Enhanced intestinal uptake of iron, zinc and calcium in rats fed pungent spice principles--piperine, capsaicin and ginger (Zingiber officinale).
In view of the wide-spread deficiency of iron and zinc in populations dependent on plant foods, it is desirable to improve the bioavailability of the same. Specific dietary spices may alter the ultrastructure and permeability characteristics of intestines. Groups of Wistar rats were fed piperine, capsaicin and ginger containing diets for 8 weeks in order to examine their possible influence on intestinal absorption of iron, zinc and calcium. Everted segments of duodenum, jejunum and ileum portions of small intestines isolated from these rats were examined for ex vivo uptake of iron, zinc and calcium from incubations containing digesta of finger millet. Higher uptake of iron, zinc and calcium by the intestinal segments from spice-fed animals was observed. The increase in the mineral uptake was the highest for calcium with >100% in some cases. The positive influence of dietary capsaicin was more pronounced on zinc uptake as compared to that of iron. Uptake of the glutamic acid standard was 87% and 62% higher in the case of jejunal segments of rats fed piperine and ginger. The higher intestinal uptake of iron and zinc as a result of consumption of pungent spices could encourage a strategy to reduce deficiency of these trace elements prevalent in population dependent on plant based foods.


Structural characterisation and identification of phenylethanoid glycosides from Cistanches deserticola Y.C. Ma by UHPLC/ESI-QTOF-MS/MS.
Phenylethanoid glycosides (PhGs) are the major active constituents of Cistanches deserticola Y.C. Ma. However, the isolation, purification and identification procedures of PhGs are difficult and time-consuming. To establish a rapid and sensitive ultrahigh-pressure liquid chromatography (UHPLC)/ESI (electrospray ion source)-quadrupole time of flight (QTOF)-MS/MS method that could be applied to rapidly profile and identify PhGs. Seven standard compounds were used for the investigation of the fragmentation pattern. Based on the UHPLC/ESI-QTOF-MS/MS method, the important structural information on the types of aglycone and saccharide sequences present should be obtained. According to the HPLC retention behaviour, the proposed fragmentation pathways provided by high-resolution MS and MS/MS spectra and literature sources, a total of 13 PhGs in the crude extract of C. deserticola were identified or tentatively identified. A rapid and accurate UHPLC/ESI-QTOF-MS/MS method was established for the identification of PhGs in the crude extract of C. deserticola. This method therefore can be used for rapid prediction of the chemical constituents and qualities of this plant.


A multiplanet system of super-Earths orbiting the brightest red dwarf star GJ 887.
The closet exoplanets to the Sun provide opportunities for detailed characterization of planets outside the Solar System. We report the discovery, using radial velocity measurements, of a compact multiplanet system of super-Earth exoplanets orbiting the nearby red dwarf star GJ 887. The two planets have orbital periods of 9.3 and 21.8 days. Assuming an Earth-like albedo, the equilibrium temperature of the 21.8-day planet is ~350 kelvin. The planets are interior to, but close to the inner edge of, the liquid-water habitable zone. We also detect an unconfirmed signal with a period of ~50 days, which could correspond to a third super-Earth in a more temperate orbit. Our observations show that GJ 887 has photometric variability below 500 parts per million, which is unusually quiet for a red dwarf.


Catching the second wave: clinical characteristics and nosocomial infection rates in major trauma and orthopaedic patients during the COVID-19 pandemic.
The new COVID-19 variant was reported by the authorities of the UK to the World Health Organization (WHO) on 14 December 2020. We aim to describe the clinical characteristics and nosocomial infection rates in major trauma and orthopaedic patients comparing the first and second wave of COVID-19 infection. A retrospective analysis of a prospectively collected trauma database was reviewed at a level 1 major trauma centre from 1 December 2020 to 18 February 2021 looking at demographics, clinical characteristics, and nosocomial infections and compared to our previously published first wave data (26 January 2020 to 14 April 2020). From 1 December 2020 to 18 February 2021, 522 major trauma patients were identified with a mean age of 54.6 years, and 53.4% (n = 279) were male. Common admissions were falls (318; 60.9%) and road traffic accidents (RTAs; 71 (13.6%); 262 of these patients (50.2%) had surgery. In all, 75 patients (14.4%) tested positive for COVID-19, of which 51 (68%) were nosocomial. Surgery on COVID-19 patients increased to 46 (61.3%) in the second wave compared to 13 (33.3%) in the first wave (p = 0.005). ICU admissions of patients with COVID-19 infection increased from two (5.1%) to 16 (20.5%), respectively (p = 0.024). Second wave mortality was 6.1% (n = 32) compared to first wave of 4.7% (n = 31). Cardiovascular (CV) disease (35.9%; n = 14); p = 0.027) and dementia (17.9%; n = 7); p = 0.030) were less in second wave than the first. Overall, 13 patients (25.5%) were Black, Asian and Minority ethnic (BAME), and five (9.8%) had a BMI > 30 kg/m2. The mean time from admission to diagnosis of COVID-19 was 13.9 days (3 to 44). Overall, 12/75 (16%) of all COVID-19 patients died. During the second wave, COVID-19 infected three-times more patients. There were double the number of operative cases, and quadruple the cases of ICU admissions. The patients were younger with less dementia and CV disease with lower mortality. Concomitant COVID-19 and the necessity of major trauma surgery showed 13% mortality in the second wave compared with 15.4% in the first wave. In contrast to the literature, we showed a high percentage of nosocomial infection, normal BMI, and limited BAME infections. Cite this article: Bone Jt Open 2021;2(8):661-670.


A general approach for developing system-specific functions to score protein-ligand docked complexes using support vector inductive logic programming.
Despite the increased recent use of protein-ligand and protein-protein docking in the drug discovery process due to the increases in computational power, the difficulty of accurately ranking the binding affinities of a series of ligands or a series of proteins docked to a protein receptor remains largely unsolved. This problem is of major concern in lead optimization procedures and has lead to the development of scoring functions tailored to rank the binding affinities of a series of ligands to a specific system. However, such methods can take a long time to develop and their transferability to other systems remains open to question. Here we demonstrate that given a suitable amount of background information a new approach using support vector inductive logic programming (SVILP) can be used to produce system-specific scoring functions. Inductive logic programming (ILP) learns logic-based rules for a given dataset that can be used to describe properties of each member of the set in a qualitative manner. By combining ILP with support vector machine regression, a quantitative set of rules can be obtained. SVILP has previously been used in a biological context to examine datasets containing a series of singular molecular structures and properties. Here we describe the use of SVILP to produce binding affinity predictions of a series of ligands to a particular protein. We also for the first time examine the applicability of SVILP techniques to datasets consisting of protein-ligand complexes. Our results show that SVILP performs comparably with other state-of-the-art methods on five protein-ligand systems as judged by similar cross-validated squares of their correlation coefficients. A McNemar test comparing SVILP to CoMFA and CoMSIA across the five systems indicates our method to be significantly better on one occasion. The ability to graphically display and understand the SVILP-produced rules is demonstrated and this feature of ILP can be used to derive hypothesis for future ligand design in lead optimization procedures. The approach can readily be extended to evaluate the binding affinities of a series of protein-protein complexes.


Molecular hydrogen in sports medicine: new therapeutic perspectives.
In the past 2 decades, molecular hydrogen emerged as a novel therapeutic agent, with antioxidant, anti-inflammatory and anti-apoptotic effects demonstrated in plethora of animal disease models and human studies. Beneficial effects of molecular hydrogen in clinical environment are observed especially in oxidative stress-mediated diseases, such as diabetes mellitus, brain stem infarction, rheumatoid arthritis, or neurodegenerative diseases. A number of more recent studies have reported that molecular hydrogen affects cell signal transduction and acts as an alkalizing agent, with these newly identified mechanisms of action having the potential to widen its application in clinical medicine even further. In particular, hydrogen therapy may be an effective and specific innovative treatment for exercise-induced oxidative stress and sports injury, with potential for the improvement of exercise performance. This review will summarize recent research findings regarding the clinical aspects of molecular hydrogen use, emphasizing its application in the field of sports medicine.


Temporal bone encephaloceles.
This paper reviews the latest literature relating to the diagnosis and treatment of temporal bone encephaloceles, defined as the herniation of meninges or brain tissue into areas of the temporal bone, for example, the petrous apex, tegmen tympani or mastoid cavity. The diagnosis of temporal bone encephaloceles can be challenging. The condition is commonly presented as cerebrospinal fluid otorrhea or rhinorrhea in addition to a variety of symptoms such as conductive hearing loss. Imaging is also important in the diagnosis stage. Management of the condition is surgical, and this review outlines the surgical options. Encephaloceles of the temporal bone are encountered rarely in otologic medicine. Given the possibility of cerebrospinal fluid leaks and meningitis, however, the otolaryngologist or otologist must have a working knowledge of the correct diagnostics and treatments.


Quantification of 11C-MADAM binding to the serotonin transporter in the human brain.
(11)C-N,N-Dimethyl-2-(2-amino-4-methylphenylthio)benzylamine ((11)C-MADAM) is a newly synthesized radioligand with high selectivity and specificity for the serotonin transporter (5-HTT) in a monkey model. The purpose of this study in humans was to examine the suitability and potential of (11)C-MADAM for quantitative PET studies of 5-HTT in applied clinical studies on the pathophysiology and treatment of neuropsychiatric disorders. PET examination was performed on each of 9 male subjects after intravenous injection of (11)C-MADAM with high specific radioactivity. Radioactive metabolites in plasma were determined with high-performance liquid chromatography. A metabolite-corrected arterial input function was used in kinetic 2- and 3-compartment analyses. Cerebellum was used as the reference region in a cross-validation of 6 reference tissue approaches. The highest radioactivity concentration was detected in the raphe nuclei, followed consecutively by the striatum, hippocampal complex, cingulate cortex, neocortex, and cerebellum. The time-activity curve for the fraction of unchanged (11)C-MADAM in plasma was best described by a sigmoid function. After 50 min, the fraction was 40%. The labeled metabolites were more polar than the mother compound. The compartment model approaches converged, and could describe the time-activity curves in all regions. The total volume of distribution (V(t)) was similar to the regional distribution volumes obtained by the linear graphic analysis. The binding potentials (BPs) for 6 different approaches yielded similar values in all regions but the raphe nuclei, where the 2 equilibrium methods provided lower values. The regional binding distribution of (11)C-MADAM is consistent with postmortem data acquired with (3)H-MADAM as well as with that of other reference ligands in vitro. The time-activity curves were well described by current major quantitative approaches. The suitability of the cerebellum as a reference region for nonspecific (11)C-MADAM binding could be confirmed, thus paving the way for experimentally less demanding approaches, such as the simplified reference tissue model, for applied clinical studies.


