Cytoprotection and immunomodulation in cancer therapy.
Bioprospecting and natural products drug development for cancer treatment has become an important area. Most of the cancer chemotherapeutic agents are associated with toxicity towards normal cells and tissues. Optimal dosing of cancer chemotherapeutic agents is often limited because of severe non-myelosuppressive and myelosuppressive toxicities. It is a continuing challenge to design therapy that is safer, effective and selective. Cytoprotective agents offer opportunities to reduce treatment related toxicity of anticancer therapy without diminution of efficacy. None of the available agents satisfy criteria for an ideal cytoprotection. This has stimulated research for discovering natural resources with immunomodulatory and cytoprotective activities. This article describes chemical agents presently employed in clinical practice and reviews ethnopharmacological agents reported to have chemoprotective, radioprotective, immunomodulating, adaptogenic and antitumour activities.


Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial.
The optimal duration of dual-antiplatelet therapy and the risk-benefit ratio for long-term dual-antiplatelet therapy after coronary stenting remain poorly defined. We evaluated the impact of up to 6 versus 24 months of dual-antiplatelet therapy in a broad all-comers patient population receiving a balanced proportion of Food and Drug Administration-approved drug-eluting or bare-metal stents. We randomly assigned 2013 patients to receive bare-metal, zotarolimus-eluting, paclitaxel-eluting, or everolimus-eluting stent implantation. At 30 days, patients in each stent group were randomly allocated to receive up to 6 or 24 months of clopidogrel therapy in addition to aspirin. The primary end point was a composite of death of any cause, myocardial infarction, or cerebrovascular accident. The cumulative risk of the primary outcome at 2 years was 10.1% with 24-month dual-antiplatelet therapy compared with 10.0% with 6-month dual-antiplatelet therapy (hazard ratio, 0.98; 95% confidence interval, 0.74-1.29; P=0.91). The individual risks of death, myocardial infarction, cerebrovascular accident, or stent thrombosis did not differ between the study groups; however, there was a consistently greater risk of hemorrhage in the 24-month clopidogrel group according to all prespecified bleeding definitions, including the recently proposed Bleeding Academic Research Consortium classification. A regimen of 24 months of clopidogrel therapy in patients who had received a balanced mixture of drug-eluting or bare-metal stents was not significantly more effective than a 6-month clopidogrel regimen in reducing the composite of death due to any cause, myocardial infarction, or cerebrovascular accident. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00611286.


A Ferroxidase, Cfo1, Regulates Diverse Environmental Stress Responses of Cryptococcus neoformans through the HOG Pathway.
The iron uptake and utilization pathways play a critical role in allowing human pathogens, including Cryptococcus neoformans, the causative agent of fatal meningoencephalitis, to survive within the mammalian body by competing with the host for iron. Here we show that the iron regulon is also required for diverse environmental stress responses and that in C. neoformans, it is regulated by the high-osmolarity glycerol response (HOG) pathway. Between CFO1 and CFO2, two ferroxidase genes in the iron regulon, CFO1 but not CFO2 was induced during oxidative and osmotic stress. Interestingly, we found that the HOG pathway repressed basal expression of both CFO1 and CFO2. Furthermore, when the HOG pathway was blocked, CFO2 also responded to oxidative and osmotic stress and the response of CFO1 was increased. We also established that CFO1 plays a major role in responding and adapting to diverse environmental stresses, including oxidative and genotoxic damage, osmotic fluctuations, heavy metal stress, and stress induced by cell membrane destabilizers. Therefore, our findings indicate that in C. neoformans, the iron uptake and utilization pathways are not only required for iron acquisition and survival, but also play a significant role in the environmental stress response through crosstalk with the HOG pathway.


Synergistic activity of combinations of recombinant human alpha interferon and acyclovir, administered concomitantly and in sequence, against a lethal herpes simplex virus type 1 infection in mice.
The nucleoside analog acyclovir [9-(2-hydroxyethoxymethyl)guanine] and the hybrid recombinant human alpha interferon (rHuIFN-alpha A/D) were evaluated in weanling mice for their efficacy alone and in combination against a lethal systemic infection with herpes simplex virus type 1. Simultaneous parenteral treatment with combinations of both agents at various doses resulted in a higher percentage of survival than when either agent was administered alone, with a synergistic interaction demonstrated at certain dose combinations. Sequential administration of parenteral rHuIFN-alpha A/D and oral acyclovir, administered by gavage or supplied ad libitum in drinking water, resulted in a synergistic interaction at all dose combinations tested. These results suggest that combinations of interferon and acyclovir may be useful in treating primary herpes simplex virus infections in humans.


Resource implications of robotic thoracic surgery: what are the wider issues?
The benefits of minimally invasive thoracic surgery are well documented when compared to the use of standard thoracotomy. Much controversy exists, however, regarding the resource implications when using robot-assisted thoracic surgery (RATS), especially when compared to video-assisted thoracoscopic surgery (VATS). Much of the costs attributed to a particular approach center around the frequency and severity of the complications that may arise. Little exists in the literature to appropriately compare and contrast the complication rate following either of the minimally invasive approaches. There is a suggestion that many conventional open surgeons are more readily persuaded to adopt a minimally invasive approach through the use of the robotic platform, therefore reducing the complication-related costs of standard thoracotomy by an increase in minimally invasive resection rates. Further gains may be made in the ability to perform more complex minimally invasive procedures via a RATS approach without recourse to open conversion when compared to VATS. As opportunities and competition increase in the commercial market place, it is reasonable to assume costs will fall and further savings will be made.


Attentional and working memory performance following alcohol and energy drink: A randomised, double-blind, placebo-controlled, factorial design laboratory study.
Alcohol mixed with energy drinks (AMED) studies have typically not shown antagonism of acute alcohol effects by energy drink (ED), particularly over relatively short time frames. This study investigated the effects of alcohol, ED, and AMED on attentional and working memory processes over a 3 h period. Twenty-four young adults took part in a randomised, double-blind, placebo-controlled, factorial, 4-arm study. They were administered 0.6g/kg alcohol and 250 ml ED (containing 80 mg caffeine), and matching placebos alone and in combination. A battery of attentional and working memory measures was completed at baseline then 45, 90 and 180 min post-treatment. Alcohol produced a characteristic shift in speed/accuracy trade-off, having little effect on reaction times while increasing errors on all attentional measures (4-choice Reaction Time, Number Pairs and Visual Search), as well as a composite Attentional error score and one working memory task (Serial Sevens). ED alone improved two working memory measures (Memory Scanning accuracy and Digit-Symbol reaction times) and improved speed of responding on a composite Working Memory score. There was no consistent pattern of AMED vs. alcohol effects; AMED produced more errors than alcohol alone on one attentional measure (Visual Search errors) at 45 min only whereas AMED resulted in fewer errors on the Serial Sevens task at 90 min and better Digit-Symbol accuracy and reaction time at 45 min. Alcohol consumption increases error rate across several attentional and working memory processes. Mutual antagonism between alcohol and ED showed no consistent pattern and likely reflects a complex interaction between caffeine and alcohol levels, phase of the blood alcohol limb, task domain and cognitive load.


Thermal treatment and leaching of biochar alleviates plant growth inhibition from mobile organic compounds.
Recent meta-analyses of plant responses to biochar boast positive average effects of between 10 and 40%. Plant responses, however, vary greatly across systems, and null or negative biochar effects are increasingly reported. The mechanisms responsible for such responses remain unclear. In a glasshouse experiment we tested the effects of three forestry residue wood biochars, applied at five dosages (0, 5, 10, 20, and 50 t/ha) to a temperate forest drystic cambisol as direct surface applications and as complete soil mixes on the herbaceous pioneers Lolium multiflorum and Trifolium repens. Null and negative effects of biochar on growth were found in most cases. One potential cause for null and negative plant responses to biochar is plant exposure to mobile compounds produced during pyrolysis that leach or evolve following additions of biochars to soil. In a second glasshouse experiment we examined the effects of simple leaching and heating techniques to ameliorate potentially phytotoxic effects of volatile and leachable compounds released from biochar. We used Solid Phase Microextraction (SPME)-gas chromatography-mass spectrometry (GC-MS) to qualitatively describe organic compounds in both biochar (through headspace extraction), and in the water leachates (through direct injection). Convection heating and water leaching of biochar prior to application alleviated growth inhibition. Additionally, growth was inhibited when filtrate from water-leached biochar was applied following germination. SPME-GC-MS detected primarily short-chained carboxylic acids and phenolics in both the leachates and solid chars, with relatively high concentrations of several known phytotoxic compounds including acetic acid, butyric acid, 2,4-di-tert-butylphenol and benzoic acid. We speculate that variable plant responses to phytotoxic organic compounds leached from biochars may largely explain negative plant growth responses and also account for strongly species-specific patterns of plant responses to biochar amendments in short-term experiments.


Microwave fixation versus formalin fixation of surgical and autopsy tissue.
Microwave irradiation of surgical and autopsy tissue penetrates, fixes, and hardens the tissue almost immediately (the fluid media used in the microwave consisted of saline, ten percent phosphate buffered formalin, and distilled water). Tissue sections from a representative sample of organs were tested. Comparable sections were simultaneously fixed in a phosphate buffered ten percent formalin bath in a vaccum oven as a control. Hematoxylin and eosin were used to stain the sections. Results equal to and superior to the control method were obtained. Saline microwave fixation was superior to formalin microwave fixation. Tissues placed in Zenker's solution and fixed in standard microwave oven (for approximately one minute) yielded results at least equal to conventional Zenker fixation (approximately two hours). No tissue hardening resulted from Zenker microwave fixation. A unique time versus temperature graph (microwave heating curve) reduces individual variation with this technique.


Development of a tissue viability nursing competency framework.
In 1999, a sub-group of the National Association for Tissue Viability Nurse Specialists (Scotland) agreed to lead the production of a competency framework. The aims were to define tissue viability specialist nursing, to provide a framework for tissue viability nurse specialists (TVNSs) that would form a basis for clinical supervision and mentorship, and to inform curricular for tissue viability education. Using a combination of models, a framework evolved which defines the multifaceted nature of the role. The framework lists competencies, which are further broken down into specific role elements, matched with measurable performance criteria for the TVNS. The competency statements that are provided within the publication describe the attitude, knowledge and skills required to fulfil the TVNS role. The document, 'A Route to Enhanced Competence for Tissue Viability Nurse Specialists', was published in June 2002. This initiative meets the national need for definition of specialist practice and provides a standard by which the public can be assured of quality care from TVNSs in Scotland.


