Localization and expression of follicle-stimulating hormone receptor gene in buffalo (Bubalus bubalis) pre-antral follicles.
Follicle-stimulating hormone (FSH) stimulates antral follicles to grow, but its role in earlier stages (pre-antral) of follicle development, if any, is obscure. Aim of this study was to study the expression of follicle-stimulating hormone receptor (FSHR) gene in different sizes of pre-antral follicles (PFs) (<150, 200, 250, 300, 350, 400 μm) and to find out an optimum dose of FSH for better growth, development and steroidogenesis of PFs in vitro. Buffalo ovaries were collected from a local abattoir, and PFs were isolated by mechanical method. A semi-quantitative RT-PCR amplification strategy was used for mRNA expression, while FSHR protein was localized by immunohistochemistry. Isolated pre-antral follicles (80-85 μm) were cultured in TCM-199 supplemented with 10% foetal bovine serum, 1% ITS and 30 ng/ml EGF served as control medium. Addition of three different doses of FSH (0.5, 1.0, 2.0 μg/ml) in control medium was considered as treatment groups. A single 2.184-kb receptor mRNA transcript was present in all sizes (<150-400 μm) of follicles. Follicle-stimulating hormone receptor was also localized immunohistochemically in granulosa cells of all sizes of follicles. Survival and growth rate of follicles significantly (p<0.05) increased following supplementation of FSH at a concentration of 1.0 μg/ml and the culture medium also showed a significantly (p<0.05) greater accumulation of oestradiol and progesterone. In conclusion, FSHR is expressed in all sizes of PFs and in vitro survival, growth and steroidogenesis of follicles are optimally stimulated by 1.0 μg/ml FSH. These findings demonstrate that FSH has an important role during the recruitment, growth and development of buffalo ovarian PFs.


[Absence of effect of the incorporation of a milk phosphopeptide on the utilization of calcium and phosphorus in the young pig].
Casein phosphopeptides are known to influence calcium absorption. A 50-day study was performed in 6-week old pigs fed either a control diet or a 5% casein phosphopeptide-containing diet (PP group). Both diets provided similar amounts of Ca (0.8%), P (0.5%), proteins, energy and vitamins. PP diet provided near 1/2 of total Ca, 1/3 of total P and 1/5 of proteins in the form of casein phosphopeptide. Ca and P excretion, absorption and retention were evaluated during a 10-day balance study. Bones were collected at slaughter to determine density, bending moment and bone mineral content. Calcium absorption and bone parameters (urinary hydroxyproline included) were not influenced by the type of diet. P absorption, but not retention, was slightly higher in the control group. Urinary Ca was higher and urinary P lower in PP pigs than in controls. These changes might result from the different kinds of dietary phosphorus, inorganic versus phosphopeptide, rather than from the difference between dietary proteins.


The effects of extinction and an explicitly unpaired treatment on the reinforcing properties of a Pavlovian conditioned stimulus.
This series of experiments examined the effects of extinction and an explicitly unpaired treatment on the ability of a conditioned stimulus (CS) to function as a reinforcer. Rats were trained to lever press for food, exposed to pairings of a noise CS and food, and, finally, tested for their willingness to lever press for the CS in the absence of the food. Experiment 1 provided a demonstration of conditioned reinforcement (using controls that were only exposed to unpaired presentations of the CS and food) and showed that it was equivalent after one or four sessions of CS-food pairings. Experiments 2 and 3 showed that, after one session of CS-food pairings, repeated presentations of the CS alone reduced its reinforcing properties; but after four sessions of CS-food pairings, repeated presentations of the CS alone had no effect on these properties. Experiment 4 showed that, after four sessions of CS-food pairings, explicitly unpaired presentations of the CS and food completely undermined conditioned reinforcement. Finally, Experiment 5 provided within-experiment evidence that, after four sessions of CS-food pairings, the reinforcing properties of the CS were disrupted by explicitly unpaired presentations of the CS and food but spared by repeated presentations of the CS alone. Together, these findings indicate that the effectiveness of extinction in undermining the reinforcing properties of a CS depends on its level of conditioning; and that, where extinction fails to disrupt these properties, they are successfully undermined by an explicitly unpaired treatment. They are discussed with respect to findings in the literature on Pavlovian-to-instrumental transfer; and the Rescorla-Wagner model, which anticipates that an explicitly unpaired treatment will be more effective than extinction in reversing the effects of conditioning.


Effects of some drugs on islet function in catfish.
Blood glucose variations and concomitant bioptical cytopathological changes in the pancreatic islets following treatment with certain drugs were studied in the catfish. Glucose loading produced a dose-related hyperglycemia, maximum within 3 hr, while alloxan caused a biphasic rise in glucose level without induction of permanent diabetes. Streptozotocin elicited a monophasic hyperglycemic state at a lower dose and biphasic response at higher doses. Glybenclamide produced hypoglycemia in normal and sham-operated fish; the depancreatized animals were unresponsive to this treatment. In all the cases, normoglycemic values were restituted within 4 days of the treatment. The beta-cells of the islets underwent varying histopathological changes with signs of regenerative activity. A depletion in heavy metal (zinc) in these cells was also evident after treatment with streptozotocin.


Single-dose antibiotic prophylaxis in appendectomy.
Prophylactic antibiotics will reduce the number of wound infections after so-called clean-contaminated gastrointestinal operations. The prophylactic regimen must be designed with the pharmacokinetical properties of the used drug, in mind. A safe and simple, easily standardized procedure, applicable in both elective and acute clinical situations is preferable. A single-dose regimen with prophylactic cephaloridine has been tried and evaluated.


An anesthetic system for small laboratory animals.
A non-rebreathing anesthetic system for administering volatile anesthetic mixtures to small laboratory animals was designed. The device is easily constructed and simple to operate, yet permits the anesthetic management of small animals by technics similar to those used for man and larger species.


The transcription factors IRF8 and PU.1 negatively regulate plasma cell differentiation.
Activated B cells undergo immunoglobulin class-switch recombination (CSR) and differentiate into antibody-secreting plasma cells. The distinct transcriptomes of B cells and plasma cells are maintained by the antagonistic influences of two groups of transcription factors: those that maintain the B cell program, including BCL6 and PAX5, and plasma cell-promoting factors, such as IRF4 and BLIMP-1. We show that the complex of IRF8 and PU.1 controls the propensity of B cells to undergo CSR and plasma cell differentiation by concurrently promoting the expression of BCL6 and PAX5 and repressing AID and BLIMP-1. As the PU.1-IRF8 complex functions in a reciprocal manner to IRF4, we propose that concentration-dependent competition between these factors controls B cell terminal differentiation.


Modeling the γ-irradiation inactivation kinetics of foodborne pathogens Escherichia coli O157:H7, Salmonella, Staphylococcus aureus and Bacillus cereus in instant soup.
The objective of the present study was to assess the inactivation kinetics of γ-irradiation of selected foodborne pathogens in instant soup. Escherichia coli O157:H7 (ATCC 25922), Salmonella enterica subsp. enterica serovar Enteritidis (ATCC 13076), Staphylococcus aureus (ATCC 2592), and Bacillus cereus (ATCC 11778) were inoculated into instant soup and irradiated at various doses of 0 (control), 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, and 10.0 kGy using 60Co source. The radiation response of these four major foodborne disease pathogens in instant soup was tested. As expected, the pathogen population decreased with increasing irradiation dose. By comparing bacterial resistance in instant soups according to D10 values, E coli O157: H7 was the most radio-resistant bacteria (D10 of 1.580 kGy), followed by Salmonella (D10 of 1.160 kGy), S aureus (D10 of 0.775 kGy), B cereus (D10 of 0.462 kGy). For modeling of inactivation kinetics, both, the conventional first-order linear model and Weibull model were compared and the goodness of fit of these models was investigated. Weibull model produced a better fit to the data. This research has shown that γ-irradiation was effective to eliminate pathogens in instant soup and it can be a great way to assure the microbiological safety of the instant soup.


A portable system for rapid bacterial composition analysis using a nanopore-based sequencer and laptop computer.
We developed a portable system for 16S rDNA analyses consisting of a nanopore technology-based sequencer, the MinION, and laptop computers, and assessed its potential ability to determine bacterial compositions rapidly. We tested our protocols using a mock bacterial community that contained equimolar 16S rDNA and a pleural effusion from a patient with empyema, for time effectiveness and accuracy. MinION sequencing targeting 16S rDNA detected all 20 of the bacterial species present in the mock bacterial community. Time course analysis indicated that the sequence data obtained during the first 5 minutes of sequencing (1,379 bacterial reads) were enough to detect all 20 bacteria in the mock sample and to determine species composition, consistent with results of those obtained from 4 hours of sequencing (24,202 reads). Additionally, using a clinical sample extracted from the empyema patient's pleural effusion, we could identify major bacterial pathogens in that effusion using our rapid sequencing and analysis protocol. All results are comparable to conventional 16S rDNA sequencing results using an IonPGM sequencer. Our results suggest that rapid sequencing and bacterial composition determination are possible within 2 hours after obtaining a DNA sample.


Thromboelastography for the prediction of bleeding after transplant renal biopsy.
The ability of prebiopsy coagulation assays to predict mild postbiopsy bleeding was evaluated in renal transplant patients undergoing renal allograft biopsy (N = 120). The coagulation assays studied included the bleeding time, prothrombin time, partial thromboplastin time, platelet count, and thromboelastograph (TEG). Coagulation results were defined as abnormal if they fell outside the established normal reference range. Bleeding was defined as a drop in the hematocrit equal to or more than 4 points 6 h after the procedure or ultrasound evidence of a new perirenal hematoma. Overall, 21% of patients showed evidence of mild bleeding. Of those who bled, 78% had normal results on all coagulation tests, indicating that most mild bleeding was not associated with coagulation abnormalities. Of the assays tested, only abnormal TEG:angle (P < 0.01) and TEG:k (P < 0.04) values were associated with an increased risk of bleeding. Bleeding times were not predictive of an increased risk of postbiopsy bleeding; five patients had abnormal bleeding times ranging from 10 to 20 min of whom only one bled. All prothrombin time, partial thromboplastin time, and platelet count abnormalities were mild (e.g., no prothrombin times longer than 15 s, no platelet counts below 129,000/microL); none of these assays predicted postbiopsy bleeding. Other clinical characteristics, including patient age, sex, serum creatinine, blood pressure (if less than 160/90 mm Hg), number of biopsy passes, or renal pathology, did not appear to influence bleeding after biopsy. It was concluded that most bleeding after transplant renal biopsy was not associated with coagulation abnormalities and that the TEG was the best assay for detecting mild coagulation abnormalities associated with an increased risk of bleeding.


