Replacing Soybean Meal with Urea in Diets for Heavy Fattening Lambs: Effects on Growth, Metabolic Profile and Meat Quality.
Thirty-six Assaf male lambs (29.4 ± 3.10 kg body weight (BW)) were used to study the feasibility of including urea (at 0, 0.6 or 0.95% of dry matter for Control, Urea1, and Urea2 diets, respectively) in substitution of soybean meal in fattening diets. Animals were individually penned and feed intake was recorded daily. Blood samples were taken at days 35 and 63 of the experimental period to determine the acid-base status and the biochemical profile. At the end of the experiment (nine weeks), lambs were slaughtered, ruminal contents were collected and carcass and meat quality were evaluated. There were not differences (p > 0.05) among treatments in dry matter intake, animal performance, ruminal fermentation pattern, and carcass and meat parameters. Serum albumin concentration was higher and concentration of HCO3 and total CO2 in blood were lower in Urea2 compared to Urea1 and Control lambs. These results, together with the tendency to lower (p = 0.065) blood pH in this group might suggest a moderate metabolic acidosis. Partial replacement of soybean meal with urea did not impair growth rate in heavy fattening Assaf lambs (from 29 to 50 kg body weight), reduced feeding costs and had no adverse effects on feed efficiency, rumen fermentation and carcass and meat quality.


Cup-feeding for preterm infants: mechanics and safety.
Cup-feeding is recommended for breastfed preterm infants to avoid artificial nipples. However, the oral mechanisms used in cup-feeding, or its safety and efficacy, have not been described. The authors measured sipping, breathing, SaO2, and volume of intake during 15 cup-feeding sessions for 8 infants (mean gestational age at birth was 30.6 weeks). Mean duration of sipping bursts and pauses was 3.6 seconds and 28.1 seconds, respectively. Mean breathing rate during bursts and pauses was similar (46.2 +/- 24.3 vs 45.7 +/- 17.7, respectively), with SaO2 > or = 90% during all bursts. Mean duration of cup-feedings was 15.2 +/- 3.9 minutes (range, 11.0-23.3), whereas mean volume of intake was only 4.6 +/- 2.2 mL (range, 1.5-8). For the 15 sessions, 38.5% of milk taken from the cup was recovered on the bib. Although infants remain physiologically stable, cup-feeding has questionable efficacy and efficiency. Differentiating between actual intake versus spillage of milk merits attention.


The impact of SLE on health-related quality of life assessed with SF-36: a systemic review and meta-analysis.
To evaluate the impact of systemic lupus erythematosus (SLE) on health-related quality of life (HRQoL) assessed with SF-36 and explore factors associated with HRQoL in SLE patients. A random-effect meta-analysis was performed to calculate extracted data. Sensitivity and subgroup analyses were performed to distinguish sources of heterogeneity. A total of 36 articles were finally included in this meta-analysis, including 6510 patients. The pooled mean scores of SF-36 physical component summary and mental component summary were 46.10 (95% confidence interval (CI): 43.09-49.10) and 50.37 (95% CI: 47.78-52.87), respectively. Spearman's correlation analysis found that mean age, proportion of female participants, and publication decades were negatively associated with some of the SF-36 domains. Sample size and SLEDAI were positively associated with some of the SF-36 domains. Patients with SLE have lower HRQoL in comparison to the general population. SLE has a significant impact on HRQoL, which proves that the necessity of improving HRQoL in SLE patients cannot be ignored. Measuring HRQoL should be considered as an indispensable part of the overall evaluation of health conditions of SLE patients.


Cell kinetic analyses of human malignant brain tumors (gliomas).
Administration of 3H-thymidine, either with or without mitostatic agents, to 24 patients with various gliomas revealed 1) in viable areas a labeling index (LI) for glioblastomas equal to 5-15%, 2) an LI of 1% or less in well-differentiated gliomas, and 3) the LI of anaplastic astrocytomas was intermediate and reflected the extent of anaplasia. Growth fraction was 0.14-0.44 in malignant gliomas (average 0.31 +/- 0.10), and cell cycle time obtained by means of stathmokinetic analysis was 75.6 +/- 45.7 hr. With few exceptions, the patients whose tumors showed an LI of 5% or more died within 1 year after the onset of disease, and no patients whose tumors at biopsy had an LI of over 5% survived more than 6 months. In contrast, there was a far better prognosis for patients whose tumors demonstrated an LI of less than 1%.


Conformational differences between hyaluronates of gel and liquid human vitreous: fractionation and circular dichroism studies.
Post-mortem human vitreous samples (liquid and gel) of comparable intrinsic viscosity values (n approximately equal to 3000 cc/g) were chromatographed on DEAE-Sephacel columns at 4 degrees C using a linear salt gradient ranging from 0----0.4 M NaCl. All samples examined produced numerous discrete hyaluronic acid (HA) fractions. The HA fractions from liquid vitreous were eluted at lower salt concentrations than those from gel vitreous. Several HA fractions from vitreous analyzed by circular dichroism (CD) displayed CD minima at 210 nm, with an ellipticity value of 14 to 16 X 10(3) deg X cm2d mole-1. However, all HA fractions from liquid vitreous showed lower ellipticity values and a weak positive signal above 240 nm. This signal was absent in HA fractions from gel vitreous. Results suggest that subtle but definite conformational differences involving carboxylic groups exist between gel and liquid vitreous hyaluronate.


Insights for the application of TILs and AR in the treatment of TNBC in routine clinical practice.
Triple negative breast cancer (TNBC), usually presenting with a very aggressive phenotype, is a heterogeneous entity. We aim to discuss new biomarkers, suitable for prognostic and predictive purposes. We retrospectively collected clinical variables and immunohistochemical characteristics of early TNBCs, specifically focusing on the prognostic and predictive significance of tumor infiltrating lymphocytes (TILs) and androgen receptor (AR) expression, assessing their correlation with clinical variables. Among 159 patients, TILs were significantly higher in younger patients and with lower BMI, and in tumors with higher ki-67 and greater nodal involvement; conversely, AR was significantly higher in older patients and in tumors with lower ki-67. Interestingly and in line with literature, both TILs level and ARs expression were lower within metastatic sites, in patients who developed distant metastases, compared to those found in the primary site. Small (pT1) and node negative tumors were highly represented and no correlation of either TILs or AR with prognosis could be observed. Our findings support the use of stromal TILs to identify a more aggressive, but chemo-sensitive phenotype, mostly represented in younger women, while AR may identify a less aggressive, slow-growing luminal TNBC subtype, more common among older patients. TILs and AR are worth implementing in routine clinical practice to refine prognosis even if, in our case series, we couldn't identify a significant correlation of the two variables with either disease-free and overall survival.


Ionizing radiation downregulates ASPM, a gene responsible for microcephaly in humans.
Microcephaly is a malformation associated with in utero exposed atomic bomb survivors and can be induced in mice by fetal exposure to ionizing radiation (IR). The pathogenesis of IR-induced microcephaly, however, has not been fully understood. Our analyses of high-coverage expression profiling (HiCEP) demonstrated that the abnormal spindle-like microcephaly associated gene (ASPM) was down-regulated in irradiated human diploid fibroblasts. ASPM was recently reported as the causative gene for MCPH-5, the most common type of congenital microcephaly in humans. Here, we show that the expression of the Aspm gene was significantly reduced by IR in various human and murine cells. Additionally, Aspm was found downregulated in the irradiated fetal mouse brain, particularly in the ventricular zones. A similar suppression was observed in the irradiated neurosphere cultures. This is the first report suggesting that the suppression of Aspm by IR could be the initial molecular target leading to the future microcephaly formation.


Two-pore potassium channels in the cardiovascular system.
Two-pore domain (K(2P)) channels emerged about a decade ago and since then have been an expanding area of interest. This is because their biophysical and pharmacological properties make them good candidates to support background potassium currents and membrane potential in many cell types. There is clear evidence for TREK-1 and TASK-1 in the heart and these channels are likely to regulate cardiac action potential duration through their regulation by stretch, polyunsaturated fatty acids, pH, and neurotransmitters. TREK-1 may also have a critical role in mediating the vasodilator response of resistance arteries to polyunsaturated fatty acids, thus contributing to their protective effect on the cardiovascular system. TASK-1, on the other hand, is a strong candidate for a role in hypoxic vasoconstriction of pulmonary arteries. Many other members of the K(2P) channel family have been identified in the cardiovascular system, although their functional roles are still to be demonstrated. This review provides an up to date summary of what is known about the involvement of members of the K(2P) channel family in cells of the heart and arterial circulation. Our knowledge of their roles will improve with the rapidly increasing interest in them and as new selective pharmacological tools emerge. As their physiological roles emerge, the K(2P) family of potassium channels may offer promising therapeutic solutions to target cardiovascular diseases.


Transcriptomic risk scores for attention deficit/hyperactivity disorder.
Attention deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder. We performed a transcriptome-wide association study (TWAS) using the latest genome-wide association study (GWAS) meta-analysis, in 38,691 individuals with ADHD and 186,843 controls, and 14 gene-expression reference panels across multiple brain tissues and whole blood. Based on TWAS results, we selected subsets of genes and constructed transcriptomic risk scores (TRSs) for the disorder in peripheral blood mononuclear cells of individuals with ADHD and controls. We found evidence of association between ADHD and TRSs constructed using expression profiles from multiple brain areas, with individuals with ADHD carrying a higher burden of TRSs than controls. TRSs were uncorrelated with the polygenic risk score (PRS) for ADHD and, in combination with PRS, improved significantly the proportion of variance explained over the PRS-only model. These results support the complementary predictive potential of genetic and transcriptomic profiles in blood and underscore the potential utility of gene expression for risk prediction and deeper insight in molecular mechanisms underlying ADHD.


Evaluation of the distortion rate of panoramic and periapical radiographs in erupted third molar inclination.
Panoramic and periapical radiographs are normally used in impacted third molar teeth surgeries. The aim of the present study was to evaluate and compare the distortion of the erupted third molar teeth on panoramic and periapical radiographs. A total of 44 radiographs were obtained of 22 patients (age range, 18-24 years) referred to the faculty of dentistry for orthodontic treatment. A plaster cast was prepared and panoramic radiography was taken for all patients to plan the orthodontic treatment and periapical radiography was taken for investigation of tooth structure details. Therefore, a total of 66 views and samples were studied by two methods: 1) Measuring the angle between the longitudinal plane of the third molar and occlusal plane. 2) Measuring the angle between the longitudinal plane of second and third molar. Finally, 132 records were evaluated by one individual. There was no significant statistical difference between the mean position of the third molar on panoramic, periapical radiographs and the casts. However, measurements of the third molars on periapical radiographs were slightly closer to the measurements of the casts compared to the panoramic radiographs. Distortion does not have a specific effect on the diagnosis of the position of the third erupted molars by periapical or panoramic radiographs, though various studies have shown that these radiographs have an amount of distortion and periapical radiographical distortion is less than that in panoramic radiography.