Impact of selective media for detecting fluoroquinolone-insusceptible/extended-spectrum beta-lactamase-producing Escherichia coli before transrectal prostate biopsy.
To investigate the prevalence of fluoroquinolone-insusceptible and/or extended-spectrum beta-lactamase-producing Escherichia coli colonizing in the male rectum before transrectal prostate biopsy. We carried out a prospective cohort study of men undergoing transrectal prostate biopsy. CHROMagar Orientation originally supplemented with levofloxacin and CHROMagar Orientation/extended-spectrum beta-lactamase were used for detecting fluoroquinolone-insusceptible and extended-spectrum beta-lactamase-producing Escherichia coli. Rectal specimens were collected before prostate biopsy, and the results of cultures in the selective medium were compared with drug susceptibility measured by standard methods. Targeted prophylactic antimicrobials were administered to patients with drug-resistant Escherichia coli and the incidence of postoperative prostatitis was investigated. In the case of prostatitis, pathogens preoperatively isolated from the rectum and those from urine were compared using pulsed-field gel electrophoresis. Rectal colonization of fluoroquinolone-insusceptible or extended-spectrum beta-lactamase-producing Escherichia coli was detected in 217 of 694 (31.3%) and 85 of 640 (13.3%) participants, respectively. The sensitivity and specificity of fluoroquinolone-insusceptible selective media were 96.8% and 88.2%, respectively. A total of 618 participants underwent transrectal prostate biopsy, and postoperative acute prostatitis was observed in four of 618 (0.6%) participants. Escherichia coli strains isolated preoperatively from the rectum and postoperatively from urine were found to be identical. The present findings showed accuracy and performance of the selective media. Screening cultures before transrectal prostate biopsy using selective media seems to be helpful for guiding antibiotic prophylaxis and thus decreasing the rate of post-biopsy acute prostatitis.


The Relationship between Aggression and Serum Thyroid Hormone Level in Individuals Diagnosed with Antisocial Personality Disorder.
Aggression is one of the leading clinical characteristics of antisocial personality disorder (APD). Studies aiming to clarify and control the biological basis of aggression are ongoing. Thyroid hormones have been indicated to play a role in the development of aggression. The aim of this study was to examine the level of aggression and serum thyroid hormone in a sample of APD and to make contributions to this field with the current findings. The sample consisted of 96 subjects with a diagnosis of APD and 97 subjects as a control group. Structured Clinical Interview for DSM-IV Axis (SCID) 1 and 2 were used for the diagnosis, and the Buss-Perry Aggression Questionnaire was administered. Based on criminal patterns, the APD group was then divided into two subgroups: "criminal" and "noncriminal" APD groups. The day after the interview, after one night of fasting, blood was collected from the subjects between 7:00 a.m. and 9:00 a.m.. Thyroid function tests and other biochemical analyses related to the confounding variables were also administered. The study group and the control group were compared in terms of their aggression scores and thyroid hormone levels. The mean score of free T3 level in the criminal APD group was found to be significantly higher than that in the noncriminal APD group. APD subjects with higher free T3 levels also had higher aggression scores. In the noncriminal APD group, as serum free T3 and T4 levels increased, there was also an increment in the aggression scores. However, in the criminal APD group, there was no significant correlation between thyroid hormone levels and aggression. The findings of this study indicated that criminal and noncriminal APD groups actually show different properties.


Measuring quality of care at the end of life.
Caring for patients at the end of life presents a series of quality-of-care problems to the health care system. In the past, concern has focused on overaggressive treatment of dying patients. Given rapid changes in the financing and delivery of care, it is time to focus on a range of quality problems and address ways to improve care and achieve outcomes desired by patients and their families. We provide a framework for conceptualizing such a task. This article addresses the purposes of measurement, definition of the patient population, timing of measurement, use of surrogates in measurement, scope of services to be evaluated, and the choice of measures. It emphasizes the necessary links between quality measurement and quality improvement.


In vitro determinants of asbestos fiber toxicity: effect on the relative toxicity of Libby amphibole in primary human airway epithelial cells.
An abnormally high incidence of lung disease has been observed in the residents of Libby, Montana, which has been attributed to occupational and environmental exposure to fibrous amphiboles originating from a nearby contaminated vermiculite mine. The composition of Libby amphibole (LA) is complex and minimal toxicity data are available. In this study, we conduct a comparative particle toxicity analysis of LA compared with standard reference asbestiform amphibole samples. Primary human airway epithelial cells (HAEC) were exposed to two different LA samples as well as standard amphibole reference samples. Analysis of the samples included a complete particle size distribution analysis, calculation of surface area by electron microscopy and by gas adsorption and quantification of surface-conjugated iron and hydroxyl radical production by the fibers. Interleukin-8 mRNA levels were quantified by qRT-PCR to measure relative pro-inflammatory response induced in HAEC in response to amphibole fiber exposure. The relative contribution of key physicochemical determinants on the observed pro-inflammatory response were also evaluated. The RTI amosite reference sample contained the longest fibers and demonstrated the greatest potency at increasing IL-8 transcript levels when evaluated on an equal mass basis. The two LA samples and the UICC amosite reference sample consisted of similar particle numbers per milligram as well as similar particle size distributions and induced comparable levels of IL-8 mRNA. A strong correlation was observed between the elongated particle (aspect ratio ≥3:1) dose metrics of length and external surface area. Expression of the IL-8 data with respect to either of these metrics eliminated the differential response between the RTI amosite sample and the other samples that was observed when HAEC were exposed on an equal mass basis. On an equal mass basis, LA is as potent as the UICC amosite reference sample at inducing a pro-inflammatory response in HAEC but is less potent than the RTI amosite sample. The results of this study show that the particle length and particle surface area are highly correlated metrics that contribute significantly to the toxicological potential of these amphibole samples with respect to the inflammogenic response induced in airway epithelial cells.


Effectiveness of an online suicide prevention program for college faculty and students.
Objective: Suicide prevention programs help college staff and students identify students at-risk for suicide. Kognito is an online, simulation-based suicide prevention program. The purpose of the current study was to evaluate Kognito's effectiveness in changing suicide prevention attitudes and behavior. Participants: 170 college students and 140 college staff completed the training module and three surveys. Methods: College staff and students from 24 public, private, and community colleges and universities in Maryland completed Kognito modules and pre-, post-, and 3-month follow-up assessments. Results: Both college staff and students exhibited significant improvements in reported Preparedness, Likelihood, and Self-Efficacy in gatekeeper attitudes. Students reported significant gains in gatekeeper intervention behaviors. Conclusions: The current results suggest that Kognito is associated with attitudinal change for college staff and students, but only college students demonstrated statistically significant behavioral impact for both being more likely to ask about suicide and refer peers to counseling.


Comparison of the results of sleeve gastrectomy, gastric pilication and liragulitide in obese rats.
Obesity, which is generally seen in adults, is a serious health problem. Diseases caused by obesity are among the leading causes of death worldwide. Liraglutide (LG) is an analogue of glucagon-like peptide-1, which slows gastrointestinal motility, resulting in decreased food consumption. Gastric plication (GP) and sleeve gastrectomy (SG) is the reduction of stomach volume by surgical means. We examined and compared the body mass index (BMI) changes, metabolic changes and changes in gastric histology in obese rats after LG injection with surgical methods such as SG and GP. In this research, 35 Wistar Albino female rats were used. Rats were divided into 5 groups with 7 rats in each group. Group (G) 1: The control group, fed with a normal calorie diet for 8 weeks. G 2: Sham group, G 3: SG group, G 4: GP group and G 5: LG group, fed with high-calorie feed for 4 weeks. At the end of the 4th week, the study was terminated by making appropriate interventions for the groups. When the blood glucose (BG) levels measured at the beginning, 4th week and 8th week of the experiment were evaluated, it was monitored that the BG level at the 8th week was the lowest in the LG group (p<0.05). It was observed that the preop Ghrelin and Leptin levels of the LG group were lower than those of the SG and GP groups (p<0.05). As a consequenc As a consequence of our metabolic investigations, we observed that the use of LG is at least as effective as SG.


Adult-onset Satoyoshi syndrome and response to plasmapheresis.
Satoyoshi syndrome is a rare disease characterized by alopecia, recurrent muscle spasms, diarrhea, and skeletal abnormalities Adult-onset disease is reported only in five patients. Most of the reports have not characterized the nature of muscle spasm in the disease. In this paper, we report the first case of adult-onset Satoyoshi syndrome from India and the clinical and electrophysiological response to plasmapheresis.


Ectopic High Expression of E2-EPF Ubiquitin Carrier Protein Indicates a More Unfavorable Prognosis in Brain Glioma.
Ubiquitination of proteins meant for elimination is a primary method of eukaryotic cellular protein degradation. The ubiquitin carrier protein E2-EPF is a key degradation enzyme that is highly expressed in many tumors. However, its expression and prognostic significance in brain glioma are still unclear. The aim of this study was to reveal how the level of E2-EPF relates to prognosis in brain glioma. Thirty low-grade and 30 high-grade brain glioma samples were divided into two tissue microarrays each. Levels of E2-EPF protein were examined by immunohistochemistry and immunofluorescence. Quantitative real-time polymerase chain reaction was used to analyze the level of E2-EPF in 60 glioma and 3 normal brain tissue samples. The relationship between E2-EPF levels and prognosis was analyzed by Kaplan-Meier survival curves. E2-EPF levels were low in normal brain tissue samples but high in glioma nuclei. E2-EPF levels gradually increased as glioma grade increased (p < 0.05). Ectopic E2-EPF levels in high-grade glioma were significantly higher than in low-grade glioma (p < 0.01). The 5-year survival rate of glioma patients with high E2-EPF levels was shorter than in patients with low expression (p < 0.05). Furthermore, the 5-year survival rate of patients with ectopic E2-EPF was significantly shorter than patients with only nuclear E2-EPF (p < 0.01). These results suggest that higher E2-EPF levels, especially ectopic, are associated with higher grade glioma and shorter survival. E2-EPF levels may play a key role in predicting the prognosis for patients with brain glioma.


