UK National Survey of Gastroenterologists' attitudes and barriers toward therapeutic drug monitoring of anti-TNF therapy in inflammatory bowel disease.
Evidence supports use of therapeutic drug monitoring (TDM) in improving efficacy and cost-effectiveness of anti-tumour necrosis factor (TNF) therapy in inflammatory bowel disease (IBD). Our objective was to assess attitudes and barriers towards TDM use with anti-TNF's in the UK. A 17-question survey was distributed to members of the British Society of Gastroenterology by email. Of 243 respondents (51.6% male), 237 respondents met inclusion criteria. Of these, 46% were consultants (gastroenterologist, GI), 39.2% IBD nurse specialists (clinical nurse specialists, CNS), 14.8% registrars. TDM is used by 96.9% for secondary loss of response; 72.5% for primary non-response and 54.1% used TDM proactively. Barriers were time lag in receiving results (49.8%), lack of awareness of guidelines (46.4%) and cost (29.9%). Clinicians working at a teaching hospital (OR 2.6, 95% CI 0.71 to 9.8), IBD CNS and GI registrars (OR 2.6, 95% CI 0.7 to 10 and OR 1.5, 95% CI 0.3 to 7.2, respectively) were more likely to use TDM. Clinicians practising for >20 years (OR 4.1, 95% CI 0.4 to 41.8) and a large volume IBD practice (>50% IBD patients per month) were more likely to use TDM (OR 45.7, 95% CI 7.5 to 275). Proactive TDM, was more likely to be used in tertiary care (OR 2.25, 95% CI 0.84 to 6.1), IBD CNS (OR 1.2, 95% CI 0.7 to 2.1) and clinicians managing >50% IBD patients per month (OR 10.8, 95% CI 1.3 to 90.3). Clinicians with 5-9 years of experience in practice were more likely to use proactive TDM (OR 2.6 and CI 1.04 to 6.4). Validation of point of care and lower cost assays, reduced time lag from test to result, lower cost of testing and dissemination of current recommendations may further optimise treatment strategies.


The identification of microRNAs in the whitespotted bamboo shark (Chiloscyllium plagiosum) liver by Illumina sequencing.
MicroRNAs are indispensable players in the regulation of a broad range of biological processes. Here, we report the first deep sequencing of the whitespotted bamboo shark (Chiloscyllium plagiosum) liver. We mapped 91 miRNAs in the Callorhinchus milii genome that have previously been described in the Danio rerio, Fugu rubripes, Oryzias latipes, Xenopus laevis, Xenopus tropicalis, Homo sapiens, and Mus musculus. In addition, 156 new putative candidate (PC) C. plagiosum miRNAs were identified. From these 247 miRNAs, 39 miRNA clusters were identified, and the expression of these clustered miRNAs was observed to vary significantly. A total of 7 candidate miRNAs were selected for expression confirmation by stem-loop RT-PCR. This study resulted in the addition of a significant number of novel miRNA sequences to GenBank and laid the foundation for further understanding of the function of miRNAs in the regulation of C. plagiosum liver development.


Ethnic variation in cardiovascular disease risk factors among children and young adults: findings from the Third National Health and Nutrition Examination Survey, 1988-1994.
Knowledge about ethnic differences in cardiovascular disease (CVD) risk factors among children and young adults from national samples is limited. To evaluate ethnic differences in CVD risk factors, the age at which differences were first apparent, and whether differences remained after accounting for socioeconomic status (SES). Third National Health and Nutrition Examination Survey, 1988-1994. Eighty-nine mobile examination centers. A total of 2769 black, 2854 Mexican American, and 2063 white (non-Hispanic) children and young adults aged 6 to 24 years. Ethnicity and household level of education (SES) in relation to body mass index (BMI), percentage of energy from dietary fat, cigarette smoking, systolic blood pressure, glycosylated hemoglobin (HbA1c), and non-high-density lipoprotein cholesterol (non-HDL-C [the difference between total cholesterol and HDL-C]). The BMI levels were significantly higher for black and Mexican American girls than for white girls, with ethnic differences evident by the age of 6 to 9 years (a difference of approximately 0.5 BMI units) and widening thereafter (a difference of >2 BMI units among 18- to 24-year-olds). Percentages of energy from dietary fat paralleled these findings and were also significantly higher for black than for white boys. Blood pressure levels were higher for black girls than for white girls in every age group, and glycosylated hemoglobin levels were highest for black and Mexican American girls and boys in every age group. In contrast, smoking prevalence was highest for white girls and boys, especially for those from low-SES homes (77% of young men and 61% of young women, aged 18-24 years, from low-SES homes were current smokers). All ethnic differences remained significant after accounting for SES and age. These findings show strong ethnic differences in CVD risk factors among youths of comparable age and SES from a large national sample. The differences highlight the need for heart disease prevention programs to begin early in childhood and continue throughout young adulthood to reduce the risk of atherosclerosis.


Prospective study of non-nutritive sucking and feeding skills in premature infants.
The aim of the present work was to assess the value of non-nutritive sucking (NNS) measures as predictors of oral feeding performance in comparison to other putative predictors of feeding skills: respiratory support, post-menstrual age (PMA) at birth and the neonatal oral motor assessment score (NOMAS). This was a prospective, observational study. Cox proportional hazards and non-parametric rank sum tests were used to assess the relationship between NNS and feeding outcome measures. The setting was neonatal intensive care units (NICU) in rural/academic, urban/tertiary centres in the USA. In all, 51 premature infants born between 25 and 34 weeks' PMA, birth weight 1512.3+/-499.4 g, were included in this study. Interventions were measurement of NNS, standardised feeding advance schedule, performance of NOMAS, and standardised, permissive, oral feeding advance schedule. were transition time from first to full oral feeding (FOF) and gestational age at FOF. Higher NNS organisation scores predicted shorter transition to FOF (p<0.05): infants with a more organised suck pattern reached independent oral feeding 3 days earlier (16 vs 13 day transition) than infants with more chaotic patterns of suck bursts. Consistency of the suck waves also corresponded with feeding milestones: infants with more regular suck wave pressure deflections became competent oral feeders approximately 3 days earlier than those with irregular suck pressure waves. PMA at birth was inversely associated with PMA at FOF. NOMAS measures were not associated with outcome measures. Measures of NNS organisation and suck consistency constitute useful candidate predictors of feeding performance by premature infants. The results accord with previous findings linking PMA at birth with age at independent feeding.