The effect of nutritional intervention in elderly subjects residing in group-living for the demented.
We studied the nutritional status and the effects of nutritional intervention on body weight, cognition and activities of daily life (ADL)-function in demented individuals. Controlled non-randomised study. Group-living for demented elderly (GLD), ie community assisted housing. Twenty-two residents living in one of two units (GLD-I), received oral liquid supplements (1720 kJ/410 kcal/day) and the personnel of the GLD-I were given nutritional education. Fourteen residents in the other unit (GLD-C) served as controls. After 6 months 21 (83 (4) y, 81% women) and 12 (85 (4) y, 100% women) of the participants, respectively, were re-examined according to body mass index (BMI, kg/m2), cognitive function (Mini Mental State Examination (MMSE, 0-30 p) and Clinical Dementia Rating Scale (CDR) and the Katz' ADL index. Body mass index (BMI) < or =20 was found in 19% of the participants and 44% had BMI< or =23. BMI correlated with MMSE (r=0.43, P<0.01). The weight of the residents in the intervention group increased by 3.4 (3) kg (P=0.001) at follow-up, whereas the weight remained unchanged in the control group. The cognitive function was low at the start in both groups, ie MMSE approximately 9 and no apparent positive effect of the nutritional intervention was seen. In addition, the ADL functions appeared to deteriorate in both groups. Being underweight was common among demented elderly in group-living and was related to low cognitive capacity. Five months of oral supplementation, along with education of personnel, was followed by a weight gain. In this study the nutritional treatment did not affect the rate of decline in cognitive function or Katz' ADL index. Supported by grants from the Swedish National Board of Health and Social Welfare. Semper Foods AB provided the liquid supplements.


Evaluation of native hyaline cartilage and repair tissue after two cartilage repair surgery techniques with 23Na MR imaging at 7 T: initial experience.
To compare the sodium normalized mean signal intensity (NMSI) values between patients after bone marrow stimulation (BMS) and matrix-associated autologous chondrocyte transplantation (MACT) cartilage repair procedures. Nine BMS and nine MACT patients were included. Each BMS patient was matched with one MACT patient according to age [BMS 36.7 ± 10.7 (mean ± standard deviation) years; MACT 36.9 ± 10.0 years], postoperative interval (BMS 33.5 ± 25.3 months; MACT 33.2 ± 25.7 months), and defect location. All magnetic resonance imaging (MRI) measurements were performed on a 7 T system. Proton images served for morphological evaluation of repair tissue using the magnetic resonance observation of cartilage repair tissue (MOCART) scoring system. Sodium NMSI values in the repair area and morphologically normal cartilage were calculated. Clinical outcome was assessed right after MRI. Analysis of covariance, t-tests, and Pearson correlation coefficients were evaluated. Sodium NMSI was significantly lower in BMS (P = 0.004) and MACT (P = 0.006) repair tissue, compared to reference cartilage. Sodium NMSI was not different between the reference cartilage in MACT and BMS patients (P = 0.664), however it was significantly higher in MACT than in BMS repair tissue (P = 0.028). Better clinical outcome was observed in BMS than in MACT patients. There was no difference between MOCART scores for MACT and BMS patients (P = 0.915). We did not observe any significant correlation between MOCART score and sodium repair tissue NMSI (r = -0.001; P = 0.996). Our results suggest higher glycosaminoglycan (GAG) content, and therefore, repair tissue of better quality in MACT than in BMS patients. Sodium imaging might be beneficial in non-invasive evaluation of cartilage repair surgery efficacy.


The effect of angiotensin II on uveoscleral outflow in rabbits.
In our previous study, we showed that the AT1 receptor antagonist increased uveoscleral outflow (USF) when topically applied to the rabbit eye. However this increase was too small to demonstrate a clear physiological role for ocular angiotensin II (AII). Hence, the purpose of this study was to determine whether ocular AII influenced USF regulation, and if so, how this occurred. USF was measured by the FITC-dextran perfusion method in albino rabbits. AII and its receptor antagonists were directly applied into the anterior chamber by adding into the perfusate and by perfusing with FITC-dextran. We also analyzed angiotensin receptors on the rabbit ciliary body membrane by a receptor binding assay with 125I-[Sar1), Ile8]-AII as a ligand. CS-088 (1 microg/ml) increased USF by 24% while AII decreased USF in a concentration-dependent manner between 10 and 500 nM. Its maximum decrease of 19% occurred at 500 nM. At this AII concentration the USF reduction was antagonized by 1 microg/ml CS-088, an AT1-receptor antagonist, but not by the same concentration of PD-123,177, an AT2-receptor antagonist. Specific 125I-[Sar1, Ile8]-AII binding to the rabbit ciliary body membranes was inhibited by CS-088 with an inhibition constant of 7.05 nM, whereas inhibition by PD-123,177 was not observed. Ocular AII was indicated to attenuate USF via AT1 receptors in rabbits, however its physiological effect was not critical in IOP regulation.


Association of malignant disease with critical leg ischaemia.
The aim of the study was to determine the prevalence of malignant disease in patients with critical leg ischaemia (CLI). : Data for all patients with CLI presenting to a tertiary vascular unit over an 18-month interval were collected prospectively. Patients with clinical, laboratory or radiological features suggestive of malignancy were evaluated further. Of 192 patients admitted with CLI, 22 (11.5 per cent) were found to have an associated malignancy; ten had lung cancer. Fifteen were anaemic on presentation. The prevalence of occult malignancy in patients with acute leg ischaemia was 16 per cent (ten of 62) compared with 9.2 per cent (12 of 130) in those with chronic CLI. Eleven of 22 of patients with CLI and malignancy died within 6 months, compared with 35 (20.6 per cent) of 170 patients with no evidence of malignancy. A high prevalence of occult cancer was found in patients presenting with CLI; this was associated with a significantly increased mortality rate at 6 months.


Magnetic resonance study of exchangeable protons in human carbonic anhydrases.
A titratable exchangeable proton resonance assignable to a histidine imidazole ring N--H proton is observed approximately minus 15 ppm downfield from tetramethylsilane. The chemical shift of this resonance is affected by sulfonamide and anion inhibitors, and by removal of zinc or replacement of zinc by cobalt, indicating that the proton is located at or near the active site. The pH dependence of the chemical shift of this resonance, which is abolished by inhibitors, reflects the titration of a group with a pK-a of 7.3 in human carbonic anhydrase B and smaller than or equal to 7.1 in human carbonic anhydrase C. These pK-a values are interpreted to be due to the ionization of a neutral imidazole to form the imidazolate anion coordinated to zinc. A mechanism for enzymatic catalysis involving reversible deprotonation and coordination of a histidine to the metal is consistent with these studies.


Type 1 diabetes incidence in children and adolescents during the COVID-19 pandemic in Germany.
The aim of this study was to analyze the incidence of type 1 diabetes in children and adolescents (<20 years of age) during the COVID-19 pandemic (3/2020 to 12/2021) in Germany. The present study was based on the IQVIA longitudinal prescription database (LRx), All persons (age ≤ 20 years) with new insulin prescriptions from 2016 to 2021 (index date) were selected and stratified by age group. Weekly (age-specific) data were used to forecast the prescription incidence for the pandemic period based on pre-pandemic data and to explore the relationship between weekly reported age-specific COVID-19 incidences and type 1 diabetes incidence and rate ratios of observed vs. predicted diabetes incidence respectively. During the pre-pandemic period, there was a stable higher insulin prescription incidence during the winter period and a lower insulin prescription incidence during summer. During the pandemic period, there was less seasonal variation in incidence related to the finding that the observed incidence during summer in 2002 and 2021 was 44 % and 65 %, higher, respectively, than the expected incidence based on pre-pandemic year. We did not find any cross-correlations between the COVID-19 incidence and the type 1 diabetes incidence for any age group. Likewise, there were no cross-correlations between the COVID-19 incidence and the incidence rate ratios of observed incidences to predicted incidences. During the COVID-19 pandemic, there was less seasonal variation in the incidence of type 1 diabetes (defined by new insulin prescriptions), with higher observed than expected incidences during summer. We found no evidence that the increase in type 1 diabetes incidence during the COVID-19 pandemic relates to direct effects of COVID-19 pandemic.


A small molecule CFTR inhibitor produces cystic fibrosis-like submucosal gland fluid secretions in normal airways.
Airway submucosal glands have been proposed as a primary site for initiating and sustaining airway disease in cystic fibrosis (CF). However, it has been difficult to define the role of CFTR in gland fluid secretion because of concerns in interpreting experiments on diseased CF human airways subjected to chronic infection and inflammation. Here, we test the role of CFTR in gland fluid secretion by using a selective CFTR inhibitor (CFTRinh-172) in pig and human airways. Measurements of single-gland fluid secretion rates showed inhibition of both cholinergic and cAMP-stimulated fluid secretion by CFTRinh-172. Secreted fluid [Na+] and [Cl-] measured by fluorescence ratio imaging were 101 and 116 mM, respectively, and not significantly altered by secretory agonists or CFTR inhibition. Gland fluid pH was 7.1 and reduced by 0.4 units after CFTR inhibition. Gland fluid viscosity, determined by photobleaching of FITC-dextran, was threefold increased in pilocarpine-stimulated gland fluid after CFTR inhibition, and protein concentration was increased from 12 to 20 mg/ml. Our data provide strong evidence that gland fluid secretion is CFTR-dependent. The relatively hyper-viscous and acidic fluid secretions produced by acute CFTR inhibition support a role for defective gland function in CF lung disease and provide a rational basis for pharmacological creation of a large animal model of CF.