Muscle mechanics and Ca2+ transport in atrophic heart transplants in rat.
Isometric contractile activity and force-frequency relationship were investigated in heterotopically isotransplanted rat hearts that performed minimal external work for 8 wk and underwent atrophy. No changes were found in the isometric contraction phase of the papillary muscles from the transplants when compared with the hearts of recipient animals that carry full hemodynamic load. However, the relaxation phase of the transplants was impaired at higher frequencies (greater than 24 stimuli/min) of stimulation and at higher levels of calcium (greater than 2.0 mM Ca2+) in the medium. When Ca2+-accumulating activities of cardiac microsomes containing fragments of the sarcoplasmic reticulum (SR) were studied, a significant decrease was seen in the transplanted hearts in comparison with the host hearts. This decrease in Ca2+-uptake activity was observed at different times of incubation as well as different concentrations of free Ca2+ (10(-7) to 10(-5) M Ca2+). Although Ca2+-stimulated ATPase activity did not change, alterations in the phospholipid contents of the SR vesicles from the transplanted hearts were observed. These results provide some evidence for a depression in the SR Ca2+ uptake in transplanted hearts undergoing atrophy and may explain the underlying alteration in the relaxation phase of these hearts.


Manganese-based superoxide dismutase mimics modify both acute and long-term outcome severity in a Drosophila melanogaster model of classic galactosemia.
The goal of this study was to use two manganese (Mn)-based superoxide dismutase (SOD) mimics to test the hypothesis that reactive oxygen species contribute to both acute and long-term outcomes in a galactose-1P uridylyltransferase (GALT)-null Drosophila melanogaster model of classic galactosemia. We tested the impact of each of two Mn porphyrin SOD mimics, MnTnBuOE-2-PyP(5+), and MnTE-2-PyP(5+), (i) on survival of GALT-null Drosophila larvae reared in the presence versus absence of dietary galactose and (ii) on the severity of a long-term movement defect in GALT-null adult flies. Both SOD mimics conferred a significant survival benefit to GALT-null larvae exposed to galactose but not to controls or to GALT-null larvae reared in the absence of galactose. One mimic, MnTE-2-PyP(5+), also largely rescued a galactose-independent long-term movement defect otherwise seen in adult GALT-null flies. The survival benefit of both SOD mimics occurred despite continued accumulation of elevated galactose-1P in the treated animals, and studies of thiolated proteins demonstrated that in both the presence and absence of dietary galactose MnTE-2-PyP(5+) largely prevented the elevated protein oxidative damage otherwise seen in GALT-null animals relative to controls. Our results confirm oxidative stress as a mediator of acute galactose sensitivity in GALT-null Drosophila larvae and demonstrate for the first time that oxidative stress may also contribute to galactose-independent adult outcomes in GALT deficiency. Finally, our results demonstrate for the first time that both MnTnBuOE-2-PyP(5+) and MnTE-2-PyP(5+) are bioavailable and effective when administered through an oral route in a D. melanogaster model of classic galactosemia.


The Role of Acculturation and Intimate Partner Violence on Post-Traumatic Stress Symptoms Among Hispanic Youth With Child Welfare Contact.
Research suggests that Hispanic youth with intimate partner violence (IPV) exposure report fewer trauma symptoms compared with youth from other racial/ethnic groups. However, no study has examined possible explanations for this finding. Our objective was to study the association between acculturation, IPV, and post-traumatic stress (PTS) symptoms among Hispanic youth and to test whether acculturation moderates the relationship between IPV and PTS symptoms. This analysis used data from 271 Hispanic youth aged 8 years or older participating in the second cohort of the National Survey of Child and Adolescent Well-being (NSCAW II). We conducted multiple linear regression analyses to achieve our study aims. We did not find a statistically significant relationship between IPV exposure and PTS symptoms among Hispanic youth (B = 0.21, 95% confidence interval [CI] = [-0.09, 0.52]), or that acculturation moderated this relationship (B = 0.04, 95% CI = [-0.23, 0.32]). However, we found a significant relationship between PTS symptoms and acculturation level. Specifically, higher levels of acculturation were associated with more reports of PTS symptoms (B = 1.03, 95% CI = [0.13, 1.93]). These study results highlight the need to consider the role of acculturation when working with Hispanic youth involved with child welfare.


The association of tissue transglutaminase with human recombinant tau results in the formation of insoluble filamentous structures.
To determine possible mechanisms by which NFTs are formed in Alzheimer's disease (AD), we investigated the ability of tissue transglutaminase (TGase) to convert human recombinant tau proteins into insoluble filamentous structures. TGase derived from guinea pig liver was activated by calcium to catalyze the in vitro cross-linking of the largest soluble recombinant tau isoform (htau40) into insoluble complexes as determined by electrophoresis following incubation in 4 M urea and SDS. The TGase-catalyzed formation of these insoluble complexes occurred within 15 min to 24 h and the decreased migration of the insoluble material correlated with increased calcium concentrations ranging from 2 mM to 50 mM when analyzed electrophoretically. TGase-treated human recombinant tau formed filamentous structures in vitro that were immunoreactive with antibodies to tau and TGase. These structures retained the insoluble characteristics typical of AD PHF/NFTs. Immunolabeling with the TGase antibody revealed that TGase is associated with the filaments formed from human recombinant tau in vitro as well as with PHFs isolated from NFTs from AD brains. These novel findings support an in vitro model for investigating the biophysical changes that occur in converting soluble tau proteins into an insoluble matrix consistent with the insoluble PHFs/NFTs which may contribute to neuronal degeneration and cell death in the AD brain.


[Orienting animal experiment studies on the effect of fenbufen on healthy and arthrosis-induced articular cartilage tissue in vivo].
Over a period of 3 months weekly intraarticular injections of fenbufen into the knee joint of hens did not induce any significant degenerative alterations of the articular cartilage. Experimental osteoarthrosis biochemically induced by iodoacetate in the knee joint of our laboratory animals was not enhanced by weekly intraarticular applications of fenbufen or its metabolite biphenyl-acetic acid. Joint space measurements as well as other radiological and macroscopical examinations of the knee joints confirmed that fenbufen and biphenyl-acetic acid had no negative influence on articular cartilage. In this respect these antiphlogistic agents differ from many other antiinflammatory drugs and may be particularly useful in the treatment of inflammatory phases of osteoarthrosis.


[Value of morphometry in the endocrine system of the kidneys].
Basing on the comparison of literature and own data on the morphofunctional analysis of the endocrine renal system (juxtaglomerular apparatus and interstitial medullary cells taken as an example) the necessity was shown to characterize first of all the changes occurring in the structures studied and to determine the stages of the pathologic process involved. Such an approach enables one to select the adequate method of quantitative analysis and to obtain reliable results. The significance of quantification is emphasized as an integral part of any morphologic study providing the performance of correction analysis with the identification of morphofunctional parallels.


A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD).
To review the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). A literature search was conducted in PubMed and EMBASE using the terms attention deficit hyperactive disorder, ADHD, pathophysiology, etiology, and neurobiology. Limits applied were the following: published in the past 10 years (January 2003 to August 2013), humans, review, meta-analysis, and English language. These yielded 63 articles in PubMed and 74 in EMBASE. After removing duplicate/irrelevant articles, 86 articles and their relevant reference citations were reviewed. ADHD is a neurological disorder that affects children, but symptoms may persist into adulthood. Individuals suffering from this disorder exhibit hyperactivity, inattention, impulsivity, and problems in social interaction and academic performance. Medications used to treat ADHD such as methylphenidate, amphetamine, and atomoxetine indicate a dopamine/norepinephrine deficit as the neurochemical basis of ADHD, but the etiology is more complex. Moreover, these agents have poor adverse effect profiles and a multitude of drug interactions. Because these drugs are also dispensed to adults who may have concomitant conditions or medications, a pharmacist needs to be aware of these adverse events and drug interactions. This review, therefore, focuses on the pathophysiology, etiology, and treatment of ADHD and details the adverse effects and drug interaction profiles of the drugs used to treat it. Published research shows the benefit of drug therapy for ADHD in children, but given the poor adverse effect and drug interaction profiles, these must be dispensed with caution.


Autologous bone marrow transplantation with monoclonal antibody purged marrow for high risk acute lymphoblastic leukemia.
Fifty-four patients with acute lymphoblastic leukemia (ALL: 1 relapse, 21 high risk first complete remission (CR 1), 29 second CR (CR 2), and 3 third CR (CR 3) were treated by autologous bone marrow transplantation at three centers. Before storage, the marrows were purged ex vivo with appropriate MAbs RFAL3 (CD10), SB4 (CD19), and RFT2 (CD7), with rabbit serum as the source of complement. All patients received total body irradiation either 750 cGy (middose 15 cGy/min) as a single fraction or 6 x 200 cGy over 3 days (midline dose 16 cGy/min) with lung shielding from 1,100 cGy. The patients who received 750 cGy also received cyclophosphamide or the same drug combined with ara-C or prednisone, teniposide, vincristine, ara-C, and dauno-rubicin. Patients receiving 200 cGy x 6 also received either cyclophosphamide, melphalan, or ara-C and cyclophosphamide. Three patients died of post transplantation complications (interstitial pneumonia, hepatitis B liver necrosis, or encephalitis). This gives a procedure related mortality of 5%. Nonfatal complications were 10 cases of septicemia, 4 interstitial pneumonia, 2 interstitial nephritis, 1 veno-occlusive disease (VOD), and 1 case of hemolytic uremic syndrome. The patient autografted in relapse died of relapse within 2 months. In CR 1 6 or 21 patients have had a relapse, and the actuarial leukemia free survival from CR is 65% (median follow-up 16 months). In CR 2-3 18 of 32 patients have relapsed, and the actuarial leukemia free survival is 31% (median follow-up 18.5 months) from CR. Twelve patients have achieved an inversion, (i.e., present CR longer than previous CR), with a further seven with the potential to achieve inversion. We conclude that ABMT in high risk ALL has a low procedure related mortality (5%), and there are few other complications. The in vitro purging with MAbs had no adverse effect on bone marrow reconstitution, but this study was not designed to demonstrate its antileukemic efficacy. The actuarial leukemia free survival time in the present study for patients with high risk CR 1 and the inversions in CF 2-3 are promising and indicate a potential beneficial effect of ABMT.