Decreased release of norepinephrine in the isolated kidney of the adult spontaneously hypertensive rat.
Renal resistance vessels of the mature spontaneously hypertensive rat (SHR) exhibit an increased reactivity to exogenous norepinephrine, but a normal response to renal nerve stimulation. This difference could be due either to depression of the exocytotic process or to accelerated disposition of the released transmitter. We compared the overflow of norepinephrine in isolated perfused kidneys from adult SHR and normotensive rats. After previous incubation with 3H-norepinephrine, renal nerve stimulation caused smaller increases in the overflow of intact tritiated transmitter and its metabolites in kidneys form SHR than in those from normotensive controls. A similar difference was found when the amounts of endogenous norepinephrine were measured radioenzymatically. The tissue content of norepinephrine was comparable in kidneys from both hypertensive and normotensive animals. The uptake of 3H-norepinephrine was comparable in kidneys from SHR and normotensive controls; cocaine caused a comparable depression of the 3H-uptake in which then explains the normal vasoconstrictor response to renal nerve stimulation despite the increased responsiveness of the vascular smooth muscle cells to norepinephrine.


[Current recommendations for prevention of thromboembolic events in patients with heart valve prostheses].
Within the last few years, marked progress has been made in the prevention of thromboembolic events in patients with mechanical heart valves. Thus, therapy has become more effective and is associated with less risk. This includes a number of developments like the introduction of the internationalized, normalized ratio (INR) for determination of the intensity of anticoagulation, the concept of a risk factor-adjusted, prosthesis specific, individualized indication for and intensity of anticoagulation and the possibility for self-determination of anticoagulation intensity by the patient. Prospective, randomized studies on the effect of different intensities of anticoagulation allowed definitions of individualized anticoagulation target levels and were the basis for guidelines on clinical management of anticoagulation. In spite of this progress, thromboembolic complications and anticoagulation associated bleedings are still the most frequent complications after valve replacement. The guidelines published by the professional societies on anticoagulation should be followed more closely in daily clinical practice. The management of oral anticoagulant treatment can be improved by following the concept of a risk factor-adjusted indication for and intensity of oral anticoagulant treatment as well as the use of the INR for monitoring the intensity of anticoagulation. Intensive education of the patient, implementation of self-testing by suitable patients and increasing the frequency of testing can further contribute to improvement.


Umbilical cord leptin predicts neonatal bone mass.
Evidence is accumulating that the risk of osteoporosis in later life may be determined in part by environmental influences on bone development during intrauterine and early postnatal life. A potential role for fetal leptin in mediating these effects is suggested by animal studies showing that leptin influences prenatal osteoblast growth and development, and that fetal leptin concentrations are altered by changes in maternal nutrition. In a group of term human infants we reported previously that maternal birthweight, smoking, fat mass, and exercise during late pregnancy independently predict neonatal bone mass. To investigate the potential role of leptin in mediating these effects, we now relate leptin concentrations in umbilical venous serum to neonatal bone mass and body composition in 117 infants. There were strong positive associations between umbilical venous leptin concentration and each of whole body bone mineral contents (BMC) (r = 0.42, P < or = 0.001) and estimated volumetric bone density (r = 0.21, P = 0.02); whole body lean mass (r = 0.21, P < or = 0.024); and whole body fat mass (r = 0.60, P < 0.001). The associations with neonatal BMC and fat mass, but not with lean mass, were independent of associations that we have reported previously between cord serum insulin-like growth factor 1 (IGF-1) concentrations and neonatal body composition. Among the maternal determinants of neonatal bone mass, cord leptin explained the relationship with maternal fat stores, but not those with the mother's own birthweight, smoking, or physical activity. We conclude that umbilical venous leptin predicts both the size of the neonatal skeleton and its estimated volumetric mineral density. In addition, among previously documented maternal determinants of neonatal bone mass in healthy pregnancies, maternal fat stores may mediate their effect on fetal bone accrual through variation in fetal leptin concentrations.


The use of blood gas parameters to predict ascites susceptibility in juvenile broilers.
Ascites syndrome is a metabolic disorder found in modern broilers that have insufficient pulmonary vascular capacity. Commercial breeding programs have heavily focused on high growth rate, which led to fast-growing chickens, but as a negative consequence, the incidence of ascites syndrome increased. However, not all birds with a high growth rate will suffer from ascites syndrome, which might indicate a genetic susceptibility to ascites. Information on blood gas parameters measured early in life and their relation to ascites susceptibility is expected to contribute to identification on the cause of ascites syndrome. In this study, several physiological parameters, such as blood gas parameters [pH, partial pressure of CO(2) in venous blood (pvCO(2)), and partial pressure of O(2) in venous blood], hematocrit, electrolytes (Na(+), Ca(2+), and K(+)), metabolites (lactate and glucose), were measured at d 11 to 12 of age from 100 female and 100 male broilers. From d 14 onward, the birds were challenged to provoke the development of ascites syndrome. Our results showed that high pvCO(2) values together with low pH values (males) or high pH values (females) in the venous blood of juvenile broilers coincided with ascites. Therefore, blood pvCO(2) and pH in both juvenile male and female broilers seem to be critical factors in ascites pathophysiology and can be used as phenotypic traits to predict ascites susceptibility in juvenile broilers at d 11 to 12. A prediction model was built on a subpopulation of the broilers without any loss in sensitivity (0.52) and specificity (0.78) when applied to the validation population. The parameter sex was included in the prediction model because levels of pvCO(2) and pH that associated with ascites susceptibility are different between males and females. Commercial breeders can include these phenotypic traits in their genetic selection programs to reduce the incidence of ascites syndrome.


Modelling the effect of diffuse light on canopy photosynthesis in controlled environments.
A layered canopy model was used to analyze the effects of diffuse light on canopy gross photosynthesis in controlled environment plant growth chambers, where, in contrast to the field, highly diffuse light can occur at high irradiance. The model suggests that high diffuse light fractions (approximately 0.7) and irradiance (1400 micromoles m-2 s-1) may enhance crop life-cycle canopy gross photosynthesis for hydroponic wheat by about 20% compared to direct light at the same irradiance. Our simulations suggest that high accuracy is not needed in specifying diffuse light fractions in chambers between approximately 0.7 and 1, because simulated photosynthesis for closed canopies plateau in this range. We also examined the effect of leaf angle distribution on canopy photosynthesis under growth chamber conditions, as these distributions determine canopy extinction coefficients for direct and diffuse light. We show that the spherical leaf angle distribution is not suitable for modeling photosynthesis of planophile canopies (e.g., soybean and peanut) in growth chambers. Also, the absorption of the light reflected from the surface below the canopy should generally be included in model simulations, as the corresponding albedo values in the photosynthetically active range may be quite high in growth chambers (e.g., approximately 0.5). In addition to the modeling implications, our results suggest that diffuse light conditions should be considered when drawing conclusions from experiments in controlled environments.


Treatment decisions in advanced disease: a conceptual framework.
This English translation, made by a professional translator in close cooperation with the author and kindly proofread by Dr. Phil Larkin, follows the original text as closely as possible. However, though we thought it was wise to maintain the official (but not unproblematic) Dutch/Belgian definition of euthanasia in the original text (written for Belgian readers), the English texts offers a new and clearer definition of euthanasia. From the very beginning of the Belgian euthanasia debate in 1999, the Flemish Palliative Care Federation has chosen not to stay on the sideline, but to take an active part in the discussion and formulate recommendations based on our expertise and experience. Time and again we have pointed out that the ethical issues at the end of life are not just restricted to those of euthanasia. We have found that there is still much confusion about, for example, the difference or the boundary between pain control and euthanasia or between euthanasia and withholding life-sustaining treatment. Therefore, we thought it appropriate to put the following conceptual framework with regard to treatment decisions in advanced illness forward.


[Chugaev's reaction for sterols].
Spectrophotometric patterns of Chugaev's reaction products of forty sterol compounds were studied. The reaction was shown to be used for identification and the quantitative determination of some sterols.


Mathematical Modeling Reveals That the Administration of EGF Can Promote the Elimination of Lymph Node Metastases by PD-1/PD-L1 Blockade.
In the advanced stages of cancers like melanoma, some of the malignant cells leave the primary tumor and infiltrate the neighboring lymph nodes (LNs). The interaction between secondary cancer and the immune response in the lymph node represents a complex process that needs to be fully understood in order to develop more effective immunotherapeutic strategies. In this process, antigen-presenting cells (APCs) approach the tumor and initiate the adaptive immune response for the corresponding antigen. They stimulate the naive CD4+ and CD8+ T lymphocytes which subsequently generate a population of helper and effector cells. On one hand, immune cells can eliminate tumor cells using cell-cell contact and by secreting apoptosis inducing cytokines. They are also able to induce their dormancy. On the other hand, the tumor cells are able to escape the immune surveillance using their immunosuppressive abilities. To study the interplay between tumor progression and the immune response, we develop two new models describing the interaction between cancer and immune cells in the lymph node. The first model consists of partial differential equations (PDEs) describing the populations of the different types of cells. The second one is a hybrid discrete-continuous model integrating the mechanical and biochemical mechanisms that define the tumor-immune interplay in the lymph node. We use the continuous model to determine the conditions of the regimes of tumor-immune interaction in the lymph node. While we use the hybrid model to elucidate the mechanisms that contribute to the development of each regime at the cellular and tissue levels. We study the dynamics of tumor growth in the absence of immune cells. Then, we consider the immune response and we quantify the effects of immunosuppression and local EGF concentration on the fate of the tumor. Numerical simulations of the two models show the existence of three possible outcomes of the tumor-immune interactions in the lymph node that coincide with the main phases of the immunoediting process: tumor elimination, equilibrium, and tumor evasion. Both models predict that the administration of EGF can promote the elimination of the secondary tumor by PD-1/PD-L1 blockade.