Differentiated short latency response increases after conditioning in inferior colliculus neurons of alert rat.
The responses of 35 inferior colliculus multiple units (MUs) to tone onset were measured in 10 freely moving rats before and after differential behavioral conditioning. MU response changes were found in the 16.8 msec after tone onset (includes 2 msec air travel time) after learning. Responses to CS+ onset increased in 12 of the 35 individual MUs, and in the group of MUs as a whole, after conditioning. The CS+--CS- difference increased in 17 of the 35 individual MUs, and in the group of MUs, after conditioning. The response differentiation was significant in the 3.6-6.4 msec interval after the tone reached the animal's ears, the time at which neuronal responses were first evident. Since the inferior colliculus increases were differentiated between CS+ and CS-, they could not be explained by sensitization caused by changed middle ear contractions or by alterations in orientation to the speakers.


The Multilevel Reliability and Interrater Agreement of the Nurse Practitioner Primary Care Organizational Climate Questionnaire.
Background and Purpose: It is critical to accurately measure and understand the nurse practitioner (NP) work environment in which individual NP information is gathered but decisions or inferences are made at an aggregated, group level. However, there is little research on preconditions of aggregating individual-level data into group level in nursing research. This study was conducted to assess the multilevel reliability and group interrater agreement (IRA) of the Nurse Practitioner Primary Care Organizational Climate Questionnaire. Methods: Secondary data analysis from a cross-sectional survey with 247 NPs in 112 practices across 6 U.S. states in 2018-2019 was used. Results: The generalizability coefficients and values of IRA were acceptable (> .70), and values of ICC(1) were significant (.18-.38). Conclusions: Aggregating individual NP data to a higher group-level work environment construct is acceptable.


Inadvertent superovulation and intrauterine insemination during pregnancy: a lesson from an ectopic gestation.
It is believed that follicular development and ovulation is suppressed during the early period of gestation in humans. In this report, we describe a patient who underwent ovarian hyperstimulation following a "presumed" menstrual bleeding. The case illustrates that the ovaries during early pregnancy seem to respond normally to exogenous gonadotrophin stimulation. Despite ongoing pregnancy, the high plasma concentrations of gonadotrophins have rescued pituitary and ovarian insensitivity. Normal follicular development and even ovulation are allowed to occur. Moreover, it is mandatory to preclude pregnancy before commencing superovulation and assisted reproductive technology.


Phototoxicity of phenothiazine derivatives. II. Photosensitized cross-linking of erythrocyte membrane proteins.
Irradiation in the presence of O2, with near-UV light of five promazine (PZ) derivatives added to erythrocyte ghost membranes, causes covalent cross-linking between proteins as revealed by a progressive decrease in the amounts of proteins separable by electrophoresis after denaturation. The induction of cross-links in the two spectrin subunits is a single-hit process as a function of the irradiation time; relatively the rate constants (in min-1) of the photoreactions were 0.060 with chlorpromazine (CPZ), 0.039 with methoxypromazine (MTPZ), 0.031 with PZ, 0.029 with triflupromazine (TFPZ) and 0.006 with acepromazine (ACPZ). A main photochemical intermediate implicated in the spectrin aggregation seems to be the cation radical of the PZ derivatives. Indeed, (i) the chemically generated cation radicals can induce the reaction in the dark; (ii) the photoaggregation is regularly reduced upon addition of increasing concentrations of NaN3; (iii) NaN3 similarly affects the amount of cross-links induced by the isolated cation radicals. Hydroxyl radicals are also involved in the photocross-linking when the reaction is initiated only by MTPZ and not by the other sensitizers. In the absence of oxygen during irradiation, PZ, MTPZ and ACPZ completely loose their cross-linking activities whereas CPZ and TFPZ remain as efficient as in the presence of oxygen.


Risk of malignancy in patients with systemic lupus erythematosus: Systematic review and meta-analysis.
Malignancy is a potential comorbidity in patients with systemic lupus erythematosus (SLE). However, risk by malignancy type remains to be fully elucidated. We evaluated the risk of malignancy type in SLE patients in a systematic review and meta-analysis. MEDLINE and EMBASE were searched from inception to July 2018 to identify observational studies that evaluated malignancy risk in adult SLE patients compared with the general population. Random-effects models were used to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). Heterogeneity was quantified using the I2 test. Forty-one studies reporting on 40 malignancies (one overall, 39 site-specific) were included in the meta-analysis. The pooled RR for all malignancies from 3694 events across 80 833 patients was 1.18 (95% CI: 1.00-1.38). The risk of 24 site-specific malignancies (62%) was increased in SLE patients. For malignancies with ≥6 studies, non-Hodgkin lymphoma and Hodgkin lymphoma risk was increased >3-fold; myeloma and liver >2-fold; cervical, lung, bladder, and thyroid ≥1.5-fold; stomach and brain >1.3-fold. The risk of four malignancies (breast, uterine, melanoma, prostate) was decreased, whereas risk of 11 other malignancies did not differ between SLE patients and the general population. Heterogeneity ranged between 0% and 96%, and 63% were non-significant. The risk of overall and some site-specific malignancies is increased in SLE compared with the general population. However, the risk for some site-specific malignancies is decreased or did not differ. Further examination of risk profiles and SLE patient phenotypes may support guidelines aimed at reducing malignancy risk. AstraZeneca. PROSPERO number: CRD42018110433.


Neuropsychological impairment in adults with moyamoya angiopathy: preoperative assessment and correlation to MRI and H215O PET.
Patients with moyamoya angiopathy (MMA) are known to have an increased risk of impaired executive function (dysexecutive cognitive syndrome (DCS)). Numbers of moyamoya patients with DCS vary strongly in the literature; evidence of a correlation to affected vascular territories is low. This study aims to identify cognitive impairment in adult moyamoya patients and to correlate findings with imaging results. In addition, the predictive value of individual tests for the identification of DCS was analyzed. Neuropsychological test data of 41 adult moyamoya patients was analyzed for a possible correlation with territorial hypoperfusion on H215O PET with acetazolamide (ACZ) challenge (cerebrovascular reserve-CVR) and infarction patterns observed in MRI. Each vascular territory was analyzed separately and correlated to neuropsychological test results and to the presence of DCS. In total, 41.5% of patients presented with DCS. Significant association of DCS and affection of the right middle cerebral artery (MCA) territory was seen for insufficient CVR in PET (p = 0.030) and for patients with infarctions seen in MRI (p = 0.014). Analysis of individual neuropsychological test results confirmed the main association with the right MCA territory, as well as some association with the right anterior cerebral artery (ACA) territory. Analysis of a subgroup of patients with chronic disease on MRI (presence of large post-infarction gliosis and brain atrophy in affected territories) revealed a significantly higher risk for DCS (85% affected) than non-chronic patients (21% affected) (p < 0.001). Analysis of neuropsychological test data in this moyamoya cohort reveals DCS in 41.5% of all patients. Correlation between DCS and an impairment of CVR seen in PET and/or infarctions seen in MRI was significant for the right MCA territory. Patients with chronic disease had a significantly higher risk for DCS than non-chronic patients (p < 0.001).


Association between composite scores of domain-specific cognitive functions and regional patterns of atrophy and functional connectivity in the Alzheimer's disease spectrum.
Cognitive decline has been found to be associated with gray matter atrophy and disruption of functional neural networks in Alzheimer's disease (AD) in structural and functional imaging (fMRI) studies. Most previous studies have used single test scores of cognitive performance among monocentric cohorts. However, cognitive domain composite scores could be more reliable than single test scores due to the reduction of measurement error. Adopting a multicentric resting state fMRI (rs-fMRI) and cognitive domain approach, we provide a comprehensive description of the structural and functional correlates of the key cognitive domains of AD. We analyzed MRI, rs-fMRI and cognitive domain score data of 490 participants from an interim baseline release of the multicenter DELCODE study cohort, including 54 people with AD, 86 with Mild Cognitive Impairment (MCI), 175 with Subjective Cognitive Decline (SCD), and 175 Healthy Controls (HC) in the AD-spectrum. Resulting cognitive domain composite scores (executive, visuo-spatial, memory, working memory and language) from the DELCODE neuropsychological battery (DELCODE-NP), were previously derived using confirmatory factor analysis. Statistical analyses examined the differences between diagnostic groups, and the association of composite scores with regional atrophy and network-specific functional connectivity among the patient subgroup of SCD, MCI and AD. Cognitive performance, atrophy patterns and functional connectivity significantly differed between diagnostic groups in the AD-spectrum. Regional gray matter atrophy was positively associated with visuospatial and other cognitive impairments among the patient subgroup in the AD-spectrum. Except for the visual network, patterns of network-specific resting-state functional connectivity were positively associated with distinct cognitive impairments among the patient subgroup in the AD-spectrum. Consistent associations between cognitive domain scores and both regional atrophy and network-specific functional connectivity (except for the visual network), support the utility of a multicentric and cognitive domain approach towards explicating the relationship between imaging markers and cognition in the AD-spectrum.


A facile solid-phase synthesis of 1,2,4,5-tetrasubstituted imidazoles using sodium benzenesulfinate as a traceless linker.
The preparation of substituted imidazoles, thiazoles, and oxazoles using traceless solid-phase sulfone linker strategy is described. Key steps involved are (i) sulfinate acidification, (ii) sulfinic acid condensation with aldehyde and amine, and (iii) traceless product release by a one-pot elimination-cyclization reaction. The elimination reaction was carried out in the presence of a thiazolium catalyst that facilitated the in situ formation of the alpha-ketoamide, which was subsequently converted to the corresponding imidazoles, oxazoles, and thiazoles by treatment with amines, PPh(3)/I(2) or Lawesson's reagent. A library of 18 compounds was synthesized.


Managing ethical uncertainty: implicit normativity and the sociology of ethics.
This article illustrates and discusses the idea of 'implicit normativity', and specifically its relevance to the management of ethical uncertainty. In particular I consider (i) the role implicit normativity plays in masking and containing potential ethical uncertainty and (ii) the contrast and boundary between implicit normativity and 'overt ethics' where ethical contestation - as well as particular processes and agents - are highlighted as salient. Using examples I show how the idea of implicit normativity can be applied not only to specific practices but also to whole fields of practice. The notion of 'moral settlements' - along with the explanatory role of the threat of 'chaos' - is introduced and elucidated to develop these points. I argue that attention to the management of ethical uncertainty shows the critically important contribution that an ambitious sociology of ethics can make to clinical ethics, including by helping to formulate and drive home questions about the 'ethics of ethics'. The account presented here has resonances with work that seeks to use sociological lenses to move beyond conventional bioethics, including Petersen's (2013) call for a 'normative sociology'.