Population-Based Pediatric Hospitalization Burden of Lineage-Specific Influenza B in Hong Kong, 2004-2014.
Influenza B virus has been perceived to cause less disease burden and milder disease compared with influenza A, but recent studies suggest that influenza B does have a significant impact. We aimed to estimate the burden of influenza B virus infections on hospitalizations in Hong Kong, in the context of virus lineage changes over time. The pediatric age-specific rates of influenza B hospitalization in Hong Kong for 2004-2014 were estimated based on admissions to 2 hospitals that together catered for 72.5% of all pediatric admissions on Hong Kong Island. Influenza B virus was detected by immunofluorescence and culture on nasopharyngeal aspirates. Lineage typing was performed by real-time reverse-transcription polymerase chain reaction. A total of 5085 children were recruited on 1 designated day each week, year-round during the 11 years, and 221 (4.3%) tested positive for influenza B. Hospitalization rates were highest in children aged 2 to <5 years with year-to-year variation. Victoria-lineage viruses appeared to be associated with a greater fraction of influenza B hospitalizations in children than of influenza B infections in the general community. Influenza B did not cause significant hospitalization in infants <1 year of age. We report one of the first population-based, age- and lineage-specific studies of pediatric hospitalization for influenza B. We found that changes in lineage were associated with higher hospitalization rates and documented that Victoria lineage viruses were associated with greater pediatric hospitalization burden compared with Yamagata lineage viruses.


Conventional detection methodology is limiting our ability to understand the roles and functions of fine roots.
We lack a thorough conceptual and functional understanding of fine roots. Studies that have focused on estimating the quantity of fine roots provide evidence that they dominate overall plant root length. We need a standard procedure to quantify root length/biomass that takes proper account of fine roots. Here we investigated the extent to which root length/biomass may be underestimated using conventional methodology, and examined the technical reasons that could explain such underestimation. Our discussion is based on original X-ray-based measurements and on a literature review spanning more than six decades. We present evidence that root-length recovery depends strongly on the observation scale/spatial resolution at which measurements are carried out; and that observation scales/resolutions adequate for fine root detection have an adverse impact on the processing times required to obtain precise estimates. We conclude that fine roots are the major component of root systems of most (if not all) annual and perennial plants. Hence plant root systems could be much longer, and probably include more biomass, than is widely accepted.


Importance of new catecholamine pathways in control of blood pressure.
The first comprehensive maps of central catecholamine pathways referred to both noradrenaline and dopamine neurons. They described the catecholamine neurons as having their cell bodies in the brainstem with spinal axons descending mainly from two medullary cell groups (A1 and A2) and with ascending axons arising mainly from more rostral groups (A3-A13). More recent work utilising immunohistochemistry has established the presence of adrenaline neurons in the brain, in two medullary cell groups (C1 and C2). While these were originally thought to lie within the rostral part of the A1 and A2 cell groups, work from this laboratory has now established that the adrenaline neurons are topographically distinct from the A1 and A2 cells, do not fluoresce with standard methods, and are collected into three groups, the third group (C3) lying in the midline of the rostral medulla. Work in this laboratory using a combination of histochemical fluorescence and retrograde transport of horseradish peroxidase has demonstrated that existence of a descending dopaminergic projection from the hypothalamus to the spinal cord, indicating that descending pathways can arise well above the medulla. Recent studies on the A1 neurons have established the presence of projections from the A1 cells to the median eminence of the hypothalamus and towards the nucleus tractus solitarius in the medulla. Other experiments have demonstrated that most of the descending catecholamine axons do not arise from the A1 and A2 cell groups in the caudal medulla, but higher up in the brainstem especially from the A5 and A7 cell groups. These new descriptions of central catecholamine neurons will necessarily modify the interpretation of many experiments on the central regulation of arterial pressure.


Deriving individual threshold doses from clinical food challenge data for population risk assessment of food allergens.
Food allergies are a significant public health issue, and the only effective management option currently available is strict avoidance of all foods containing the allergen. In view of the practical impossibility of limiting risks to zero, quantitative allergen risk assessment and management strategies are needed. We sought to develop appropriate methods for informing population-based risk assessments and risk management programs to benefit all stakeholders but particularly patients with food allergy. Individual thresholds for food allergens (maximum tolerable doses and minimum eliciting doses) can ideally be established through double-blind, placebo-controlled food challenges. If double-blind, placebo-controlled food challenge data are not available, data from widely used open food challenges using predefined objective criteria can also provide useful data regarding minimum eliciting doses. For more than 20 years, the Netherlands Organisation for Applied Scientific Research and the Food Allergy Research and Resource Program at the University of Nebraska-Lincoln have been collecting individual maximum tolerable doses and minimum eliciting doses that produce objective symptoms from published and unpublished clinical data to better refine knowledge regarding the sensitivity of the population to food allergens. In this article we provide in-depth insights into the methodology applied by the Netherlands Organisation for Applied Scientific Research and Food Allergy Research and Resource Program to derive individual maximum tolerable doses and minimum eliciting doses for objective symptoms from clinical food challenge data. More than 90 examples for determining individual allergic thresholds are presented. With the methodology presented in this article, we aim to stimulate harmonization and transparency in quantitative food allergen risk assessment and risk management programs, encouraging their wider adoption.


[Management of aortic disease: the importance of an organized care network].
Pathologies of the aorta are a complex cardiovascular diseases requiring multidisciplinary management coordinated by specialized centers able to ensure adequate patient volume. This article describes the care pathways, based on the most recent data of the literature, to optimize the management of aortic diseases).


Altered glucose homeostasis is associated with increased serum apelin levels in type 2 diabetes mellitus.
Apelin is an adipokine that plays a role in the regulation of glucose homeostasis and in obesity. The relationship between apelin serum concentration and dysmetabolic conditions such as type 2 diabetes (T2D) is still controversial. Aims of our study are: 1) determine the circulating levels of apelin in a large cohort of Italian subjects with T2D, T1D and in non-diabetic controls; 2) identify putative metabolic determinants of modified apelin concentrations, in order to search possible mechanism of apelin control; 3) investigate changes in apelin levels in response to sharp modifications of glucose/insulin metabolism in T2D obese subjects before and 3 days after bariatric surgery. We recruited 369 subjects, 119 with T2D, 113 with T1D and 137 non-diabetic controls. All subjects underwent a complete clinical examination, including anthropometric and laboratory measurements. Serum apelin levels were determined by EIA (immunoenzyme assay). Patients with T2D had significantly higher serum apelin levels compared to controls (1.23 ± 1.1 ng/mL vs 0.91 ± 0.7 ng/mL, P<0.001) and to T1D subjects (0.73 ± 0.39 ng/mL, P<0.001). Controls and T1D subjects did not differ significantly in apelin levels. Apelin concentrations were directly associated with fasting blood glucose (FBG), body mass index (BMI), basal Disposition Index (DI-0), age, and diagnosis of T2D at bivariate correlation analysis. Multiple regression analysis confirmed that diagnosis of T2D, basal DI-0 and FBG were all determinants of serum apelin levels independently from age and BMI. Bariatric surgery performed in a subgroup of obese diabetic subjects (n = 12) resulted in a significant reduction of apelin concentrations compared to baseline levels (P = 0.01). Our study demonstrates that T2D, but not T1D, is associated with increased serum apelin levels compared to non-diabetic subjects. This association is dependent on impaired glucose homeostasis, and disappears after bariatric surgery, providing further evidence regarding the relationship between apelin and the regulation of glucose metabolism.


Survey of prevalence of extended spectrum beta-lactamases among enterobacteriaceae.
During the first six months of 1990 and 1994 respectively, 3179 and 2721 non-repetitive strains of Enterobacteriaceae were isolated at the teaching hospital of Clermont-Ferrand. Extended-spectrum beta-lactamases were found in 147 isolates, mainly in Klebsiella pneumoniae (n = 73), Enterobacter aerogenes (n = 37) and Proteus mirabilis (n = 15). TEM-3/CTX-1, SHV-4/CAZ-5 and TEM-24/CAZ-6 were the prevalent enzymes. However, the most frequently involved enzyme in 1990 was TEM-3 (48.6%) whereas in 1994 it was SHV-4 (56.0%). Two salient features emerged from this study: the high frequency of TEM-3 production in P. mirabilis and the production of SHV-4 enzyme, heretofore observed solely in K. pneumoniae, in two other species, E. aerogenes and Escherichia coli.


Involvement of Primary Care Physicians in the Decision Making and Care of Patients With Breast Cancer.
Purpose Collaborative care between cancer specialists and primary care providers (PCPs) may improve the delivery of high-quality cancer care. Yet, patient perspectives about how involved the PCPs were in their breast cancer care and treatment decisions remain unknown. Patients and Methods A weighted random sample of women newly diagnosed with breast cancer in 2013 to 2014, as reported to the SEER registries in Los Angeles, California, and Georgia, were sent a survey approximately 6 months after diagnosis (N = 2,279, 71% response rate). The distributions of patient-perceived PCP quality (six questions about PCP access and awareness of values) and the following three measures of patient-reported PCP involvement were assessed: how informed the respondent felt her PCP was about her breast cancer (engagement); how often the respondent talked with her PCP (communication); and how often the respondent felt the PCP participated in treatment decisions (participation). Adjusted mean scores of patient-reported satisfaction with and deliberation about the surgical treatment decision were then compared across levels of PCP engagement, communication, and participation using multivariable linear regression. Results The majority of women in this sample perceived high PCP quality (63.6%), high PCP breast cancer engagement (66.2%), and high PCP communication (69.1%). More than a third of women (35.4%) reported that their PCP participated in their treatment decisions. Higher PCP engagement was associated with higher decision satisfaction when compared with low PCP engagement (adjusted P = .003). Conclusion Patient perceptions of PCP quality and PCP involvement in breast cancer care during treatment are high for most women, and PCPs often participate in breast cancer treatment decisions. However, PCP involvement did not lead to meaningful improvements in patients' appraisals of their decision making.