Lasalocid for improved weight gains and control of Coccidia in lambs.
Lasalocid at 25 mg/kg of feed was highly effective in reducing numbers of oocysts in feces of naturally infected ewes and lambs. Treated ewes were fed lasalocid-medicated feed before and after parturition, and the 17 lambs from these ewes also were fed medicated feed gained 5.26 kg more (P less than 0.05) than did the 17 nontreated lambs from nontreated ewes. Naturally infected lambs maintained in semiconfinement acquired coccidia infections between 23 and 64 (mean of 38) days after birth. A coccidiostat given before and during the time coccidia-naive lambs were first exposed to coccidia was necessary to achieve the greatest production response to treatment. When naturally infected feeder lambs (30.9 kg) maintained in semiconfinement were fed lasalocid-medicated feed at 25 mg/kg of feed or unmedicated feed for 91 days, no significant difference (P greater than 0.05) in rate or efficiency of gain was detected, even though lasalocid was highly effective against coccidia.


High-resolution profiling of the LEDGF/p75 chromatin interaction in the ENCODE region.
Lens epithelium-derived growth factor/p75 (LEDGF/p75) is a transcriptional coactivator involved in stress response, autoimmune disease, cancer and HIV replication. A fusion between the nuclear pore protein NUP98 and LEDGF/p75 has been found in human acute and chronic myeloid leukemia and association of LEDGF/p75 with mixed-lineage leukemia (MLL)/menin is critical for leukemic transformation. During lentiviral replication, LEDGF/p75 tethers the pre-integration complex to the host chromatin resulting in a bias of integration into active transcription units (TUs). The consensus function of LEDGF/p75 is tethering of cargos to chromatin. In this regard, we determined the LEDGF/p75 chromatin binding profile. To this purpose, we used DamID technology and focused on the highly annotated ENCODE (Encyclopedia of DNA Elements) regions. LEDGF/p75 primarily binds downstream of the transcription start site of active TUs in agreement with the enrichment of HIV-1 integration sites at these locations. We show that LEDGF/p75 binding is not restricted to stress response elements in the genome, and correlation analysis with more than 200 genomic features revealed an association with active chromatin markers, such as H3 and H4 acetylation, H3K4 monomethylation and RNA polymerase II binding. Interestingly, some associations did not correlate with HIV-1 integration indicating that not all LEDGF/p75 complexes on the chromosome are amenable to HIV-1 integration.


Detection of orbital implant infection with technetium 99m-labeled leukocytes.
Orbital implant infection is a rare cause of anophthalmic socket pain. Because of the potential danger of infection spreading to nearby structures, it is of paramount importance to diagnose the condition as soon as possible. Scintigraphy is a method for diagnosis of graft infections by radioisotopic imaging of inflammatory sites. We report on a patient with socket pain 3 months after implantation of an acrylic implant. The socket appearance was normal and there were no signs of infection other than culture-positive socket exudation. Three consecutive computed tomography scans revealed no abnormalities. 99mTc leukocyte scintigraphy revealed white blood cell accumulation at the implantation site. The implant was removed and cultured. This produced Staphylococcus epidermidis and R. equii. A parenteral antibiotic treatment was instituted with subsequent improvement of symptoms. Four months later, after negative scintigraphy, a hydroxyapatite implant was inserted, demonstrating full vascularization on a bone scan after 2 months. Two months later, the patient developed the previous symptoms, with all of the former findings, including positive scintigraphy. The implant was removed, revealing a microabscess on the anterior aspect, producing S. epidermidis on culture. We conclude that scintigraphy using 99mTc-labeled leukocytes is a useful technique in diagnosing low-grade orbital infection.


Acute toxic effect of lipopolysaccharides to blood tissue in rats and responses to vitamin E and sodium selenite.
This work has been prepared to find out changes in the biochemicals with DNA damage, micronucleus, and apoptosis to lipopolysaccharides (LPS) alone or vitamin E (VE) and sodium selenite (SS) in rats' blood tissue. Rats were divided into eight groups according to the treatment into control vitamin E (VE) treatment group (200 mg/kg bw), sodium selenite (SS) treatment (0.35 mg/kg bw) group, VE + SS treatment group (200 + 0.35 mg/kg bw), LPS treatment group (10 mg/kg bw), LPS + VE (10 + 200 mg/kg bw), LPS + SS treatment (10 + 0.35 mg/kg bw), and LPS + SS+VE treatment (10 + 0.35 + 200 mg/kg bw) group for 6 hr. LPS increased malondialdehyde (MDA) level and decreased antioxidant enzymes' activities in rat erythrocytes and leukocytes. DNA damage of leukocytes with comet assay and RAPD-PCR was detected in LPS treatment group. The levels of micronucleus and apoptosis percentage were increased significantly at the end of 6 hr. VE and/or SS protected the LPS-induced erythrocytes and leukocytes against damage as they have caused amelioration of rats by altering the results. As a result, the co-administration of VE and/or SS against LPS-induced damage provides protection. VE and/or SS in patients and animal models with sepsis must be taken in the diet because they are protective against the cellular degradation caused by oxidative damage. PRACTICAL APPLICATIONS: LPS obtained from E. coli is used more frequently in experimental sepsis studies. When LPS is administered to experimental animals, interstitial pneumonia, adult respiratory fatal syndrome, acute tubular necrosis, and fatal effects such as coagulopathy and hypoglycemia may be seen in these animals. The co-treatment of VE and SS may be more effective than using them alone against LPS.


Pharmacokinetic and tolerability of i.m. disodium clodronate 200 mg/lidocaine 1%, given twice monthly, in comparison with i.m. disodium clodronate 100 mg/lidocaine 1%, given weekly, in healthy postmenopausal female patients.
Clodronate is a bisphosphonate effective in the prevention and treatment of osteoporosis in postmenopausal women. Non-adherence to bisphosphonates, however, is a major issue in clinical practice. Simplifying dose regimens may increase compliance. To assess bioequivalence between an intramuscular (i.m.) clodronate 200 mg/lidocaine 1% twice-a-month formulation and a clodronate 100 mg/lidocaine 1% weekly formulation in 32 postmenopausal women. In this double-blind, randomized, two-way crossover study, test and reference formulations were administered in single dose, with a 2-week wash-out between administrations. The primary endpoint was clodronic acid cumulative excretion in the first 24 hours after injection (Xu0-24h). Cumulative excretion in the 72 hours post-dose (Xu0-72h) and maximum excretion rate (Ratemax) were also evaluated. Bioequivalence was assumed if the 90% confidence intervals (CIs) of the geometric means ratios of the dose-normalized parameters were within the 80.00 - 125.00% range. Local tolerability was evaluated. Mean Xu0-24h values were 114.03 ±23.13 mg and 55.22 ±9.73 mg for clodronate 200 mg and 100 mg. The 90% CIs for dose-normalized Xu0-24h, Xu0-72h and Ratemax ere 95 -110%, 94 -107% and 95 - 113%. Local tolerability of both treatments was good. The differences in pain intensity between formulations were not sigificantly different at most assessment times. Headache was the only treatment-related adverse event. Bioequivalence of the two formulations was confirmed in terms of dose-normalized rate and amount of clodronic acid excretion. This result, together with the favorable tolerability of the novel 200 mg formulation, suggests the possibility of reducing the number of i.m. administrations from once-a-week to twice-a-month.


