees for 30 min. The silylated sample is chromatographed using a column packed with 1% methyl vinyl silicone gum on Gas Chrom Q. Quantitation is achieved by computer calculation of the peak area ratios. The observed peak is the 16alpha,17beta-bistrimethylsilyl derivative of the new drug substance. The GLC method was applied to the quantitative determination of the estrogenic compound in a tablet formulation containing 25 mug/tablet.


Effects of pretreatment with spironolactone of pharmacokinetics of 4'''-methyldigoxin in man.
Pharmacokinetics of 3H-4''' -methyldigoxin (md) were studied in three paired experiments with and without pretreatment with spironolactone (7 mg/kg/day for 7 days) and in one additional test person after pretreatment only. The results were compared with controls after oral (n equals 6) and intravenous (n equals 6) administration of md. In addition the biliary excretion of md and its metabolites was investigated in biliary fistula patients with and without pretreatment with spironolactone. After pretreatment of normal persons maximum plasma levels of tritium were approximately 35% lower and they were reached on average 60 min after oral administration as compared with approximately 15 min without pretreatment. Already 12 hrs after oral administration the plasma concentrations, with and without pretreatment, no longer differed and the biological half lives of radioactivity in plasma were equal. With or without pretreatment, the cumulative excretion of tritium in urine and faeces was nearly identical in the paired experiments within 7 days. It was in the range of the controls which eliminated 55.2 +/- 2.8 and 28.6 +/- 5.7% of the dose in urine and faeces, respectively, after oral, and 62.2 +/- 2.1 and 28.9 +/- 5.2%, respectively, after i.v. administration. Accordingly after pretreatment the radioactivity excreted in bile within 48 hrs (14.9% of the dose) did not differ from controls. Examination of the composition of labelled compounds excreted in urine and bile revealed no significant alterations in the metabolic degradation of md under the influence of spironolactone. Thus the profound effects of spironolactone upon pharmacokinetics of md previously observed in rats are without any significance for human conditions.


A randomized, double-blind phase 2 study comparing the efficacy and safety of an oral fusidic acid loading-dose regimen to oral linezolid for the treatment of acute bacterial skin and skin structure infections.
Fusidic acid (CEM-102), an orally bioavailable fusidane antibiotic with a unique mode of action, is under development for treatment of acute gram-positive bacterial skin and skin structure infections, including those caused by methicillin-susceptible and methicillin-resistant Staphylococcus aureus and streptococci. A phase 2, adaptive design, randomized, double-blind, multiple-center study of 198 adult patients with cellulitis or wound infections was conducted to evaluate an oral CEM-102 loading-dose regimen (1500 mg twice per day on day 1 followed by 600 mg twice per day) compared with oral linezolid (600 mg twice per day) administered for 10-14 days. The CEM-102 loading-dose regimen demonstrated efficacy, safety, and tolerability that was comparable to linezolid for the treatment of acute gram-positive bacterial skin and skin structure infections. Clinical Trials registration. NCT00948142.