Power Relations: Their Embodiment in Research.
The purpose of this column is to consider the notion of power in research. To that end, the idea of power is considered from the perspective of philosophy and then linked to a nursing concept analysis that compares the differences between power over and power to. Then, the nature of power relations is compared and contrasted between quantitative and qualitative methodologies.


[An application of a study of medical history to clinical medicine - for better understanding of medical history and its application to clinical medicine].
A study of medical history aims to correctly understand the progress in basic and clinical medical science and to effectively offer better medical service to our patients. The study of medical history has several important advantages, such as; 1) to understand the present medical science in depth and to shorten the duration of time needed to understand the present medicine, 2) to understand the disadvantages of the present medical sciences realizing that they are not perfect, 3) to correctly understand literature and historical documents on medical science, 4) to make and maintain accurate medical records and documents, 5) to create new concepts and 6) to prevent us from developing a rigid way of thinking. Two cases of the application of medical history to clinical medicine are shown. The first is in regard to perioperative blood transfusion. As it was suggested to me by a report that preoperative blood transfusion caused suppression of immune response in kidney transplantation, I thought a routine use of blood transfusion for surgical patients with malignant tumors would lead to a high postoperative recurrence rate of malignancy. Therefore, such a routine use of blood has been avoided inn our institution for these twenty years. The second case is in regard to excitement during the induction of inhaled anesthetics. At present the excitement is considered to be caused by inhibition of the cerebral cortical function. However, our recent clinical study based on Dr. Maeda's report published in 1935 has revealed that the excitement observed during the induction of inhaled anesthesia is caused mainly by stimulation of the trigeminal nerves. The importance of medical history should be much more stressed for medical training of students and residents as well as physicians. It should be widely and deeply applied to the clinical practice of medicine, though it is not so easy to do this. Otherwise, the study of medical history may be considered as only a hobby for retired physicians.


Central nervous system lesions associated with hereditary hemorrhagic telangiectasia--three case reports.
Hereditary hemorrhagic telangiectasia (HHT) is easily overlooked in patients with central nervous system (CNS) lesions. Our clinical experience of three patients with CNS lesions associated with HHT stresses the importance of considering HHT. A 23-year-old male presented with consciousness disturbance and right hemiparesis. Emergency cerebral digital subtraction angiography revealed occlusion of the left middle cerebral artery and the left anterior cerebral artery. Pulmonary arteriography showed three pulmonary arteriovenous malformations (AVMs). A 62-year-old male presented with consciousness disturbance and sensory aphasia. Magnetic resonance imaging revealed a ring-enhanced lesion in the left temporal lobe which was removed by left frontotemporal craniotomy. The diagnosis was brain abscess. Chest computed tomography (CT) revealed two pulmonary AVMs. A 32-year-old female presented with progressive mild weakness in her left hand. Initial CT showed subcortical hemorrhage in the right frontal lobe. Cerebral angiography revealed no vascular malformations, but chest CT disclosed five pulmonary AVMs. All three patients had a family history of HHT. The possibility of HHT is important to consider in patients with cerebrovascular disease (CVD) or brain abscess to prevent complications, not only in the patients but also their blood relatives. Therefore, the medical and family history of patients with CVD or brain abscess should be investigated and HHT should be considered during the physical examination.


Marine natural products. XXXIII. Theonellapeptolide IId, a new tridecapeptide lactone from the Okinawan marine sponge Theonella swinhoei.
Following the characterization of theonellapeptolides Ia-Ie (2-6), another new tridecapeptide lactone named theonellapeptolide IId (1) was isolated from the Okinawan marine sponge Theonella swinhoei. The structure of 1 has been determined on the bases of chemical and physicochemical examinations which included an HPLC-CD combined analysis of the amino acid composition. Theonellapeptolide IId (1) prevented fertilization of the sea urchin Hemicentrotus pulcherrimus at the concentration of 25 micrograms/ml or greater but did not affect early embryonic development of fertilized eggs up to the gastrula stage.


[The changes of main upper gastrointestinal diseases and Helicobacter pylori infection status in the past thirty five years].
To study the spectrum of upper gastrointestinal diseases and infection rate of Helicobacter pylori(Hp)in our hospital during the past 35 years. Patients who were 16 or older with duodenal ulcer, gastric ulcer, reflux esophagitis, gastric cancer and esophageal cancer diagnosed by gastroscopy and pathology were retrospectively enrolled in our study from January 1980 to December 2014.Patients with chronic superficial gastritis, chronic atrophic gastritis or Hp infection from January 1989 to December 2014 were also included in our study according to the same diagnostic criteria.The incidences of diseases and the infection rates of Hp were studied. A total of 213 495 patients underwent gastroscopy in our department during the past 35 years.The overall diagnostic rates of duodenal ulcer, gastric ulcer, reflux esophagitis, gastric cancer and esophageal cancer were 9.87%, 3.79%, 6.66%, 1.59% and 0.66% respectively.There were 183 426 patients receiving gastroscopy in our department from January 1989 to December 2014. The overall endoscopic diagnosis rates of chronic superficial gastritis and chronic atrophic gastritis were 49.83% and 22.43% respectively.The overall infection rate of Hp was 36.18%, which had a declining trend consistent with peptic ulcer (all P=0.000). Yet, the prevalence of reflux esophagitis, chronic superficial gastritis and chronic atrophic gastritis were increasing (all P=0.000). The diagnostic rates of gastric cancer and esophageal cancer were persistent (P=0.266, P=0.156). The Hp infection during years has been decreasing, consistent with the declining tendency of peptic ulcer.On the other hand, reflux esophagitis, chronic superficial gastritis and chronic atrophic gastritis show an ascendant trend.The proportion of patients with gastric cancer and esophageal cancer is relatively stable.


Multiview Rectification of Folded Documents.
Digitally unwrapping images of paper sheets is crucial for accurate document scanning and text recognition. This paper presents a method for automatically rectifying curved or folded paper sheets from a few images captured from multiple viewpoints. Prior methods either need expensive 3D scanners or model deformable surfaces using over-simplified parametric representations. In contrast, our method uses regular images and is based on general developable surface models that can represent a wide variety of paper deformations. Our main contribution is a new robust rectification method based on ridge-aware 3D reconstruction of a paper sheet and unwrapping the reconstructed surface using properties of developable surfaces via conformal mapping. We present results on several examples including book pages, folded letters and shopping receipts.


Ultrafast relaxation and reaction of diiodide anion after photodissociation of triiodide in room-temperature ionic liquids.
Vibrational dephasing, vibrational relaxation, and rotational relaxation of diiodide (I(2)(-)) after photodissociation of triiodide (I(3)(-)) in room-temperature ionic liquids (RTILs) were investigated by ultrafast transient absorption spectroscopy. The vibrational energy relaxation (VER) rate of I(2)(-) produced by the photodissociation reaction of I(3)(-) was determined from the spectral profile of the transient absorption. The rates in RTILs were slightly slower than those in conventional liquids. On the other hand, the coherent vibration of I(2)(-) was not observed in RTILs, and the vibrational dephasing of the photoproduced I(2)(-) was accelerated. This was explained by the interaction between I(2)(-) and I consisting of a caged contact pair in RTILs. The orientational relaxation time of I(2)(-) determined by the transient absorption anisotropy was much longer in RTILs than in conventional liquids due to their high viscosities although the relaxation time was shorter than the prediction from the Stokes-Einstein-Debye (SED) theory. The deviation from the SED prediction was interpreted by the frequency dependence of the shear stress acting on the molecule. The dynamics of I(2)(-) in 1-butyl-3-methylimidazolium iodide ([BMIm]I) were quite different from those in other conventional RTILs: the coherent vibration of I(2)(-) was observed for the time profile of the transient absorption and the initial value of the anisotropy was reduced to 0.31 from 0.36 in conventional RTILs. These results suggest that an ultrafast reaction between the photofragment I and the solvent I(-) may occur during the photodissociation process of I(3)(-). The anomaly in the ground state coherent vibration and steady state Raman spectrum of I(3)(-) also suggest the possibility that I(3)(-) and I(-) can be located in vicinity and interact strongly with each other in [BMIm]I.


Pro-Angiogenesis Therapy and Aging: A Mini-Review.
Apart from major illnesses and chronic afflictions, the elderly experience lesser ailments, such as muscle weakness, cold intolerance, and transient memory lapses. Physical signs in the aged include wrinkled skin and the slow healing of skin abrasions. These ailments and signs are grouped together because they may be due in part to an age-linked, waning microcirculation. A reduced capillary density (CD) throughout the body of aged people and animals has been reported in over 40 papers. The reduced CD is due in turn to declining levels of angiogenic growth factors (AGFs) throughout the body during old age, as documented in 7 reports in the literature. From this perspective, old age is a deficiency state of AGFs, much like the reduced testosterone levels in elderly males. The above data on reduced CD and AGFs are the basis for the "angiogenesis hypothesis of aging", whose corollary suggests pro-angiogenesis therapy for symptoms and signs of old age. Several AGFs are now available in recombinant forms (e.g., vascular endothelial growth factor) and have been used safely in animal experiments and in short-term clinical trials.


Spatial Epidemiology of Alcohol- and Drug-Related Health Problems Among Northern Plains American Indians: Nebraska and South Dakota, 2007 to 2012.
Despite high abstinence rates, American Indians experience elevated rates of many alcohol and other drug problems. American Indians also predominantly reside in poor and rural areas, which may explain some observed health disparities. We investigated whether geographic areas including reservations or large American Indian populations exhibited greater incidence of alcohol- and drug-related hospitalizations. We obtained inpatient hospitalization records for 2 Northern Plain states (Nebraska and South Dakota) for the years 2007 to 2012. We constructed zip code counts for 10 categories of hospitalization with diagnoses or injury causation commonly associated with alcohol or drug use. We related these to community sociodemographic characteristics using Bayesian Poisson space-time regression models and examined associations with and without controls for whether each zip code was located within an American Indian reservation. Controlling for other demographic and economic characteristics, zip codes with greater percentage of American Indians exhibited greater incidence for all 10 substance abuse-related health outcomes (9 of 10 well supported); zip code areas within American Indian reservations had greater incidence of self-inflicted injury and drug dependence and abuse, and reduced incidence of alcohol cirrhosis and prescription opioid poisoning. However, the analyses generally demonstrated no well-supported differences in incidence associated with local residence percentages of American Indian versus African American. In our analyses, ethnicity or heredity alone did not account for alcohol- and drug-related hospitalizations among Native populations. Aspects of social, economic, and political dimensions of Native lives must be considered in the etiology of alcohol- and drug-related problems for rural-dwelling indigenous peoples.