The association between lumbar spine radiographic features and low back pain: a systematic review and meta-analysis.
Low back pain (LBP) is a prevalent musculoskeletal condition and represents a substantial socioeconomic burden. Plain film radiography is a commonly used imaging technique. Radiographic features (RFs) such as disc space narrowing, osteophytes, spondylosis, endplate sclerosis, spondylolisthesis, and facet joint osteoarthritis have all been debated as potential pain generators in the lumbar spine. The aim of this study is to (1) determine the association between LBP and lumbar spine RFs in both community- and occupation-based groups and (2) to determine if there are differences in these associations between these two groups. A systematic electronic search of PubMed, EMBASE, CINAHL, and Cochrane was conducted with keywords related to LBP and lumbar spine RFs. The search was restricted from inception of each respective database to April 2014. Inclusion criteria consisted of observational studies of adults (≥18 years) with and without nonspecific LBP. Studies were excluded if they investigated LBP related to infection, malignancy, or rheumatologic nature or were conducted in cadavers. Quality assessment was conducted with the Item Bank for Assessment of Risk of Bias and Precision for Observational Studies of Interventions or Exposures. Random effect models were used for all pooled analyses with associations represented by odds ratios (OR) and 95% confidence intervals (95% CIs). Statistical heterogeneity was assessed with I(2), with significant heterogeneity represented as >50%. Overall, 28 (22 community-based and six occupation-based) studies met the eligibility criteria consisting of 26,107 subjects. A significant, positive association was found between disc space narrowing and LBP, which did not differ (p = 0.22) in both community- and occupation-based studies [OR = 1.47 (95% CI: 1.36-1.58)] and [OR = 1.76 (95% CI: 1.34-2.33)], respectively. No significant statistical heterogeneity was present in either estimate (I(2) = 0.0%). A significant association was found between spondylolisthesis and LBP in occupation-based studies [OR = 2.21 (95% CI: 1.44-3.39)] that differed significantly (p < 0.01) from community-based studies [OR = 1.12 (95% CI: 1.03-1.23)]. These individual estimates were also homogeneous (I(2) = 0.0%). The association between other radiographic features was modest (i.e., spondylosis and osteophytes) or non-significant (i.e., endplate sclerosis and facet joint). Quality of included studies varied, with the majority demonstrating good quality. A significant association was found between disc space narrowing in both community- and occupational-based populations without significant differences between the associations. A significant strong association was found between spondylolisthesis and LBP among the occupational group but was weakly associated in the community-based group, which supports that spondylolisthesis may contribute a specific cause for LBP.


Weight management strategies for patients with PCOS: current perspectives.
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of reproductive-aged women. Overweight and obesity commonly accompany the syndrome at the clinic and are significant concerns for women with PCOS. Herein, we provide an overview of the relevant literature on weight management strategies in women with PCOS. We performed an electronic-based search using PubMed until February 2021. We aimed to summarize available evidence of different weight-reducing interventions in PCOS and outline the gaps in our current knowledge and recommend areas for further research. PCOS is closely linked to obesity and increased adiposity enhances severity and expression of PCOS phenotype. Current data suggest that weight loss is associated with improved metabolic, endocrine, reproductive, cardiovascular and psychological features in overweight and obese women with PCOS. Lifestyle interventions including diet and exercise, anti-obesity medications and bariatric surgery have been used as therapeutic approaches for short-term management of obesity in PCOS with varying success rates. Large and sufficiently powered studies are required in order to determine long-term effects of weight management strategies and potential benefits beyond weight loss in the syndrome. This would allow informing the guidelines to make PCOS specific evidence-based recommendations.


Blocking Myristoylation of Src Inhibits Its Kinase Activity and Suppresses Prostate Cancer Progression.
Protein N-myristoylation enables localization to membranes and helps maintain protein conformation and function. N-myristoyltransferases (NMT) catalyze co- or posttranslational myristoylation of Src family kinases and other oncogenic proteins, thereby regulating their function. In this study, we provide genetic and pharmacologic evidence that inhibiting the N-myristoyltransferase NMT1 suppresses cell-cycle progression, proliferation, and malignant growth of prostate cancer cells. Loss of myristoylation abolished the tumorigenic potential of Src and its synergy with androgen receptor in mediating tumor invasion. We identified the myristoyl-CoA analogue B13 as a small-molecule inhibitor of NMT1 enzymatic activity. B13 exposure blocked Src myristoylation and Src localization to the cytoplasmic membrane, attenuating Src-mediated oncogenic signaling. B13 exerted its anti-invasive and antitumor effects against prostate cancer cells, with minimal toxic side-effects in vivo Structural optimization based on structure-activity relationships enabled the chemical synthesis of LCL204, with enhanced inhibitory potency against NMT1. Collectively, our results offer a preclinical proof of concept for the use of protein myristoylation inhibitors as a strategy to block prostate cancer progression. Cancer Res; 77(24); 6950-62. ©2017 AACR.


First Trimester Pregnancy Loss and the Expression of Alternatively Spliced NKp30 Isoforms in Maternal Blood and Placental Tissue.
Capsule: We observed that first trimester pregnancy loss is associated with an altered expression profile of the three isoforms of the NK receptor NKp30 expressed by NKs in PBMC and placental tissue. In this study, we aimed to investigate whether first trimester pregnancy loss is associated with differences in expression of NKp30 splice variants (isoforms) in maternal peripheral blood or placental tissue. We conducted a prospective case-control study; a total of 33 women undergoing dilation and curettage due to first trimester pregnancy loss were further subdivided into groups with sporadic or recurrent pregnancy loss. The control group comprises women undergoing elective termination of pregnancy. The qPCR approach was employed to assess the relative expression of NKp30 isoforms as well as the total expression of NKp30 and NKp46 receptors between the selected groups. Results show that in both PBMC and placental tissue, NKp46 and NKp30 expressions were mildly elevated in the pregnancy loss groups compared with the elective group. In particular, NKp46 elevation was significant. Moreover, expression analysis of NKp30 isoforms manifested a different profile between PBMC and the placenta. NKp30-a and NKp30-b isoforms in the placental tissue, but not in PBMC, showed a significant increase in the pregnancy loss groups compared with the elective group. Placental expression of NKp30 activating isoforms-a and -b in the pregnancy loss groups was negatively correlated with PLGF expression. By contrast, placental expression of these isoforms in the elective group was positively correlated with TNFα, IL-10, and VEGF-A expression. The altered expression of NKp30 activating isoforms in placental tissue from patients with pregnancy loss compared to the elective group and the different correlations with cytokine expression point to the involvement of NKp30-mediated function in pregnancy loss.


[Efficacy of inhalation therapy with water of Salsomaggiore (Italy) in chronic and recurrent nasosinusal inflammation treatment].
Aim of the research was the demonstration of the efficacy of thermal water vs saline in the recurrent and chronic nasosinusal pathologies treatment. 120 patients randomized into 2 groups of 60 subjects each, all affected by recurrent or chronic rhinosinusitis with/without I degree nasal polyposis. At the beginning and at the end of the study, in all the subjects the clinical history, objective examination and the instrumental analysis of nasal functions by active anterior rhinometry, acustic rhinometry, nasal mucociliary transport time determination and nasal mucosa scraping were performed. Patients of the study group underwent crenotherapy treatment (vapour inhalation, aerosol and nasal douching) with thermal water for 14 days at Salsomaggiore Thermal baths. Other patients underwent nasal douching and aerosol with saline twice a day for 14 days at the Rhinologic Centre of the ENT Clinic of Siena University. At the end of the study, only the patients undergone to crenothrapic treatment with salt-bromine-iodic water showed a significant improvement of nasal obstruction, rinorrea and number of nocturnal arousals. The improvement, even if present, was not significant in the control group. Same positive variations were observed concerning nasal mucosa congestion, nasal secretion and mucociliary transport time reaching the significance in the study group. Crenotherapy with salt-bromine-iodic water should be considered as efficacious therapeutic tool in the management of chronic and recurrent rhinosinusitis.


Association of chronic rhinosinusitis with nasal polyps and asthma: clinical and radiological features, allergy and inflammation markers.
Chronic rhinosinusitis (CRS) with and without nasal polyps represent different stages of one chronic inflammatory disease of the mucosa of the nasal cavity and paranasal sinuses. Coexistence of chronic rhinosinusitis with nasal polyps and asthma and rather similar characteristics of inflammation support assumption that chronic rhinosinusitis and nasal polyps and asthma may be, at least in part, the same disease process. We therefore aimed to evaluate the differences of sinus radiologic findings, systemic inflammation and allergy markers, pulmonary function of chronic rhinosinusitis associated with nasal polyps and asthma. A total of 121 patients with chronic rhinosinusitis referred to tertiary center were evaluated; 23 healthy persons served as controls. Sinus CT scans and nasal endoscopy were performed. Allergic rhinitis was diagnosed according to history and positive skin prick tests to common inhalant allergens. Asthma was diagnosed according to GINA by history and pulmonary function tests. Aspirin intolerance was assessed by history. Total IgE, Aspergillus fumigatus-specific IgE levels, leukocyte and eosinophil count in the peripheral blood were measured. Nasal polyps were detected in 84 patients (69.4%), asthma diagnosed in 48 patients (39.6%), associated with nasal polyps (91.7%) and allergic rhinitis in 45.5% of patients. Forty-four patients with chronic rhinosinusitis and having nasal polyps and asthma were characterized by older age (P<0.01), greater duration of nasal symptoms (P<0.001), higher number previous surgeries (P<0.01), more severe sinus disease on CT scan (P<0.001), greater blood leukocyte and eosinophil count, total IgE level (P<0.01), bronchial obstruction (P<0.05), incidence of allergic rhinitis (P<0.01), and sensitivity to house dust mite D. pteronyssinus (47.7%, P<0.01) and mold allergens (29.5%, P<0.01) comparing to the patients with isolated chronic rhinosinusitis. The extent of sinus CT changes was greater in asthmatics and correlated with greater duration of asthma (P<0.0001), higher number of previous surgeries (P=0.001), leukocyte count in blood (P=0.025), and age (P=0.039). CONCLUSION. Our data indicate that patients with chronic rhinosinusitis compose clinically heterogeneous group and when associated with nasal polyps and asthma constitutes the most severe form of unified respiratory tract disease, which is characterized by older age of the patients, greater duration of nasal symptoms, extent of sinus radiological changes, more prominent systemic inflammation markers, greater bronchial obstruction, incidence of perennial allergic rhinitis.