Rad51-Rad52 mediated maintenance of centromeric chromatin in Candida albicans.
Specification of the centromere location in most eukaryotes is not solely dependent on the DNA sequence. However, the non-genetic determinants of centromere identity are not clearly defined. While multiple mechanisms, individually or in concert, may specify centromeres epigenetically, most studies in this area are focused on a universal factor, a centromere-specific histone H3 variant CENP-A, often considered as the epigenetic determinant of centromere identity. In spite of variable timing of its loading at centromeres across species, a replication coupled early S phase deposition of CENP-A is found in most yeast centromeres. Centromeres are the earliest replicating chromosomal regions in a pathogenic budding yeast Candida albicans. Using a 2-dimensional agarose gel electrophoresis assay, we identify replication origins (ORI7-LI and ORI7-RI) proximal to an early replicating centromere (CEN7) in C. albicans. We show that the replication forks stall at CEN7 in a kinetochore dependent manner and fork stalling is reduced in the absence of the homologous recombination (HR) proteins Rad51 and Rad52. Deletion of ORI7-RI causes a significant reduction in the stalled fork signal and an increased loss rate of the altered chromosome 7. The HR proteins, Rad51 and Rad52, have been shown to play a role in fork restart. Confocal microscopy shows declustered kinetochores in rad51 and rad52 mutants, which are evidence of kinetochore disintegrity. CENP-ACaCse4 levels at centromeres, as determined by chromatin immunoprecipitation (ChIP) experiments, are reduced in absence of Rad51/Rad52 resulting in disruption of the kinetochore structure. Moreover, western blot analysis reveals that delocalized CENP-A molecules in HR mutants degrade in a similar fashion as in other kinetochore mutants described before. Finally, co-immunoprecipitation assays indicate that Rad51 and Rad52 physically interact with CENP-ACaCse4 in vivo. Thus, the HR proteins Rad51 and Rad52 epigenetically maintain centromere functioning by regulating CENP-ACaCse4 levels at the programmed stall sites of early replicating centromeres.


Comparison of gene expression of umbilical cord vein and bone marrow-derived mesenchymal stem cells.
Mesenchymal stem cells (MSCs) give origin to the marrow stromal environment that supports hematopoiesis. These cells present a wide range of differentiation potentials and a complex relationship with hematopoietic stem cells (HSCs) and endothelial cells. In addition to bone marrow (BM), MSCs can be obtained from other sites in the adult or the fetus. We isolate MSCs from the umbilical cord (UC) veins that are morphologically and immunophenotpically similar to MSCs obtained from the BM. In culture, these cells are capable of differentiating in vitro into adipocytes, osteoblasts, and condrocytes. The gene expression profiles of BM-MSCs and of UC-MSCs were compared by serial analysis of gene expression, then validated by reverse transcription polymerase chain reaction of selected genes. The two lineages shared almost all of the first thousand most expressed transcripts, including vimentin, galectin 1, osteonectin, collagens, transgelins, annexin A2, and MMP2. Nevertheless, a set of genes related to antimicrobial activity and to osteogenesis was more expressed in BM-MSCs, whereas higher expression in UC-MSCs was observed for genes that participate in pathways related to matrix remodeling via metalloproteinases and angiogenesis. Finally, cultured endothelial cells, CD34+ HSCs, MSCs, blood leukocytes, and bulk BM clustered together, separated from seven other normal nonhematopoietic tissues, on the basis of shared expressed genes. MSCs isolated from UC veins are functionally similar to BM-MSCs, but differentially expressed genes may reflect differences related to their sites of origin: BM-MSCs would be more committed to osteogenesis, whereas UC-MSCs would be more committed to angiogenesis.


The hypervolume under the ROC hypersurface of "near-guessing" and "near-perfect" observers in N-class classification tasks.
We express the performance of the N-class "guessing" observer in terms of the N2-N conditional probabilities which make up an N-class receiver operating characteristic (ROC) space, in a formulation in which sensitivities are eliminated in constructing the ROC space (equivalent to using false-negative fraction and false-positive fraction in a two-class task). We then show that the "guessing" observer's performance in terms of these conditional probabilities is completely described by a degenerate hypersurface with only N-1 degrees of freedom (as opposed to the N2-N-1 required, in general, to achieve a true hypersurface in such a ROC space). It readily follows that the hypervolume under such a degenerate hypersurface must be zero when N > 2. We then consider a "near-guessing" task; that is, a task in which the N underlying data probability density functions (pdfs) are nearly identical, controlled by N-1 parameters which may vary continuously to zero (at which point the pdfs become identical). With this approach, we show that the hypervolume under the ROC hypersurface of an observer in an N-class classification task tends continuously to zero as the underlying data pdfs converge continuously to identity (a "guessing" task). The hypervolume under the ROC hypersurface of a "perfect" ideal observer (in a task in which the N data pdfs never overlap) is also found to be zero in the ROC space formulation under consideration. This suggests that hypervolume may not be a useful performance metric in N-class classification tasks for N > 2, despite the utility of the area under the ROC curve for two-class tasks.


The effect of hemodynamic factors on cardiac performance following open heart surgery.
Sixteen patients who had undergone open heart surgery were studied in order to determine the factors influencing cardiac performance in the postoperative period. Hemodynamic influences during and following cardiopulmonary bypass were found to be more important than the preoperative cardiac function. The flow rate used during cardiopulmonary bypass had a pronounced influence on the post-operative cardiac performance. A low flow can result in the development of vasoconstriction postoperative with an increased chance of low cardiac output. A high flow during bypass is recommended, and in the postoperative period vasoconstriction must be treated vigorously to forecome low cardiac output.


Hydroxylation of salicylate by microsomal fractions and cytochrome P-450. Lack of production of 2,3-dihydroxybenzoate unless hydroxyl radical formation is permitted.
Attack by hydroxyl radicals (.OH) upon salicylate (2-hydroxybenzoate) leads to formation of both 2,3-dihydroxybenzoate (2,3-DHB) and 2,5-dihydroxybenzoate (gentisate, 2,5-DHB). It has been suggested that formation of 2,3-DHB from salicylate is a means of monitoring .OH formation. Production of 2,3-DHB and 2,5-DHB by liver microsomal fractions and isoforms of cytochrome P-450 was investigated. Liver microsomes prepared from variously treated rats and rabbits catalysed the formation of 2,5-DHB but not 2,3-DHB. Formation of 2,5-DHB was inhibited by CO, metyrapone and SKF-525A, but not by the .OH scavengers mannitol and formate or by the iron chelator desferrioxamine. Purified P-450s IIE1, IIB4 or IA2 from rabbit liver microsomes, reconstituted together with NADPH-cytochrome P-450 reductase, led to formation of equal amounts of 2,3-DHB and 2,5-DHB in reactions that were almost completely inhibited by mannitol or formate. Addition of Fe3+/EDTA either to microsomes or to membranes containing reconstituted P-450 caused formation of approximately equal amounts of 2,3-DHB and 2,5-DHB, consistent with an .OH-dependent attack on salicylate. The data indicate that the microsomal P-450 system catalyses hydroxylation of salicylate to 2,5-DHB, but not formation of 2,3-DHB. Hence measurement of 2,3-DHB might provide a means of monitoring .OH formation. Care must be taken in studies of substrate hydroxylation by microsomes or reconstituted P-450 systems to avoid artefacts resulting from .OH generation.


Swainsonine induces apoptosis through mitochondrial pathway and caspase activation in goat trophoblasts.
The indolizidine alkaloid swainsonine (SW) has been reported to impair placentae and ultimately cause abortion in pregnant goats. Up to now, however, the precise effects of SW on goat trophoblast cells (GTCs) are still unclear. In this study, the cytotoxicity effects of SW on GTCs were detected and evaluated by MTT assay, AO/EB double staining, DNA fragmentation assay and flow cytometry analysis. Results showed that SW treatment significantly suppressed GTCs viability and induced typical apoptotic features in a time- and concentration-dependent manner. SW treatment increased Bax protein levels, reduced Bcl-2 protein levels, induced Bax translocation to mitochondria, and triggered the release of cytochrome c from mitochondria into cytosol, which in turn activated caspase-9 and caspase-3, and cleaved PARP, resulting in GTCs apoptosis. However, caspase-8 activity and the level of Bid did not exhibit significant changes in the process of SW-induced apoptosis. In addition, TUNEL assay suggested that SW induced GTCs apoptosis but not other cells in goat placenta cotyledons. Taken together, these data suggest that SW selectively induces GTCs apoptosis via the activation of mitochondria-mediated apoptosis pathway in goat placenta cotyledons, which might contribute to placentae impairment and abortion in pregnant goats fed with SW-containing plants. These findings may provide new insights to understand the mechanisms involved in SW-caused goat's abortion.


Armstrong strain lymphocytic choriomeningitis virus infection after accidental laboratory exposure.
Lymphocytic choriomeningitis virus (LCMV) is a human pathogen naturally present in wild rodents. In addition, LCMV is routinely used in immunology research as a model of viral infection in mice. The Armstrong common laboratory strain and the Clone-13 variant induce acute and chronic infections in mice, respectively. The frequent use of this virus in laboratory settings is associated with a risk of human infection for laboratory personnel. In contrast to LCMV Clone-13, few human laboratory infections with LCMV Armstrong have been reported, leading to a poor understanding of symptoms related to infection with this specific LCMV strain. A researcher accidentally infected herself percutaneously with LCMV Armstrong. Symptoms including headaches, dizziness, eye pain and nausea appeared seven days post-exposure and lasted ten days. LCMV-IgM antibodies were detected at 28 days post-infection and IgG seroconversion was observed later. Complete recovery was confirmed three months post exposure. Research involving live viruses comes with the risk of infection for research personnel. This case is the first reported accidental human infection with LCMV Armstrong. The symptoms differed from reported infections with LCMV Clone-13, by the absence of fever and vomiting, and presence of leg numbness. This report will therefore help clinicians and public health authorities to recognize the symptoms associated with LCMV Armstrong infections and to offer appropriate counselling to individuals who accidentally expose themselves.


MRI of non-neoplastic cranial complications of malignant disorders.
To depict the well-known and atypical magnetic resonance imaging (MRI) findings of non-neoplastic central nervous system (CNS) complications of extra- CNS tumors and portray additional information from advanced techniques, such as diffusion and perfusion MRI. MRI scans of 92 patients were retrospectively evaluated based on the non-neoplastic effects induced by treatment or the remote effects of the tumor itself. Patients with brain metastases and/or patients who had whole brain radiation therapy were excluded so as not to take the primary radiation effects into consideration. Sixteen patients (9 females and 7 males; age range, 11-68 years; median age, 45 years) had positive findings other than brain metastases. Six patients had posterior reversible encephalopathies, 3 patients had chemotherapy toxicity to the white matter, and 2 patients had acute strokes involving the posterior fossa and bilateral anterior circulation territory. Three patients had bilateral radionecrosis of the temporal lobe due to radiotherapy given for the vicinal tumor (nasopharyngeal carcinoma). One patient had encephalitis in the bitemporal region and one patient had cerebellar degeneration, each of whom had a paraneoplastic syndrome. One of the major and noteworthy complications of malignancies directly affecting survival is brain metastasis, but non-neoplastic complications are infrequently encountered and are thus underestimated, either due to the absence of a true diagnosis or the lack of information pertaining to the clinical outcome. It is important for the radiologist to recognize these effects so as to help the clinician develop an optimal treatment strategy and avoid irreversible complications.