Extraarticular drilling for stable osteochondritis dissecans in the skeletally immature knee.
Osteochondritis dissecans of the knee is an increasingly frequent diagnosis in the skeletally immature, in whom it is known as juvenile osteochondritis dissecans (JOCD). Although many stable lesions heal with nonoperative treatment, surgical management may be necessary when this treatment fails. Our objective is to determine if extraarticular drilling is an effective treatment for JOCD. Patients who underwent extraarticular drilling for stable JOCD of the knee at the authors' institution between 1998 and 2006 were identified. Demographic information, the location of the lesion, duration of symptoms before surgery, occurrence of complications, postoperative course, and length of follow-up were documented from each patient's medical record. The outcome measures were normal examination, radiographic evidence of healing, and full return to activity. Fifteen skeletally immature patients (16 knees) were identified. There were 8 boys and 7 girls, with 8 right and 8 left knees. One girl had bilateral lesions. The lesions were located in the medial femoral condyle in 12 knees and in the lateral femoral condyle in 4 knees. The average duration of symptoms before surgery was 21 months (range, 3 months-9 years). The average age at the time of surgery was 12 years, 4 months (range, 9-15 years). There were no intraoperative or postoperative complications. The average follow-up was 21 months (range, 8-38 months). Three of the 15 patients were lost to follow-up. In the remaining 12 patients, 12 knees had excellent outcomes with full return to activities, normal examinations, and radiographic evidence of healing. One knee had fair results. On average, these criteria were met at 8.5 months after surgery. When nonoperative management of stable JOCD fails, arthroscopic extraarticular drilling is an effective treatment to protect the articular surface and promote bone healing. Level IV case series.


Oxypurines, protein, glucose and the functional state of blood vasculature are markers of renal calcium stone-forming processes? Observations in men with idiopathic recurrent calcium urolithiasis.
In idiopathic calcium urolithiasis the relationships between oxypurines, accompanying proteins and glucose in urine and plasma, and the associated metabolic activity (MA) are unknown. To establish whether MA is related to these parameters and to calcium oxalate crystallization, or whether it reflects a reaction of metabolism to systemic insults was the major goal of the work. One hundred fifty one males were studied in three trials: trial 1 (n=130 patients) and trial 2 (n=24 patients) were cross-sectional; trial 3 included 11 patients and 14 controls). Mean age was 46 years (trials 1 and 2) and 29 years (trial 3). In trial 1 the stratification was based on the median urinary oxypurine excretion, in trial 2 on the median plasma oxypurine concentration (below or above: Low and High subgroups). No dietary restrictions were imposed, but standardized ambulatory laboratory testing was carried out. MA was quantitated by a score. Established analytical methods were used, except for oxypurine measurement which was done by high performance liquid chromatography. Patients with kidney stones tended to be overweight (body mass index >25 kg/(m)2) and to have fasting hyperglycemia. In trial 1 severe oxypurinuria, and especially severe xanthinuria, was associated with an increase in urinary pH, creatinine clearance, proteins, uric acid, malonedialdehyde (indicator of lipid peroxidation), systolic blood pressure, and with a decrease in plasma uric acid (synonymous with a decrease of antioxidant capacity). Tubular reabsorption of proteins and stone-forming substances was diminished but MA remained unchanged despite slightly increased calcium oxalate crystal growth. In trial 2 high adenosine and xanthine coincided with elevated systolic and diastolic blood pressure, high uric acid with high urinary malonedialdehyde, high summed oxypurines minus uric acid with an increase of diastolic blood pressure, glycemia and MA; urinary nitrate (indicator of systemic vasodilation) was unchanged. In trial 3 patients' oxypurinemia and proteinuria were normal, but body mass index, glycemia and insulinemia were increased. Urinary total protein, albumin and non-albumin proteins were positively predicted (multivariate regression analysis) by urinary xanthine, glucose and pH (trial 1); MA was positively (trial 3) or negatively (trial 2) predicted by urinary total protein. In calcium urolithiasis, a disorder of affluence, 1) oxypurinuria and proteinuria and oxypurinemia and MA appear causally linked, presumably via oxidant/antioxidant imbalance-induced renal tissue damage; 2) urinary proteins may act as inhibitors or promoters of stone-forming processes; 3) a stone-initiating role of impaired vasodilatation is conjectural; 4) overweight, obesity, mild glucosuria and hyperdynamic blood circulation are regular signs.


Diagnostic outpatient aspiration curettage. Two years experience.
Endometrial aspiration curettage was performed on 1001 women, without anaesthesia. Our experience confirms that Vabra-curettage is, for patients, a simple and well tolerated sampling technic. We were not able to perform the technic in 18 patients for close cervical stenosis. In 41 patients the samples were quantitatively not adequate for a correct histological diagnosis. In all these cases a control by D & C was performed, in general anaesthesia, and no proliferative pathology was found. The most common presenting symptom in Intraepithelial Carcinoma of Endometrium (ICE) and in carcinoma was abnormal vaginal bleeding; nevertheless 5 cases of ICE and 2 cases of adenocarcinoma did not show any symptom. This study confirms that systematic screening of asymptomatic perimenopausal and postmenopausal women may lead to the discovery of occult endometrial cancers, some of which are advanced.


Neoadjuvant gemcitabine-based accelerated hyperfractionation chemoradiotherapy for patients with borderline resectable pancreatic adenocarcinoma.
We report the response to pre-operative gemcitabine-based chemoradiotherapy for pancreatic adenocarcinoma. Thirty-five consecutive patients with borderline resectable pancreatic adenocarcinoma of UICC Stage II or III with portal vein invasion or tumor abutment of artery received radiotherapy (twice daily fractions of 1.5 Gy, 5 days/week, total dose: 36 Gy; 30 Gy for Phase I Level 1) with weekly intravenous infusions of gemcitabine (400, 600 and 800 mg/m(2)) at Days 1 and 8 for Phase I and 800 mg/m(2) for Phase II. Restaging was repeated after completion of chemoradiotherapy. Twenty-six of the 35 (74.3%) patients underwent resection. The dose-limiting toxicities were Grade 4 neutropenia and thrombocytopenia. The recommended regimen was total radiation dose of 36 Gy with gemcitabine 800 mg/m(2). Surgical resection was conducted in 11 of the 15 (73.3%) patients in Phase I study and 15 of the 20 (75.0%) in Phase II. After recommended dose chemoradiotherapy and surgical resection, the median disease-free survival was 17.4 months (5-year survival rate = 14.3%). The median overall survival time and 5-year survival rate were 41.2 months and 28.6%, respectively, for the 21 patients who underwent resection and 10.0 months and 0%, respectively, for those 5 who did not (P = 0.004). Our pre-operative gemcitabine-based chemoradiotherapy was well tolerated and safe.


Metabolic Dysfunction in Alzheimer's Disease: From Basic Neurobiology to Clinical Approaches.
Clinical trials have extensively failed to find effective treatments for Alzheimer's disease (AD) so far. Even after decades of AD research, there are still limited options for treating dementia. Mounting evidence has indicated that AD patients develop central and peripheral metabolic dysfunction, and the underpinnings of such events have recently begun to emerge. Basic and preclinical studies have unveiled key pathophysiological mechanisms that include aberrant brain stress signaling, inflammation, and impaired insulin sensitivity. These findings are in accordance with clinical and neuropathological data suggesting that AD patients undergo central and peripheral metabolic deregulation. Here, we review recent basic and clinical findings indicating that metabolic defects are central to AD pathophysiology. We further propose a view for future therapeutics that incorporates metabolic defects as a core feature of AD pathogenesis. This approach could improve disease understanding and therapy development through drug repurposing and/or identification of novel metabolic targets.


Counting stem cells: methodological constraints.
The number of stem cells contributing to hematopoiesis has been a matter of debate. Many studies use retroviral tagging of stem cells to measure clonal contribution. Here we argue that methodological factors can impact such clonal analyses. Whereas early studies had low resolution, leading to underestimation, recent methods may result in an overestimation of stem-cell counts. We discuss how restriction enzyme choice, PCR bias, high-throughput sequencing depth and tagging method could affect the conclusions of clonal studies.


Enhanced Photoluminescence Detection of Immunocomplex Formation by Antibody-Functionalized, Ge-Doped Biosilica from the Diatom Cyclotella sp.
Diatoms are single-celled algae that biosynthesize cell walls of biogenic silica called "frustules" that are intricately patterned at the submicron- and nanoscale. In this study, we amplified the intrinsic luminescent properties of antibody-functionalized diatom biosilica frustules for enhanced, label-free, photoluminescence (PL) detection of immunocomplex formation. It was hypothesized that metabolically doped GeO centers in antibody-functionalized diatom biosilica would enhance PL emission associated with nucleophilic immunocomplex formation. Germanium (Ge) was metabolically inserted into the frustule biosilica by two-stage cell cultivation of the centric diatom Cyclotella sp. The biosilica frustules were isolated by hydrogen peroxide treatment and thermally annealed to convert Ge oxides in the biosilica (0.4 wt% Ge) to luminescent GeO centers. The Ge-doped biosilica frustules were then functionalized with Rabbit Immunoglobulin G (IgG). Upon immunocomplex formation with its complimentary antigen goat anti-Rabbit IgG, the Ge-oxide doped, antibody-functionalized frustule biosilica increased the intensity of PL emission by a factor of 2.6 relative to immunocomplex formation by antibody-functionalized frustule biosilica without Ge. It is proposed that the luminescent GeO centers in the Ge-oxide doped frustule biosilica were more sensitive to radiative recombination than luminescent silanol groups in frustule biosilica without Ge, resulting in a higher PL emission upon immunocomplex formation.