Metabolic studies of glycosphingolipid accumulation in mucopolysaccharidosis IIID.
Severe neurological deficits and mental retardation are frequently associated with disrupted ganglioside metabolism in a variety of gangliosidoses and lysosomal storage disorders. Accumulation of glycosphingolipids (GSLs) in the central nervous system (CNS) of humans and animals affected with several types of mucopolysaccharidoses (MPS) also correlates with the severity of neurological dysfunction. Mucopolysaccharidosis type IIID (MPS IIID) is characterized by deficiency in lysosomal N-acetylglucosamine 6-sulfatase activity and the accumulation and excretion of heparan sulfates and N-acetylglucosamine 6-sulfate. We investigated the metabolism of GSLs in the prenatal, neonatal, and adult MPS IIID caprine brains and an MPS experimental cell culture model. The amounts of total glycolipids in prenatal, neonatal, and adult MPS IIID caprine brains were about 2-fold higher than those in control samples. GM3, GD3, and lactosyl ceramide were the principal GSLs which abnormally accumulated in caprine MPS IIID brains. These changes may be, in part, due to the reduction of sialidase and UDP-N-acetylgalactosamine:GM3 N-acetylgalactosaminyltransferase (GalNAc-T) activities in MPS IIID caprine brain. To further examine the possible mechanism of GSL accumulation in MPS IIID brains, we employed a cell culture model using suramin-treated neuronal cultures of differentiated P19 cells. HPTLC analysis showed elevated GSLs in suramin-treated cells. Metabolic pulse-chase labeling study revealed that the GSL accumulation in suramin-treated cells may be attributed to both disturbed biosynthesis and significantly slower degradation of GSLs. In addition, the consistency of observations in the cell culture and caprine models supports the cell culture system as a means of evaluating GSL metabolic perturbations.


Physiotherapist-patient communication in entry-level physiotherapy education: A national survey in Nigeria.
Clinical communication impacts on physiotherapy treatment outcome and its competence warrants being assessed during training for physiotherapists given the increasing need to improve patient outcomes. This study aimed to investigate the assessment of clinical communication in entry-level physiotherapy programs in Nigeria. In a cross-sectional survey, questionnaires were sent by e-mail or hand-delivered to the heads of physiotherapy programs, asking them to consult with faculty members involved in the assessment of clinical communication in undergraduate education. Six of seven physiotherapy programs responded (an 86% response rate). Assessment of clinical communication and methods of assessing clinical communication by the programs showed wide variation. There was an average of two assessments per year. The objective structured clinical examination with patients (21; 38%) and written communications (report/chart) (13; 23%) were the most commonly used assessment methods. Perceived challenges included a lack of facilities, validity, inexperienced examiners, and difficulties in integrating processes and content. A variety of assessment methods are being used in entry-level physiotherapy programs in Nigeria, which target different components of clinical communication skills acquisition. More effort is needed to improve limited facilities and human resources training to enhance clinical communication assessment in Nigerian physiotherapy programs.


Effect of pneumococcal vaccination on nasopharyngeal carriage of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus in Fijian children.
The 7-valent pneumococcal conjugate vaccine (PCV7) reduces carriage of vaccine type Streptococcus pneumoniae but leads to replacement by nonvaccine serotypes and may affect carriage of other respiratory pathogens. We investigated nasopharyngeal carriage of S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus in Fijian infants participating in a pneumococcal vaccine trial using quantitative PCR. Vaccination did not affect pathogen carriage rates or densities, whereas significant differences between the two major ethnic groups were observed.


Oxidative damage and autophagy in the human trabecular meshwork as related with ageing.
Autophagy is an intracellular lysosomal degradation process induced under stress conditions. Autophagy also plays a major role in ocular patho-physiology. Molecular aging does occur in the trabecular meshwork, the main regulator of aqueous humor outflow, and trabecular meshwork senescence is accompanied by increased oxidative stress. However, the role of autophagy in trabecular meshwork patho-physiology has not yet been examined in vivo in human ocular tissues. The purpose of the herein presented study is to evaluate autophagy occurrence in ex-vivo collected human trabecular meshwork specimens and to evaluate the relationship between autophagy, oxidative stress, and aging in this tissue. Fresh trabecular meshwork specimens were collected from 28 healthy corneal donors devoid of ocular pathologies and oxidative DNA damage, and LC3 and p62 protein expression analyzed. In a subset of 10 subjects, further to trabecular meshwork proteins, the amounts of cathepesin L and ubiquitin was analyzed by antibody microarray in aqueous humor. Obtained results demonstrate that autophagy activation, measured by LC3II/I ratio, is related with. oxidative damage occurrence during aging in human trabecular meshwork. The expression of autophagy marker p62 was lower in subjects older than 60 years as compared to younger subjects. These findings reflect the occurrence of an agedependent increase in the autophagy as occurring in the trabecular meshwork. Furthermore, we showed that aging promotes trabecular-meshwork senescence due to increased oxidative stress paralleled by autophagy increase. Indeed, both oxidative DNA damage and autophagy were more abundant in subjects older than 60 years. These findings shed new light on the role of oxidative damage and autophagy during trabecular-meshwork aging.


[Synovial cytokines facilitate the development of spontaneous nerve root activity following compression].
The nerve roots of Wistar rats were studied electrophysiologically following exposure to synovial cytokines. A total of 12 rats was examined. In the experimental series a preparation of synovial cytokines (50 microliters, 250 micrograms protein) was injected into the S1 nerve root of 6 Wistar rats. Six animals served as controls and were injected with a similar solution lacking cytokines. Forty-eight hours after this procedure the S1 nerve root was compressed by a force of 0.2 N for 1 hour. EMG recordings at mid-gastrocnemius levels were performed during, and 3 hours after, compression. The neurophysiological testing performed 3 hours after compression showed a significantly higher level of compression-induced muscle activity in the cytokine group compared to the control.


Extreme genetic structure in a small-bodied freshwater fish, the purple spotted gudgeon, Mogurnda adspersa (Eleotridae).
Freshwater fish are a group that is especially susceptible to biodiversity loss as they often exist naturally in small, fragmented populations that are vulnerable to habitat degradation, pollution and introduction of exotic species. Relatively little is known about spatial dynamics of unperturbed populations of small-bodied freshwater fish species. This study examined population genetic structure of the purple spotted gudgeon (Mogurnda adspersa, Eleotridae), a small-bodied freshwater fish that is widely distributed in eastern Australia. The species is threatened in parts of its range but is common in coastal streams of central Queensland where this study took place. Microsatellite (msat) and mitochondrial DNA (mtDNA) variation was assessed for nine sites from four stream sections in two drainage basins. Very high levels of among population structure were observed (msat F(ST) = 0.18; mtDNA Φ(ST) = 0.85) and evidence for contemporary migration among populations was rare and limited to sites within the same section of stream. Hierarchical structuring of variation was best explained by stream section rather than by drainage basin. Estimates of contemporary effective population size for each site was low (range 28 - 63, Sibship method), but compared favorably with similar estimates for other freshwater fish species, and there was no genetic evidence for inbreeding or recent population bottlenecks. In conclusion, within a stable part of its range, M adspersa exists as a series of small, demographically stable populations that are highly isolated from one another. Complimentary patterns in microsatellites and mtDNA indicate this structuring is the result of long-term processes that have developed over a remarkably small spatial scale. High population structure and limited dispersal mean that recolonisation of locally extinct populations is only likely to occur from closely situated populations within stream sections. Limited potential for recolonisation should be considered as an important factor in conservation and management of this species.


Internal relocation as a relevant and feasible adaptation strategy in Rangiroa Atoll, French Polynesia.
Atoll islands face increasing coastal risks (coastal erosion and marine flooding) due to climate change, especially sea-level rise. To face increasing coastal risks, various adaptation options are considered by atoll countries and territories, including in particular hard protection (preferred option to date), Nature-based Solutions (increasingly used) and island raising (considered a longer-term solution and a potential alternative to international migration, e.g. in the Maldives). Internal relocation within the same atoll island or atoll, which refers to long-term community movement from one threatened island area or island to a safer island area or island, has previously been disregarded by scholars as a potentially relevant climate adaptation strategy. However, in low-lying coastal areas, it offers real potential to address the dual context of increasing climate risks and the shrinking of the solution space. This paper assesses the potential of internal relocation for atolls by applying to Rangiroa Atoll, French Polynesia, Central Pacific, a two-fold assessment framework questioning its physical relevance (are some islands high enough to host settlements in the future?) and its societal feasibility (are the political-institutional and socio-economic conditions in place? Are people willing to relocate?). The findings show that internal relocation is both relevant and feasible on Rangiroa Atoll and should therefore serve as a pillar to develop robust in situ adaptation pathways in this atoll.


Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments.
Receptor endocytosis is a fundamental step in controlling the magnitude, duration, and nature of cell signaling events. Confluent endothelial cells are contact inhibited in their growth and respond poorly to the proliferative signals of vascular endothelial growth factor (VEGF). In a previous study, we found that the association of vascular endothelial cadherin (VEC) with VEGF receptor (VEGFR) type 2 contributes to density-dependent growth inhibition (Lampugnani, G.M., A. Zanetti, M. Corada, T. Takahashi, G. Balconi, F. Breviario, F. Orsenigo, A. Cattelino, R. Kemler, T.O. Daniel, and E. Dejana. 2003. J. Cell Biol. 161:793-804). In the present study, we describe the mechanism through which VEC reduces VEGFR-2 signaling. We found that VEGF induces the clathrin-dependent internalization of VEGFR-2. When VEC is absent or not engaged at junctions, VEGFR-2 is internalized more rapidly and remains in endosomal compartments for a longer time. Internalization does not terminate its signaling; instead, the internalized receptor is phosphorylated, codistributes with active phospholipase C-gamma, and activates p44/42 mitogen-activated protein kinase phosphorylation and cell proliferation. Inhibition of VEGFR-2 internalization reestablishes the contact inhibition of cell growth, whereas silencing the junction-associated density-enhanced phosphatase-1/CD148 phosphatase restores VEGFR-2 internalization and signaling. Thus, VEC limits cell proliferation by retaining VEGFR-2 at the membrane and preventing its internalization into signaling compartments.