Spinal dural arteriovenous fistula formation after scoliosis surgery: case report.
Spinal dural arteriovenous fistulas are diagnostically challenging lesions, and they are not well described in patients with a history of a spinal deformity correction. The authors present the challenging case of a 74-year-old woman who had previously undergone correction of a spinal deformity with subsequent revision. Several years after the last deformity operation, she developed a progressive myelopathy with urinary incontinence over a 6-month period. After evaluation at the authors' institution, an angiogram was obtained, demonstrating a fistula at the T12-L1 region. Surgical ligation of the fistula was performed with subsequent improvement of the neurological symptoms. This case is thought to represent the first fistula documented in an area of the spine that had previously been operated on, and to the authors' knowledge, it is the first case report to be associated with spinal deformity surgery. A brief historical overview and review of the pathophysiology of spinal dural arteriovenous fistulas is also included.


Cereal processing at Early Neolithic Göbekli Tepe, southeastern Turkey.
We analyze the processing of cereals and its role at Early Neolithic Göbekli Tepe, southeastern Anatolia (10th / 9th millennium BC), a site that has aroused much debate in archaeological discourse. To date, only zooarchaeological evidence has been discussed in regard to the subsistence of its builders. Göbekli Tepe consists of monumental round to oval buildings, erected in an earlier phase, and smaller rectangular buildings, built around them in a partially contemporaneous and later phase. The monumental buildings are best known as they were in the focus of research. They are around 20 m in diameter and have stone pillars that are up to 5.5 m high and often richly decorated. The rectangular buildings are smaller and-in some cases-have up to 2 m high, mostly undecorated, pillars. Especially striking is the number of tools related to food processing, including grinding slabs/bowls, handstones, pestles, and mortars, which have not been studied before. We analyzed more than 7000 artifacts for the present contribution. The high frequency of artifacts is unusual for contemporary sites in the region. Using an integrated approach of formal, experimental, and macro- / microscopical use-wear analyses we show that Neolithic people at Göbekli Tepe have produced standardized and efficient grinding tools, most of which have been used for the processing of cereals. Additional phytolith analysis confirms the massive presence of cereals at the site, filling the gap left by the weakly preserved charred macro-rests. The organization of work and food supply has always been a central question of research into Göbekli Tepe, as the construction and maintenance of the monumental architecture would have necessitated a considerable work force. Contextual analyses of the distribution of the elements of the grinding kit on site highlight a clear link between plant food preparation and the rectangular buildings and indicate clear delimitations of working areas for food production on the terraces the structures lie on, surrounding the circular buildings. There is evidence for extensive plant food processing and archaeozoological data hint at large-scale hunting of gazelle between midsummer and autumn. As no large storage facilities have been identified, we argue for a production of food for immediate use and interpret these seasonal peaks in activity at the site as evidence for the organization of large work feasts.


Emergence of norovirus strains: A tale of two genes.
Noroviruses are a very diverse group of viruses that infect different mammalian species. In humans, norovirus is a major cause of acute gastroenteritis. Multiple norovirus infections can occur in a lifetime as the result of limited duration of acquired immunity and cross-protection among different strains. A combination of advances in sequencing methods and improvements on surveillance has provided new insights into norovirus diversification and emergence. The generation of diverse norovirus strains has been associated with (1) point mutations on two different genes: ORF1, encoding the non-structural proteins, and ORF2, encoding the major capsid protein (VP1); and (2) recombination events that create chimeric viruses. While both mechanisms are exploited by all norovirus strains, individual genotypes utilize each mechanism differently to emerge and persist in the human population. GII.4 noroviruses (the most prevalent genotype in humans) present an accumulation of amino acid mutations on VP1 resulting in the chronological emergence of new variants. In contrast, non-GII.4 noroviruses present co-circulation of different variants over long periods with limited changes on their VP1. Notably, genetic diversity of non-GII.4 noroviruses is mostly related to the high number of recombinant strains detected in humans. While it is difficult to determine the precise mechanism of emergence of epidemic noroviruses, observations point to multiple factors that include host-virus interactions and changes on two regions of the genome (ORF1 and ORF2). Larger datasets of viral genomes are needed to facilitate comparison of epidemic strains and those circulating at low levels in the population. This will provide a better understanding of the mechanism of norovirus emergence and persistence.


[Recurrent falls in the elderly].
Approximately 30% of community-dwelling elderly people in developed countries fall at least once each year. Although only 10% of falls lead to serious injuries, these represent a considerable share of all injury-related hospital admissions, with high mortality and morbidity and high health care costs. Early detection of persons at risk and effective intervention measures are needed. The article gives an overview of current knowledge in this field. A limited literature search (1989-2001) and a telephone survey among all geriatric units in Norway. Recurrent falls are a multifactorial problem requiring a multifactorial intervention strategy at any care level and between levels. Exercise/balance training and hip protectors seem to be the most effective measures in preventing falls and fall injuries. Feasible selection criteria, good cooperation routines and knowledge of local resources are important. Awareness of the problem is needed not only in geriatricians, but all health professionals caring for elderly patients.


[Intrauterine renal vein thrombosis (author's transl)].
One case of renal venous thrombosis in a male foetus, born of a diabetic mother is reported. The intrauterine origin and the long age of the thrombosis were confirmed by pathologic studies. Some speculation about the etiopathogenic mechanisms of intrauterine renal venous thrombosis are made.


Is mercury from small-scale gold mining prevalent in the southeastern Peruvian Amazon?
There is an ongoing debate on the fate of mercury (Hg) in areas affected by artisanal and small-scale gold mining (ASGM). Over the last 30 years, ASGM has released 69 tons of Hg into the southeastern Peruvian Amazon. To investigate the role of suspended matter and hydrological factors on the fate of ASGM-Hg, we analysed riverbank sediments and suspended matter along the partially ASGM-affected Malinowski-Tambopata river system and examined Hg accumulation in fish. In addition, local impacts of atmospheric Hg emissions on aquatic systems were assessed by analysing a sediment core from an oxbow lake. Hg concentrations in riverbank sediments are lower (20-53 ng g-1) than in suspended matter (∼400-4000 ng g-1) due to differences in particle size. Elevated Hg concentrations in suspended matter from ASGM-affected river sections (∼1400 vs. ∼30-120 ng L-1 in unaffected sections) are mainly driven by the increased amount of suspended matter rather than increased Hg concentrations in the suspended matter. The oxbow lake sediment record shows low Hg concentrations (64-86 ng g-1) without evidence of any ASGM-related increase in atmospheric Hg input. Hg flux variations are mostly an effect of variations in sediment accumulation rates. Moreover, only 5% of the analysed fish (only piscivores) exceed WHO recommendations for human consumption (500 ng g-1). Our findings show that ASGM-affected river sections in the Malinowski-Tambopata system do not exhibit increased Hg accumulation, indicating that the released Hg is either retained at the spill site or transported to areas farther away from the ASGM areas. We suspect that the fate of ASGM-Hg in such tropical rivers is mainly linked to transport associated with the suspended matter, especially during high water situations. We assume that our findings are typical for ASGM-affected areas in tropical regions and could explain why aquatic systems in such ASGM regions often show comparatively modest enrichment in Hg levels.


Cortical afferents to the entorhinal cortex of the Rhesus monkey.
Although the entorhinal cortex is a major contributor of afferents to the hippocampus and dentate gyrus, knowledge of its own afferents has been vague. Regions of both the frontal and temporal lobes were found to contribute afferents to this region of the brain. These afferents form probable multisynaptic links in pathways connecting the classical sensory areas of the cortex and the limbic system.


Colonization and infection with Enterococcus faecalis in intensive care units: the role of antimicrobial agents.
We studied the influences of antimicrobial agents on the colonization of the respiratory tract and infection with Enterococcus faecalis in intensive care unit (ICU) patients receiving mechanical respiration for at least 3 days. In a matched-cohort analysis, patients receiving topical antimicrobial prophylaxis (TAP) of the oropharynx and stomach with antimicrobial agents not treating E. faecalis were compared with patients not receiving TAP. Patients were matched with controls on the basis of their duration in the ICU, their use of systemic antibiotics treating and not treating E. faecalis, the administration of TAP, their APACHE II score, and surgical procedures they had undergone. In all, 276 patients were analyzed. The colonization of the oropharynx and/or trachea by E. faecalis at admission was demonstrated for 43 patients (16%). Twenty patients (9%) acquired tracheal colonization and 91 patients (40%) acquired oropharyngeal colonization with E. faecalis. In the matched-cohort analysis, 43 patients receiving TAP were matched in two controls each. TAP patients more frequently acquired tracheal colonization (15 of 43 versus 2 of 86 patients, P < 0.00001) and infections with E. faecalis (6 of 43 versus 1 of 86 patients, P < 0.01). The use of topical antibiotics and treating E. faecalis increased the risk for colonization and infection with E. faecalis.


Age at menarche, the leg length to sitting height ratio, and risk of diabetes in middle-aged and elderly Chinese men and women.
To evaluate the associations of age at menarche and the leg length-to-sitting-height ratio, markers of adolescent growth, with risk of diabetes in later life. Information from 69,385 women and 55,311 men, aged 40-74 years from the Shanghai Women's Health Study and Shanghai Men's Health Study, were included in the current analyses. Diabetes status was ascertained through biennial in person follow-up. Cox models, with age as the time scale, were used. There were 2369 cases of diabetes (1831 women; 538 men) during an average of 7.3 and 3.6 years of follow-up of the women and men, respectively. In females, menarche age was inversely associated with diabetes risk after adjustment for birth cohort, education, and income (HR = 0.95, 0.92-0.98). In both genders, leg length-to-sitting-height ratio was inversely related to diabetes (HR = 0.88, 0.80-0.97 for men; HR = 0.91, 0.86-0.96 for women) after adjustment for birth cohort, education, and income. Further adjustment for adult BMI at study enrollment completely eliminated the associations of age at menarche (HR = 0.99, 0.96-1.02) and the leg length-to-sitting-height ratio (HR = 1.00, 0.91-1.10 for men; HR = 1.01, 0.96-1.07 for women) with diabetes risk. Our study suggests that markers of an early age at peak height velocity, i.e. early menarche age and low leg-length-to-sitting height ratio, may be associated with diabetes risk later in life and this association is likely to be mediated through obesity.