Personality traits of the Five-Factor Model are associated with work-related stress in special force police officers.
The police work is particularly stressful. The aim of this work was to clarify whether the personality factors are associated with perceived stress levels or reactivity to environmental stressors in a special body of police. The police officers in charge of guaranteeing public order at the L'Aquila G8 meeting were subjected to a control of their levels of work-related stress in anticipation of the event. Personality was assessed by the Italian version of the Five-Factor Model questionnaire, while stress was measured three times (during routine work in January 2009, preparation and imminence of the event, in April and July 2009, respectively) with the demand/control/support model of Karasek and the effort/reward imbalance model of Siegrist. A total of 289 of 294 officers took part in the survey. Some personality traits of the Five-Factor Model were associated with stress levels and stress reactivity. Neuroticism (low emotional stability) showed the strongest associations with job strain (demand/control ratio) (β = 0.115, p < 0.05) and effort/reward imbalance (β = 0.270, p < 0.001) and was associated with most of the stress variables. High agreeableness was associated with low effort/reward imbalance (β = -0.157, p < 0.01). Personality factors may mitigate or increase the strain induced by environmental stressors.


[Weibel-Palade bodies in endothelial cells in human dental pulp].
The bodies of Weibel-Palade (BWP) were first described in 1964 in the endothelial cells of human and rat pulmonary arteries. They are probably present in the blood vessels of all human and animal tissues. Their high concentration in blood capillaries of human dental pulp makes this tissue is a good model for their study. 107 transverse pulpal sections of BWP were selected from 15 pulps. The distribution of the tubules in the matrix from regular patterns. A simple linear regression study showed that the transverse diameter of BWP is proportional to the number of contained tubules. The functions of the Von Willebrand factor or antigenic portion of factor VIII being stored in BWP of endothelial cells of other tissues is discussed.


Quantitative flow measurements on phantoms and on blood vessels with MR.
A broad spectrum of MR methods has been published in the last few years for the visualization and the quantification of flow in human blood vessels. We describe the results of an extended study to measure the flow quantitatively using the MR phase modulation method. A gradient echo sequence which allows short repetition times was synchronized with the ECG. The instantaneous velocity profiles and the integrated flow rate can be determined throughout the cardiac cycle in up to 45 consecutive time intervals. The instantaneous velocity distributions can be displayed as 2D profiles over the lumen of the blood vessel. The technique has been successfully evaluated with a set of phantom experiments. Following this, quantifications of the blood flow rates in vivo were performed on the abdominal aortas of healthy volunteers. The MR flow results were compared to those obtained with conventional Doppler ultrasound examinations. The results of both methods are in good quantitative agreement.


Yield stress-enabled microencapsulation of field responsive microparticle suspensions.
Try and encapsulate microparticles inside the cores of microcapsules and you will often find that particles adhere to the liquid-liquid interface in a phenomenon known as Pickering stabilization. Particles will remain irreversibly trapped and embedded within the subsequently formed microcapsule membrane. In cases where the encapsulant particles must remain suspended inside the microcapsule core to retain their desired properties or behaviours, Pickering stabilization is detrimental. Here we demonstrate a general procedure using yield stress materials as the core material, where the yield stress of the gel is strong enough to suspend particles against sedimentation, but weak enough to allow spatial manipulation of encapsulant particles using an external field. This external field imparts enough force on particles to disrupt the supporting network and allow particle mobility after encapsulation.


An assessment of the effects of neurokinin1 receptor antagonism against nausea and vomiting: Relative efficacy, sites of action and lessons for future drug development.
A broad-spectrum anti-vomiting effect of neurokinin1 receptor antagonists (NK1 RA), shown in pre-clinical animal studies, has been supported by a more limited range of clinical studies in different indications. However, this review suggests that compared with vomiting, the self-reported sensation of nausea is less affected or possibly unaffected (depending on the stimulus) by NK1 receptor antagonism, a common finding for anti-emetics. The stimulus-independent effects of NK1 RAs against vomiting are explicable by actions within the central pattern generator (ventral brainstem) and the nucleus tractus solitarius (NTS; dorsal brainstem), with additional effects on vagal afferent activity for certain stimuli (e.g., highly emetogenic chemotherapy). The central pattern generator and NTS neurones are multifunctional so the notable lack of obvious effects of NK1 RAs on other reflexes mediated by the same neurones suggests that their anti-vomiting action is dependent on the activation state of the pathway leading to vomiting. Nausea requires activation of cerebral pathways by projection of information from the NTS. Although NK1 receptors are present in cerebral nuclei implicated in nausea, and imaging studies show very high receptor occupancy at clinically used doses, the variable or limited ability of NK1 RAs to inhibit nausea emphasizes: (i) our inadequate understanding of the mechanisms of nausea; and (ii) that classification of a drug as an anti-emetic may give a false impression of efficacy against nausea vs. vomiting. We discuss the potential mechanisms for the differential efficacy of NK1 RA and the implications for future development of drugs that can effectively treat nausea, an area of unmet clinical need.


Fructated apolipoprotein A-I exacerbates cellular senescence in human umbilical vein endothelial cells accompanied by impaired insulin secretion activity and embryo toxicity.
Glycation of apolipoproteins is a major feature of the production of dysfunctional high-density lipoprotein (HDL), which is associated with the incidence of several metabolic diseases such as coronary artery disease and diabetes. In this report, fructated apoA-I (fA-I) induced by fructose treatment showed a covalently multimerized band without cross-linking, and lysine residues were irreversibly modified to prevent crosslinking. Using pancreatic β-cells, insulin secretion was impaired by fA-I in the lipid-free and reconstituted HDL (rHDL) states, by up to 35%, and 40%, respectively, under hyperglycemic conditions (25 mmol/L glucose). Treatment of human umbilical vein endothelial cells (HUVECs) with fA-I and HDL from elderly patients caused a 1.8-fold and 1.5-fold increased cellular senescence, respectively, along with increased lysosomal enlargement. In the lipid-free and rHDL states, fA-I increased embryo death by 1.5-fold and 2.5-fold, respectively, along with the production of oxidized species. Furthermore, rHDL containing fA-I (fA-I-rHDL) showed a higher isoelectric point (pI, approximately 8.5), whereas rHDL containing nA-I (nA-I-rHDL) showed a narrow band range with lower pI (around 8.0) as well as a much smaller particle size than that of nA-I-rHDL. In conclusion, fructose-mediated apoA-I fructation resulted in the severe loss of several beneficial functions of apoA-I and HDL, including anti-senescence and insulin secretion activities, accompanied with increased susceptibility to protein degradation and structural modification.


An exchange method to investigate the kinetics of Cd complexation in soil solutions.
Knowledge of the dynamic speciation of metals in soil solution is necessary for soil-plant transfer models. The lability of a metal in a given context partly depends on the kinetics of interconversion between the free ion (M) and one complex (ML), governed by the association (c(k)a) and dissociation (c(k)d) rate constants of the reaction of formation of ML If only one single complex is assumed to be present in solution, a single kinetic experiment will enable estimation of ckd and cka', that is, the product of cka by the concentration of free ligand in solution. The method consists of the measurements over time of the radioactive metal remaining in solution after the labeling of a Ca resin--solution system in balanceforthe nonlabeled metal initially present. The method is described for Cd and was applied on four soil solution extracts. The order of magnitude of the estimated c(k)a'- and c(k)d-values was about 10(-3) s(-1). The advantages and drawbacks of the method are discussed.


Structural basis for three-step sequential catalysis by the cholesterol side chain cleavage enzyme CYP11A1.
Mitochondrial cytochrome P450 11A1 (CYP11A1 or P450 11A1) is the only known enzyme that cleaves the side chain of cholesterol, yielding pregnenolone, the precursor of all steroid hormones. Pregnenolone is formed via three sequential monooxygenation reactions that involve the progressive production of 22R-hydroxycholesterol (22HC) and 20α,22R-dihydroxycholesterol, followed by the cleavage of the C20-C22 bond. Herein, we present the 2.5-Å crystal structure of CYP11A1 in complex with the first reaction intermediate, 22HC. The active site cavity in CYP11A1 represents a long curved tube that extends from the protein surface to the heme group, the site of catalysis. 22HC occupies two-thirds of the cavity with the 22R-hydroxyl group nearest the heme, 2.56 Å from the iron. The space at the entrance to the active site is not taken up by 22HC but filled with ordered water molecules. The network formed by these water molecules allows the "soft" recognition of the 22HC 3β-hydroxyl. Such a mode of 22HC binding suggests shuttling of the sterol intermediates between the active site entrance and the heme group during the three-step reaction. Translational freedom of 22HC and torsional motion of its aliphatic tail are supported by solution studies. The CYP11A1-22HC co-complex also provides insight into the structural basis of the strict substrate specificity and high catalytic efficiency of the enzyme and highlights conserved structural motifs involved in redox partner interactions by mitochondrial P450s.


Ischemia/reperfusion injury: The role of CD26/dipeptidyl-peptidase-IV-inhibition in lung transplantation.
CD26/Dipeptidyl peptidase (DPP) IV is an integral membrane protein of lymphocytes that modulates the activities of chemokines, interleukins, and neuropeptides. We investigated the effect of enzymatic DPP IV inhibition on ischemia/reperfusion injury after extended ischemia prior to transplantation. We used a syngeneic rat (Lewis) orthotopic left lung transplantation model. In the control group (group I), donor lungs were flushed and preserved in Perfadex for 18 hours at 4 degrees C, then transplanted and reperfused for 2 hours. Group II donor lungs were perfused with and stored in Perfadex +25mol/L AB192 (bis(4-acetamidophenyl) 1-(S)-prolylpyrrolidine-2(R,S)-phosphonate), a small molecular weight DPP IV inhibitor. After 2-hour reperfusion, we measured blood gas, peak airway pressure, and thiobarbituric acid reactive substances. Grafts from group II versus group I showed a significantly increased oxygenation capacity (II: 298.4 +/- 87.6 mm Hg vs 120.9 +/- 48.0, P < .01), lower peak airway pressure (11.8 +/- 0.9 mm Hg vs 16.0 +/- 1.4, P < .01), and less lipid peroxidation (9.3 +/- 2.0 micromol/L vs 13.8 +/- 1.8, P < .01). Inhibition of intragraft DPP IV enzymatic activity significantly reduced ischemia/reperfusion-associated pulmonary injury, allowing for successful transplantation after 18 hours of ischemia.


A Newly Developed Tri-Leaflet Polymeric Heart Valve Prosthesis.
The potential of polymeric heart valves (PHV) prostheses is to combine the hemodynamic performances of biological valves with the durability of mechanical valves. The aim of this work is to design and develop a new tri-leaflet prosthetic heart valve (HV) made from styrenic block copolymers. A computational finite element model was implemented to optimize the thickness of the leaflets, to improve PHV mechanical and hydrodynamic performances. Based on the model outcomes, 8 prototypes of the designed valve were produced and tested in vitro under continuous and pulsatile flow conditions, as prescribed by ISO 5840 Standard. A specially designed pulse duplicator allowed testing the PHVs at different flow rates and frequency conditions. All the PHVs met the requirements specified in ISO 5840 Standard in terms of both regurgitation and effective orifice area (EOA), demonstrating their potential as HV prostheses.