Bimodality of glycosylated hemoglobin distribution in Pima Indians: relationship to fasting hyperglycemia.
Glycosylated hemoglobin (HbA1) concentrations were determined in 300 Pima Indians aged 15 yr and older. Frequency distributions of HbA1 were unimodal in the 15--24-yr-old age group, but were bimodal in those aged 25 yr and over. The bimodality indicated that the subpopulation with diabetes could be identified by the presence of elevated HbA1 levels. This group was comprised primarily of subjects who also had fasting plasma glucose levels of less than or equal to 140 mg/dl, but subjects with impaired glucose tolerance without fasting hyperglycemia had HbA1 levels that were not significantly higher than those with normal glucose tolerance. The prevalence of diabetic retinopathy was much higher in the subgroup with elevated HbA1 levels and increased with increasing HbA1 level. HbA1 levels and triglyceride concentrations showed only a modest association. HbA1 determinations provided no advantage over fasting or post challenge glucose levels in the diagnosis of diabetes.


Tumefactive demyelinating lesions (TDLs): A case series of clinicoradiological features.
Diagnosis of tumefactive demyelination lesions (TDLs) is challenging to neurophysician, neuroradiologist or neurosurgeon. Our objective in this study was to analyze clinicoradiological features of TDLs. A retrospective analysis with prospective follow-up of 11 cases of TDLs was performed. Study was conducted in the neurology department of a tertiary care centre of North-West India from August 2014 to March 2017. MRI of brain and cervical spine with contrast, visual evoked potential, oligoclonal bands, serum anti-AQP4 antibody and MRS performed in most of the patients. Mean age of tumefactive demyelinating lesions was 19.63 years (10-41) with male preponderance (M: F=1.4) and one of the patients was in a pediatric age group. Relapsing and demyelinating courses of disease, seizure and incomplete ring enhancement were found in 6 out of 11(54.5%), 4 out of 11 (36.3%) 3 out of 11(27.2) respectively. OCBs were positive in 4 out of 5 patients (80%). Recognition of atypical presentation or clinicoradiological features would aid in diagnosis along with visual evoked potential, oligoclonal bands and responsiveness to steroids may obviate the need for invasive procedure like brain biopsy.


Lymphopenia predicts poor prognosis in older gastric cancer patients after curative gastrectomy.
Total lymphocyte count in preoperative peripheral blood is associated with prognosis in various cancers. The predictive value of preoperative total lymphocyte count for survival was assessed in older gastric cancer patients after gastrectomy. A total of 200 gastric cancer patients aged ≥75 years who underwent curative resection from 2000 to 2014 were included in this retrospective study. The cut-off value of total lymphocyte count in preoperative peripheral blood was determined using receiver operating characteristic curve analysis, and the association with prognosis was examined. The cut-off value of total lymphocyte count was 1462/μL, and 94 patients were classified as low total lymphocyte count patients and 106 patients were classified as high total lymphocyte count patients. In univariate analysis, American Society of Anesthesiologists score ≥3, Charlson Comorbidity Index ≥3, total lymphocyte count <1462/μL, stage III, open approach, total gastrectomy, splenectomy and infectious complication were significantly associated with overall survival. In multivariate analysis, total lymphocyte count <1462/μL (P = 0.003), American Society of Anesthesiologists score ≥3 (P = 0.01) and stage III (P = 0.017) were independent prognostic factors. Low total lymphocyte count significantly reduced overall survival in stage I (P = 0.037) and II (P = 0.009) patients, but not stage III patients (P = 0.29). Total lymphocyte count in preoperative peripheral blood can predict postoperative survival of older patients with relatively early-stage gastric cancer. Geriatr Gerontol Int 2019; 19: 1215-1219.


Either High or Low Risk: The Acinar Score at the Resection Margin Dichotomizes the Risk Spectrum of Pancreas-specific Complications After Pancreatoduodenectomy.
Pancreatic acinar content (Ac) has been associated with pancreas-specific complications after pancreatoduodenectomy. The aim of this study was to improve the prediction ability of intraoperative risk stratification by integrating the pancreatic acinar score. A training and validation cohort underwent pancreatoduodenectomy with a subsequent histologic assessment of pancreatic section margins for Ac, fibrosis (Fc), and fat. Intraoperative risk stratification (pancreatic texture, duct diameter) and pancreas-specific complications (postoperative hyperamylasemia [POH], postpancreatectomy acute pancreatitis [PPAP], pancreatic fistula [POPF]) were classified according to ISGPS definitions. In the validation cohort (n= 373), the association of pancreas-specific complications with higher Ac and lower Fc was replicated (all P <0.001). In the entire cohort (n= 761), the ISGPS classification allocated 275 (36%) patients into intermediate-risk classes B (POH 32%/PPAP 3%/POPF 17%) and C (POH 36%/PPAP 9%/POPF 33%). Using the acinar score (Ac ≥60% and/or Fc ≤10%), intermediate-risk patients could be dichotomized into a low-risk (POH 5%/PPAP 1%/POPF 6%) and a high-risk (POH 51%/PPAP 9%/POPF 38%) group (all P <0.001). The acinar score AUC for POPF prediction was 0.70 in the ISGPS intermediate-risk classes. Overall, 239 (31%) patients were relocated into the high-risk group from lower ISGPS risk classes using the acinar score. The risk of pancreas-specific complications appears to be dichotomous-either high or low-according to the acinar score, a tool to better target the application of mitigation strategies in cases of intermediate macroscopic features.


Opposing effects of ketamine and acetyl L-carnitine on the serotonergic system of zebrafish.
Ketamine, a pediatric anesthetic, is a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist. Studies show that ketamine is neurotoxic in developing mammals and zebrafish. In both mammals and zebrafish, acetyl L-carnitine (ALCAR) has been shown to be protective against ketamine toxicity. Ketamine is known to modulate the serotonergic system in mammals. Here, we measured the levels of serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) in the embryos exposed to ketamine in the presence and absence of ALCAR. Ketamine, at lower doses, did not produce significant changes in the 5-HT or 5-HIAA levels in 3 dpf (day post-fertilization) embryos. However, 2 mM ketamine (internal embryo exposure levels comparable to human anesthetic plasma concentration) significantly reduced 5-HT level, and 5-HIAA was not detectable indicating that 5-HT metabolism was abolished. In the presence or absence of 2 mM ketamine, ALCAR by itself did not significantly alter 5-HT or 5-HIAA levels compared to the control. Ratios of metabolite/5-HT indicated that 2 mM ketamine inhibited 5-HT metabolism to 5-HIAA whereas lower doses (0.1-0.3 mM) of ketamine did not have any effect. ALCAR reversed the effects of 2 mM ketamine not only by restoring 5-HT and 5-HIAA levels but also 5-HT turnover rate to control levels. Whole mount immunohistochemical studies showed that 2 mM ketamine reduced the serotonergic area in the brain whereas ALCAR expanded it with increased axonal sprouting and branching. These results indicate that ketamine and ALCAR have opposing effects on the zebrafish serotonergic system.


Prevention of Influenza in Children.
Influenza infects 5% to 20% of school-age children annually. Although universal influenza vaccine is recommended for children and adults 6 months of age and older, uptake is below national targets. Influenza immunization of the child and the family is the key to decreasing annual disease burden. Antiviral therapy is an important treatment strategy for children and adults, especially those who are at high risk of complications from influenza, irrespective of immunization status or whether illness onset is greater than 48 hours. Although antiviral therapy may also be used for pre-exposure and postexposure prophylaxis, it should not replace immunization as a preventive strategy when immunization is feasible.


Advances and limitations for the treatment of spinal muscular atrophy.
Spinal muscular atrophy (5q-SMA; SMA), a genetic neuromuscular condition affecting spinal motor neurons, is caused by defects in both copies of the SMN1 gene that produces survival motor neuron (SMN) protein. The highly homologous SMN2 gene primarily expresses a rapidly degraded isoform of SMN protein that causes anterior horn cell degeneration, progressive motor neuron loss, skeletal muscle atrophy and weakness. Severe cases result in limited mobility and ventilatory insufficiency. Untreated SMA is the leading genetic cause of death in young children. Recently, three therapeutics that increase SMN protein levels in patients with SMA have provided incremental improvements in motor function and developmental milestones and prevented the worsening of SMA symptoms. While the therapeutic approaches with Spinraza®, Zolgensma®, and Evrysdi® have a clinically significant impact, they are not curative. For many patients, there remains a significant disease burden. A potential combination therapy under development for SMA targets myostatin, a negative regulator of muscle mass and strength. Myostatin inhibition in animal models increases muscle mass and function. Apitegromab is an investigational, fully human, monoclonal antibody that specifically binds to proforms of myostatin, promyostatin and latent myostatin, thereby inhibiting myostatin activation. A recently completed phase 2 trial demonstrated the potential clinical benefit of apitegromab by improving or stabilizing motor function in patients with Type 2 and Type 3 SMA and providing positive proof-of-concept for myostatin inhibition as a target for managing SMA. The primary goal of this manuscript is to orient physicians to the evolving landscape of SMA treatment.


Introducing new vaccines in the poorest countries: what did we learn from the GAVI experience with financial sustainability?
This paper reviews the experience of the Global Alliance for Vaccines and Immunization (GAVI) in introducing hepatitis B and Haemophilus influenzae type b vaccines in the poorest countries, and explores how financing for immunization has changed since GAVI Fund resources were made available during its first wave of support between 2000 and 2006. The analysis of Financial Sustainability Plans in 50 countries allowed for some of the original funding assumptions of the GAVI approach to be tested against the realities in a wide set of countries, and to highlight implications for future immunization efforts. While the initial GAVI experience with financial sustainability has proved successful through the development of plans, and many countries have been able to both introduce new vaccines and mobilize additional financing for immunization, for future GAVI supported vaccine introduction, some country co-financing of these will be needed upfront for the approach to be more sustainable.


WITHDRAWN: Maternal cortisol and cord brain derived neurotrophic factor in preterm pregnancy: implications for fetal neurodevelopment.
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.