Modulation of MicroRNA-194 and cell migration by HER2-targeting trastuzumab in breast cancer.
Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER2 oncoprotein, can effectively target HER2-positive breast cancer through several mechanisms. Although the effects of trastuzumab on cancer cell proliferation, angiogenesis and apoptosis have been investigated in depth, the effect of trastuzumab on microRNA (miRNA) has not been extensively studied. We have performed miRNA microarray profiling before and after trastuzumab treatment in SKBr3 and BT474 human breast cancer cells that overexpress HER2. We found that trastuzumab treatment of SKBr3 cells significantly decreased five miRNAs and increased three others, whereas treatment of BT474 cells significantly decreased two miRNAs and increased nine. The only change in miRNA expression observed in both cell lines following trastuzumab treatment was upregulation of miRNA-194 (miR-194) that was further validated in vitro and in vivo. Forced expression of miR-194 in breast cancer cells that overexpress HER2 produced no effect on apoptosis, modest inhibition of proliferation, significant inhibition of cell migration/invasion in vitro and significant inhibition of xenograft growth in vivo. Conversely, knockdown of miR-194 promoted cell migration. Increased miR-194 expression markedly reduced levels of the cytoskeletal protein talin2 and specifically inhibited luciferase reporter activity of a talin2 wild-type 3'-untranslated region, but not that of a mutant reporter, indicating that talin2 is a direct downstream target of miR-194. Trastuzumab treatment inhibited breast cancer cell migration and reduced talin2 expression in vitro and in vivo. Knockdown of talin2 inhibited cell migration/invasion. Knockdown of trastuzumab-induced miR-194 expression with a miR-194 inhibitor compromised trastuzumab-inhibited cell migration in HER2-overexpressing breast cancer cells. Consequently, trastuzumab treatment upregulates miR-194 expression and may exert its cell migration-inhibitory effect through miR-194-mediated downregulation of cytoskeleton protein talin2 in HER2-overexpressing human breast cancer cells.


Flocculation gene variability in industrial brewer's yeast strains.
The brewer's yeast genome encodes a 'Flo' flocculin family responsible for flocculation. Controlled floc formation or flocculation at the end of fermentation is of great importance in the brewing industry since it is a cost-effective and environmental-friendly technique to separate yeast cells from the final beer. FLO genes have the notable capacity to evolve and diverge many times faster than other genes. In actual practice, this genetic variability may directly alter the flocculin structure, which in turn may affect the flocculation onset and/or strength in an uncontrolled manner. Here, 16 ale and lager yeast strains from different breweries, one laboratory Saccharomyces cerevisiae and one reference Saccharomyces pastorianus strain, with divergent flocculation strengths, were selected and screened for characteristic FLO gene sequences. Most of the strains could be distinguished by a typical pattern of these FLO gene markers. The FLO1 and FLO10 markers were only present in five out of the 18 yeast strains, while the FLO9 marker was ubiquitous in all the tested strains. Surprisingly, three strongly flocculating ale yeast strains in this screening also share a typical 'lager' yeast FLO gene marker. Further analysis revealed that a complete Lg-FLO1 allele was present in these ale yeasts. Taken together, this explicit genetic variation between flocculation genes hampers attempts to understand and control the flocculation behavior in industrial brewer's yeasts.


[Sensitivity spectrum of Francisella tularensis to antibiotics and synthetic antibacterial drugs].
Sensitivity of 6 F. tularensis strains to 57 antibiotics and synthetic antibacterial drugs was studied. It was shown that the strains were highly sensitive to aminoglycosides, tetracyclines, anzamycins, quinolones, chloramphenicol, nitrofurantoin, nitroxoline, novobiocin and fusidin and resistant to penicillins, cephalosporins, polypeptides, vancomycin and sulfanylamides. The interrace differences in F. tularensis could be detected only by sensitivity to erythromycin, oleandomycin and spiramycin. There was observed no cross resistance to streptomycin and other aminoglycosides in F. tularensis. Assay of F. tularensis sensitivity to antibacterial drugs of various groups with the rapid photometric procedure and the agar diffusion method revealed that the results were highly comparable.


Possible role of calcium in parathyroid hormone actions in rabbit renal proximal tubules.
Using a glucose microassay and in vitro isolated renal tubule perfusion technique, we have studied the actions of parathyroid hormone (PTH) on gluconeogenesis (GNG) and fluid (Jv) and phosphate (Jp) transport rates in isolated rabbit renal proximal tubules. In proximal straight tubules (PST), PTH stimulated GNG and inhibited Jv and Jp. In proximal convoluted tubules (PCT), PTH inhibited Jv but failed to affect GNG and Jp. An increase in Ca concentration, however, stimulated GNG and allowed PTH to inhibit Jp in PCT. Addition of the intracellular Ca antagonists trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) abolished the inhibitory effects of PTH on Jv and Jp in both PCT and PST. In conclusion, these studies suggest that Ca-dependent intracellular pathways may be involved in the actions of PTH in rabbit renal proximal tubules. The altered response to PTH in rabbit PCT may be due to alterations in the response of intracellular Ca to the hormone.