Ursodeoxycholic acid for chronic liver diseases.
Different bile acids have different effects on liver cells, depending on the degree of hydroxylation of the bile acid and the orientation of hydroxy groups. In decreasing order of hydrophobicity, and therefore hepatotoxicity, the bile acids may be ranked as follows: lithocholic greater than deoxycholic greater than chenodeoxycholic greater than cholic greater than ursodeoxycholic acid. The rationale for the use of ursodeoxycholic acid in chronic liver disease is to increase the overall hydrophilicity of the bile acid pool, which, because of cholestasis, retains potentially hepatotoxic bile acids. Recent clinical studies have indicated that ursodeoxycholic acid improves liver function indices in patients with primary biliary cirrhosis and chronic hepatitis at doses ranging between 10 and 15 mg/kg/day. These doses would be considered in the high range in the use of ursodeoxycholic acid for gallstone dissolution. In a preliminary study we found that also lower doses were effective in primary biliary cirrhosis. Two studies to determine the optimal dose of ursodeoxycholic acid for chronic hepatitis and anicteric primary biliary cirrhosis were then carried out. Eighteen patients with primary biliary cirrhosis and 12 patients with chronic hepatitis were treated with 250, 500, and 750 mg of ursodeoxycholic acid per day for three consecutive 2-month periods. Highly significant decreases in serum enzyme levels were seen with the 250 mg/day dose, which were further improved by the higher doses. The improvement roughly paralleled the enrichment of conjugated bile acids with ursodeoxycholic acid. A separate study investigating the effect of shifting the bile acid pool composition toward less detergent moieties was also done.(ABSTRACT TRUNCATED AT 250 WORDS)


Brain Natriuretic Peptide Is a Powerful Predictor of Outcome in Stroke Patients with Atrial Fibrillation .
Since stroke patients with nonvalvular atrial fibrillation (NVAF) have poor outcomes in general, the prediction of outcomes following discharge is of utmost concern for these patients. We previously reported that brain natriuretic peptide (BNP) levels were significantly higher in NVAF patients with larger infarcts, higher modified Rankin Scale (mRS) score, and higher CHADS2 score. In the present study, we evaluated an array of variables, including BNP, in order to determine significant predictors for functional outcome in patients with NVAF after acute ischemic stroke (AIS). A total of 615 consecutive patients with AIS within 48 h of symptom onset, admitted to our hospital between April 2010 and October 2015, were retrospectively searched. Among these patients, we enrolled consecutive patients with NVAF. We evaluated the mRS score 3 months after onset of stroke and investigated associations between mRS score and the following clinical and echocardiographic variables. Categorical variables included male sex, current smoking, alcohol intake, hypertension, diabetes mellitus, dyslipidemia, coronary artery disease, peripheral artery disease, use of antiplatelet drugs, anticoagulants, or tissue plasminogen activator (tPA), and infarct size. Continuous variables included age, systolic blood pressure (SBP), diastolic blood pressure, hemoglobin, creatinine, D-dimer, brain natriuretic peptide (BNP), left atrial diameter, left ventricular ejection fraction (EF), and early mitral inflow velocity/diastolic mitral annular velocity (E/e'). We also analyzed the association of prestroke CHADS2, CHA2DS2-VASc, and R2CHADS2 scores, and National Institutes of Health Stroke Scale (NIHSS) score on admission with mRS score 3 months after the onset of stroke. Patients were classified into 2 groups according to mRS score: an mRS score ≤2 was defined as good outcome, an mRS score ≥3 was defined as poor outcome. To clarify the correlations between categorical or continuous variables and mRS score, uni- and multivariate logistic regression models using the stepwise variable selection method were applied. Among 157 patients with NVAF after AIS, 63.7% were male and the mean age was 75.9 years. In univariate regression analysis, poor outcome (mRS score ≥3) was associated with use of tPA, infarct size, age, SBP, BNP, EF, and NIHSS score. In multivariate regression analysis, BNP levels (odds ratio [OR] 6.40; 95% confidence interval [CI] 1.26-32.43; p = 0.0235) and NIHSS score (OR 2.87; 95% CI 1.84-4.47; p < 0.001) were significantly associated with poor outcome (mRS score ≥3) after adjusting for use of tPA, infarct size, age, BNP, EF, and NIHSS score. Apart from NIHSS score, BNP was a very useful predictor for long-term outcomes of patients with NVAF after AIS. .


Serum nitric oxide levels in patients with coronary artery disease.
Nitric oxide (NO) plays a pivotal role in the pathophysiology of coronary artery disease. The roles of NO are not only physiological but also pathological in the cardiovascular system. An inappropriate release of NO has been linked to the pathogenesis of CAD. The authors investigated whether serum NOx (nitrate and nitrite), a stable end product of NO, level was related to patients with coronary artery disease. The blood chemistry, such as cholesterol, triglyceride, LDL-C, HDL-C and blood sugar, was also measured in comparison with serum NOx. Serum NOx was measured in samples from 20 healthy controls, 20 angina patients without angiographic evidence of coronary lesions (CAG) and 20 angina patients with angiographic evidence of coronary lesions (CAD) by using modified Griess reaction. The mean serum NOx levels in the CAD groups was higher than CAG and control groups (41.3 +/- 5.5, 32.7 +/- 3.9 and 25.7 +/- 3.5 micromol/L, respectively). NOx levels in the CAD group was only significantly higher than the control groups (p < 0.05) but not the CAG groups. There were no significant differences of NOx levels in all age groups. In the CAD group, women showed significantly higher NOx levels than men (64.0 +/- 7.5 and 29.0 +/- 4.7 microl/L, respectively, p < 0.05). Interestingly, the mean serum NOx levels in the CAD groups was significantly higher in a group of abnormal lipid profiles (cholesterol, triglyceride, LDL-C) and blood sugar than in a group of normal profiles. The results suggested that there was an increased NOx levels in patients with coronary artery disease and much higher in patients with multiple underlying conditions such as hyperlipidemia and hyperglycemia. Thus, the measurement of the NOx levels at different times may help to monitor the state and severity of coronary artery disease.


Root dentine thickness in C-shaped lower second molars after instrumentation: A CBCT and micro-CT study.
Stripping perforation is a possible complication in instrumentation of C-shaped canals. This study evaluated the minimum thickness of the root canal wall in C-shaped teeth after instrumentation. Twelve extracted C-shaped mandibular second molars (four teeth of type I, II and III each) were examined by CBCT (voxel size 90 μm) before and after instrumentation with WOG primary file. Micro-CT scans (voxel size 30 μm) were obtained after instrumentation. Percentage of canal wall area touched by the file and minimum thickness of dentine were measured and compared between CBCT and micro-CT. In type I C-shape canals, less than 10% of the canal wall area was touched by the instrument. In ten teeth, the shortest distance to root surface was from the instrumented area; no perforations occurred. CBCT and micro-CT measurements were in good agreement in ten cases; in two teeth, micro-CT revealed considerably shorter distance to root surface. The two shortest distances were 0.27 and 0.41 mm.


The cue-familiarity heuristic in metacognition.
Four experiments contrasted the cue-familiarity hypothesis of feeling-of-knowing judgments (FKJs) and tip-of-the-tongue feelings (TOTs) to the target-retrievability hypothesis. Familiarity of the cues was contrasted to memorability of the targets in a paired-associate design (e.g., A-B A-B, A-B A-B', A-B A-D, A-B C-D), in which the number of repetitions of the cue A terms was dissociated from the memorability of the target B terms. Little support was found for the target-retrievability hypothesis, because in none of the 4 experiments were FKJs related to target memorability. In one experiment, an omnibus retrieval hypothesis (which implicates total retrieval rather than just correct retrieval) and the cue-familiarity hypothesis produced isomorphic predictions that were borne out by the FKJ and TOT results. All 4 experiments supported the cue-familiarity hypothesis, because FKJs and TOTs were directly related to the number of presentations (and thereby the familiarity) of the cues.


Local effects of inbreeding on embryo number and consequences for genetic diversity in Kerguelen mouflon.
A classical paradigm in population genetics is that homozygosity or inbreeding affects individual fitness through increased disease susceptibility and mortality, and diminished breeding success. Using data from an insular population of mouflon (Ovis aries) founded by a single pair of individuals, we compare embryo number of ewes with different levels of inbreeding. Contrary to expectations, ewes with the highest levels of homozygosity showed the largest number of embryos. Using two different statistical approaches, we showed that this relationship is probably caused by heterozygosity at specific genes. The genetics of embryo number coupled with cyclic dynamics could play a central role in promoting genetic variation in this population.


Detection and characterization of defective mycoplasmacidal antibody produced by rodents against Mycoplasma arthritidis.
A procedure has been developed for the detection of mycoplasmacidal antibody in the serum of rats and mice infected with Mycoplasma arthritidis. Antibody activity can apparently be measured only by using resting mycoplasma cells. The reaction is complement dependent and is usually complete within 3 h. Early antibody (5 days) could be detected only within the immunoglobulin (Ig)M fraction, whereas late antibody (42 days) is found within the IgG fraction. The mycoplasmacidal antibody was highly specific and cross reactions were not observed with other mycoplasma species. Antibody activity could be removed from serum by absorption with either viable or nonviable M. arthritidis. Cidal antibody produced by rats against other mycoplasma species was active against both resting and multiplying cells. Mycoplasmacidal antibody against M. arthritidis was detected in rats 2 days after injection of the organisms and persisted at least through 300 days. Mice usually developed antibodies by 3 days after injection of the organisms and moderate titers have been observed for as long as 487 days. Since viable mycoplasmas can persist in the peripheral circulation in the presence of antibody, it is likely that viable mycoplasma-antibody complexes are also present.


[Identity and psychoanalysis: particularity and universality of the Jewish question according to Freud].
Although he was an atheist, Freud always affirmed his Jewish identity - without religious practice, but within a community commitment. He was proud of his Jewish origin and this helped him to face his hostile scientific environment and to develop his ideas despite the majority against him. What exactly is the role of his Jewish identity in his heritage?