Different levels of hyphal self-incompatibility modulate interconnectedness of mycorrhizal networks in three arbuscular mycorrhizal fungi within the Glomeraceae.
Arbuscular mycorrhizal fungi (AMF) live in symbiosis with most plant species and produce underground extraradical hyphal networks functional in the uptake and translocation of mineral nutrients from the soil to host plants. This work investigated whether fungal genotype can affect patterns of interconnections and structural traits of extraradical mycelium (ERM), by comparing three Glomeraceae species growing in symbiosis with five plant hosts. An isolate of Funneliformis coronatus consistently showed low ability to form interconnected ERM and self-incompatibility that represented up to 21% of hyphal contacts. The frequency of post-fusion self-incompatible interactions, never detected before in AMF extraradical networks, was 8.9%. In F. coronatus ERM, the percentage of hyphal contacts leading to perfect hyphal fusions was 1.2-7.7, while it ranged from 25.8-48 to 35.6-53.6 in Rhizophagus intraradices and Funneliformis mosseae, respectively. Low interconnectedness of F. coronatus ERM resulted also from a very high number of non-interacting contacts (83.2%). Such findings show that AMF genotypes in Glomeraceae can differ significantly in anastomosis behaviour and that ERM interconnectedness is modulated by the fungal symbiont, as F. coronatus consistently formed poorly interconnected networks when growing in symbiosis with five different host plants and in the asymbiotic stage. Structural traits, such as extent, density and hyphal self-compatibility/incompatibility, may represent key factors for the differential performance of AMF, by affecting fungal absorbing surface and foraging ability and thus nutrient flow from soil to host roots.


Synergistic effect of serotonin 1A and serotonin 1B/D receptor agonists in the treatment of L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats.
The gold standard for symptomatic relief of Parkinson's disease (PD) is L-DOPA. However, long-term treatment often leads to motor complications such as L-DOPA-induced dyskinesia (LID). While amantadine (Gocovri™) is the only approved therapy for dyskinesia in PD patients on the American market, it is associated with neurological side effects and limited efficacy. Thus, there remains a high unmet need for addressing LID in PD patients worldwide. The objective of this study was to evaluate the efficacy, safety and performance compared to approved treatments of the serotonin receptor 1A (5-HT1A) and 5-HT1B/D agonists buspirone and zolmitriptan in the 6-hydroxydopamine unilaterally lesioned rat model for PD. The hemiparkinsonian 6-OHDA-lesioned rats underwent chronic treatment with L-DOPA to induce dyskinesia and were subsequently used for efficacy testing of buspirone, zolmitriptan and comparison with amantadine, measured as abnormal involuntary movement (AIM) scores after L-DOPA challenge. Safety testing was performed in model and naïve animals using forelimb adjusting, rotarod and open field tests. 5-HT1A and 5-HT1B/D agonism effectively reduced AIM scores in a synergistic manner. The drug combination of buspirone and zolmitriptan was safe and did not lead to tolerance development following sub-chronic administration. Head-to-head comparison with amantadine showed superior performance of buspirone and zolmitriptan in the model. The strong anti-dyskinetic effect found with combined 5-HT1A and 5-HT1B/D agonism renders buspirone and zolmitriptan together a meaningful treatment for LID in PD.


[E. coli-based production of recombinant HMG-17 and its antibacterial domain].
Total RNA was extracted from human LAK cell, and a cDNA encoding mature peptide HMG-17 and its alpha helix domain was amplified by RT-PCR. The recombinant prokaryotic expression vector pGEX-1lambdaT-HMG-17 and pGEX-1lambdaT HMG-17alpha helix was constructed. Using affinity chromatography, thrombin cleaving and AU-PAGE elution, we obtained the purified HMG-17. Analyses of MIC, MEC and MBC indicated that HMG-17 and HMG-17alpha had strong antibacterial activity. MIC of the alpha-helic domain was almost the same as that of HMG17, suggesting that the alpha-helic structure would be essential for the antibacterial activity of HMG-17.


Analytical methods for Bacillus cereus and other Bacillus species.
Bacillus cereus can give rise to two distinct forms of foodborne disease, the emetic and the diarrhoeal syndromes. The emetic syndrome is believed to be associated with an emetic toxin pre-formed in food. Cooked rice is the most common vehicle, and the symptoms are similar to those of Staphylococcus aureus intoxication. The diarrhoeal type is caused by an enterotoxin and the symptoms generally parallel those of the Clostridium perfringens food poisoning. The heat resistance of B. cereus spores and the non-fastidious nature of the organism facilitates its survival and/or growth in a wide variety of foods. This review describes analytical methods available for the isolation, identification, and enumeration of the organism, in addition to details about biological and immunological methods for toxin assay. Data are also presented concerning the incidence and epidemiology of B. cereus food poisoning around the world, and especially in Japan.


Transient erythroblastopenia of childhood: implications for nurse practitioners.
Pediatric nurse practitioners in all areas of practice encounter anemic children. This article describes transient erythroblastopenia of childhood (TEC), a rare type of anemia that baffles health care providers and causes anxiety in parents. Understanding the cause, course, and treatment of TEC allows the nurse practitioner to educate and reassure affected children and their parents.


Maintaining glucose integrity ex-vivo: Impact of preanalytical specimen handling.
Adopting the WHO protocol for glucose analysis is arguably impractical in the routine clinical setting. Deviations may develop due to a lack of understanding regarding the impact of glycolysis on the accuracy of results. We sought to assess the stability of glucose in two different blood collection tubes (BCT), BD Vacutainer® FX 'Fl-Ox' and Greiner Vacuette® FC-Mix 'FC-Mix' stored at room temperature (RT:18-22°C) and 4°C over 8.5 days. Each participant provided venous whole blood collected into 51 BCTs; 'Fl-Ox' (n = 26) and 'FC-Mix' (n = 25). One Fl-Ox sample from each participant was handled according to the WHO recommended method. The remaining BCTs were stored at 4°C/RT prior to analyses at designated study timepoints. Glucose was measured using the hexokinase assay on the Cobas® 8000 platform. Participants (n = 8, Male = 2) were aged 24-56 years. Plasma glucose measured in FI-Ox BCTs according to the WHO sample-handling method had a median concentration of 5.73 mmol/L (Range: 5.39-10.37 mmol/L). Glucose decreased by greater than minimal difference (>0.26 mmol/L) in blood collected into Fl-Ox and stored @4°C/RT within 24 h of phlebotomy. FC-Mix BCT maintained glucose <0.26 mmol/L @4°C over a period of 8.5 days and up to 4 days @RT when compared to the WHO recommended method. Glucose in FC-Mix BCT stored @4°C demonstrated the best agreement with results determined using the WHO specifications. When FC-Mix tubes were stored @RT, glucose was stable for 4 days. These findings suggest that the FC-Mix BCT effectively inhibits glycolysis and should be introduced into routine clinical practice.


Adenosine and ventricular automaticity.
Adenosine is considered a cardiodepressant agent due to its negative chronotropic and inotropic effects. However, the effect of adenosine on ventricular automaticity is less well established since both an increase and a decrease in ventricular automaticity have been reported. The experimental and clinical evidence dealing with the effects of adenosine on ventricular automaticity as well as the possible mechanisms involved, is presented in this review.


Is mode of presentation of B3 breast core biopsies (screen-detected or symptomatic) a distinguishing factor in the final histopathologic result or risk of diagnosis of malignancy?
The relation between histopathologic subclassification and mode of patient presentation (with a screen-detected vs. symptomatic lesion) with an abnormality in the breast core biopsy classified as having uncertain malignant potential (B3) has not been previously examined. We compared the histopathologic subclassification of these lesions and the frequency of malignancy in screen-detected and symptomatic patient groups. All B3 core biopsies from one breast unit at the Royal Berkshire Hospital over a 5-year period (2006-2010) were analyzed (n = 131). After dividing the B3 biopsies into screen-detected and symptomatic groups, the National Health Service Breast Screening Programme histopathologic subclassification was used to further divide the groups into six subtypes. After surgery, a final diagnosis of invasive or in situ carcinoma was also noted. B3 classification comprised 3.8 % (131/3,440) of all core biopsies during that time period. There were 78 specimens from symptomatic (59 %) and 53 from screen-detected (41 %) patients. There was no statistically significant difference between papillary and fibroepithelial diagnoses between the two groups (47 vs. 42 %, p = 0.59, NS). There was no difference between the groups for atypia, lobular neoplasia, or sclerosing lesions (49 vs. 51 %, p = 0.8, NS). Cancer was found in 20 % of the symptomatic patients and in 17 % of the screen-detected group (p = 0.65, NS). Mode of patient presentation (with a screen-detected or symptomatic lesion) was not a distinguishing factor for breast histopathologic subclassification or for the final cancer diagnosis in patients whose breast core biopsy was classified as B3.


Improvement in overall survival with Apalutamide, Darolutamide and Enzalutamide in patients with non-metastatic castration-resistant prostate cancer.
Since 2018, apalutamide, darolutamide, and enzalutamide have been approved for the treatment of men with non-metastatic castration-resistant prostate cancer (M0CRPC). These approvals were based on the results of three separate randomized, placebo-controlled, phase III trials: SPARTAN (apalutamide), ARAMIS (darolutamide) and PROSPER (enzalutamide). These trials included men with M0CRPC and a short PSA doubling time (≤10 months). Results demonstrated a longer metastasis-free survival with these agents when used in conjunction with androgen deprivation therapy (ADT), compared to ADT alone. Updated results of these trials presented in the 2020 annual meeting of American Society of Oncology (ASCO) showed significantly improved overall survival with these agents. Based on these results, apalutamide, darolutamide, and enzalutamide can now be considered the standard of care treatment options for the treatment of men with M0CRPC.


Cats with cancer: where to start.
Many cats develop cancer and may or may not present with an obvious mass lesion. As our feline patients are living longer and their owners are increasingly seeking veterinary care, the apparent incidence and prevalence of cancer is increasing. Neoplasia is a differential for many clinical presentations in cats. Often tumours are relatively advanced at the point of presentation, and this can make management difficult. In addition, many cats find clinic visits stressful and this can influence owners' decisions about treatment. This review provides an overview of the approach to the feline cancer patient, and is aimed at all veterinary practitioners that see cats. It is intended as a starting point for more detailed discussions in accompanying articles in this special issue on feline oncology. There is limited data on most feline tumours compared with tumours in canine or human patients, so a robust evidence base is often lacking.


Enterolithiasis with imperforate anus. Report of two cases with sonographic demonstration and occurrence in a female.
Enterolithiasis has been previously described as a plain film finding of rectovesical or rectourethral fistula in patients with anorectal malformation. Two cases of enterolithiasis with anorectal malformation are described in which the intraluminal nature of the calcifications was identified using ultrasound. The use of ultrasound for this purpose has not been previously reported to our knowledge. This simple, noninvasive technique permits antenatal differentiation between enterolithiasis and meconium peritonitis in some patients and can suggest the prenatal diagnosis of rectourinary communication when enterolithiasis is present. In addition, one of our cases occurred in a female. The entity of enterolithiasis with imperforate anus in a female has not been previously reported.