A case of multicentric Castleman's disease associated with renal amyloidosis and pure red cell aplasia.
This is the first reported case of multicentric Castleman's disease (MCD) associated with renal amyloidosis and pure red cell aplasia (PRCA). Inguinal lymph node biopsy showed follicular hyperplasia with prominent germinal centers and plasma cell proliferation in the interfollicular areas. Renal biopsy specimens revealed intraglomerular amyloid deposits, defined as AA amyloidosis. Since amyloid deposits were not present in the gastric and rectal mucosal tissues, his renal disorder was found to be an unusual secondary amyloidosis associated with MCD. Following treatment by plasma exchange, there was progressive deterioration of anemia due to PRCA detected by bone marrow aspiration. Subsequently he was successfully treated with steroid pulse therapy not only for anemia but also for renal function.


Relation between Dental Caries and Body Mass Index-for-age among Schoolchildren of Jazan City, Kingdom of Saudi Arabia.
To analyze and report the type of relation present between dental caries and body mass index (BMI)-for-age among schoolchildren in Jazan region of Kingdom of Saudi Arabia. A cross-sectional study with multi-staged random sampling technique was designed to recruit the sample of schoolchildren. Caries was examined using the World Health Organization recommended "decayed and filled teeth"/"decayed missing and filled teeth (dft/DMFT)" method. The BMI-for-age was calculated using the value obtained from body weight and height (kg/m2) of each child. The obtained results were plotted on age- and gender-specific percentile curves by the Centers for Disease Control and Prevention and categorized accordingly. Chi-squared test was conducted to analyze the relation between BMI-for-age and dental caries. Logistic regression was performed to judge the predictor variables. The p-value < 0.05 was considered as significant. A total of 360 children were part of this study with equal recruitment from both genders. The mean dft/DMFT value for girls (2.52) was more than that for boys (1.88); and the (p = 0.00) calculated value was statistically significant. Most of the children had normal BMI-for-age (60.6%) and very few were obese (4.7%). Dental caries, fast food, and snacks between meals were significant independent predictor variables for BMI (p < 0.05). Dental caries was a strong predictor, and the analysis showed that children with untreated caries had 81% (odds ratio = 0.19; confidence interval = 0.65, 0.58) higher chance of suffering from low BMI. To conclude, this is the first study attempted to see the relationship between BMI-for-age and dental caries among schoolchildren in Jazan city of Kingdom of Saudi Arabia. Negative relation between dental caries and BMI should warrant health promoters about dental caries as a reason for low BMI in a subset of children. High and alarming percentage of untreated dental caries demonstrates the oral health needs among the schoolgoing children in Jazan region. Public health dentists should develop and implement prevention programs so that the oral health issues among schoolchildren are addressed.


Timing and side effects of flumazenil for dental outpatients receiving intravenous sedation with midazolam.
We studied the timing and side effects of flumazenil treatment for 10 healthy volunteers and 46 dental outpatients who received intravenous sedation with midazolam. For the volunteers, vital signs were monitored before and after intravenous injection of midazolam and flumazenil. In addition, grip strength, signs and symptoms, and performance on the Romberg's test and addition tests were evaluated 30 min and 60 min after midazolam injection as well as after flumazenil injection. There were no significant changes in vital signs before, immediately after, or 50 min after injection of flumazenil, the latter time corresponding to the half-life of the drug. Thus, awakening from sedation was associated with no effects on the cardiovascular or respiratory systems. Distinct effects of flumazenil were demonstrated by the Romberg's test and the assessment of sedation status. Flumazenil had no effect on the outcome of the addition test. For the outpatients, sedation status and signs and symptoms were studied in patients undergoing procedures lasting 30 min or less (group S) and those undergoing procedures lasting 31 to 60 min (group L). Three patients in group S and one in group L had signs and symptoms of resedation. After treatment with flumazenil, abnormalities such as excitability and nausea were reported by only two patients in group L. One patient in group S had drowsiness that did not resolve after injection of flumazenil and continued until the following day. Our results indicate that flumazenil should be given at least 60 min after intravenous sedation with midazolam in dental outpatients. Moreover, caution should be exercised with regard to the potential side effects of flumazenil.


Exposures to Bleach, Peroxide, Disinfectants, Antimalarials, and Ivermectin Reported to the California Poison Control System Before and During the COVID-19 Pandemic, 2015-2021.
The COVID-19 pandemic led to widespread fear of infection, with many people expanding their use of cleaning products and trying unproven prevention and treatment strategies. We described shifts in reported exposures related to COVID-19 home interventions. This study considered suspected toxicity exposures involving household cleaning products (bleach, peroxide, disinfectants), antimalarials (hydroxychloroquine and chloroquine), and ivermectin reported to the California Poison Control System from 2015 through 2021 and assessed trends in exposures by using interrupted time-series analyses. We found a significant increase in exposures reported to the California Poison Control System related to household cleaning products and ivermectin during the COVID-19 pandemic. As of January 1, 2015, the baseline level of reported exposures to household cleaning products was 707.33 per month and was declining at a rate of 1.71 (95% CI, -2.87 to -0.56) per month through February 29, 2020. In March 2020, an increase of 466.57 (95% CI, 328.08-605.07) reported exposures above baseline occurred, after which exposures to cleaning products decreased at a rate of 23.40 (95% CI, -32.48 to -14.32) per month. The number of reported exposures to antimalarials did not change significantly before or during the pandemic. The number of reported ivermectin exposures before December 2020 was initially stable at 14.50 per month and then increased by 2.05 per month through December 2021. Our observations suggest that while some dangerous home prevention and treatment efforts resolve over time, further interventions may be needed to reduce the public health effects related to attempts to self-treat COVID-19 with ivermectin.