Inertial particle collisions in turbulent synthetic flows: quantifying the sling effect.
Turbulent motion increases very significantly the collision rate between particles in dilute suspensions. In the case of heavy inertial particles, the collision rate enhancement results both from the intermittent concentration in the flow, and also from the large relative velocity between colliding particles. The latter effect is a consequence of the ejection of particles out of curved streamlines, denoted here as the "sling effect." Here, we quantitatively study the collision rate between heavy particles in the presence of gravity, with the simplified synthetic model of turbulent flow known as kinematic simulation. Monitoring the velocity of colliding particles and comparing it with the local velocity gradient of the flow of particles allowed us to identify the collision induced by the sling effect and to evaluate their contribution to the total collision rate. Our numerical results are then systematically compared with the estimates based on the properties of particle trajectories in the flow recently proposed by Falkovich and Pumir [G. Falkovich and A. Pumir, J. Atmos. Sci. 64, 4497 (2007)]. At moderate values of the Stokes numbers (St<1) , we demonstrate that the resulting parametrization describes quantitatively correctly the collision rate, and that the sling effect can be responsible for up to approximately 50% of the total collision rate.


Solutions in microbiome engineering: prioritizing barriers to organism establishment.
Microbiome engineering is increasingly being employed as a solution to challenges in health, agriculture, and climate. Often manipulation involves inoculation of new microbes designed to improve function into a preexisting microbial community. Despite, increased efforts in microbiome engineering inoculants frequently fail to establish and/or confer long-lasting modifications on ecosystem function. We posit that one underlying cause of these shortfalls is the failure to consider barriers to organism establishment. This is a key challenge and focus of macroecology research, specifically invasion biology and restoration ecology. We adopt a framework from invasion biology that summarizes establishment barriers in three categories: (1) propagule pressure, (2) environmental filtering, and (3) biotic interactions factors. We suggest that biotic interactions is the most neglected factor in microbiome engineering research, and we recommend a number of actions to accelerate engineering solutions.


Application of phthalocyanine derivatives as hole transporting layer to organic light emitting devices.
We fabricated organic light emitting devices (OLEDs) with thermally stable metal tetra-aminophthalocyanine (MT4APc, where M is Co, Cu, or Zn) dispersed in poly(bisphenol A-co-4-nitrophthalic anhydride-co-l,3-phenylenediamine) (polyetherimide, PEI) or 2,2-bis(3,4-dicarboxy-phenyl) hexafluoroisopropane dianhydride-2,4,5,6-trimethyl-1,4-phenylene-diamine (6FDA-4MPDA) polyimide (PI) as a hole transporting layer (HTL). The relative efficiency of the MT4APc as a HTL was found to be in the order CuT4APc > CoT4APc approximately TPD > ZnT4APc. It was found that the 6FDA-4MPDA PI as a matrix of HTL exhibited better hole transporting properties than PEI.


[Alpha-interferon therapy in Crohn's disease: initial clinical results].
4 therapies in 3 patients (1 female, 2 male) suffering from steroid dependent Crohn's disease are described. Interferon alpha-2b was administered for 24 weeks (3 million I.U. per day for 4 weeks, and 3 x 3 million U.I. per week for 20 weeks). Prednisolone dosage at start of therapy depended on initial inflammatory activity (CDAI). The daily dose was reduced stepwise and omitted after 12 weeks. In two courses patients did not respond and therapy had to be halted after 12 and 14 weeks' duration because of increasing disease activity. During the other two treatments a decrease in disease activity of 118 and 70 CDAI units (in both cases after 8 weeks) could be achieved. In particular, the course in one patient with abundant intestinal and extraintestinal inflammatory activity was quite impressive: extraintestinal activity disappeared completely within 10 days, CDAI ameliorated substantially for 30 weeks and the patient could be treated without steroids for a total period of 18 weeks. As a preliminary conclusion from the cases described up to now, it can be speculated that females probably respond more favorably to a combined therapy with interferon alpha and corticosteroids. Moreover, we suggest that the potential of interferon in Crohn's disease might be to overcome a steroid refractory disease state rather than to allow omission of steroid medication which could not be further reduced without exacerbation. Clearly, present experience of interferon therapy in Crohn's disease is still too scarce and more work needs to be done to define the role of interferon in IBD.


A low-drift, low-noise, multichannel dc voltage source for segmented-electrode Paul traps.
We present the design, construction, and characterization of a multichannel, low-drift, low-noise dc voltage source specially designed for biasing the electrodes of segmented linear Paul traps. The system produces 20 output voltage pairs having a common-mode range of 0 to +120 V with 3.7 mV/LSB (least significant bit) resolution and differential ranges of ±5 V with 150 μV/LSB or ±16 V with 610 μV/LSB resolution. All common-mode and differential voltages are independently controllable, and all pairs share the same ground reference. The measured drift of the voltages after warm-up is lower than 1 LSB peak-to-peak on the time scale of 2 h. The noise of an output voltage measured with respect to ground is <10 μVRMS within 10 Hz-100 kHz, with spectral density lower than 3 nV Hz-1/2 above 50 kHz. The performance of the system is limited by the external commercial multichannel DAC unit NI 9264, and in principle, it is possible to achieve higher stability and lower noise with the same voltage ranges. The system has a compact, modular, and scalable architecture, having all parts except for the DAC chassis housed within a single 19″ 3HE rack.


Participation of a pure neuronal mechanism in the control of gonadal functions.
The present review summarizes the data on the existence of a neural connection between the gonads and the central nervous system. As an experimental model the development of compensatory ovarian hypertrophy following unilateral ovariectomy was studied. Unilateral ovariectomy or orchidectomy resulted in a higher cellular activity in the hypothalamic arcuate neurons contralateral to hemigonadectomy and an increased luteinizing hormone-releasing hormone content in the medio-basal hypothalamus ipsilateral to the removed gonad. Local treatment of the remaining ovary with 6-hydroxy-dopamine prevented the development of compensatory ovarian hypertrophy after unilateral ovariectomy. Hemitransection of the spinal cord contralateral to hemigonadectomy, different unilateral hypothalamic deafferentations of the medio-basal hypothalamus as well as unilateral lesion of the medial preoptic area or of the arcuate nucleus blocked the compensatory ovarian growth when the brain surgery was on the same side as ovariectomy. Furthermore, in hypophysectomized + unilaterally ovariectomized rats a less severe ovarian atrophy occurred than in animals solely with hypophysectomy. All these data favour the view that - besides the hormonal control - a pure neuronal mechanism is also involved in the regulation of gonadal functions.


Cultural models, consensus analysis, and the social organization of knowledge.
The introductory essay to this collection correctly observes that there are many "challenges for rapprochement" between anthropology and (the rest of) cognitive science. Still, the possibilities of fruitful interchanges provide some hope for the parties getting back together, at least on an intermittent basis. This response offers some views concerning the "incompatibility" of psychology and anthropology, reviews why cognitive anthropology drifted away from cognitive science, and notes two areas of contemporary interest within cognitive anthropology that may lead to a re-engagement.


[Analysis of the usefulness of Candid 1 vaccine in preventing Argentine hemorrhagic fever in children].
To determine the most rational strategy of vaccination with Candid 1 vaccine in order to prevent Argentine hemorrhagic fever among children under 15 years old living an endemic area. To analyze the estimated effectiveness, a decision tree model was designed, with two possible options: vaccinate all the children under age 15 in the endemic area ("expanded vaccination") or vaccinate only the children at greater risk ("selective vaccination"). These two options were compared with the alternative of not vaccinating. The evaluation was complemented with a sensitivity analysis to identify the threshold values of the critical variables that could change the decision. The probabilities that were used were taken from earlier clinical and epidemiological trials. According to the model that we used, the expanded vaccination strategy was the best option, with a total expected utility of 9.99998 (out of a maximum possible 10.0). The sensitivity analysis showed that selective vaccination would be the best strategy if the incidence in the population with low risk drops to less than 3 per 1,000,000 population or if the rate of serious adverse reactions to the vaccine reaches more than 9 per 100,000 inhabitants. No variation in the parameters used in the model supported the option of not vaccinating. Given the risk and benefit parameters that we used, we recommend vaccinating with Candid 1 all the children under age 15 who live in the area endemic for Argentine hemorrhagic fever. The proposed model can be fitted to future needs, and it can help in decision-making by incorporating prospective disease surveillance data. These results can be used as a basis for cost and efficacy studies and for other quantitative analyses.


A new machine learning classifier for high dimensional healthcare data.
Data sets with many discrete variables and relatively few cases arise in health care, commerce, information security, and many other domains. Learning effective and efficient prediction models from such data sets is a challenging task. In this paper, we propose a new approach that combines Metaheuristic search and Bayesian Networks to learn a graphical Markov Blanket-based classifier from data. The Tabu Search enhanced Markov Blanket (TS/MB) procedure is based on the use of restricted neighborhoods in a general Bayesian Network constrained by the Markov condition, called Markov Blanket Neighborhoods. Computational results from two real world healthcare data sets indicate that the TS/MB procedure converges fast and is able to find a parsimonious model with substantially fewer predictor variables than in the full data set. Furthermore, it has comparable or better prediction performance when compared against several machine learning methods, and provides insight into possible causal relations among the variables.