Deep Learning-Based Multi-Omics Integration Robustly Predicts Survival in Liver Cancer.
Identifying robust survival subgroups of hepatocellular carcinoma (HCC) will significantly improve patient care. Currently, endeavor of integrating multi-omics data to explicitly predict HCC survival from multiple patient cohorts is lacking. To fill this gap, we present a deep learning (DL)-based model on HCC that robustly differentiates survival subpopulations of patients in six cohorts. We built the DL-based, survival-sensitive model on 360 HCC patients' data using RNA sequencing (RNA-Seq), miRNA sequencing (miRNA-Seq), and methylation data from The Cancer Genome Atlas (TCGA), which predicts prognosis as good as an alternative model where genomics and clinical data are both considered. This DL-based model provides two optimal subgroups of patients with significant survival differences (P = 7.13e-6) and good model fitness [concordance index (C-index) = 0.68]. More aggressive subtype is associated with frequent TP53 inactivation mutations, higher expression of stemness markers (KRT19 and EPCAM) and tumor marker BIRC5, and activated Wnt and Akt signaling pathways. We validated this multi-omics model on five external datasets of various omics types: LIRI-JP cohort (n = 230, C-index = 0.75), NCI cohort (n = 221, C-index = 0.67), Chinese cohort (n = 166, C-index = 0.69), E-TABM-36 cohort (n = 40, C-index = 0.77), and Hawaiian cohort (n = 27, C-index = 0.82). This is the first study to employ DL to identify multi-omics features linked to the differential survival of patients with HCC. Given its robustness over multiple cohorts, we expect this workflow to be useful at predicting HCC prognosis prediction. Clin Cancer Res; 24(6); 1248-59. ©2017 AACR.


Assessment of the VDW interaction converting DMAPS from the thermal-motion form to the hydrogen-bonded form.
Assessment of van der Waals (VDW) interactions is fundamental to all of the central quest of structure that regulates the biological function. VDW interactions contributing to intramolecular weak hydrogen bonding are regarded as an important force to regulate the thermal stimuli-sensitive function of sulfobetaine methacrylate, DMAPS. We present here the conversion from the thermal-motion form at room temperature to the weak-hydrogen-bonded form against thermal motion as a terahertz spectral change with a definite isosbestic point from an absorption peak of one form to the other. Vibrational absorptions are used as a probe for assessing VDW interactions in conjunction with highly reliable and well-established density functional theory (DFT) calculations for analysis. Complicated spectral features and uncertain conformations of DMAPS in the amorphous state are clearly resolved under the polarizable continuum model and the dispersion correction for the pure DFT calculations.


High-Dose Methotrexate and Cytarabine-Based Multi-Agent Chemotherapy (Modified Bonn Protocol) for Systemic Lymphoma with CNS Involvement.
The prognosis of patients with systemic lymphoma with central nervous system (CNS) involvement is very poor and there is no established standard therapy. We retrospectively analyzed 18 patients (4 untreated and 14 relapsed) with systemic lymphoma with CNS involvement who received methotrexate and cytarabine-based multiagent chemotherapy (modified Bonn protocol). Complete and partial responses were achieved in 56 and 22% of the patients, respectively. The 1-year overall survival (OS) and progression-free survival (PFS) was 81.0 and 39.2%, respectively. Patients with parenchymal involvement showed a better 1-year PFS than those with either leptomeningeal involvement or both. In a multivariate analysis, poor performance status (PS) was the only independent prognostic factor for the 1-year OS and PFS (HR 10.8, 95% CI 1.09-108, p = 0.042; HR 20.8, 95% CI 2.39-181, p = 0.006, respectively). Grade 4 neutropenia and thrombocytopenia occurred in 17 patients each (94%), but there were no grade 4 nonhematopoietic adverse events. The modified Bonn protocol resulted in relatively favorable response and survival, and provided clinical benefits to patients with good PS, in particular. This study demonstrated that the modified Bonn protocol could be a feasible and encouraging treatment approach for lymphoma with CNS and systemic involvement.


Gill and liver histopathological changes in yellow perch (Perca flavescens) and goldfish (Carassius auratus) exposed to oil sands process-affected water.
The extraction of bitumen from the Athabasca oil sands (Alberta, Canada) produces significant volumes of process-affected water containing elevated levels of naphthenic acids (NAs), ions, and polycyclic aromatic hydrocarbons (PAHs). The sublethal response of aquatic organisms exposed to oil sands constituents in experimental aquatic environments that represent possible reclamation options has been studied. In this study, the effects of process-affected waters on gill and liver tissues in yellow perch (Perca flavescens) and caged goldfish (Carassius auratus) held in several reclamation ponds at Syncrude's Mildred Lake site have been assessed. Following a 3-week exposure, significant gill (epithelial cell necrosis, mucous cell proliferation) and liver (hepatocellular degeneration, inflammatory cell infiltration) histopathological changes were noted in fish held in waters containing high levels of oil sands process-affected water. In addition, measurements of gill dimensions (gill morphometrical indices) proved sensitive and provided evidence of a physiological disturbance (gas exchange) with exposure to oil sands materials. Due to the complexity of oil sands process-affected water, the cause of the alterations could not be attributed to specific oil sands constituents. However, the histopathological parameters were strong indicators of exposure to oil sands process-affected water and morphometrical data were sensitive indicators of pathological response, which can be used to identify the interactive effects of ionic content, NAs, and PAHs in future laboratory studies.


Interaction of hydroxycinnamic acids and their conjugates with organic anion transporters and ATP-binding cassette transporters.
Hydroxycinnamic acids are abundant antioxidants in our diet. In humans, hydroxycinnamic acids are metabolized to form sulfates and glucuronides, with the majority recovered in urine. We assessed the potential roles of organic anion transporters (OATs) and ATP-binding cassette (ABC) transporters in the renal uptake and efflux of hydroxycinnamic acid conjugates. Uptake studies using OAT1 (SLC22A6)-, OAT2 (SLC22A7)-, and OAT3 (SLC22A8)-expressing 293H embryonic kidney cells showed that OAT1 and OAT3, but not OAT2, accepted hydroxycinnamic acid conjugates as substrates. OAT1 and OAT3 mediated the basolateral uptake of hydroxycinnamic acid sulfates and glucuronide conjugates, respectively. Hydroxycinnamic acid sulfates are substrates of OAT4 and were capable of trans-stimulating 5-carboxyfluorescein uptake mediated by OAT4. On the other hand, hydroxycinnamic acid conjugates are not substrates for the ABC transporters, multidrug resistance protein 2 (MRP2/ABCC2) or breast cancer resistance protein (BCRP/ABCG2), demonstrated by the inability to alter ATPase activity. Cis-inhibition studies with OATs and MRPs revealed that hydroxycinnamic acid conjugates have limited impact on the transport of model substrates significantly at physiological concentrations. Concerted action of OAT1, OAT3, and OAT4 is involved in the elimination of hydroxycinnamic acid conjugates into urine, whereas MRP2 and breast cancer resistance protein are not involved in the disposition of these conjugates.


Awareness and knowledge of human papillomavirus (HPV) infection among high-risk men of Hispanic origin attending a sexually transmitted infection (STI) clinic.
Genital human papillomavirus (HPV) is one of the most commonly diagnosed sexually transmitted infection (STIs) in men and women. Knowledge about HPV infection among men is limited. This study aims to determine correlates of adequate knowledge of HPV infection among men who attend an STI clinic in Puerto Rico. A cross-sectional study of 206 men was conducted at an STI clinic in San Juan, PR. Adequate knowledge was defined as a score of at least 70% of correct responses among those men who reported having ever heard of HPV. Variables that achieved statistical significance in the bivariate analysis (p<0.05) were included in the multivariate logistic regression model. Although 52.5% of men reported having heard of HPV infection before the survey, only 29.3% of this sub-group had an adequate knowledge of HPV. Most men did not know that HPV is a risk factor for anal (38.7%), penile (50.0%) and oral (72.6%) cancer. Factors associated with adequate knowledge of HPV in age-adjusted models were being men who have sex with men (MSM) (OR=2.6;95%CI=1.1-6.1), self-report of genital warts (OR=3.2;95%CI=1.3-7.9) and herpes (OR=7.4;95% CI=2.2-25.1). MSM was marginally associated with adequate knowledge (OR=2.3;95% CI=0.9-5.9) and self-report of herpes remained significantly associated (OR=5.0;95%CI=1.3-18.4) in multivariate logistic regression analysis. Awareness and knowledge of HPV was very low in this group of men. Interventions to increase knowledge and awareness in this group are necessary to promote preventive practices for HPV-related cancers in high-risk groups.


Genotypic and phenotypic changes in the emergence of Escherichia coli O157:H7.
Escherichia coli O157:H7 is a foodborne pathogen distinguished from typical E. coli by the production of Shiga toxins (Stx) and the inability to ferment sorbitol (SOR) and to express beta-glucuronidase (GUD) activity. An allele-specific probe for the GUD gene (uidA) and multilocus enzyme electrophoresis were used to elucidate stages in the evolutionary emergence of E. coli O157: H7. A point mutation at +92 in uidA was found only in O157:H7 and its nonmotile relatives, including a SOR+ O157:H clone implicated in outbreaks of hemolytic-uremic syndrome in Germany. The results support a model in which O157:H7 evolved sequentially from an O55:H7 ancestor, first by acquiring the Stx2 gene and then by diverging into two branches; one became GUD- SOR- , resulting in the O157:H7 clone that spread worldwide, and the other lost motility, leading to the O157:H clone that is an increasing public health problem in Europe.