Recent Advances in Antiepileptic Herbal Medicine.
Epilepsy is one of the most common neurological disorders worldwide, with about 80 percent of cases thought to be in developing nations where it is mostly linked to superstition. The limited supply, high cost as well as low efficacy and adverse side effects of antiepileptic drugs (AEDs) is a matter of major concern. Herbal medicine has always been traditionally part of treatment of epilepsy. Herbal medicines are generally well tolerated, with fewer side effects. To highlight some herbal extracts that have been studied for their anticonvulsant activity in animal models, literature search from PubMed and Science Direct, was performed. The keywords for the search consisted of combinations of the following terms: Herbal antiepileptic and/or anticonvulsant, botanicals + epilepsy. Literature published in the last five years was considered. Eighteen (18) anticonvulsant herbal agents are reported and discussed. Experiments mostly consisted of phenotypic screens in rodents, with little diversity in screening methods. In most experiments, the tested extracts prolonged the time to onset of seizures and decreased their duration. Most experimenters implicate potentiation of GABAergic activity as the mode of action of the extracts, even though some experimenters did not fully characterise the bioactive chemical composition of their extracts. Potential herbal remedies have shown positive results in animal models. It remains unclear how many make it into clinical trials and eventually making part of the AED list. More rigorous research, applying strict research methodology with uniform herbal combinations, as well as clinical studies are urgently needed.


Development of a cell-free split-luciferase biochemical assay as a tool for screening for inhibitors of challenging protein-protein interaction targets.
Targeting the interaction of proteins with weak binding affinities or low solubility represents a particular challenge for drug screening. The NanoLuc â ® Binary Technology (NanoBiT â ®) was originally developed to detect protein-protein interactions in live mammalian cells. Here we report the successful translation of the NanoBit cellular assay into a biochemical, cell-free format using mammalian cell lysates. We show that the assay is suitable for the detection of both strong and weak protein interactions such as those involving the binding of RAS oncoproteins to either RAF or phosphoinositide 3-kinase (PI3K) effectors respectively, and that it is also effective for the study of poorly soluble protein domains such as the RAS binding domain of PI3K. Furthermore, the RAS interaction assay is sensitive and responds to both strong and weak RAS inhibitors. Our data show that the assay is robust, reproducible, cost-effective, and can be adapted for small and large-scale screening approaches. The NanoBit Biochemical Assay offers an attractive tool for drug screening against challenging protein-protein interaction targets, including the interaction of RAS with PI3K.


A liquid metal-based self-adaptive sulfur-gallium composite for long-cycling lithium-sulfur batteries.
Lithium-sulfur (Li-S) batteries have been regarded as a promising candidate for energy storage owing to their ultrahigh theoretical capacity and low cost. However, the commercial application of Li-S batteries has been plagued by the huge volume change of sulfur, the insulative nature of solid active materials (S and Li2S) and the polysulfide shuttle. Here, a uniform sulfur-gallium core-shell structure (S@Ga) with an ultrathin liquid gallium shell was prepared by harnessing the reaction between sulfur and gallium via a facile mixing process. In this S@Ga composite, the thin gallium shell not only exhibits the self-adaptive characteristic to perfectly adapt to the varying volume change of sulfur, restraining the polysulfide shuttle, but also acts as a conductive agent to enhance the electronic/ion transmission, improving the rate capacity of the S@Ga cathode. Therefore, the resultant S@Ga cathode exhibits a high capacity of 1295 mA h g-1 at 0.1C and a high cycling stability with a small decay of 0.043% per cycle for 1000 cycles at 1C.


[Computation disorders in the clinical picture of focal brain lesions].
Disturbances of calculation were studied in 76 patients with arterio-venous aneurysms, located in the left and right hemisphere. An analysis of errors made by the patients in the process of calculation makes it possible to assume that in the organization of calculation functions, both hemispheres are involved, but the different stages of it have different morphological and functional bases. It was demonstrated that the right hemisphere provides the proceeding of the most automatized links during calculation.


Ukumela impilo randomised trial: preliminary findings of height-adjustable sit-to-stand workstations on health outcomes of South African office workers.
The prevalence of sedentary behaviour has concurrently risen with multiple cardiometabolic risk markers independent of physical activity levels. Office-based workers accumulate the highest levels of sitting time during occupational times. This study aims to investigate the short-term effects of using height-adjustable sit-to-stand workstations on cardiometabolic risk markers of office-based workers in South Africa. Sixty-two office-based workers were randomized into intervention (n = 44), and the control group (n = 18). Small improvements were observed in BMI, blood pressure, and cholesterol levels in this cohort. This preliminary investigation confirms that short-term height-adjustable sit-stand interventions are effective in reducing workplace sitting time and selected health outcomes. South Africa has been attributed with the highest burden of obesity in Sub-Saharan Africa, as a result, there is a need to implement long-term workplace intervention to reverse these implications. Pan African Clinical Trial Registry, PACTR201911656014962 on the 12th of November 2019.


Anthropometric measurements in children having transfusion-dependent beta thalassemia.
The aim of this study was to determine the anthropometric measurements in transfusion-dependent β-thalassemia children in Pakistan. The secondary aim was to correlate serum ferritin with the physical growth. We enrolled 367 children (aged 5-17 years) with transfusion-dependent beta-thalassemia major in the study. Anthropometric measurements, serum ferritin levels, and pre-transfusion hemoglobin levels were measured. Serum ferritin was correlated with the height z-score for age. Laboratory evaluation showed that patients had significantly low mean pre-transfusion hemoglobin of 7.66 ± 1.34 g/dl (range 2.5-10.5) and high median (Q3-Q1) serum ferritin of 5012 ng/ml (6829-3532). The median (Q3-Q1) height-for-age z-score of children was low at -2.69 and (-1.46 to -3.80) and 65.4% children had stunted growth (height for age z-score <-2). There was a significant negative correlation between height for age z-score and serum ferritin levels (p < 0.000). Stunting of growth began early during 5-10 years of age but increased markedly with the progress of time. The study showed that children with beta thalassemia major had delayed physical growth possibly secondary to iron overload. Effective and early iron chelation is needed for preventing growth failure in transfusion-dependent beta thalassemia.


Insulin-induced cell cycle progression is impaired in chinese hamster ovary cells overexpressing insulin receptor substrate-3.
To analyze the roles of insulin receptor substrate (IRS) proteins in insulin-stimulated cell cycle progression, we examined the functions of rat IRS-1 and IRS-3 in Chinese hamster ovary cells overexpressing the human insulin receptor. In this type of cell overexpressing IRS-1 or IRS-3, we showed that: 1) overexpression of IRS-3, but not IRS-1, suppressed the G1/S transition induced by insulin; 2) IRS-3 was more preferentially localized to the nucleus than IRS-1; 3) phosphorylation of glycogen synthase kinase 3 and MAPK/ERK was unaffected by IRS-3 overexpression, whereas that of protein kinase B was enhanced by either IRS; 4) overexpressed IRS-3 suppressed cyclin D1 expression in response to insulin; 5) among the signaling molecules regulating cyclin D1 expression, activation of the small G protein Ral was unchanged, whereas insulin-induced gene expression of c-myc, a critical component for growth control and cell cycle progression, was suppressed by overexpressed IRS-3; and 6) insulin-induced expression of p21, a cyclin-dependent kinase inhibitor, was decreased by overexpressed IRS-3. These findings imply that: 1) IRS-3 may play a unique role in mitogenesis by inhibiting insulin-stimulated cell cycle progression via a decrease in cyclin D1 and p21 expressions as well as suppression of c-myc mRNA induction in a manner independent of the activation of MAPK, protein kinase B, glycogen synthase kinase 3 and Ral; and 2) the interaction of IRS-3 with nuclear proteins may be involved in this process.