Electroacupuncture to treat with Overactive Bladder in Postmenopausal Women: study protocol for a multicenter, randomized, controlled, parallel clinical trial.
Electroacupuncture has been used for treatment in patients with overactive bladder. This study was conducted to evaluate the efficacy and safety of electroacupuncture for treating overactive bladder of postmenopausal women. This is a multicenter, randomized controlled, parallel clinical trial. Two hundred ninety participants with overactive bladder syndrome will be recruited from Dongguk University Bundang Oriental Hospital and Cheonan Korean Medicine Hospital of Daejeon University and randomly allocated into one of two groups in a 1:1 ratio. One group will receive electroacupuncture (EA) and the other acupuncture (AC). The allocation will be concealed from both participants and assessors. The study period will be about 10 weeks, including 6 weeks of electroacupuncture or acupuncture treatment and a four week follow-up period. Both EA group and AT group will undergo acupuncture at 7 fixed points, and the EA group will undergo electronic stimulation at 6 points. The primary outcome will be the average number of micturitions per 24 h based on a 3-day bladder diary. The secondary outcome will comprise the 3-day bladder diary, the overactive bladder symptom score and the results of the King's health questionnaire. The results of this trial will provide information regarding the efficacy and safety of electroacupuncture for treating overactive bladder in postmenopausal women. ClinicalTrials.gov, NCT03260907 . Registered on 24 August 2017.


Previous Disability and Benefit of Acute Phase Therapy in Functional Prognosis of Selected Patients with Ischemic Stroke.
Patients' previous disability (PD) is a key factor when considering acute stroke therapy. PD's exact impact on functional prognosis of patients with acute ischemic stroke remains not entirely clarified. We aimed to analyze PD's influence on functional outcome three months after ischemic stroke. Retrospective analysis of prospectively collected data concerning patients with acute ischemic stroke admitted to Stroke Unit of a tertiary center who underwent acute phase therapy between 2017 and 2019. Modified Rankin Scale (mRS) was used to define PD (with previous mRS≥3). Patients with PD were selected for treatment based on similar baseline characteristics to patients without PD. Patients were classified into two groups according to previous mRS: mRS<3 and mRS≥3. We defined bad outcome at three months after stroke as mRS≥3 for patients with previous mRS<3, and as a higher score than baseline mRS for patients with previous mRS≥3. We identified 1169 eligible patients - 1016 patients with previous mRS<3 and 153 patients with previous mRS≥3. Most baseline characteristics did not differ significantly between them. For patients ≤75 years old, PD was associated with worse outcome (odds ratio estimate [OR] 4.50, p < 0.001). For patients >75 years old, PD was protective against worse outcome (OR 0.42, p < 0.001). In patients with previous mRS≥3 and >75 years old, there was a higher proportion of women (p = 0.005). PD might not be a relevant factor when considering acute stroke therapy in selected patients >75 years old, especially women. Further studies are needed to clarify these findings.


Magnetic resonance imaging of intraspinal epidermoid cyst: a case report.
Intraspinal epidermoid cysts are considered rare lesions. We report such a case in a 12-year-old boy that was diagnosed by magnetic resonance imaging. The magnetic resonance imaging characteristics of the lesion and the importance of proper imaging sequences are discussed.


The thyroid disease in the elderly: Our experience.
The number of elderly people in Italy is growing, so it is important to study the presentation of diseases in these subjects. We selected 1362 patients who underwent thyroidectomy for different thyroid diseases from January 2008 to December 2014. The patients weredivided into two groups, according to the age. The patients aged 65 years and over were included in the group A, and the patients under the age of 65 years were included in the group B. Thyroid diseases in the elderly often present with atypical symptoms which are very similar to symptoms of the aging process. In elderly hypothyroidism occurs frequently sub-clinically and hyperthyroidism is often presented with cardiovascular symptoms. In our study we evaluated the differences in incidence of thyroid diseases in the elderly and in the younger groups of patients. The data analyzed in this study showed that in the elderly we have a reduced secretion and metabolization of thyroid hormones. The symptomatology in the elderly is nonspecific and can create a delay in the correct diagnosis.


Neural sensitivity to natural image statistics changes during middle childhood.
Natural images have properties that adults' behavioral and neural responses are sensitive to, but the development of this sensitivity is not clear. Behaviorally, children acquire adult-like sensitivity to natural image statistics during middle childhood (Ellemberg et al., 2012), but infants exhibit sensitivity to deviations of natural image structure (Balas & Woods, 2014). We used event-related potentials (ERPs) to examine sensitivity to natural image statistics during childhood at distinct processing stages (the P1 and N1 components). We presented children (5-10 years old) and adults with natural images varying in positive/negative contrast, and natural/synthetic texture appearance to compare electrophysiological responses to images that did or did not violate natural statistics. We hypothesized that children would acquire sensitivity to these deviations late in middle childhood. Instead, we observed significant responses to unnatural contrast and texture statistics at the N1 in all age groups. At the P1, however, only young children exhibited sensitivity to contrast polarity. The latter effect suggests greater sensitivity earlier in development to some violations of natural image statistics. We discuss these results in terms of changing patterns of invariant texture processing during middle childhood and ongoing refinement of the representations supporting natural image perception.


Simultaneous bilateral cataract surgery.
To evaluate the safety and outcomes of simultaneous bilateral cataract surgery (SBCS). York Finch Eye Associates and Humber River Regional Hospital, Toronto, Ontario, Canada. This retrospective study reviewed the results of 1020 consecutive patients (2040 eyes) who had SBCS by endolenticular phacoemulsification through a clear corneal incision on the corneal steep axis with foldable posterior chamber intraocular lens implantation. The surgeries were performed by the same surgeon from January 1996 to January 2002 as 2 consecutive independent procedures under topical and intracameral anesthesia. Outcome measures included intraoperative and postoperative complications, postoperative uncorrected and best spectacle-corrected visual acuities, refractive error, and patient satisfaction. Complications were few and would not likely have been prevented had the surgery been performed monocularly. Simultaneous bilateral cataract surgery did not lead to an increased incidence of intraoperative or postoperative complications. The visual acuity results were good, and the patients were pleased. No complications were observed that could be attributed to the procedures being done bilaterally.


Testicular cancer, histologic classification and staging, topography of lymph node metastases.
From the clinical point of view, histologic classification is intended to give suggestions for therapy (therapeutic classification) and to provide the basis for an assessment of end results (prognostic classification). In adults, the essential therapeutic question is: seminoma (only seminoma) or non-seminoma? The frequency of seminoma among the germinal testicular tumours influenced by the subtlety of the histologic examination. The histologic report should include the MOSTOFI (25) classification and the prognostic group classification of DIXON and MOORE (7). Staging of testicular cancer and criteria for the comparison of treatment results are discussed. The topography of lymphatic metastases of testicular cancer was investigated. The great majority of testicular cancers metastasize regularly, i.e., primarily into the testicular lymph center and/or along the testicular vein, and only secondarily in other lymph nodes. This provides a foundation for the increasing tendency to modified bilateral retroperitioneal node dissection.


Reduced bactericidal activity and nitric oxide production in metallothionein-deficient macrophages in response to lipopolysaccharide stimulation.
This study was designed to investigate bactericidal activity of and nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated peritoneal exudate macrophages (Mvarphi) from metallothionein (MT)-null mice. Control Mvarphi had a bactericidal effect on Staphylococcus aureus, but MT-null Mvarphi had significantly lower activity. NO is an important factor in the bactericidal function of Mvarphi. LPS-stimulated MT-null Mvarphi produced less NO than those of control mice. LPS-stimulated Mvarphi produce cytokines such as tumor necrosis factor (TNF)-alpha. TNF-alpha activate Mvarphi and stimulates NO production. We evaluated NO production by TNF-alpha-stimulated Mvarphi. MT-null Mvarphi produced less NO in response to TNF-alpha stimulation. Levels of expression of inducible NO synthase (iNOS) mRNA and production of iNOS protein in response to LPS stimulation were similar in MT-null and control cells, as were levels of expression of arginase, which competes in arginine metabolism with iNOS. No notable changes were found in arginine uptake or in expression of cationic amino acid transporter 2 (a major arginine transporter in Mvarphi) between control and MT-null Mvarphi. The rate of conversion of [(14)C]-l-arginine to citrulline, which is formed with NO by the action of iNOS, was much lower in MT-null Mvarphi than in control cells. These results indicate that the reduced production of NO in MT-deficient Mvarphi is due mainly to reduced activity of iNOS. Thus, MT plays important roles in bactericidal activity, NO production, and arginine metabolism in activated Mvarphi.


Endogenous ATP potentiates only vasopressin secretion from neurohypophysial terminals.
Exogenous ATP induces inward currents and causes the release of arginine-vasopressin (AVP) from isolated neurohypophysial terminals (NHT); both effects are inhibited by the P2X2 and P2X3 antagonists, suramin and PPADS. Here we examined the role of endogenous ATP in the neurohypophysis. Stimulation of NHT caused the release of both AVP and ATP. ATP induced a potentiation in the stimulated release of AVP, but not of oxytocin (OT), which was blocked by the presence of suramin. In loose-patch clamp recordings, from intact neurohypophyses, suramin or PPADS produces an inhibition of action potential currents in a static bath, that can be mimicked by a hyperpolarization of the resting membrane potential (RMP). Correspondingly, in a static versus perfused bath there is a depolarization of the RMP of NHT, which was reduced by either suramin or PPADS. We measured an accumulation of ATP (3.7 +/- 0.7 microM) released from NHT in a static bath. Applications of either suramin or PPADS to a static bath decreased burst-stimulated capacitance increases in NHT. Finally, only vasopressin release from electrically stimulated intact neurohypophyses was reduced in the presence of Suramin or PPADS. These data suggest that there was sufficient accumulation of ATP released from the neurohypophysis during stimulations to depolarize its nerve terminals. This would occur via the opening of P2X2 and P2X3 receptors, inducing an influx of Ca2+. The subsequent elevation in [Ca2+](i) would further increase the stimulated release of only vasopressin from NHT terminals. Such purinergic feedback mechanisms could be physiologically important at most CNS synapses.