Dietary energy restriction reduces high-fat diet-enhanced metastasis of Lewis lung carcinoma in mice.
The objective of this study was to determine whether a reduction in energy intake ameliorated the high-fat diet-enhanced spontaneous metastasis of Lewis lung carcinoma in mice. Male C57BL/6 mice were fed the AIN93G diet, a high-fat diet or a high-fat diet with a 5% restriction of the intake. Energy restriction reduced body adiposity and body weight, but maintained growth similar to mice fed the AIN93G diet. The high-fat diet significantly increased the number and size (cross-sectional area and volume) of metastases formed in lungs. Restricted feeding reduced the number of metastases by 23%, metastatic cross-sectional area by 32% and volume by 45% compared to the high-fat diet. The high-fat diet elevated plasma concentrations of proinflammatory cytokines (monocyte chemotactic protein-1, plasminogen activator inhibitor-1, leptin), angiogenic factors (vascular endothelial growth factor, tissue inhibitor of metalloproteinase-1) and insulin. Restricted feeding significantly reduced the high-fat diet-induced elevations in plasma concentrations of proinflammatory cytokines, angiogenic factors and insulin. These results demonstrated that a reduction in diet intake by 5% reduced high-fat diet-enhanced metastasis, which may be associated with the mitigation of adiposity and down-regulation of cancer-promoting proinflammatory cytokines and angiogenic factors.


Are the children of fathers whose jobs involve contact with many people at an increased risk of leukaemia?
To investigate the hypothesis that children of men whose jobs involve contact with many people (particularly children) are at an increased risk of leukaemia. A population based dataset obtained from routinely collected death certificates involving 14,168 cancer deaths occurring before the age of 15 years registered in England and Wales between 1959-63 and 1970-90. Associations were assessed with the proportional cancer mortality ratio (PCMR), with all childhood cancer deaths forming the standard for comparison. The PCMRs were adjusted, by stratification, for age and year of death (in 1-year bands) and paternal social class (nine categories). Analyses were performed by estimated level of paternal occupational social contact (high, medium, and low) for all leukaemias, leukaemia subtype, age at death, year of death, and individual occupation. Out of 223 occupations, 36 (16%) were identified as having potentially high levels of social contact, and 27 (12%) as having potentially medium levels of social contact. No associations were found between paternal occupational social contact and death during childhood from leukaemia (high social contact: PCMR 94, 95% confidence interval (95% CI) 87 to 102; medium social contact: 101, 95 to 106). No associations were found when the data were analysed by leukaemia subtype, age at death, year of death, or individual occupation. The findings presented here do not support the suggestion that childhood leukaemia is related to the amount of social contact that fathers experience at work.


Effect of resistance training and aerobic conditioning on muscular strength and submaximal fitness for individuals with chronic heart failure: influence of age and gender.
The hallmark characteristic of chronic heart failure (CHF) is exercise intolerance. This study evaluated a combined exercise program that would be consistent with current cardiac rehabilitation guidelines. The program consisted of progressive resistance training (intensity progressing from 50 to 80% maximum) and aerobic conditioning (70% of heart rate reserve). Outcomes included muscular strength measured as 8-repetition maximum and submaximal aerobic fitness indicators (measured at 50% of predicted maximal oxygen consumption) including heart rate, blood pressure, and rate pressure product. Subjects were taken retrospectively from a database of CHF patients who underwent cardiac rehabilitation between 1998 and 2004 with the Cardiac Rehabilitation Center of River Cities Cardiology in Jeffersonville, IN. The same data set was used to evaluate 2 research questions: to compare training outcomes between gender (men and women) and to compare outcomes between young (<or=65 years) and old (>65 years) subjects. Forty-two subjects (15 women and 27 men; 19 were <or=65 and 23 were >65 years of age) met inclusion and exclusion criteria and underwent 36 sessions of cardiac rehabilitation over a 14-week time period. Repeated-measures analysis of variance was used to test whether strength and submaximal responses differed across gender or age. Analysis indicated that regardless of gender or age, subjects significantly increased their strength on each of 6 strength tests. Heart rate, systolic blood pressure, and rate pressure product were lower after training indicating increased aerobic efficiency. Progressive resistance training and aerobic conditioning prescribed in a manner consistent with cardiac rehabilitation guidelines resulted in similar improvements regardless of gender or age for individuals with CHF suggesting that no training program adjustments are necessary to accommodate age or gender.