A Bayesian method for oscillator stability analysis.
The power spectral density of frequency fluctuations of an oscillator is generally modeled as a sum of power laws with integer exponents (from -2 to +2). However, a power law with a fractional exponent may exist. We propose a method for measuring the level of such a noise process and determining the probability density of the exponent. This yields a criterion for compatibility with an integer exponent. This method is based on a Bayesian approach called the reference analysis of Bernardo-Berger. The application to a sequence of frequency measurement from a quartz oscillator illustrates this paper.


Causes of renal allograft loss. Progress in the 1980s, challenges for the 1990s.
A variety of refinements in the care of kidney transplant recipients have been instituted over the past decade. The authors studied the overall impact of these refinements on kidney allograft losses at a single institution. To do this they compared the causes and rates of graft loss for primary kidney transplants in the 1970s (January 1, 1970 to December 31, 1979; n = 1012; 657 nondiabetics, 355 diabetics; 617 living donors, 395 cadaver donors) versus the 1980s (January 1, 1980 to December 31, 1989; n = 1,384; 756 nondiabetics, 628 diabetics; 740 living donors, 644 cadaver donors). Overall patient survival improved significantly, with rates at 1, 5, and 10 years of 94%, 84%, and 68% for the 1980s, compared with 86%, 69%, and 57% for the 1970s (p less than 0.001). Actuarial graft survival also improved significantly, with rates at 1, 5, and 10 years of 86%, 71%, and 52% for the 1980s, compared with 73%, 58%, and 43% for the 1970s (p less than 0.001). This improvement occurred even though there were proportionately more cadaver donors and diabetic recipients in the 1980s. For both decades combined, 24% of the lost grafts were due to chronic rejection, 18% to cardiovascular causes of death with function, 13% to infectious causes of death with function, and 11% to acute rejection. The overall gain in graft survival rates in the 1980s was principally due to fewer cases of acute rejection and fewer infectious deaths. Improvement in graft survival due to the two leading causes--chronic rejection and cardiovascular causes of death--was relatively small, if any. These data indicate that future kidney transplantation research should emphasize prevention of chronic rejection and cardiovascular death.


Does long-term use of antidiabetic drugs changes cancer risk?
Antidiabetic medications are commonly used around the world, but their safety is still unclear. The aim of this study was to investigate whether long-term use of insulin and oral antidiabetic medications is associated with cancer risk.We conducted a well-designed case-control study using 12 years of data from Taiwan's National Health Insurance Research Database and investigated the association between antidiabetic medication use and cancer risk over 20 years. We identified 42,500 patients diagnosed with cancer and calculated each patient's exposure to antidiabetic drugs during the study period. We matched cancer and noncancer subjects matched 1:6 by age, gender, and index date, and used Cox proportional hazard regression and conditional logistic regression, adjusted for potential confounding factors, that is, medications and comorbid diseases that could influence cancer risk during study period.Pioglitazone (adjusted odds ratio [AOR], 1.20; 95% confidence interval [CI], 1.05-1.38); and insulin and its analogs for injection, intermediate or long acting combined with fast acting (AOR, 1.22; 95% CI, 1.05-1.43) were significantly associated with a higher cancer risk. However, metformin (AOR, 1.00; 95% CI, 0.93-1.07), glibenclamide (AOR, 0.98; 95% CI, 0.92-1.05), acarbose (AOR, 1.06; 95% CI, 0.96-1.16), and others do not show evidence of association with cancer risk. Moreover, the risk for specific cancers among antidiabetic users as compared with nonantidiabetic medication users was significantly increased for pancreas cancer (by 45%), liver cancer (by 32%), and lung cancer (by 18%).Antidiabetic drugs do not seem to be associated with an increased cancer risk incidence except for pioglitazone, insulin and its analogs for injection, intermediate or long acting combined with fast acting.


Enlarged hyperechogenic substantia nigra is related to motor performance and olfaction in the elderly.
Enlarged substantia nigra hyperechogenicity (SN+) assessed by transcranial sonography (TCS) may be associated with Parkinson's disease (PD) risk markers such as impaired motor performance and hyposmia. The aim of this multicenter cross-sectional study was to define the association between SN+ and these risk markers in a large population older than 50 years without the diagnosis of PD. In three centers (Tuebingen, Homburg, and Innsbruck), 1,839 individuals were examined. The echostatus of the SN was assessed by TCS, motor performance by the Unified Parkinson's Disease Rating Scale (UPDRS) motor score, and olfactory function with Sniffin' Sticks. From the 1,603 subjects included in the analysis, 16.2% were SN+, 23.0% scored above zero in the UPDRS motor section, and 28.0% were hyposmic as defined by less than 75% correctly classified Sniffin' Sticks. SN+ was associated with a UPDRS motor score above zero (OR 1.45, 95% CI 1.08-1.96) and with a lower odor identification capability (OR 1.48, 95% CI 1.12-1.96). The combination of these two features (OR 1.98, 95% CI 1.25-3.15) and UPDRS motor scores >or=3 lead to higher OR. It is concluded that SN+, impaired motor performance, and hyposmia are frequently observed in the elderly and in isolation are unspecific and of limited use to predict a subject's risk for PD. Whether the association of SN+ with both impaired motor performance and hyposmia as seen in this study predicts an increased risk for the development of PD needs to be evaluated in the follow-up investigations.