Motor hyperactivation during cognitive tasks: An endophenotype of juvenile myoclonic epilepsy.
Juvenile myoclonic epilepsy (JME) is the most common genetic generalized epilepsy syndrome. Myoclonus may relate to motor system hyperexcitability and can be provoked by cognitive activities. To aid genetic mapping in complex neuropsychiatric disorders, recent research has utilized imaging intermediate phenotypes (endophenotypes). Here, we aimed to (a) characterize activation profiles of the motor system during different cognitive tasks in patients with JME and their unaffected siblings, and (b) validate those as endophenotypes of JME. This prospective cross-sectional investigation included 32 patients with JME, 12 unaffected siblings, and 26 controls, comparable for age, sex, handedness, language laterality, neuropsychological performance, and anxiety and depression scores. We investigated patterns of motor system activation during episodic memory encoding and verb generation functional magnetic resonance imaging (fMRI) tasks. During both tasks, patients and unaffected siblings showed increased activation of motor system areas compared to controls. Effects were more prominent during memory encoding, which entailed hand motion via joystick responses. Subgroup analyses identified stronger activation of the motor cortex in JME patients with ongoing seizures compared to seizure-free patients. Receiver-operating characteristic curves, based on measures of motor activation, accurately discriminated both patients with JME and their siblings from healthy controls (area under the curve: 0.75 and 0.77, for JME and a combined patient-sibling group against controls, respectively; P < .005). Motor system hyperactivation represents a cognitive, domain-independent endophenotype of JME. We propose measures of motor system activation as quantitative traits for future genetic imaging studies in this syndrome.


Conserved roles of glucose in suppressing reactive oxygen species-induced cell death and animal survival.
Carbohydrate overconsumption increases blood glucose levels, which contributes to the development of various diseases including obesity and diabetes. It is generally believed that high glucose metabolism increases cellular reactive oxygen species (ROS) levels, damages insulin-secreting cells and leads to age-associated diabetic phenotypes. Here we find that in contrast, high glucose suppresses ROS production induced by paraquat in both mammalian cells and the round worm C. elegans. The role of glucose in suppressing ROS is further supported by glucose's ability to alleviate paraquat's toxicity on C. elegans development. Consistently, we find that the ROS-regulated transcription factor SKN-1 is inactivated by glucose. As a result, the ROS/SKN-1-dependent lifespan extension observed in paraquat-treated animals, mitochondrial respiration mutant isp-1 and germline-less mutant glp-1 are all suppressed by glucose. Our study reveals an unprecedented interaction of glucose with ROS, which could have significant impact on our current understanding of glucose- and ROS-related diseases.


Mucus and the goblet cell.
The discovery of an inner mucus layer normally impervious to bacteria has changed our way of understanding the interaction between commensal bacteria and the host epithelial cells. This inner colon mucus layer is rapidly renewed and converted into the outer mucus layer by host controlled endogenous proteolytic processing. The mucus characteristics esteem from the properties of the main protein component of these layers, the MUC2 mucin. This forms an enormously large net-like structure that builds the laminated inner mucus layer that largely acts as a size exclusion filter excluding bacteria. In the absence of MUC2 mucin, there is no inner mucus layer and bacteria reach the epithelial cell surface, penetrate the crypts and are also found inside epithelial cells, something that leads to severe inflammation. Other mouse models that spontaneously develop colitis due to different defects, like an absent ion channel (Nhe3) or immunological mediators (Tlr5, IL-10), all also have a defective inner colon mucus layer. Human patients with active ulcerative colitis have this layer penetrable to bacteria and beads the size of bacteria. Some of the ulcerative colitis patients in remission have a normal mucus layer whereas others have a penetrable inner mucus layer. Together, this suggests that the inner mucus layer and its integrity is important for the protection of the colon epithelium and inhibiting activation of the immune system as in ulcerative colitis.


Relationship between cerebral blood flow and blood pressure in long-term heart transplant recipients.
Heart transplant recipients are at an increased risk for cerebral hemorrhage and ischemic stroke; yet, the exact mechanism for this derangement remains unclear. We hypothesized that alterations in cerebrovascular regulation is principally involved. To test this hypothesis, we studied cerebral pressure-flow dynamics in 8 clinically stable male heart transplant recipients (62±8 years of age and 9±7 years post transplant, mean±SD), 9 male age-matched controls (63±8 years), and 10 male donor controls (27±5 years). To increase blood pressure variability and improve assessment of the pressure-flow dynamics, subjects performed squat-stand maneuvers at 0.05 and 0.10 Hz. Beat-to-beat blood pressure, middle cerebral artery velocity, and end-tidal carbon dioxide were continuously measured during 5 minutes of seated rest and throughout the squat-stand maneuvers. Cardiac baroreceptor sensitivity gain and cerebral pressure-flow responses were assessed with linear transfer function analysis. Heart transplant recipients had reductions in R-R interval power and baroreceptor sensitivity low frequency gain (P<0.01) compared with both control groups; however, these changes were unrelated to transfer function metrics. Thus, in contrast to our hypothesis, the increased risk of cerebrovascular complication after heart transplantation does not seem to be related to alterations in cerebral pressure-flow dynamics. Future research is, therefore, warranted.


Myoepithelial cell-specific expression of stefin A as a suppressor of early breast cancer invasion.
Mammography screening has increased the detection of early pre-invasive breast cancers, termed ductal carcinoma in situ (DCIS), increasing the urgency of identifying molecular regulators of invasion as prognostic markers to predict local relapse. Using the MMTV-PyMT breast cancer model and pharmacological protease inhibitors, we reveal that cysteine cathepsins have important roles in early-stage tumorigenesis. To characterize the cell-specific roles of cathepsins in early invasion, we developed a DCIS-like model, incorporating an immortalized myoepithelial cell line (N1ME) that restrained tumor cell invasion in 3D culture. Using this model, we identified an important myoepithelial-specific function of the cysteine cathepsin inhibitor stefin A in suppressing invasion, whereby targeted stefin A loss in N1ME cells blocked myoepithelial-induced suppression of breast cancer cell invasion. Enhanced invasion observed in 3D cultures with N1ME stefin A-low cells was reliant on cathepsin B activation, as addition of the small molecule inhibitor CA-074 rescued the DCIS-like non-invasive phenotype. Importantly, we confirmed that stefin A was indeed abundant in myoepithelial cells in breast tissue. Use of a 138-patient cohort confirmed that myoepithelial stefin A (cystatin A) is abundant in normal breast ducts and low-grade DCIS but reduced in high-grade DCIS, supporting myoepithelial stefin A as a candidate marker of lower risk of invasive relapse. We have therefore identified myoepithelial cell stefin A as a suppressor of early tumor invasion and a candidate marker to distinguish patients who are at low risk of developing invasive breast cancer, and can therefore be spared further treatment. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Habitual Minimalist Shod Running Biomechanics and the Acute Response to Running Barefoot.
The aim of the study was to determine whether habitual minimalist shoe runners present with purported favorable running biomechanithat reduce running injury risk such as initial loading rate. Eighteen minimalist and 16 traditionally cushioned shod runners were assessed when running both in their preferred training shoe and barefoot. Ankle and knee joint kinetics and kinematics, initial rate of loading, and footstrike angle were measured. Sagittal ankle and knee joint stiffness were also calculated. Results of a two-factor ANOVA presented no group difference in initial rate of loading when participants were running either shod or barefoot; however, initial loading rate increased for both groups when running barefoot (p=0.008). Differences in footstrike angle were observed between groups when running shod, but not when barefoot (minimalist:8.71±8.99 vs. traditional: 17.32±11.48 degrees, p=0.002). Lower ankle joint stiffness was found in both groups when running barefoot (p=0.025). These findings illustrate that risk factors for injury potentially differ between the two groups. Shoe construction differences do change mechanical demands, however, once habituated to the demands of a given shoe condition, certain acute favorable or unfavorable responses may be moderated. The purported benefits of minimalist running shoes in mimicking habitual barefoot running is questioned, and risk of injury may not be attenuated.


Microplastics provide new microbial niches in aquatic environments.
Microplastics in the biosphere are currently of great environmental concern because of their potential toxicity for aquatic biota and human health and association with pathogenic microbiota. Microplastics can occur in high abundance in all aquatic environments, including oceans, rivers and lakes. Recent findings have highlighted the role of microplastics as important vectors for microorganisms, which can form fully developed biofilms on this artificial substrate. Microplastics therefore provide new microbial niches in the aquatic environment, and the developing biofilms may significantly differ in microbial composition compared to natural free-living or particle-associated microbial populations in the surrounding water. In this article, we discuss the composition and ecological function of the microbial communities found in microplastic biofilms. The potential factors that influence the richness and diversity of such microbial microplastic communities are also evaluated. Microbe-microbe and microbe-substrate interactions in microplastic biofilms have been little studied and are not well understood. Multiomics tools together with morphological, physiological and biochemical analyses should be combined to provide a more comprehensive overview on the ecological role of microplastic biofilms. These new microbial niches have so far unknown consequences for microbial ecology and environmental processes in aquatic ecosystems. More knowledge is required on the microbial community composition of microplastic biofilms and their ecological functions in order to better evaluate consequences for the environment and animal health, including humans, especially since the worldwide abundance of microplastics is predicted to dramatically increase. Key Points • Bacteria are mainly studied in community analyses: fungi are neglected. • Microbial colonization of microplastics depends on substrate, location and time. • Community ecology is a promising approach to investigate microbial colonization. • Biodegradable plastics, and ecological roles of microplastic biofilms, need analysis.


The high-mobility-group box protein SSRP1/T160 is essential for cell viability in day 3.5 mouse embryos.
The high-mobility-group (HMG) SSRP1 protein is a member of a conserved chromatin-remodeling complex (FACT/DUF/CP) implicated in DNA replication, basal and regulated transcription, and DNA repair. To assist in the functional analysis of SSRP1, the Ssrp1 gene was targeted in murine embryonic stem cells, and the mutation was introduced into the germ line. Embryos homozygous for the targeted allele die soon after implantation, and preimplantation blastocysts are defective for cell outgrowth and/or survival in vitro. The Ssrp1 mutation was also crossed into a p53 null background without affecting growth and/or survival defects caused by loss of Ssrp1 function. Thus, Ssrp1 appears to encode nonredundant and p53-independent functions that are essential for cell viability.


White Light Emission from Vegetable Extracts.
A mixture of extracts from two common vegetables, red pomegranate and turmeric, when photoexcited at 380 nm, produced almost pure white light emission (WLE) with Commission Internationale d'Eclairage (CIE) chromaticity index (0.35, 0.33) in acidic ethanol. It was also possible to obtain WLE in polyvinyl alcohol film (0.32, 0.25), and in gelatin gel (0.26, 0.33) using the same extract mixture. The colour temperature of the WLE was conveniently tunable by simply adjusting the concentrations of the component emitters. The primary emitting pigments responsible for contributing to WLE were polyphenols and anthocyanins from pomegranate, and curcumin from turmeric. It was observed that a cascade of Forster resonance energy transfer involving polyphenolics, curcumin and anthocyanins played a crucial role in obtaining a CIE index close to pure white light. The optimized methods of extraction of the two primary emitting pigments from their corresponding plant sources are simple, cheap and fairly green.