Clinical course and risk factors for recurrence of positive SARS-CoV-2 RNA: a retrospective cohort study from Wuhan, China.
The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The objective of this study was to determine the clinical course and risk factors for patients showing recurrent SARS-CoV-2 RNA positivity. A total of 1087 COVID-19 patients confirmed by RT-PCR from February 24, 2020 to March 31, 2020 were retrospectively enrolled. Advanced age was significantly associated with mortality. In addition, 81 (7.6%) of the discharged patients tested positive for SARS-CoV-2 RNA during the isolation period. For patients with recurrent RT-PCR positivity, the median duration from illness onset to recurrence was 50 days. Multivariate regression analysis identified elevated serum IL-6, increased lymphocyte counts and CT imaging features of lung consolidation during hospitalization as the independent risk factors of recurrence. We hypothesized that the balance between immune response and virus toxicity may be the underlying mechanism of this phenomenon. For patients with a high risk of recurrence, a prolonged observation and additional preventative measures should be implemented for at least 50 days after illness onset to prevent future outbreaks.


[Peroperative measurement of peripheral vascular resistance. Significance for the indications, technic and prognosis of distal bypasses. Apropos of 35 cases].
The authors report their experience of the per-operative measurement of the "absorption capacity" of a distal vascular network. This constitutes an absolute measurement and provides a reliable per-operative indication of a bypass, and eventually that of surgical reintervention in early thrombosis. The techniques are described with a brief overview of the major physical laws in this field. As a predictive test, the measurement is highly reliable, and a threshold value of 3 PRU was found in the series; beyond this value, all bypasses were thrombotic. A brief survey of the literature considers the theme of peripheric resistances. A table of clinical indications is situated at the end of the study, and is related to values of residual pressure and peripheric resistance. Glossary: R: peripheral resistance PAF: Pressure in femoral artery P: Pressure (mmHg) Pr: residual pressure Rp: Physiological resistance RS: stenotic resistance RC: Resistance due to collateral flow D: Femoral flow d and d': successive variations of flow.


Prescribing errors in antibiotic prophylaxis by dentists in a large Brazilian city.
Prescribing errors may contribute to antibiotic resistance and other drug-related problems. To investigate the quality of prescriptions involving antibiotic prophylaxis by dentists in a large Brazilian city, 366 dental prescriptions were randomly selected from 31,105. A prophylaxis indication represented 24.9% of the prescriptions, and only 12 (13.2%; 95% confidence interval, 7.7%-21.7%) were correct regarding the generic name, dose, and length of antibiotic use. Prescriptions for antibiotic prophylaxis by dentists are mostly inadequate in this city.


Inferior reach of ileal reservoir in ileoanal anastomosis. Experimental anatomic and angiographic study.
A possible technical problem encountered when performing ileoanal anastomosis with reservoir is the occurrence of tension when the reservoir is drawn to the anal canal. An anatomic study was performed to assess the gain of caudad reach that can be obtained by dissection of the mesentery root and vascular divisions applied to S- and J-shaped reservoirs, in association with angiographic control of terminal ileum vascularization. The study confirms the clinical experience that caudad reach of ileal reservoirs can be critical in some cases. Complete dissection of the root of the mesentery is a poor lengthening technique, the limiting factor being tension of the superior mesenteric artery. It is simple, however, and should be performed systematically because it can provide 1 or 2 useful centimeters of caudad reach. Division of the ileocecal pedicle is a safe, reproducible, efficient lengthening procedure that can serve all types of reservoirs. In this study, it gave a 5 cm or more gain in caudad reach in 80 percent of the cases, with a slight advantage to the S-shaped reservoir. Distal division of the superior mesenteric pedicle seems more hazardous and can serve only the J-shaped reservoir. For J-shaped reservoirs, maximum caudad reach was achieved when the pouch was built over the most inferior ileal point, which should be checked prior to the procedure, not judged according to predefined measures. The angiographic study showed that, in 38 percent of the cases, cecal vessels participated in vascularization of the last centimeters of the terminal ileum by means of recurrent ileal arteries, which, in 28 percent of the cases, provided exclusive blood supply to this area. Vascularization of the terminal ileum can and should be carefully preserved.


Analysis of historical variables, risk factors and the resting electrocardiogram as an aid in the clinical diagnosis of recurrent chest pain.
A prospective study on 184 consecutive patients presenting with the chief complaint of recurrent chest pain (RP) for diagnostic coronary arteriography (CA) was conducted utilizing a simple questionnaire of historical, physical and electrocardiographic variables. A linear logistic regression analysis yielded a final data set of 13 variables. Concurrently, staff cardiologists who obtained the questionnaire data through direct questioning rendered a clinical diagnosis of either angina (coronary artery disease [CAD]) or noncardiac chest pain. Utilization of the regression analysis increased diagnostic accuracy from 69 to 86% (p less than 0.0003); sensitivity from 83 to 88% (NS) and specificity from 49 to 84% (p less than 0.0001). The best predictive variables for the presence or absence of obstructive CAD documented by CA were in order of decreasing value: age, electrocardiogram, pain aggravated by sex, sex (gender), pain aggravated by movement, diabetes mellitus, pain described as prickling, pain described as burning, pain relieved by rest, pain with radiation to both arms, associated nausea, associated dyspnea, and a history of a lipid disorder. Four variables were predictive of normal coronary anatomy (NCA), pain aggravated by movement, prickling, nausea, and dyspnea. Although this set of predictor variables may not apply equally well to all populations of cardiac patients, the availability and relative simplicity of the program allow for adding or deleting variables and thus provide for considerable potential in the diagnostic assessment of RP. An inexpensive pocket computer can utilize the coefficients generated by the logistic regression program to calculate the probability of CAD as the cause of RP.


Uridine diphosphate galactose 4-epimerase. pH dependence of the reduction of NAD+ by a substrate analog.
Neutron activation analysis of UDP-galactose 4-epimerase from Escherichia coli for 53 metals shows that the enzyme does not contain any of these metals at significant levels. The substrate analog P1-5'-uridine-P2-glucose-6-yl pyrophosphate (UGP), a structural isomer of UDP-glucose with the sugar linked to UDP through the C-6 hydroxyl group, is an inactivator that irreversibly reduces epimerase.NAD+ to epimerase.NADH. The pH dependence of kobs reveals the essential involvement of an acidic group, kinetically measured pKa = 5.48 +/- 0.08, in unprotonated form and two weakly acidic or basic groups, apparent pKa values of 10.03 +/- 0.43, in protonated forms. Measurements of kobs as a function of [UGP] show that it is given by kobs = k[UGP]/(K + [UGP]) at a given pH, where K = 0.19 +/- 0.04 mM throughout the pH range 4.8-10.4. The pH-dependent first order rate constants range from 0.28 to 1.94 s-1, with the maximum value at pH 7.6 and decreasing at acidic and basic pH values. Reaction of [glucose-1-2H]UGP proceeds with kinetic isotope effects of 5.0, 2.1, 2.0, 1.9, and 3.5 at pH values 5.0, 6.2, 7.6, 9.0, and 10.0, respectively. Therefore, hydride transfer becomes rate-limiting at pH extremes but is not limiting at neutral pH, although deuteride transfer is significantly limiting at all pH values. The isotope effects facilitated correction of the kinetic pK values to the thermodynamic values 6.1-6.2 on the acid side and 9.0-9.6 on the alkaline side. We postulate that the group with pK1 = 5.5 (6.1-6.2 corrected) functions as an enzymic general base that abstracts the glucosyl C-1 hydroxyl proton in concert with transfer of the C-1 hydrogen and two electrons to NAD+. The pH dependence on the alkaline side may be related to the uridine nucleotide-dependent conformational transition that is an essential step in the reduction of epimerase.NAD+ to epimerase.NADH by sugars.


Liability exposure for surgical robotics instructors.
Surgical robotics instructors provide an essential service in improving the competency of novice gynecologic surgeons learning robotic surgery and advancing surgical skills on behalf of patients. However, despite best intentions, robotics instructors and the gynecologists who use their services expose themselves to liability. The fear of litigation in the event of a surgical complication may reduce the availability and utility of robotics instructors. A better understanding of the principles of duty of care and the physician-patient relationship, and their potential applicability in a court of law likely will help to dismantle some concerns and uncertainties about liability. This commentary is not meant to discourage current and future surgical instructors but to raise awareness of liability issues among robotics instructors and their students and to recommend certain preventive measures to curb potential liability risks.


Continuous circulation of an antigenically modified very virulent infectious bursal disease virus for fifteen years in Egypt.
Infectious bursal disease virus (IBDV), the agent of an immunosuppressive and sometimes lethal disease in chickens, is causing recurrent outbreaks in broiler chickens in Egypt. In particular, an antigenically modified isolate of very virulent IBDV (vvIBDV) called 99323 was detected in Egypt nearly twenty years ago; this isolate was shown to be experimentally controlled by an antigenically classical live vaccine. However, acute IBD is still reported, even in vaccinated flocks, and little is known about the genetic and antigenic properties of viruses currently circulating in Egypt. In the present study, ten samples collected in Egyptian broiler farms in 2015 as well as five samples collected in 2001 were analyzed. Genetic analyses of partial VP2 sequences revealed that 8 isolates clustered with vvIBDV strains, and 5 with tissue culture adapted and vaccine strains. Similar results were observed for partial VP1 sequences with the exception of isolate 160019, for which VP2 clustered with the vaccine strain Bursine while VP1 clustered with vvIBDV, suggesting reassortment. For isolates genetically related to vvIBDV, antigenic profiling revealed two patterns: while some isolates exhibited typical European vvIBDV reactivity with lack of binding of mAbs 5, other revealed extensive antigenic modifications, with lack of binding of mAbs 3, 5, 6, 8 and 9, similar to isolate 99323. These different patterns were associated with a single amino acid mutation at position 321 of VP2 that is located within peak PHI. Full genome sequencing was performed for three isolates, among which two were representative of the two antigenic patterns observed for vvIBDV as well as the reassortant isolate 160019. This study highlights the co-circulation of both antigenically typical and modified vvIBDV during the last fifteen years in Egypt.


System dynamics-based evaluation of interventions to promote appropriate waste disposal behaviors in low-income urban areas: A Baltimore case study.
Inappropriate waste disposal is a serious issue in many urban neighborhoods, exacerbating environmental, rodent, and public health problems. Governments all over the world have been developing interventions to reduce inappropriate waste disposal. A system dynamics model is proposed to quantify the impacts of interventions on residential waste related behavior. In contrast to other models of municipal solid waste management, the structure of our model is based on sociological and economic studies on how incentives and social norms interactively affect waste disposal behavior, and its parameterization is informed by field work. A case study of low-income urban neighborhoods in Baltimore, MD, USA is presented. The simulation results show the effects of individual interventions, and also identify positive interactions among some potential interventions, especially information and incentive-based policies, as well as their limitations. The model can help policy analysts identify the most promising intervention packages, and then field test those few, rather than having to pilot test all combinations. Sensitivity analyses demonstrate large uncertainties about behavioral responses to some interventions, showing where information from survey research and social experiments would improve policy making.