Independent brain 18F-FDG PET attenuation correction using a deep learning approach with Generative Adversarial Networks.
Attenuation correction (AC) of positron emission tomography (PET) data poses a challenge when no transmission data or computed tomography (CT) data are available, e.g. in stand alone PET scanners or PET/magnetic resonance imaging (MRI). In these cases, external imaging data or morphological imaging data are normally used for the generation of attenuation maps. Newly introduced machine learning methods however may allow for direct estimation of attenuation maps from non attenuation-corrected PET data (PETNAC). Our purpose was thus to establish and evaluate a method for independent AC of brain fluorine-18-fluorodeoxyglucose (18F-FDG) PET images only based on PETNAC using Generative Adversarial Networks (GAN). After training of the deep learning GAN framework on a paired training dataset of PETNAC and the corresponding CT images of the head from 50 patients, pseudo-CT images were generated from PETNAC of 40 validation patients, of which 20 were used for technical validation and 20 stemming from patients with CNS disorders were used for clinical validation. Pseudo-CT was used for subsequent AC of these validation data sets resulting in independently attenuation-corrected PET data. Visual inspection revealed a high degree of resemblance of generated pseudo-CT images compared to the acquired CT images in all validation data sets, with minor differences in individual anatomical details. Quantitative analyses revealed minimal underestimation below 5% of standardized uptake value (SUV) in all brain regions in independently attenuation-corrected PET data compared to the reference PET images. Color-coded error maps showed no regional bias and only minimal average errors around ±0%. Using independently attenuation-corrected PET data, no differences in image-based diagnoses were observed in 20 patients with neurological disorders compared to the reference PET images. Independent AC of brain 18F-FDG PET is feasible with high accuracy using the proposed, easy to implement deep learning framework. Further evaluation in clinical cohorts will be necessary to assess the clinical performance of this method.


Coarse-Grained Density Functional Theory Predictions via Deep Kernel Learning.
Scalable electronic predictions are critical for soft materials design. Recently, the Electronic Coarse-Graining (ECG) method was introduced to renormalize all-atom quantum chemical (QC) predictions to coarse-grained (CG) resolutions using deep neural networks (DNNs). While DNNs can learn complex representations that prove challenging for kernel-based methods, they are susceptible to overfitting and the overconfidence of uncertainty estimations. Here, we develop ECG within a GPU-accelerated Deep Kernel Learning (DKL) framework to enable CG QC predictions using range-separated hybrid density functional theory (DFT), obtaining a 107 speedup relative to naive all-atom QC. By treating the predicted electronic properties as random Gaussian Processes, DKL incorporates CG mapping degeneracy by learning the distribution of electronic energies as a function of CG configuration. DKL-ECG accurately reproduces molecular orbital energies from range-separated DFT while facilitating efficient training via active learning using the uncertainties provided by DKL. We show that while active learning algorithms enable efficient sampling of a more diverse configurational space relative to random sampling, all explored query methods exhibit comparable performance for the examined system. We attribute this result to the significant overlap of the feature space and output property distributions across multiple temperatures.


Modification of motivated behavior elicited by electrical stimulation of the hypothalamus.
Previous reports demonstrated that hypothalamic stimulation may elicit either eating, drinking, or gnawing and emphasized both the specificity of the neural circuits mediating these behaviors and the similarity to behavior during natural-drive states such as hunger and thirst. We find that, after a period of very consistent elicitation of one of these behaviors, the animal may exhibit an equally consistent alternate behavior. A learning component is implicated in the association of hypothalamic stimulation with a particular behavior pattern.


Remarkable structural effects on the complexation of actinides with H-phosphonates: a combined experimental and quantum chemical study.
The structural effects of the carbon chain on the extraction of actinides by organo-phosphorus extractants have been examined experimentally and by computation. Branched butyl H-phosphonates and their linear chain isomer, n-butyl H-phosphonate (DBHP), were synthesised and characterised using IR, NMR and GC-MS techniques. Their physical properties viz. viscosity, density and aqueous solubility have been examined. DBHP, Di-iso-butyl H phosphonate (DiBHP) and Di-sec-butyl H phosphonate (DsBHP) were employed for the extraction of uranium and americium ions from nitric acid. 233U (α-tracer) and 241Am (γ-tracer) were employed as representative isotopes for the extraction of U and Am, respectively, and their distribution ratios (D) were obtained as a function of nitric acid concentration (0.01-8 M). Branching of the alkyl chain at the secondary carbon atom showed unexpected neutral extractant behaviour for DsBHP which is generally classified as an acidic extractant. The acid-dependent dual extraction mechanisms for the H-phosphonates have been examined both experimentally and through quantum chemical calculations. This dramatic effect can be partly attributed to the hindrance in the formation of the enol tautomer through the strengthening of the P[double bond, length as m-dash]OH hydrogen bonding in the DsBHP extractant. Density functional theory (DFT) based calculations were carried out to understand the complexation behaviour of actinides with the two extractants. Possible structures and binding affinities of actinides with H-phosphonates have been deduced from electronic structure calculations. Finally, the trends in distribution ratios were additionally explored and correlated with experimental observations for both metal ions.


Chemotaxis in Escherichia coli: construction and properties of lambda tsr transducing phage.
The tsr gene of Escherichia coli, located at approximately 99 min on the chromosomal map, encodes a methyl-accepting protein that serves as the chemoreceptor and signal transducer for chemotactic responses to serine and several repellents. To determine whether any other chemotaxis or motility genes were located in the tsr region, we constructed and characterized two lambda tsr transducing phages that each contain about 12 kilobases of chromosomal material adjacent to tsr. lambda tsr70 carries sequences from the promoter-proximal side of tsr; lambda tsr72 carries sequences from the promoter-distal side of tsr. Restriction maps of the bacterial inserts in these phages and Southern hybridization analyses of the bacterial chromosome indicated that the tsr gene is transcribed in the counterclockwise direction on the genetic map. Insert deletions were isolated in lambda tsr70 and transferred into the host chromosome to examine the null phenotype of tsr. All such strains exhibited wild-type swimming patterns and chemotactic responses to a variety of stimuli, but were specifically defective in serine taxis and other Tsr-mediated responses. In addition, UV programming experiments demonstrated that Tsr and several of its presumptive degradation products were the only bacterial proteins encoded by lambda tsr70 and lambda tsr72 that required host FlbB/FlaI function for expression. These findings indicate that there are probably no other chemotaxis-related genes in the tsr region. A series of tsr point mutations were isolated by propagating lambda tsr70 on a mutD host and used to construct a fine-structure map of the tsr locus. These mutations should prove valuable in exploring structure-function relationships in the Tsr transducer.