Practice-based learning and improvement.
Workplace learning is becoming increasingly important in all fields. While workplace learning in medicine, also called practice-based learning and improvement (PBLI) is not new, understanding how it works and how it fits with an individual physician's continuing professional development is new. In this article, we describe seven issues associated with PBLI and then pose questions for reflections, as continuing medical education (CME) planners consider working with PBLI.


[Weight gain after functional surgery for Parkinsons disease].
The origin of weight gain after functional surgery for Parkinson's disease (PD) is incompletely known. We have done a prospective study to determine the possible causes of weight gain after pallidal and subthalamic surgery. Twenty-seven patients were studied (9 unilateral pallidotomy, 9 bilateral deep brain stimulation (DBS) of palidum, and 9 bilateral DBS of suthalamic nucleus) with a follow-up of 12 months. The relationship between weight gain and changes in motor situation, levodopa dosage, dyskinesias, dysphagia and mood state were analyzed. The patients filled a questionnaire about the severity and etiology of weight gain. Weight gain was noted in 26 patients (mean of 4.7 kg at 12 months). It was found a significant correlation between weight gain and improvement of dyskinesias (AIMS) (r = 0.461; p = 0.023), the scores of the UPDRS part III, (r = 0.479; p = 0.028), and a significant inverse correlation with the pre-operative weight of the patient (r = 0.399; p = 0.050). Weight gain was most pronounced with bilateral than unilateral pallidal surgery (p = 0.021). The majority of patients referred weight gain as an slight adverse event and secondary to the improvement of dyskinesias. Functional surgery for PD, independently of the surgical target, provokes weight gain which is benign in the majority of cases. Reduction of energy expenditure with respect to the pre-operative situation would be the responsible of that phenomenon.


Identification of Genes that Maintain Behavioral and Structural Plasticity during Sleep Loss.
Although patients with primary insomnia experience sleep disruption, they are able to maintain normal performance on a variety of cognitive tasks. This observation suggests that insomnia may be a condition where predisposing factors simultaneously increase the risk for insomnia and also mitigate against the deleterious consequences of waking. To gain insight into processes that might regulate sleep and buffer neuronal circuits during sleep loss, we manipulated three genes, fat facet (faf), highwire (hiw) and the GABA receptor Resistance to dieldrin (Rdl), that were differentially modulated in a Drosophila model of insomnia. Our results indicate that increasing faf and decreasing hiw or Rdl within wake-promoting large ventral lateral clock neurons (lLNvs) induces sleep loss. As expected, sleep loss induced by decreasing hiw in the lLNvs results in deficits in short-term memory and increases of synaptic growth. However, sleep loss induced by knocking down Rdl in the lLNvs protects flies from sleep-loss induced deficits in short-term memory and increases in synaptic markers. Surprisingly, decreasing hiw and Rdl within the Mushroom Bodies (MBs) protects against the negative effects of sleep deprivation (SD) as indicated by the absence of a subsequent homeostatic response, or deficits in short-term memory. Together these results indicate that specific genes are able to disrupt sleep and protect against the negative consequences of waking in a circuit dependent manner.


Chronic stimulation induces adaptive potassium channel activity that restores calcium oscillations in pancreatic islets in vitro.
Insulin pulsatility is important to hepatic response in regulating blood glucose. Growing evidence suggests that insulin-secreting pancreatic β-cells can adapt to chronic disruptions of pulsatility to rescue this physiologically important behavior. We determined the time scale for adaptation and examined potential ion channels underlying it. We induced the adaptation both by chronic application of the ATP-sensitive K+ [K(ATP)] channel blocker tolbutamide and by application of the depolarizing agent potassium chloride (KCl). Acute application of tolbutamide without pretreatment results in elevated Ca2+ as measured by fura-2AM and the loss of endogenous pulsatility. We show that after chronic exposure to tolbutamide (12-24 h), Ca2+ oscillations occur with subsequent acute tolbutamide application. The same experiment was conducted with potassium chloride (KCl) to directly depolarize the β-cells. Once again, following chronic exposure to the cell stimulator, the islets produced Ca2+ oscillations when subsequently exposed to tolbutamide. These experiments suggest that it is the chronic stimulation, and not tolbutamide desensitization, that is responsible for the adaptation that rescues oscillatory β-cell activity. This compensatory response also causes islet glucose sensitivity to shift rightward following chronic tolbutamide treatment. Mathematical modeling shows that a small increase in the number of K(ATP) channels in the membrane is one adaptation mechanism that is compatible with the data. To examine other compensatory mechanisms, pharmacological studies provide support that Kir2.1 and TEA-sensitive channels play some role. Overall, this investigation demonstrates β-cell adaptability to overstimulation, which is likely an important mechanism for maintaining glucose homeostasis in the face of chronic stimulation.


Clinical characteristics and serum essential fatty acid levels in hyperactive children.
This study compared 48 hyperactive children with 49 age-and-sex-matched controls. Significantly more hyperactive children had auditory, visual, language, reading, and learning difficulties, and the birth weight of hyperactive children was significantly lower than that of controls (3,058 and 3,410 g, respectively; p less than 0.01). In addition, significantly more hyperactive children had frequent coughs and colds, polydypsia, polyuria, and a serious illness or accident in the past year than controls, but there was no increase in asthma, eczema, or other allergies. Serum essential fatty acid (EFA) levels were measured in 44 hyperactive subjects and 45 controls. The levels of docasahexaenoic, dihomogammalinolenic, and arachidonic acids were significantly lower in hyperactive children than controls (docosahexaenoic: 41.6 and 49.5 micrograms/ml serum respectively, p = 0.045; dihomogammolinolenic: 34.9 and 41.3 micrograms/ml serum, p = 0.007; arachidonic: 127.1 and 147.0 micrograms/ml serum, p = 0.027). These findings have possible therapeutic and diagnostic implications, but further research is needed to attempt to replicate these differences.


Nitrate use and changes in bone mineral density: the Canadian Multicentre Osteoporosis Study.
Nitrates may have beneficial effects on bone. To determine if nitrates were associated with increased bone mineral density (BMD), we conducted a secondary analysis using data from subjects in a prospective study. Subjects reporting nitrate use had increased BMD compared with non-users, confirming that nitrates have positive BMD effects in women and men. Prior studies suggest positive associations between nitrates and bone. We used linear regression models, stratified by gender and adjusted for age, weight, and baseline differences, to determine the association between daily nitrate use and BMD among subjects participating in the Canadian Multicentre Osteoporosis Study. All results are reported as annualised percent change in BMD at the hip and spine among nitrate users compared to non-users. We included 1,419 men (71 reported daily nitrate use) and 2,587 women (97 reported daily nitrate use). Male non-users had decreased hip BMD (-1.3%; 95% confidence interval [95%CI] = -1.6 to -1.1) and increased spine BMD (2.8%; 95%CI = 2.5 to 3.1). Male nitrate users had increased hip BMD (1.4%; 95%CI = 0.1 to 2.8) and spine BMD (4.5%; 95%CI = 3.2 to 5.7). Among women, non-users had decreased hip BMD (-1.9; 95%CI = -2.1 to -1.7) and increased spine BMD (2.1%; 95%CI = 1.9 to 2.4) whilst users had an increase in hip BMD (2.0%; 95%CI = 1.2 to 2.8) and spine BMD (4.1%; 95%CI = 3.4 to 4.9). Nitrate use is associated with increased BMD at the hip and spine in men and women.


[Quality and shortages of patient safety--how big is the problem?].
Patient safety is essential to quality health care, to ensure patients are not harmed, but also to ensure that resources are not wasted. More research evidence is becoming available about deficiencies in health care quality and safety. This evidence is reviewed in three consecutive articles in Läkartidningen. Research has discovered high rates of "adverse events" in health care services. The actual rate varies depending on definition, methods of measurement, and type of service. Rates as high as 46% of patients admitted to hospital have been reported. Sometimes high reported rates indicate that a service is serious about collecting data, rather than being an unsafe service. Generally, half of the events can be classified as "avoidable", and a significant proportion as "serious" causing death, disability or a longer hospital stay. Adverse drug events account for a high proportion and are probably the most well studied of patient safety problems. Although most of the current research has been done in the US, there is some evidence which suggests that problems within Swedish health care are of a similar magnitude and type. This article summarises the main studies and focuses on evidence of the economic consequences of deficiencies in patient safety and quality.


Burden of prostate cancer in the Middle East: A comparative analysis based on global cancer observatory data.
Prostate cancer represents a significant global health issue, yet our understanding of its impact in the Middle East remains limited. This study aimed to assess the incidence and mortality of prostate cancer in the Middle East, and compare these rates to those in Europe and North America. We utilized the 2020 Global Cancer Observatory data, compiling incidence and mortality rates of prostate cancer in 20 Middle Eastern countries. We calculated mortality-to-incidence ratios (MIR) and compared the age-standardized incidence rate (ASIR) and MIR between the Middle East and the combined regions of North America and Europe. The countries were further stratified based on the Human Development Index (HDI) and income level for additional analysis. In 2020, the Middle East documented an estimated 51,649 new prostate cancer diagnoses, accounting for 3.7% of global cases. Despite a significantly lower ASIR in the Middle East compared with Europe and North America (10.50 vs. 21.50, p = 0.0087), the region had a higher MIR (12.35 vs. 3.00, p = 0.0476). When stratified based on HDI or income levels, there was no significant difference in MIRs; however, a significant trend of increasing MIR with decreasing HDI (p = 0.028) and income levels (p = 0.016) was observed. Despite a lower incidence, our analysis showed a significantly higher MIR for prostate cancer in the Middle East compared with Europe and North America. These findings underscore the unique challenges posed by prostate cancer in the Middle East and emphasize the necessity of tailored strategies to address this pressing public health issue.