[The role of external signal regulated kinase and transforming growth factor beta(1) in asthma airway remodeling and regulation of glucocorticoids].
To study role of external signal regulated kinase (ERK) and transforming growth factor beta(1) (TGF-beta1) in asthma airway remodeling and to explore the regulation of glucocorticoids on ERK, TGF-beta1, and airway remodeling. Thirty SD rats were randomly divided into 3 equal groups: control group; asthma group, undergoing intra-peritoneal injection of ovalbumin (OVA) on days 1 and 8 and inhalation of OVA every other day for 8 weeks since day 15 to establish chronic asthma models; dexamethasone (DM) intervention group, undergoing intra-peritoneal injection of DM 30 min before every inhalation instigation; and control group, receiving normal saline instead of DM. 1 - 2 hours after the last instigation the left lungs were taken out. The total bronchial wall thickness (Wat) and smooth muscle thickness (Wam) were measured by image analysis system. Phosphorylated ERK (P-ERK) was detected by immunohistochemistry. 1 - 2 hours after the last instigation blood samples were collected from the femoral artery. The concentration of transforming growth factor (TGF)-beta1 in the serum was measured by sandwich ELISA. Rat airway epithelial cells were cultured, stimulated with platelet-derived growth factor-BB (PDGF-BB, 1, 10, 25, or 50 microg/L), U0126 (specific inhibitor of phosphorylation of ERK), or budesonide (BUD). Western blotting was used to detect the P-ERK level. The level of TGF-beta1 in the cell culture supernatant was detected by sandwich ELISA. The Wat and Wam of the asthma group was significantly higher than those of the control group (both P < 0.01), and the Wat and Wam of the DM group were both significantly lower than those of the asthma group (both P < 0.01). The mean optical density of P-ERK and concentration of TGF-beta1 in the serum of the asthma group were 31.1 +/- 2.2 and 28.1 +/- 7.4 microg/L respectively, both significantly higher than those of the control group (12.8 +/- 2.4 and 13.6 +/- 2.7 microg/L respectively, both P < 0.01), and the mean optical density of P-ERK and concentration of TGF-beta1 in the serum of the DM group were 18.7 +/- 3.1 and 15.0 +/- 3.2 microg/L respectively, both significantly lower than those asthma group (both P < 0.01). In the PDGF-BB (25 microg/L) stimulated cells marked phosphorylation of ERK occurred 15 min later, the level of P-ERK remained high up to 8 hour later, and the maximal activation occurred at the period of 2 h - 4 h later, 6.5 +/- 0.4 times that of the control value (P < 0.01). The phosphorylation levels of ERK depended on the concentration of PDGF-BB and the maximal level phosphorylation was detected with the concentration of PDGF-BB of 50 microg/L, which was 4.1 +/- 0.3 times that of the control value (P < 0.01). U0126 and BUD inhibited the phosphorylation of ERK in the cells stimulated by PDGF-BB of the concentration of 25 microg/L. there was no difference in the level of TGF-beta1 in the cell culture supernatant among different groups. Phosphorylation of ERK and TGF-beta1 have an important role in asthma airway remodeling; PDGF-BB does not induce normal rat airway epithelial cells to product or release TGF-beta1 by phosphorylation of ERK. Glucocorticoids can inhibit phosphorylation of ERK.


Etiology of melanoma.
Epidemiological and etiological research on the pathogenesis of melanoma remins a controversial issue. The main reason for this appears to rest on the relation between the genetically determined susceptibility of the host and ultraviolet radiation (UVR). Basic to understanding this, however, is the knowledge of the clinical and histopathological, the genotypical and phenotypical heterogeneity of this tumor entity. In terms of the multistage concept of carcinogenesis, melanocytes, atypical or normal, are exposed to a mutagenic event, predominantly UVR, initiating malignant growth in a genetically altered and susceptible genome. The initiation could also occur spontaneously or as the result of other insults such as chemical carcinogens, viral infections, ionizing radiation, etc. Promotion through the stage of melanocytic dysplasia or de novo from unaltered skin follows additional exposure to UVR or cocarcinogens and is likely to be modulated by ethnic, dietary, endocrine, but also protective factors and concomitant disease. In terms of descriptive epidemiology, melanoma may be caused by exposure to intermittent and intense sunlight on unacclimatized skin. The mechanism of this association, such as the wavelength responsible, effects of total dose, intensity of dose rate, latency period between exposure and the clinical incidence of disease, and finally, the stage of carcinogenesis affected by UVR and other initiating factors, as well as the impact of any specific modulation for the pathogenesis and clinical course of the disease remain to be elucidated.


Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors.
Proteasome inhibition is a validated strategy for therapy of multiple myeloma, but this disease remains challenging as relapses are common, and often associated with increasing chemoresistance. Moreover, nonspecific proteasome inhibitors such as bortezomib can induce peripheral neuropathy and other toxicities that may compromise the ability to deliver therapy at full doses, thereby decreasing efficacy. One novel approach may be to target the immunoproteasome, a proteasomal variant found predominantly in cells of hematopoietic origin that differs from the constitutive proteasome found in most other cell types. Using purified preparations of constitutive and immunoproteasomes, we screened a rationally designed series of peptidyl-aldehydes and identified several with relative specificity for the immunoproteasome. The most potent immunoproteasome-specific inhibitor, IPSI-001, preferentially targeted the beta1(i) subunit of the immunoproteasome in vitro and in cellulo in a dose-dependent manner. This agent induced accumulation of ubiquitin-protein conjugates, proapoptotic proteins, and activated caspase-mediated apoptosis. IPSI-001 potently inhibited proliferation in myeloma patient samples and other hematologic malignancies. Importantly, IPSI-001 was able to overcome conventional and novel drug resistance, including resistance to bortezomib. These findings provide a rationale for the translation of IPSIs to the clinic, where they may provide antimyeloma activity with greater specificity and less toxicity than current inhibitors.


Photoresponse of an electrically tunable ambipolar graphene infrared thermocouple.
We explore the photoresponse of an ambipolar graphene infrared thermocouple at photon energies close to or below monolayer graphene's optical phonon energy and electrostatically accessible Fermi energy levels. The ambipolar graphene infrared thermocouple consists of monolayer graphene supported by an infrared absorbing material, controlled by two independent electrostatic gates embedded below the absorber. Using a scanning infrared laser microscope, we characterize these devices as a function of carrier type and carrier density difference controlled at the junction between the two electrostatic gates. On the basis of these measurements, conducted at both mid- and near-infrared wavelengths, the primary detection mechanism can be modeled as a thermoelectric response. By studying the effect of different infrared absorbers, we determine that the optical absorption and thermal conduction of the substrate play the dominant role in the measured photoresponse of our devices. These experiments indicate a path toward hybrid graphene thermal detectors for sensing applications such as thermography and chemical spectroscopy.


A collagen hydrogel loaded with HDAC7-derived peptide promotes the regeneration of infarcted myocardium with functional improvement in a rodent model.
Myocardial infarction (MI) leads to the loss of cardiomyocytes, left ventricle (LV) dilation, and cardiac dysfunction, eventually developing into heart failure. Most of the strategies for MI therapy require biomaterials that can support tissue regeneration. In this study, we hypothesized that the extracellular matrix (ECM)-derived collagen I hydrogel loaded with histone deacetylase 7 (HDAC7)-derived-phosphorylated 7-amino-acid peptide (7Ap) could restrain LV remodeling and improve cardiac function after MI. An MI model was established by ligation of the left anterior descending coronary artery (LAD) of C57/B6 mice. The 7Ap-loaded collagen I hydrogel was intramyocardially injected to the infarcted region of the LV wall of the heart. After local delivery, the 7Ap-collagen increased neo-microvessel formation, enhanced stem cell antigen-1 positive (Sca-1+) stem cell recruitment and differentiation, decreased cellular apoptosis, and promoted cardiomyocyte cycle progression. Furthermore, the 7Ap-collagen restricted the fibrosis of the LV wall, reduced the infarct wall thinning, and improved cardiac performance significantly at 2 weeks post-MI. These results highlight the promising implication of 7Ap-collagen as a novel candidate for MI therapy. STATEMENT OF SIGNIFICANCE: The mammalian myocardium has a limited regenerative capability following myocardial infarction (MI). MI leads to extensive loss of cardiomyocytes, thus culminating in adverse cardiac remodeling and congestive heart failure. In situ tissue regeneration through endogenous cell mobilization has great potential for tissue regeneration. A 7-amino-acid-peptide (7A) domain encoded by a short open-reading frame (sORF) of the HDAC7 gene. The phosphorylated from of 7A (7Ap) has been reported to promote in situ tissue repair via the mobilization and recruitment of endogenous stem cell antigen-1 positive (Sca-l+) stem cells. In this study, 7Ap was shown to improve H9C2 cell survival, in vitro. In vivo investigations in a mouse MI model demonstrated that intra-myocardial delivery of 7Ap-loaded collagen hydrogel promoted neovascularization, stimulated Sca-l+ stem cell recruitment and differentiation, reduced cardiomyocyte apoptosis and promoted cell cycle progression. As a result, treated infarcted hearts had increased wall thickness, had improved heart function and exhibited attenuation of adverse cardiac remodeling, observed for up to 2 weeks. Overall, these results highlighted the positive impact of implanting 7Ap-collagen as a novel constituent for MI repair.


School recess, social connectedness and health: a Canadian perspective.
Children need opportunities to establish positive social connections at school, yet many school playgrounds are challenged by social conflict that can undermine these connections. When children's social needs go unmet, the resultant feelings of loneliness, isolation and self-doubt can cumulatively lead to mental and physical illness. Because recess is typically the only time during the school day that children are free to socialize and play, we propose a more thoughtful way of thinking about it: from the lens of belongingness. Schools are, historically, designed for instruction. We argue, however, that we need to attend to children's social needs at school. We highlight current research from social neuroscience, belonging and social connectedness in order to delineate the pathways between daily school recess and developmental health trajectories. We then consolidate an array of research on play, social interaction and school change to suggest four areas that could benefit from consideration in research, practice and policy: (i) the culture of recess, (ii) the importance of healthy role models on the playground, (iii) the necessity of activities, options and variety during recess and (iv) the significance of space and spatial layout (indoor and outdoor). We bridge our discussion with the conception of health as described in the Ottawa Charter and emphasize the need to build alliances across sectors to assist schools in their efforts to support children's overall health needs.


Hepatolithiasis: outcome of cholangioscopic lithotomy and dilation of bile duct stricture.
Cholangioscopic lithotomy (CSL) for hepatolithiasis, a minimally invasive procedure, has a place in complicated or recurrent hepatolithiasis. CSL itself, however, carries inherent risk for recurrence. We analyzed follow-up data after CSL for primary or repeat hepatolithiasis to determine the frequency of recurrence. This retrospective analysis includes 21 patients with hepatolithiasis admitted to the hospital from September 1992 to December 1995 who underwent CSL. Through a percutaneous biliary drainage route, cholangioscopy was inserted to remove calculi with basket forceps or electrohydraulic lithotripter. Stenotic ducts, defined as less than 2 mm in diameter, were dilated with silicone rubber stenting or a balloon dilator. Ten patients were treated for primary hepatolithiasis and 11 for repeat hepatolithiasis. Of the patients with primary hepatolithiasis, one died of complications and the other nine patients underwent complete lithotomy. Among 11 patients who had repeat hepatolithiasis, four had undergone hepatectomy for hepatolithiasis and two previous CSLs; 10 patients (91%) underwent complete lithotomy. During the follow-up, four (40%) of the 10 patients with biliary stenosis at the time of cholangioscopic treatment showed recurrent calculi, whereas all eight patients without stricture had uneventful courses. Of the 19 patients who underwent complete lithotomy, calculi recurred in four (21%), three cases of which recurred less than 1 year after CSL. Against hepatolithiasis of primary and postoperative repeat cases, CSL can allow complete lithotomy. The bile duct stricture, however, carries a high risk for recurrent calculi; hence, permanent relief of stricture is mandatory.