A double-blinded, placebo-controlled, randomized trial of the neuropsychologic efficacy of cranberry juice in a sample of cognitively intact older adults: pilot study findings.
The aim of this research was to conduct the first known clinical trial of the short-term (i.e., 6 weeks) efficacy of cranberry juice on the neuropsychologic functioning of cognitively intact older adults. Fifty (50) community-dwelling, cognitively intact volunteers, > or = 60 years old, who reported no history of dementia or significant neurocognitive impairments, participated in this study. A 6-week, double-blind, placebo-controlled, randomized, parallel-group, clinical trial was utilized. Participants were randomly assigned to receive either 32 ounces/day of a beverage containing 27% cranberry juice per volume (n = 25) or placebo (n = 25) for 6 weeks, and administered a series of neuropsychologic tests at both pretreatment baseline and again after 6 weeks of either cranberry juice or placebo treatment to assess treatment-related changes. Efficacy measures consisted of participants' raw scores on the following standardized neuropsychologic tests: Selective Reminding Test, Wechsler Memory Scale-III Faces I and Faces II subtests, Trail Making Test (Parts A and B), Stroop Color and Word Test, and the Wechsler Adult Intelligence Scale- III Digit Symbol-Coding subtest. A subjective Follow-up Self-report Questionnaire was also administered to participants at the conclusion of the end-of-treatment phase assessments. Two-factor, mixed analyses of variance (ANOVA) revealed no significant group (cranberry juice and placebo) by trial (pretreatment baseline and end-of-treatment assessments) interactions across all of the neuropsychologic tests and measures utilized in this study when a Bonferroni corrected alpha level was used to correct for multiple comparisons (i.e., .05/17 group by trial comparisons = .003). Pearson Chi-Square analyses of the groups' self-reported changes over the 6-week treatment phase in their abilities to remember, thinking processes, moods, energy levels, and overall health on the Follow-up Self-report Questionnaire revealed no significant relationships. However, a nonsignificant trend (X2(1) = 2.373, p = 0.123) was noted for participants' self-reported overall abilities to remember from pretreatment baseline to the end-of-treatment assessment. Specifically, more than twice as many participants in the cranberry group (n = 9, 37.5%) rated their overall abilities to remember by treatment end as "improved" as compared to placebo controls (n = 4, 17.4%). Taken together, no significant interactions were found between the cranberry and placebo groups and their pretreatment baseline and end-of-treatment phase (after 6 weeks) standardized neuropsychologic assessments. A nonsignificant trend was noted, however, on a subjective, self-report questionnaire where twice as many participants in the cranberry group rated their overall abilities to remember by treatment end as "improved" compared to placebo controls.


State-specific influenza vaccination coverage among adults--United States, 2006-07 influenza season.
Adult groups included in the 2008 Advisory Committee on Immunization Practices (ACIP) recommendation for annual influenza vaccination include all persons aged >/=50 years, women who will be pregnant during the influenza season, persons aged 18-49 years with high-risk conditions, and other persons at increased risk for complications from influenza. Health-care personnel and household contacts and caregivers of persons at high risk also should receive annual influenza vaccination, as should adults who want to reduce their risk for becoming ill with influenza or for transmitting it to others. Healthy People 2010 influenza vaccination coverage targets are 90% among all persons aged >/=65 years and 60% among persons aged 18-64 years who have one or more high-risk conditions. Data from the 2006 and 2007 Behavioral Risk Factor Surveillance System (BRFSS) surveys indicate that influenza vaccination coverage among adults for the 2006-07 season increased significantly compared with the 2005-06 season, reaching 35.1% among persons aged 18-49 years with high-risk conditions, 42.0% among all persons aged 50-64 years, and 72.1% among all persons aged >/=65 years. However, vaccination coverage remained well below Healthy People 2010 targets. Increasing influenza vaccination coverage among adults in the United States will require more cooperation among health-care providers, professional organizations, vaccine manufacturers, and public health departments to raise public awareness about influenza vaccination and to ensure continued distribution and administration of available vaccine throughout the vaccination season.


Reduced susceptibility to interference in the consolidation of motor memory before adolescence.
Are children superior to adults in consolidating procedural memory? This notion has been tied to "critical," early life periods of increased brain plasticity. Here, using a motor sequence learning task, we show, in experiment 1, that a) the rate of learning during a training session, b) the gains accrued, without additional practice, within a 24 hours post-training interval (delayed consolidation gains), and c) the long-term retention of these gains, were as effective in 9, 12 and 17-year-olds and comparable to those reported for adults. However, a follow-up experiment showed that the establishment of a memory trace for the trained sequence of movements was significantly more susceptible to interference by a subsequent motor learning experience (practicing a reversed movement sequence) in the 17-year-olds compared to the 9 and 12-year-olds. Unlike the 17-year-olds, the younger age-groups showed significant delayed gains even after interference training. Altogether, our results indicate the existence of an effective consolidation phase in motor learning both before and after adolescence, with no childhood advantage in the learning or retention of a motor skill. However, the ability to co-consolidate different, successive motor experiences, demonstrated in both the 9 and 12-year-olds, diminishes after puberty, suggesting that a more selective memory consolidation process takes over from the childhood one. Only the adult consolidation process is gated by a recency effect, and in situations of multiple, clashing, experiences occurring within a short time-interval, adults may less effectively establish in memory experiences superseded by newer ones.


The time-resolved hard X-ray diffraction endstation KMC-3 XPP at BESSY II.
The time-resolved hard X-ray diffraction endstation KMC-3 XPP for optical pump/X-ray probe experiments at the electron storage ring BESSY II is dedicated to investigating the structural response of thin film samples and heterostructures after their excitation with ultrashort laser pulses and/or electric field pulses. It enables experiments with access to symmetric and asymmetric Bragg reflections via a four-circle diffractometer and it is possible to keep the sample in high vacuum and vary the sample temperature between ∼15 K and 350 K. The femtosecond laser system permanently installed at the beamline allows for optical excitation of the sample at 1028 nm. A non-linear optical setup enables the sample excitation also at 514 nm and 343 nm. A time-resolution of 17 ps is achieved with the `low-α' operation mode of the storage ring and an electronic variation of the delay between optical pump and hard X-ray probe pulse conveniently accesses picosecond to microsecond timescales. Direct time-resolved detection of the diffracted hard X-ray synchrotron pulses use a gated area pixel detector or a fast point detector in single photon counting mode. The range of experiments that are reliably conducted at the endstation and that detect structural dynamics of samples excited by laser pulses or electric fields are presented.


Chronic ingestion of polystyrene microparticles in low doses has no effect on food consumption and growth to the intertidal amphipod Echinogammarus marinus?
The ingestion of microplastics (plastic particles <5 mm) has been observed in a range of marine organisms, and adverse effects have been reported in several species after high concentration exposure. However, the long-term effects of low-dose ingestion remains unclear. The aim of this study was thus to assess the chronic effects of low concentrations of polystyrene microparticles to the intertidal amphipod Echinogammarus marinus, using food consumption, growth, and moulting as endpoints. Amphipods were fed a gelatinous algal feed spiked with microbeads (8 μm) in concentrations of ∼0.9, 9 and 99 microplastics/g for 35 days. E. marinus was also analysed for retention of microplastics, and egestion rate was calculated in a separate high-dose feeding experiment. No significant effects were found in the food consumption or growth assays. There was no accumulation of microplastics in the gut, with only one microbead recorded internally in three (8%) of the exposed amphipods. The low number is likely linked to gastrointestinal functions, allowing for easy egestion of indigestible items. This assumption was supported by the observation that after high-dose exposure, 60% of E. marinus egested all microbeads within 24 h. This study suggests that ingesting low concentrations of 8 μm microplastics do not impair the feeding or growth of amphipods along the exposure period. We hope that negative results such as these may further assist in assessing the impact posed by microplastics to marine organisms.