Spectrum and subcellular determinants of fluorinated anesthetic-mediated proximal tubular injury.
Currently used fluorinated anesthetics are chemically related to methoxyflurane (MF), a drug that caused many cases of clinical acute renal failure during previous widespread use. To determine whether newer fluorinated anesthetics might also have nephrotoxic effects, three currently used agents (isoflurane (IF), sevoflurane (SF), and desflurane) or MF were added to rat proximal tubular segments, followed by assessments of cell integrity (ATP levels and percent lactic dehydrogenase release). Ether served as a negative control. MF, IF, and SF each induced lethal proximal tubular segment injury (up to 92, 71, and 30% lactic dehydrogenase release, respectively) and massive ATP depletion. ATP losses were observed at or near clinically relevant drug levels, they preceded lethal injury, and they correlated with approximately 50% and approximately 100% reductions in total and Na,K-ATPase-driven respiration, respectively. Clinically relevant inorganic fluoride levels simulated fluorinated anesthetic toxicity. However, fluoride release from the anesthetics (a cytochrome P450 process) did not appear to be required for toxicity (no protection with P450 inhibitors and no detectable inorganic fluoride release). As IF was judged to be one-third as toxic as MF, subclinical tubular injury (increased urine N-acetyl-beta-D-glucosaminidase (NAG) levels) after its use was sought in 19 surgical patients. Fifteen patients undergoing comparable operations with SF (approximately one-half as toxic as IF in vitro) and nine patients undergoing regional/ local anesthesia were controls. The IF group doubled its urinary NAG levels by the end of surgery (P < 0.005). Conversely, NAG levels remained stable in both control groups. The conclusions are that 1) currently used fluorinated anesthetics, particularly IF, share (but to a lesser degree) MFs tubulotoxic effects, 2) ATP depletion (probably due to decreased production) and Na,K-ATPase inhibition are likely contributing mechanisms, 3) fluoride is a prime determinant of this toxicity, and 4) tubular injury can be expressed at or near clinically relevant anesthetic/inorganic fluoride levels. That increased enzymuria can develop in patients after IF anesthesia suggests that the above in vitro data could have potential clinical relevance in selected patients.


Clear cell renal cell carcinoma with smooth muscle stroma.
A recent publication described 5 unusual clear cell renal tumors with prominent smooth muscle stroma that were characterized only by immunostaining. We report 3 additional tumors composed of clear cell renal cell carcinoma intimately admixed with abundant smooth muscle stroma. Epithelial differentiation of the malignant clear cell components and smooth muscle differentiation of the benign spindle cell stroma was confirmed by the immunostaining profiles and by electron microscopy. Fluorescence in situ hybridization analysis of chromosome 3 showed loss of the entire chromosome in 2 cases and loss of 3p in the third case. We therefore interpret these tumors as unique low-grade variants of clear cell renal cell carcinoma that have induced a prolific metaplastic stromal reaction. Extensive tissue sampling and immunostaining are recommended to distinguish cases with an extensive smooth muscle component from morphologically similar but benign lesions including angiomyolipoma, leiomyoma, or mixed epithelial and stromal tumor of the kidney.


Frequency dependence of spike timing reliability in cortical pyramidal cells and interneurons.
Pyramidal cells and interneurons in rat prefrontal cortical slices exhibit subthreshold oscillations when depolarized by constant current injection. For both types of neurons, the frequencies of these oscillations for current injection just below spike threshold were 2--10 Hz. Above spike threshold, however, the subthreshold oscillations in pyramidal cells remained low, but the frequency of oscillations in interneurons increased up to 50 Hz. To explore the interaction between these intrinsic oscillations and external inputs, the reliability of spiking in these cortical neurons was studied with sinusoidal current injection over a range of frequencies above and below the intrinsic frequency. Cortical neurons produced 1:1 phase locking for a limited range of driving frequencies for fixed amplitude. For low-input amplitude, 1:1 phase locking was obtained in the 5- to 10-Hz range. For higher-input amplitudes, pyramidal cells phase-locked in the 5- to 20-Hz range, whereas interneurons phase-locked in the 5- to 50-Hz range. For the amplitudes studied here, spike time reliability was always highest during 1:1 phase-locking, between 5 and 20 Hz for pyramidal cells and between 5 and 50 Hz for interneurons. The observed differences in the intrinsic frequency preference between pyramidal cells and interneurons have implications for rhythmogenesis and information transmission between populations of cortical neurons.


Watch and wait policy in advanced neuroendocrine tumors: What does it mean?
Neuroendocrine neoplasms (NENs) are a group of rare and heterogeneous malignancies, which can develop in various organs. The clinical course of NENs is quite heterogeneous, with different spontaneous growth rates after diagnosis, and different degrees of sensitivity to the same therapy even when they have similar characteristics. Watch and wait (W and W), is a term coined to indicate observation being conducted to assess the evolution of the tumor without administering any anti-tumor therapy. It has been applied to NENs since in extremely rare cases they tend to remain stable for a long time. Although W and W has been reported in several guidelines and recommendations it has never been validated, nor has it been specifically investigated. Furthermore it is not standardized. Therefore its application in clinical practice can differ in terms of tumor status assessment, type and timing of imaging or other exams utilized. In conclusion, while undertaking W and W to delay the first-line therapy by some weeks may be justified in good performance asymptomatic patients with low-grade NENs in order to usefully characterize the disease and patient and thereby choose the best therapy and therapeutic strategy, it seems to be far more difficult to justify W and W with the intent of avoiding an anti-tumor treatment. It should be considered that not only do NENs tend to grow even when they have very favorable biological characteristics but also that the alternative to W and W is most commonly a low toxic and effective treatment with somatostatin analogs.


[Clinical effects of the alterations that emerge in the signaling mechanisms of the insulin receptor].
Phosphorilation of subunit beta from insulin receptor induced mainly by insulin, it begins a series of intracellular complex signaling in cascade. Through this way establish multiple effects, which permits to the cell initiate its biological activity. This activity include the glucose metabolism, the regulation of ions and amino acids transport, lipids metabolism, glycogen synthesis, genetic transcription, mRNA expression, synthesis and degradation of proteins, as well as synthesis of DNA. Therefore, a modification in anyone of the proteins involved in the insulin signaling, can take place a dysfunction in the glucose metabolism. The impaired glucose can be due because there are many proteins, ions and enzymes that participate in the downstream pathways of the insulin signaling, it has become difficult to find a single phatophysiologic level as cause of diabetes. In spite of the advances in the study of this disease, it has been reached the conclusion that the glucose control is not enough to impede the complications that characterize to type 2 diabetes, since the organic worsening does not stop, which indicates that insulin signaling dysfunction is directly involved in all cellular process, and a better understanding in the communication ways of this hormone will take to new forms of treatment to impaired insulin response.


Serious renal transplant rejection and adrenal hypofunction after gradual withdrawal of prednisolone two years after transplantation.
Ten patients with stable renal function two years after transplantation had their sole immunosuppressive treatment (oral prednisolone 10 mg daily) withdrawn by reducing the daily dose by 1 mg at monthly intervals. Plasma prednisolone concentration, cortisol concentration, creatinine clearance, and serum creatinine concentration were measured in all patients, and the adrenal response to corticotrophin was determined in five by measuring plasma cortisol concentrations before and after tetracosactrin injection. No episodes of rejection occurred in patients taking over 7 mg prednisolone daily. Although three patients apparently required only minimal immunosuppressive treatment (less than 5 mg daily) the remainder suffered episodes of rejection at daily doses below 7 mg. There was a tenuous association between rejection and low plasma cortisol concentration, but neither the pattern of plasma prednisolone concentrations nor the response to tetracosactrin were related to episodes of rejection. Reducing the daily dose of oral prednisolone to under 7 mg should not be attempted in patients with renal transplants unless there are extenuating circumstances.


Multinuclear group 4 catalysis: olefin polymerization pathways modified by strong metal-metal cooperative effects.
Polyolefins are produced today catalytically on a vast scale, and the manufactured polymers find use in everything from artificial limbs and food/medical packaging to automotive and electrical components and lubricants. Although polyolefin monomers are typically cheap (e.g., ethylene, propylene, α-olefins), the resulting polymer properties can be dramatically tuned by the particular polymerization catalyst employed, and reflect a rich interplay of macromolecular chemistry, materials science, and physics. For example, linear low-density polyethylene (LLDPE), produced by copolymerization of ethylene with linear α-olefin comonomers such as 1-butene, 1-hexene, or 1-octene, has small but significant levels of short alkyl branches (C2, C4, C6) along the polyethylene backbone, and is an important technology material due to outstanding rheological and mechanical properties. In 2013, the total world polyolefin production was approximately 211 million metric tons, of which about 11% was LLDPE. Historically, polyolefins were produced using ill-defined but highly active heterogeneous catalysts composed of supported groups 4 or 6 species (usually halides) activated by aluminum alkyls. In 1963, Karl Ziegler and Giulio Natta received the Nobel Prize for these discoveries. Beginning in the late 1980s, a new generation of group 4 molecule-based homogeneous olefin polymerization catalysts emerged from discoveries by Walter Kaminsky, a team led by James Stevens at The Dow Chemical Company, this Laboratory at Northwestern University, and a host of talented groups in Germany, Italy, Japan, the United Kingdom, and the United States. These new "single-site" catalysts and their activating cocatalysts were far better defined and more rationally tunable in terms of structure, mechanism, thermodynamics, and catalyst activity and selectivity than ever before possible. An explosion of research advances led to new catalysts, cocatalysts, deeper mechanistic understanding of both the homogeneous and heterogeneous systems, macromolecules with dramatically altered properties, and large-scale industrial processes. It is noteworthy that many metalloenzymes employ multiple active centers operating in close synergistic proximity to achieve high activity and selectivity. Such enzymes were the inspiration for the research discussed in this Account, focused on the properties of multimetallic olefin polymerization catalysts. Here we discuss how modifications in organic ligand architecture, metal···metal proximity, and cocatalyst can dramatically modify polyolefin molecular weight, branch structure, and selectively for olefinic comonomer enchainment. We first discuss bimetallic catalysts with identical group 4 metal centers and then heterobimetallic systems with either group 4 or groups 4 + 6 catalytic centers. We compare and contrast the polymerization properties of the bimetallic catalysts with their monometallic analogues, highlighting marked cooperative enchainment effects and unusual polymeric products possible via the proximate catalytic centers. Such multinuclear olefin polymerization catalysts exhibit the following distinctive features: (1) unprecedented levels of polyolefin branching; (2) enhanced enchainment selectivity for linear and encumbered α-olefin comonomers; (3) enhanced polyolefin tacticity and molecular weight; (4) unusual 1,2-insertion regiochemistry for styrenic monomers; (5) modified chain transfer kinetics, such as M-polymer β-hydride transfer to the metal or incoming monomer; (6) LLDPE synthesis with a single binuclear catalyst and ethylene.