Organic chemistry using weakly electrophilic salts: efficient formation of O,O-mixed, O,S- and N,O-acetals.
A mild and efficient method for the preparation of O,O-mixed, O,S- and N,O-acetals from symmetrical O,O-acetals has been developed. Thus, the treatment of symmetrical O,O-acetals with TESOTf and 2,4,6-collidine formed weakly electrophilic collidinium salts. The addition of nucleophiles, such as an alcohol, lithium thioxide, and sodium azide, to the salts afforded the corresponding O,O-mixed, O,S- and N,O-acetals in good yields. The reaction proceeded under weakly basic conditions. No overreaction then occurred and many acid-labile functional groups could remain intact.


Risk of bloodstream infection in patients with chronic kidney disease not treated with dialysis.
Patients with end-stage renal disease requiring dialysis are at high risk for bloodstream infection and infection-related death. Whether patients with chronic kidney disease who are not receiving dialysis are also at increased risk of bloodstream infection is less clear. We examined the association between chronic kidney disease not being treated with dialysis and bloodstream infection in a cohort of patients 66 years or older. All patients required at least 1 outpatient serum creatinine measurement enabling estimation of glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease Study equation. Cox proportional hazards models with censoring at the initiation of renal replacement therapy or death were used to determine associations between eGFR, bloodstream infection, and death within 30 days of community-onset bloodstream infection, adjusting for potential confounders. In 25 675 patients followed up for a median of 3.2 years, 797 developed at least 1 bloodstream infection, of which most (75%) were community-onset infections. Compared with patients with an eGFR of 60 mL/min/1.73 m(2) or higher, adjusted hazard ratios (95% confidence intervals) for bloodstream infection according to eGFR were, respectively, 1.24 (1.01-1.52), 1.59 (1.24-2.04), and 3.54 (2.69-4.69) in those with an eGFR of 45 to 59, 30 to 44, and less than 30 mL/min/1.73 m(2). The associations were consistent for both community-onset and nosocomial infections. Compared with patients with an eGFR of 60 mL/min/1.73 m(2) or higher, the risk of death within 30 days of community-onset bloodstream infection was significantly greater in those with an eGFR less than 30 mL/min/1.73 m(2) (hazard ratio, 4.10; 95% confidence interval, 2.06-8.14). Older adults with chronic kidney disease not being treated with dialysis are at increased risk of bloodstream infection and of death following community-onset bloodstream infection.


Long-term clinical outcomes of salvage pelvic radiation therapy for oligo-recurrent pelvic lymph nodes after definitive external-beam radiation therapy for non-metastatic prostate cancer.
Although salvage external-beam radiation therapy (EBRT) is an attractive treatment option for pelvic lymph nodal recurrence (PeNR) in patients with prostate cancer (PCa), limited data are available regarding its long-term efficacy. This study examined the long-term clinical outcomes of patients who underwent salvage pelvic radiation therapy (sPRT) for oligo-recurrent pelvic lymph nodes after definitive EBRT for non-metastatic PCa. Patients who developed PeNR after definitive EBRT and were subsequently treated with sPRT at our institution between November 2007 and December 2015 were retrospectively analyzed. The prescribed dose was 45-50.4 Gy (1.8-2 Gy per fraction) to the upper pelvis, with up to 54-66 Gy (1.8-2 Gy per fraction) for recurrent nodes. Long-term hormonal therapy was used as neoadjuvant and/or adjuvant therapy. The study population consisted of 12 consecutive patients with PeNR after definitive EBRT (median age: 73 years). The median follow-up period was 58.9 months. The 5-year overall survival, PCa-specific survival, biochemical failure-free, clinical failure-free, and castration-resistant PCa-free rates were 82.5, 100.0, 62.3, 81.8, and 81.8%, respectively. No grade 2 or higher sPRT-related late toxicities occurred. In conclusion, more than half of the study patients treated with sPRT had a long-term disease-free status with acceptable morbidities. Moreover, most of the patients maintained hormonal sensitivity. Therefore, this approach may be a promising treatment method for oligo-recurrent pelvic lymph nodes.


ARMC 5 Variants and Risk of Hypertension in Blacks: MH- GRID Study.
Background We recently found that ARMC 5 variants may be associated with primary aldosteronism in blacks. We investigated a cohort from the MH - GRID (Minority Health Genomics and Translational Research Bio-Repository Database) and tested the association between ARMC 5 variants and blood pressure in black s. Methods and Results Whole exome sequencing data of 1377 black s were analyzed. Target single-variant and gene-based association analyses of hypertension were performed for ARMC 5, and replicated in a subset of 3015 individuals of African descent from the UK Biobank cohort. Sixteen rare variants were significantly associated with hypertension ( P=0.0402) in the gene-based (optimized sequenced kernel association test) analysis; the 16 and one other, rs116201073, together, showed a strong association ( P=0.0003) with blood pressure in this data set. The presence of the rs116201073 variant was associated with lower blood pressure. We then used human embryonic kidney 293 and adrenocortical H295R cells transfected with an ARMC 5 construct containing rs116201073 (c.*920T>C). The latter was common in both the discovery ( MH - GRID ) and replication ( UK Biobank) data and reached statistical significance ( P=0.044 [odds ratio, 0.7] and P=0.007 [odds ratio, 0.76], respectively). The allele carrying rs116201073 increased levels of ARMC5 mRNA , consistent with its protective effect in the epidemiological data. Conclusions ARMC 5 shows an association with hypertension in black s when rare variants within the gene are considered. We also identified a protective variant of the ARMC 5 gene with an effect on ARMC 5 expression confirmed in vitro. These results extend our previous report of ARMC 5's possible involvement in the determination of blood pressure in blacks.


A novel testis-specific protein, PRAMEY, is involved in spermatogenesis in cattle.
Preferentially expressed antigen in melanoma (PRAME) is a cancer/testis antigen that is predominantly expressed in normal testicular tissues and a variety of tumors. The function of the PRAME family in spermatogenesis remains unknown. This study was designed to characterize the Y-linked PRAME (PRAMEY) protein during spermatogenesis in cattle. We found that PRAMEY is a novel male germ cell-specific, and a germinal granule-associated protein that is expressed in spermatogenic cells during spermatogenesis. The intact PRAMEY protein (58 kDa) was detected in different ages of testes but not in epididymal spermatozoa. A PRAMEY isoform (30 kDa) was highly expressed only in testes after puberty and in epididymal spermatozoa. This isoform interacts with PP1γ2 and is likely the mature protein present in the testes and sperm. Immunofluorescent staining demonstrated that PRAMEY was located predominantly in the acrosome granule of spermatids, and in acrosome and flagellum of spermatozoa. Immunogold electron microscopy further localized the PRAMEY protein complex to the nucleus and several cytoplasmic organelles, including the rough endoplasmic reticulum, some small vesicles, the intermitochondrial cement, the chromatoid body and the centrioles, in spermatogonia, spermatocytes, spermatids and/or spermatozoa. PRAMEY was highly enriched in and structurally associated with the matrix of the acrosomal granule (AG) in round spermatids, and migrated with the expansion of the AG during acrosomal biogenesis. While the function of PRAMEY remains unclear during spermatogenesis, our results suggest that PRAMEY may play an essential role in acrosome biogenesis and spermatogenesis.Free Chinese abstract: A Chinese translation of this abstract is freely available at http://www.reproduction-online.org/content/153/6/847/suppl/DC1.FreeSpanish abstract: A Spanish translation of this abstract is freely available at http://www.reproduction-online.org/content/153/6/847/suppl/DC2.


[Marker chromosome study of murine cell line tumor tissues].
By C-method of chromosome staining three transplantable murine tumor lines passaged in vivo were studied. Marker chromosomes were discovered in all cell lines under observation. The previously described marker chromosomes B and C were found in transplantable Ehrlich ascites carcinoma cells, acrocentric chromosome with additional C-band --in cells of line C-37, acrocentric chromosome with double quantity of subcentrometric heterochromatin in cells of line TG-180. The data obtained make it possible to distinguish the lines under study by C-method of chromosome staining.


Genetics education for non-genetic health care professionals in the Netherlands (2002).
The aim of the present study was to investigate whether medical care providers in the Netherlands are adequately educated in genetics by collecting information about the current state of genetics education of non-genetics health care professionals. The curricula of the 8 universities providing medical education and of all varieties of specialised medical training were examined for the year 2002. In most universities, the number of hours spent on genetics education is small, and genetics is relatively invisible, being integrated within several courses, comprising only a small proportion of the total course (a mean of 8%). Only 3 of the programmes for medical specialist training and the training of medical doctors for mentally handicapped people indicated a formal genetics education programme. Continued education courses on genetics are offered irregularly. Training in midwifery involves at least 3 weeks of genetics education. Courses on genetics are offered frequently to practicing midwives. There appear to be no general, nationally defined final goals for education in genetics for non-genetics health care professionals in the Netherlands. Furthermore, the lack of visibility of genetics in medical education in the Netherlands was striking.


Spatial Frequency Shifts From Counterphase Flicker and From Simultaneous Contrast.
In simultaneous contrast of spatial frequency (SF), a test grating surrounded by a coarser inducing grating looks apparently finer. We combined this effect with another visual illusion; the fact that flickering the inducing grating raises its apparent SF. We found that the inducer's apparent, not physical spatial frequency, drove the simultaneous contrast that it induced into a test grating. Thus, when the inducer was made to flicker, its SF appeared to be higher and consequently, the test's SF appeared lower than before. This suggests that simultaneous contrast of spatial frequency exists further downstream than the flicker-induced increase in perceived SF.


Effective Response of Intrahepatic Cholangiocarcinoma to Pembrolizumab: A Case Report.
The efficacy of pembrolizumab for intrahepatic cholangiocellular carcinoma (IHCCC) is not widely reported. We began pembrolizumab treatment in a 69-year-old male with recurrent IHCCC at 18 months after his surgery because of the proven microsatellite instability (MSI)-high status. The patient had partial response, with an 82.5% reduction at the end of 18 courses. Immunostaining of the primary tumor revealed intra-tumoral infiltration of both PD-1+ and CD8+ T cells, and a low expression of PD-L1. Intra-tumoral infiltration of both PD-1+ and CD8+ T cells may be a predictive factor of the efficacy of pembrolizumab. Expression of PD-L1 did not correlate with a therapeutic effect, but the tumor microenvironment of our patient's recurrent lesions may have been modified by conventional chemotherapy and CD8+ T cells.