The association of profilin-1 levels with survival in chronic kidney disease.
Profilin-1 is a ubiquitous, actin-binding protein that plays an important role in the regulation of actin polymerization and cytoskeleton remodelling and contributes to vascular dysfunction. We conducted this study to investigate the association of serum profilin-1 levels with fatal and nonfatal CVE in a cohort of patients with stage 1-5 CKD. Serum concentrations of profilin-1 levels were determined by enzyme-linked immunosorbent assay. Endothelium-dependent vasodilatation (flow-mediated dilatation [FMD]) and endothelium-independent vasodilatation (nitroglycerine-mediated dilatation [NMD]) of the brachial artery were assessed noninvasively, using high-resolution ultrasound. Both fatal and nonfatal CVE were significantly higher in patients with high profilin-1 levels. Kaplan-Meier survival curves showed that patients with profilin-1 below the median value (114 pg/mL) had higher cumulative survival compared with patients who had profilin-1 levels above the median value (log-rank test, P < .001). This is the first study that demonstrates the serum profilin-1 is independently associated with endothelial dysfunction, cardiovascular events and survival in patients with CKD.


Distinction between myocardial ischemia and postural changes in continuous ECG monitoring based on ST-segment amplitude and vector orientation--preliminary results.
Myocardial ischemia, commonly defined as ST-segment elevation or depression on the electrocardiogram (ECG), is plagued by a large number of false positive events. To present a new method that attempts to distinguish between 'highly probable ischemia' and positional changes. Continuous three-lead orthogonal ECG monitoring was performed in three groups of subjects: 16 healthy volunteers undergoing a body position change protocol, 22 patients undergoing percutaneous transluminal coronary angioplasty (PTCA) and 17 patients with acute coronary syndromes (ACS). For each event (ischemic or postural), the change in ST-segment amplitude was calculated, as well as the angle between the ST-segment vector of the reference beat and the beats demonstrating ST-segment elevation or depression. Angles and ST-segment amplitude changes from well-documented ischemic events obtained from the PTCA patients and from the healthy volunteers in six different body positions were compared. Using both ST-segment amplitude and vector angle changes, ischemic events could be detected and differentiated from a postural change with a sensitivity of 91% and a specificity of 96%. Finally, the approach was blindly applied to continuous ECG recordings of ACS patients. The method allowed the classification of 37% of all ST-segment changes detected as highly probable ischemic events as opposed to only 7% using the standard 100 microV threshold. The current approach showed that highly probable ischemic events could be better distinguished from positional changes with objective criteria using ST-segment amplitude and vector orientation.


Cardiovascular MRI: current role in patient management.
The role of cardiovascular MRI in patient management is still evolving. Its capability to demonstrate anatomy without risk has made it an important supplement to ultrasound and a replacement for CT and angiography in many settings. In vivo metabolic studies of congenital and acquired diseases may be the most important future developments.


Effects of aquaculture waste feeds and antibiotics on marine benthic ecosystems in the Mediterranean Sea.
Intensive aquaculture is an important source of organic waste and antibiotics into the marine environment. Yet, their impacts on benthic marine ecosystems are poorly understood. Here, we investigated the ecological impacts of fish feed waste alone and in combination with three different antibiotics (i.e., oxytetracycline, florfenicol and flumequine) in benthic ecosystems of the Mediterranean Sea by performing a field experiment. We assessed the fate of the antibiotics in the sediment and their accumulation in wild fauna after two weeks of exposure. Moreover, we investigated the impact of the feed waste alone and in combination with the antibiotics on sediment physico-chemical properties, on benthic invertebrates, as well as on the microbiota and resistome of the sampled sediments. One week after the last antibiotic application, average oxytetracycline and flumequine concentrations in the sediment were <1% and 15% of the applied dose, respectively, while florfenicol was not detected. Flumequine concentrations in wild invertebrates reached 3 μg g-1, while concentrations of oxytetracycline were about an order of magnitude lower, and florfenicol was not detected. Feed waste, with and without antibiotics, increased the concentration of fine particulate matter, affected the pH and redox conditions, and significantly reduced the biodiversity and abundance of benthic invertebrates. Feed waste also had a significant influence on the structure of sediment microbial communities, while specific effects related to the different antibiotics ranged from insignificant to mild. The presence of antibiotics significantly influenced the normalized abundance of the measured antibiotic resistance genes. Florfenicol and oxytetracycline contributed to an increase of genes conferring resistance to macrolides, tetracyclines, aminoglycosides and chloramphenicol, while flumequine had a less clear impact on the sediment resistome. This study demonstrates that feed waste from aquaculture farms can rapidly alter the habitat and biodiversity of Mediterranean benthic ecosystems, while antibiotic residual concentrations can contribute to the enrichment of bacterial genes resistant to antibiotic classes that are of high relevance for human medicine.


Current status of class III antiarrhythmic drug therapy.
Studies in animal models, as well as clinical experience with amiodarone and sotalol, suggest that action potential prolongation may be a useful antiarrhythmic mode of action. A number of agents that produce this class III effect are currently under development. The single greatest liability for further development of this group of drugs is the occasional, and apparently unpredictable, development of exaggerated QT prolongation and polymorphic ventricular tachycardia (torsades de pointes). Available data suggest that QT interval prolongation is not a good indicator of whether or not a class III antiarrhythmic will suppress a target arrhythmia; however, exaggerated QT prolongation is a predictor of torsades de pointes. Further studies to delineate the mechanism underlying the development of torsades de pointes might lead to safer and more effective antiarrhythmic drugs.


Easy construction of an improved fine wire electrode for chronic single neuron recording in freely moving animals.
An easy and improved method for construction and implantation of fine wire electrodes is described. These electrodes have been found to be effective in long-term recording of single unit activity in freely behaving and ingesting animals when chronically implanted in any region of the brain in rats.


Antibacterial activities and conformations of bovine beta-defensin BNBD-12 and analogs:structural and disulfide bridge requirements for activity.
Structure and biological activities of synthetic peptides corresponding to bovine neutrophil beta-defensin BNBD-12, GPLSC(1)GRNGGVC(2)IPIRC(3) PVPMRQIGTC(4) FGRPVKC(5) C(6)RSW with disulfide connectivities C(1)-C(5), C(2)-C(4) and C(3)-C(6) and its variants with one, two and three disulfide bridges have been investigated. Selective protection of cysteine thiols was necessary in the four and six cysteine containing peptides for the formation of disulfide connectivities as observed in BNBD-12. Circular dichroism (CD) spectra indicate that in aqueous medium, only a small fraction of molecules populate turn-like conformations. In the presence of micelles and lipid vesicles, the single, two and three disulfide containing peptides adopt beta-hairpin or beta-sheet structures. Antibacterial activity was observed for all the peptides, irrespective of the number of disulfide bridges or how they were connected. Our results suggest that a rigid beta-sheet structure or the presence of three disulfide bridges does not appear to be stringent requirements for antibacterial activity in beta-defensins.


Tear of the anterior cruciate ligament as a late complication of meniscectomy.
During the years 1973-5 we performed 190 meniscectomies. We report 4 cases of tears of the anterior cruciate ligament after meniscectomy. Although this complication is mentioned in the literature, very few orthopaedic surgeons are familiar with it.


Safety of induced hypertension therapy in patients with acute ischemic stroke.
The management of blood pressure in acute stroke is controversial. Small pilot studies have suggested that blood pressure augmentation improves short-term neurological function, but the rate of adverse events with induced hypertension (IH) therapy is unknown. We reviewed 100 consecutive patients who underwent perfusion magnetic resonance imaging for acute ischemic stroke. IH therapy was employed in 46 patients and standard therapy (ST) in 54. The two groups had similar baseline characteristics, but more patients in the IH group had significant large-artery stenoses. The IH group achieved significantly higher mean arterial pressure (MAP) than the ST group within 3 days of initiation of therapy with a variety of vasopressor agents. Only 35% of patients in the IH group actually achieved the target MAP augmentation of 10-20% above baseline, however. All patients survived to discharge. Four patients experienced major adverse events in each group. Two patients in the IH group experienced intra cerebral hemorrhage compared to none in the ST group. Two patients in the ST group experienced myocardial ischemia, compared to none in the IH group. The National Institutes of Health Stroke Scale during the hospitalization and place of discharge were similar in both groups. Patients in the IH group were more likely to be admitted to the intensive care unit and had a longer hospital stay by nearly 4 days compared to the ST group. These data demonstrate the relative safety of IH therapy in acute stroke patients. Given the greater use of resources, however, the role of IH in improving clinical outcomes requires a prospective, randomized trial.


Eosinophils are dispensable for the regulation of IgA and Th17 responses in Giardia muris infection.
IgA and Th17 responses are pivotal for the control of Giardia infections. Eosinophils support IgA class switching, the survival of intestinal IgA+ plasma cells at steady state and can control Th17 activity in the small intestine. To see whether eosinophils regulate adaptive immune responses during giardiasis, we investigated Giardia muris infections in wild-type BALB/c and eosinophil-deficient ∆dblGATA-1 mice. Infected ∆dblGATA-1 mice did not differ markedly in parasite control from wild-type mice. Confirming previous studies, naive ∆dblGATA-1 mice displayed diminished IgA+ B cell frequencies in Peyer's patches. However, IgA class switching and intestinal IgA secretion in response to G muris infection were comparable in wild-type BALB/c and ∆dblGATA-1 mice. Both strains displayed similarly low intestinal Th17 responses, accompanied by a mild expansion of type 3 innate lymphoid cells (ILC3). Contrasting previous reports on overt small intestinal Th17 activity in eosinophil-deficient mice, IL-17A production is kept in check in the absence of eosinophils during Giardia infection. Suboptimal homeostatic IgA responses in the absence of eosinophils are transiently fostered in infected mice and the maintenance of IgA+ plasma cells appears to be restored during persisting Giardia infection.


New method for detecting changes in the surface appearance of human red blood cells.
A new method for examining the surface of blood cells, using the Stereoscan electron microscope, is described. Some of the cellular appearances revealed by this technique are illustrated. The potentialities and limitations of scanning electron microscopy are discussed.