Confounding in Studies on Metacognition: A Preliminary Causal Analysis Framework.
By definition, metacognitive processes may monitor or regulate various stages of first-order processing. By combining causal analysis with hypotheses expressed by other authors we derive the theoretical and methodological consequences of this special relation between metacognition and the underlying processes. In particular, we prove that because multiple processing stages may be monitored or regulated and because metacognition may form latent feedback loops, (1) without strong additional causal assumptions, typical measures of metacognitive monitoring or regulation are confounded; (2) without strong additional causal assumptions, typical methods of controlling for first-order task performance (i.e., calibration, staircase, including first-order task performance in a regression analysis, or analyzing correct and incorrect trials separately) not only do not deconfound measures of metacognition but may even introduce bias; (3) that the first two problems cannot be solved by using simple models of decision-making derived from Signal Detection Theory. We conclude the paper by advocating robust methods of discovering properties of latent mechanisms.


Reversed ileal segment for treatment of ileostomy dysfunction. Clinical application.
Persistent, profuse ileostomy diarrhea developed gradually in a patient over a 12-hour period after proctocolectomy for ulcerative colitis. There was no evidence of ileostomy stenosis or dilation of the ileum proximal to the stoma. He was successfully treated with a reverse ileal segment of 10 cm, and gained 14 to 18 kg. ileostomy output became semisolid and decreased from 1,000 to 2,000 ml/day to 600 ml/day. The transit time changed from 12 minutes to 2 1/2 hours. Antiperistaltic segments of intestine prolong transit time and allow for greater absorption. While most patients with ileostomies are not troubled by severe diarrhea, the small proportion who are may be candidates for a reversed ileal segment.


Emotions in Depression: What Do We Really Know?
Major depressive disorder is among the most common and costly of all mental health conditions, and in the last 20 years, emotional dysfunction has been increasingly seen as central to depression. Accordingly, research on emotions in depression has proceeded with fury. The urgency of the work has tempted investigators to issue premature declarations and to sometimes overlook theoretical and methodological challenges entailed in studying emotion. I report on what we have learned thus far about how depression influences emotional reactivity and emotion regulation, and also carefully demarcate the vast terrain of what we do not yet know. Ironically, an attitude of humility may enable the field to achieve the ambitious but elusive goal of developing a rich, contextually specific account of depression-related changes in emotional reactivity and regulation. Such an account is a precondition for using knowledge about emotion to intervene more effectively to reduce depression's worldwide burden.


Outcomes for births booked under an independent midwife and births in NHS maternity units: matched comparison study.
To compare clinical outcomes between women employing an independent midwife and comparable pregnant women using NHS services. Anonymised matched cohort analysis. Cases from the database of the Independent Midwives' Association (IMA) matched up to 1:5 with Scottish National Health Service (NHS) records for age, parity, year of birth, and socioeconomic status. Multivariable logistic regression models used to explore the relation between explanatory variables and outcomes; analyses controlled for potential confounding factors and adjusted for stratification. UK databases 2002-5. Anonymised records for 8676 women (7214 NHS; 1462 IMA). Unassisted vertex delivery, live birth, perinatal death, onset of labour, gestation, use of analgesia, duration of labour, perineal trauma, Apgar scores, admission to neonatal intensive care, infant feeding. IMA cohort mothers were significantly more likely to achieve an unassisted vertex delivery than NHS cohort mothers (77.9% (1139) v 54.3% (3918); odds ratio 3.49, 95% confidence interval 2.99 to 4.07) but also significantly more likely to experience a stillbirth or a neonatal death (1.7% (25) v 0.6% (46); 5.91, 3.27 to 10.7). All odds ratios are adjusted for confounding factors. Exclusion of "high risk" cases from both cohorts showed a non-significant difference (0.5% (5) v 0.3% (18); 2.73, 0.87 to 8.55); the "low risk" IMA perinatal mortality rate is comparable with other studies of low risk births. Women in the IMA cohort had a higher incidence of pre-existing medical conditions (1.5% (22) v 1.0% (72) in the NHS cohort) and previous obstetric complications (21.0% (307) v 17.8% (1284)). The incidence of twin pregnancy was also higher (3.4% (50) v 3.1% (224)). In the IMA cohort, 66.0% of mothers (965/1462) had home births, compared with only 0.4% of NHS cohort mothers (27/7214). Spontaneous onset of labour was more common in the IMA group (96.6% (1405) v 74.5% (5365); 10.43, 7.74 to 14.0), and fewer mothers used pharmacological analgesia (40.2% (588) v 60.6% (4370); 0.42, 0.38 to 0.47). Mothers in the IMA cohort were much more likely to breast feed (88.0% (1286) v 64.0% (2759); 3.46, 2.84 to 4.20). Prematurity (4.3% (63) v 6.9% (498); 0.49, 0.35 to 0.69), low birth weight (4.0% (60) v 7.1%) (523); 0.93, 0.62 to 1.38), and rate of admission to neonatal intensive care (4.4% (65) v 9.3% (667); 0.43, 0.32 to 0.59) were all higher in the NHS dataset. Healthcare policy tries to direct patient choice towards clinically appropriate and practicable options; nevertheless, pregnant women are free to make decisions about birth preferences, including place of delivery and staff in attendance. While clinical outcomes across a range of variables were significantly better for women accessing an independent midwife, the significantly higher perinatal mortality rates for high risk cases in this group indicate an urgent need for a review of these cases. The significantly higher prematurity and admission rates to intensive care in the NHS cohort also indicate an urgent need for review.


Strong desmin immunoreactivity in the myocardial sleeves around pulmonary veins, superior caval vein and coronary sinus supports the presumed arrhythmogenicity of these regions.
Myocardial sleeve around human pulmonary veins plays a critical role in the pathomechanism of atrial fibrillation. Besides the well-known arrhythmogenicity of these veins, there is evidence that myocardial extensions into caval veins and coronary sinus may exhibit similar features. However, studies investigating histologic properties of these structures are limited. We aimed to investigate the immunoreactivity of myocardial sleeves for intermediate filament desmin, which was reported to be more abundant in Purkinje fibers than in ventricular working cardiomyocytes. Sections of 16 human (15 adult and 1 fetal) hearts were investigated. Specimens of atrial and ventricular myocardium, sinoatrial and atrioventricular nodes, pulmonary veins, superior caval vein and coronary sinus were stained with anti-desmin monoclonal antibody. Intensity of desmin immunoreactivity in different areas was quantified by the ImageJ program. Strong desmin labeling was detected at the pacemaker and conduction system as well as in the myocardial sleeves around pulmonary veins, superior caval vein, and coronary sinus of adult hearts irrespective of sex, age, and medical history. In the fetal heart, prominent desmin labeling was observed at the sinoatrial nodal region and in the myocardial extensions around the superior caval vein. Contrarily, atrial and ventricular working myocardium exhibited low desmin immunoreactivity in both adults and fetuses. These differences were confirmed by immunohistochemical quantitative analysis. In conclusion, this study indicates that desmin is abundant in the conduction system and venous myocardial sleeves of human hearts.


Identification and classification of chemicals using terahertz reflective spectroscopic focal-plane imaging system.
We present terahertz (THz) reflective spectroscopic focal-plane imaging of four explosive and bio-chemical materials (2, 4-DNT, Theophylline, RDX and Glutamic Acid) at a standoff imaging distance of 0.4 m. The 2 dimension (2-D) nature of this technique enables a fast acquisition time and is very close to a camera-like operation, compared to the most commonly used point emission-detection and raster scanning configuration. The samples are identified by their absorption peaks extracted from the negative derivative of the reflection coefficient respect to the frequency (-dr/dv) of each pixel. Classification of the samples is achieved by using minimum distance classifier and neural network methods with a rate of accuracy above 80% and a false alarm rate below 8%. This result supports the future application of THz time-domain spectroscopy (TDS) in standoff distance sensing, imaging, and identification.


Patient acceptance of HIV testing services in rural emergency departments in South Africa.
South Africa faces the highest burden of HIV infection globally. The National Strategic Plan on HIV recommends provider-initiated HIV counselling and testing (HCT) in all healthcare facilities. However, HIV continues to overwhelm the healthcare system. Emergency department (ED)-based HCT could address unmet testing needs. This study examines the reasons for accepting or declining HCT in South African EDs to inform the development of HCT implementation strategies. We conducted a prospective observational study in two rural EDs, from June to September 2017. Patients presenting to the ED were systematically approached and offered a point-of-care test in accordance with national guidelines. Patients demographics, presenting compaint, medical history and reasons for accepting/declining testing, were recorded. A pooled analysis is presented. Across sites, 2074 adult, non-critical patients in the ED were approached; 1880 were enrolled in the study. Of those enrolled, 19.7% had a previously known positive diagnosis, and 80.3% were unaware of their HIV status. Of those unaware, 90% patients accepted and 10% declined testing. The primary reasons for declining testing were 'does not want to know status' (37.6%), 'in too much pain' (34%) and 'does not believe they are at risk' (19.9%). Despite national guidelines, a high proportion of individuals remain undiagnosed, of which a majority are young men. Our study demonstrated high patient acceptance of ED-based HCT. There is a need for investment and innovation regarding effective pain management and confidential service delivery to address patient barriers. Findings support a routine, non-targeted HCT strategy in EDs.