Faecal immunochemical tests (FIT) versus colonoscopy for surveillance after screening and polypectomy: a diagnostic accuracy and cost-effectiveness study.
The English Bowel Cancer Screening Programme (BCSP) recommends 3 yearly colonoscopy surveillance for patients at intermediate risk of colorectal cancer (CRC) postpolypectomy (those with three to four small adenomas or one ≥10 mm). We investigated whether faecal immunochemical tests (FITs) could reduce surveillance burden on patients and endoscopy services. Intermediate-risk patients (60-72 years) recommended 3 yearly surveillance were recruited within the BCSP (January 2012-December 2013). FITs were offered at 1, 2 and 3 years postpolypectomy. Invitees consenting and returning a year 1 FIT were included. Participants testing positive (haemoglobin ≥40 µg/g) at years one or two were offered colonoscopy early; all others were offered colonoscopy at 3 years. Diagnostic accuracy for CRC and advanced adenomas (AAs) was estimated considering multiple tests and thresholds. We calculated incremental costs per additional AA and CRC detected by colonoscopy versus FIT surveillance. 74% (5938/8009) of invitees were included in our study having participated at year 1. Of these, 97% returned FITs at years 2 and 3. Three-year cumulative positivity was 13% at the 40 µg/g haemoglobin threshold and 29% at 10 µg/g. 29 participants were diagnosed with CRC and 446 with AAs. Three-year programme sensitivities for CRC and AAs were, respectively, 59% and 33% at 40 µg/g, and 72% and 57% at 10 µg/g. Incremental costs per additional AA and CRC detected by colonoscopy versus FIT (40 µg/g) surveillance were £7354 and £180 778, respectively. Replacing 3 yearly colonoscopy surveillance in intermediate-risk patients with annual FIT could reduce colonoscopies by 71%, significantly cut costs but could miss 30%-40% of CRCs and 40%-70% of AAs. ISRCTN18040196; Results.


White-light channeled imaging polarimeter using broadband polarization gratings.
A white-light snapshot channeled linear imaging (CLI) polarimeter is demonstrated by utilizing polarization gratings (PGs). The CLI polarimeter is capable of measuring the two-dimensional distribution of the linear Stokes polarization parameters by incorporating two identical PGs, in series, along the optical axis. In this configuration, the general optical shearing functionality of a uniaxial crystal-based Savart plate is realized. However, unlike a Savart plate, the diffractive nature of the PGs creates a linear dependence of the shear versus wavelength, thus providing broadband functionality. Consequently, by incorporating the PG-based Savart plate into a Savart plate channeled imaging polarimeter, white-light interference fringes can be generated. This enables polarimetric image data to be acquired at shorter exposure times in daylight conditions, making it more appealing over the quasi-monochromatic channeled imaging polarimeters previously described in the literature. Furthermore, the PG-based device offers significantly more compactness, field of view, optical simplicity, and vibration insensitivity than previously described white-light CLI polarimeters based on Sagnac interferometers. Included in this paper are theoretical descriptions of the linear (S(0), S(1), and S(2)) and complete (S(0), S(1), S(2), and S(3)) channeled Stokes imaging polarimeters. Additionally, descriptions of our calibration procedures and our experimental proof of concept CLI system are provided. These are followed by laboratory and outdoor polarimetric measurements of S(0), S(1), and S(2).