Search for meaningful support and the meaning of illness in German cancer patients.
Spiritual needs are an essential component of holistic health care. Several studies have shown that religious involvement and spirituality are associated with better health outcome, coping skills and health-related quality of life. Using the newly developed SpREUK inventory, we examined how German cancer patients (n=115) by themselves view the impact of spirituality and religiosity (SpR) on their health and how they cope with illness. Cancer patients with both a religious and spiritual attitude had significantly higher values in the search for meaningful support and in addressing the stabilizing effects of SpR than patients without such attitudes. Patients with non-spiritual religious attitudes had a lower perception of the beneficial effects of their SpR and significantly lower needs for meaningful support. Female cancer patients were convinced that finding access to a spiritual source has a positive influence on their illness, that illness has meaning, regard illness as a chance for their own development and as a hint to change life. Knowledge of a patient's spirituality can help service providers predict aspects of psychosocial needs and to respond sensitively and appropriately. The SpREUK questionnaire is a useful tool to define patients who are more in need of spiritual support than others.


Neurotoxicity studies with the monoamine oxidase B substrate 1-methyl-3-phenyl-3-pyrroline.
The neurotoxic properties of the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are dependent on its metabolic activation in a reaction catalyzed by centrally located monoamine oxidase B (MAO-B). This reaction ultimately leads to the permanently charged 1-methyl-4-phenylpyridinium species MPP(+), a 4-electron oxidation product of MPTP and a potent mitochondrial toxin. The corresponding 5-membered analogue, 1-methyl-3-phenyl-3-pyrroline, is also a selective MAO-B substrate. Unlike MPTP, the MAO-B-catalyzed oxidation of 1-methyl-3-phenyl-3-pyrroline is a 2-electron process that leads to the neutral 1-methyl-3-phenylpyrrole. MPP(+) is thought to exert its toxic effects only after accumulating in the mitochondria, a process driven by the transmembrane electrochemical gradient. Since this energy-dependent accumulation of MPP(+) relies upon its permanent charge, 1-methyl-3-phenyl-3-pyrrolines and their pyrrolyl oxidation products should not be neurotoxic. We have tested this hypothesis by examining the neurotoxic potential of 1-methyl-3-phenyl-3-pyrroline and 1-methyl-3-(4-chlorophenyl)-3-pyrroline in the C57BL/6 mouse model. These pyrrolines did not deplete striatal dopamine while analogous treatment with MPTP resulted in 65-73% depletion. Kinetic studies revealed that both 1-methyl-3-phenyl-3-pyrroline and its pyrrolyl oxidation product were present in the brain in relatively high concentrations. Unlike MPP(+), however, 1-methyl-3-phenylpyrrole was cleared from the brain quickly. These results suggest that the brain MAO-B-catalyzed oxidation of xenobiotic amines is not, in itself, sufficient to account for the neurodegenerative properties of a compound like MPTP. The rapid clearance of 1-methyl-3-phenylpyrroles from the brain may contribute to their lack of neurotoxicity.


Short-Term Hypoxic Exposure and Training Improve Maximal Anaerobic Running Test Performance.
Oriishi, M, Matsubayashi, T, Kawahara, T, and Suzuki, Y. Short-term hypoxic exposure and training improve maximal anaerobic running test performance. J Strength Cond Res 32(1): 181-188, 2018-The purpose of this study was to examine the effectiveness of short-term hypoxic exposure and training in the performance of competitive 400- or 800-m runners. Fifteen female competitive 400- and 800-m runners volunteered to participate and were assigned to either the hypoxic (n = 7) or normoxic (n = 8) group. The subjects completed 6 days of training. The hypoxic group trained and slept in normobaric hypoxia, with oxygen concentrations of 14.4 and 16.5% for training and sleep, respectively. The normoxic group trained and slept at sea level. The subjects completed 4 sprint and 5 endurance training sessions during the camp. The subjects underwent a maximal anaerobic running test before and 8 days after the training camp. The maximal power determined by the anaerobic running test improved significantly in the hypoxic group (p ≤ 0.05). Blood lactate concentration at submaximal running speed (275, 300, and 375 m·min) in the hypoxic group decreased significantly (p ≤ 0.05) after the training period. No significant changes in these values were found in the normoxic group. These results suggest that 6 days of hypoxic exposure and training enhanced performance and improved lactate metabolism in 400- and 800-m runners.


Visualizing Oxazine 4 nerve-specific fluorescence ex vivo in frozen tissue sections.
Nerve damage plagues surgical outcomes and remains a major burden for patients, surgeons, and the healthcare system. Fluorescence image-guided surgery using nerve specific small molecule fluorophores offers a solution to diminish surgical nerve damage through improved intraoperative nerve identification and visualization. Oxazine 4 has shown superior nerve specificity in initial testing in vivo, while exhibiting a red shifted excitation and emission spectra compared to other nerve-specific fluorophores. However, Oxazine 4 does not exhibit near-infrared (NIR) excitation and emission, which would be ideal to improve penetration depth and nerve signal to background ratios for in vivo imaging. Successful development of a NIR nerve-specific fluorophore will require understanding of the molecular target of fluorophore nerve specificity. While previous small molecule nerve-specific fluorophores have demonstrated excellent ex vivo nerve specificity, Oxazine 4 ex vivo nerve specific fluorescence has been difficult to visualize. In the present study, we examined each step of the ex vivo fluorescence microscopy sample preparation procedure to discover how in vivo nerve-specific fluorescence is changed during ex vivo tissue sample preparation. Through step-by-step examination we found that Oxazine 4 fluorescence was significantly diminished by washing and mounting tissue sections for microscopy. A method to preserve Oxazine 4 nerve specific fluorescence ex vivo was determined, which can be utilized for visualization by fluorescence microscopy.


Histologic classification of glomerular diseases: clinicopathologic correlations, limitations exposed by validation studies, and suggestions for modification.
The value of classification systems applied to the examination of renal biopsies is based on several factors: first, on the ability to provide efficient communication between pathologists and between pathologists and clinicians; second, on the possibility to implement diagnostic information with prognostic indication. Even more important, the practical value of a classification is proved by the ability of providing elements that guide therapeutic decisions and can be used in the follow-up of the patient. With these aims, new histologic classification systems have been proposed in the last decade for lupus nephritis and IgA nephropathy under the leadership of the Renal Pathology Society and the International Society of Nephrology. These classifications have gained a significant level of worldwide acceptance and have been the subject of multiple single-center and multicenter validation studies, which have underpinned their clinical benefits and limitations and served to highlight remaining questions and difficulties of interpretation of the biopsy sample. More recently, a classification system has also been proposed for ANCA-associated crescentic glomerulonephritis (ANCA-GN), although the validation process for this is still in an early stage. In this review, we examine in some detail the ISN/RPS classification for lupus nephritis and the Oxford classification for IgA nephropathy, with emphasis on clinicopathologic correlations, their value for and evolving impact on clinical studies and clinical practice, and their significant limitations in this regard as exposed by validation studies. We also suggest possible ways by which these classifications might be modified to make them more applicable to clinical practice. Finally, we more briefly discuss the newly proposed classification for ANCA-GN.


Molecular simulation study of hydrated Na-rectorite.
The swelling behavior of clay minerals is an important issue in industrial processes and environmental applications. Mixed-layer clay minerals containing a smectite fraction, such as rectorite, are neglected even though they could swell and exist in nature widely. The hydration of rectorite has not been well comprehended even though they are meaningful to mineralogy and industry. This study combines molecular dynamics (MD) and Monte Carlo (MC) simulations to disclose the swelling behavior of rectorite and compare with montmorillonite. From grand canonical Monte Carlo (GCMC) and MD simulations, we obtain swelling curves and swelling free-energy curves of rectorite with a relative humidity of 100%. With the comparisons of swelling free-energy minima, we find that the bilayer hydrate of Na-rectorite is more thermodynamically stable than the monolayer hydrate, which is similar to Na-montmorillonite. However, the interlayer sodium ions in rectorite show an asymmetrical distribution quite different from the symmetrical distribution in montmorillonite. Because of unequal layer charges between the smectite part and illite part of retorite, sodium ions prefer to distribute close to the illite part surface.


Hypnosis and its place in modern pain management - review article.
This is an evidence-based review of the efficacy of hypnosis in pain management. Hypnosis is as old as mankind. It is reported in the Ebers Papyrus in ancient Egyptian cures. It went into decline in the Middle Ages with the rise of Christianity, being erroneously associated with witchcraft. There was resurgence of interest in the 19th century. In the early 1950s, the British Medical Association endorsed the teaching of hypnosis in all medical schools. The literature is replete with anecdotal and controlled studies of the efficacy of hypnotherapy in pain management. Not much is found of the effectiveness in acute pain conditions. Nevertheless, in spite of some methodological flaws in many reports, there seems to be sufficient clinical evidence of sufficient quality, to conclude that hypnosis has demonstrable efficacy in the treatment of chronic pain.


Clinical utility of new three-dimensional model using a zero-echo-time sequence in endoscopic endonasal transsphenoidal surgery.
Recognizing the anatomical orientation surrounding the sellar floor is crucial in endoscopic endonasal transsphenoidal surgery (ETSS). Zero-echo-time (ZTE) sequences were recently suggested for a new bone identification technique on magnetic resonance imaging (MRI). This study aimed to evaluate the clinical usefulness of three-dimensional (3D)-ZTE-based MRI models in providing anatomical guidance for ETSS. ZTE-based MRI and magnetic resonance angiography (MRA) data from 15 consecutive patients with pituitary tumor treated between September 2018 and May 2019 were used to create 3D-MRI models. From these, the architecture surrounding the sellar floor, particularly anatomical relationships between tumors and internal carotid arteries (ICAs), was visualized to preoperatively plan surgical procedures. In addition, 3D-ZTE-based MRI models were compared to actual surgical views during ETSS to evaluate model applicability. These 3D-ZTE-based MRI models clearly demonstrated the morphology of the sellar floor and matched well with intraoperative views, including pituitary tumor, by successively eliminating sphenoidal structures. The models also permitted determination of the maximum marginal line of the opening of the sellar floor by presenting vital structures such as ICAs and tumors. With such 3D-MRI models, the surgeon could access the intracranial area through the sellar floor more safely, and resect the pituitary tumor maximally without complications. Our 3D-MRI models based on ZTE sequences allowed distinct visualization of vital structures and pituitary tumor around the sellar floor. This new method using 3D-ZTE-based MRI models showed low invasiveness for patients and was useful in preoperative planning for ETSS, facilitating maximum tumor resection without complications.