Identification of AHNAK expression associated with the pathogenesis of chronic obstructive pulmonary disease by bioinformatic analysis.
Chronic obstructive pulmonary disease (COPD) was a risk factor for lung cancer tumorigenesis. This study aimed to discover novel diagnostic biomarkers for COPD patients and determine their underlying pathogenetic mechanisms. Differentially expressed genes (DEGs) in COPD samples and normal controls were analyzed and utilized to construct a network associated with a high risk for COPD occurrence. Enrichment analysis was applied on the strength of Gene Ontology (GO) annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The RT-qPCR analysis was performed to determine 10 hub genes in COPD. ELISA assay was utilized to measure IL-1β, IL-6, and IL-10 levels. Spearman's correlation analysis was conducted to detect the correlation between inflammatory cytokines and AHNAK expression. Cell proliferation and apoptosis were evaluated by CCK-8 and flow cytometry assays. AHNAK was significantly increased in COPD serum samples compared with non-COPD smokers and strongly correlated with inflammation. AHNAK level could also discriminate COPD from non-COPD with high accuracy. AHNAK may be a feasible biomarker playing crucial functions in the diagnosis and progression of COPD.


Effect of replacing conventional soybean meal with low-oligosaccharide soybean meal on growth performance and carcass characteristics of wean-to-finish pigs1.
A trial was conducted to determine the effect of replacing conventional soybean meal (CSBM) with low-oligosaccharide soybean meal (LOSBM) on growth performance and carcass characteristics of wean-to-finish pigs. A total of 432 crossbred pigs (19 d and 6.6 ± 1.2 kg BW) were blocked by sex and BW and assigned to 1 of 6 dietary treatments: 1) CSBM in all phases and fishmeal and spray-dried plasma protein (FM/SDPP) in phases 1 to 3, 2) CSBM in all phases but with no FM/SDPP, 3) LOSBM and FM/SDPP in phases 1 to 3 and CSBM in phases 4 to 6, 4) LOSBM in phases 1 to 3 and CSBM in phases 4 to 6, 5) LOSBM in phases 1 to 6 and FM/SDPP in phases 1 to 3, and 6) LOSBM in phases 1 to 6. The results showed that pig growth performance (ADG, ADFI, and G:F) during the overall period (phases 1 to 6) and carcass traits (HCW, dressing percentage, fat depth, loin depth, and lean percentage) were not affected ( > 0.05) by dietary treatments. Moreover, replacing CSBM with LOSBM in phases 1 to 3 did not affect early phase growth performance in the absence of FM/SDPP but reduced ( ≤ 0.05) ADFI and increased ( < 0.05) G:F during the nursery period (phases 1 and 2) in the presence of FM/SDPP. In phase 2, LOSBM increased ( < 0.05) blood urea nitrogen in comparison with CSBM. In conclusion, reduction of oligosaccharide by replacing CSBM with LOSBM in the early, late, or entire phase of the wean-to-finish period did not improve growth performance and carcass characteristics of pigs.


Characterization of Biodiesel and Diesel Combustion Particles: Chemical Composition, Lipid Metabolism, and Implications for Health and Environment.
Biodiesel, derived from alkyl esters of vegetable oils or animal fats, has gained prominence as a greener alternative to diesel due to its reduced particle mass. However, it remains debatable whether biodiesel exposure has more severe health issues than diesel. This study performed high-resolution mass spectrometry to examine the detailed particle chemical compositions and lipidomics analysis of human lung epithelial cells treated with emissions from biodiesel and diesel fuels. Results show the presence of the peak substances of CHO compounds in biodiesel combustion that contain a phthalate ester (PAEs) structure (e.g., n-amyl isoamyl phthalate and diisobutyl phthalate). PAEs have emerged as persistent organic pollutants across various environmental media and are known to possess endocrine-disrupting properties in the environment. We further observed that biodiesel prevents triglyceride storage compared to diesel and inhibits triglycerides from becoming phospholipids, particularly with increased phosphatidylglycerols (PGs) and phosphatidylethanolamines (PEs), which potentially could lead to a higher probability of cancer metastasis.


Direct Interaction between the Two Z Ring Membrane Anchors FtsA and ZipA.
The initiation of Escherichia coli cell division requires three proteins, FtsZ, FtsA, and ZipA, which assemble in a dynamic ring-like structure at midcell. Along with the transmembrane protein ZipA, the actin-like FtsA helps to tether treadmilling polymers of tubulin-like FtsZ to the membrane. In addition to forming homo-oligomers, FtsA and ZipA interact directly with the C-terminal conserved domain of FtsZ. Gain-of-function mutants of FtsA are deficient in forming oligomers and can bypass the need for ZipA, suggesting that ZipA may normally function to disrupt FtsA oligomers, although no direct interaction between FtsA and ZipA has been reported. Here, we use in vivo cross-linking to show that FtsA and ZipA indeed interact directly. We identify the exposed surface of FtsA helix 7, which also participates in binding to ATP through its internal surface, as a key interface needed for the interaction with ZipA. This interaction suggests that FtsZ's membrane tethers may regulate each other's activities.IMPORTANCE To divide, most bacteria first construct a protein machine at the plane of division and then recruit the machinery that will synthesize the division septum. In Escherichia coli, this first stage involves the assembly of FtsZ polymers at midcell, which directly bind to membrane-associated proteins FtsA and ZipA to form a discontinuous ring structure. Although FtsZ directly binds both FtsA and ZipA, it is unclear why FtsZ requires two separate membrane tethers. Here, we uncover a new direct interaction between the tethers, which involves a helix within FtsA that is adjacent to its ATP binding pocket. Our findings imply that in addition to their known roles as FtsZ membrane anchors, FtsA and ZipA may regulate each other's structure and function.


Protective effect of Triphala on cold stress-induced behavioral and biochemical abnormalities in rats.
Stress is one of the basic factors in the etiology of number of diseases. Cold-stress occurs when the surrounding temperature drops below 18 degrees C, the body may not be able to warm itself, and hence serious cold-related illnesses, permanent tissue damage and death may results. The present study was aimed to investigate the effect of Triphala (Terminalia chebula, Terminalia belerica and Emblica officinalis) against the cold stress-induced alterations in the behavioral and biochemical abnormalities in four different groups (saline control, Triphala, cold-stress and Triphala with cold-stress) of Wistar strain albino rats. In this study cold-stress (8 degrees C for 16 h/d/15 days) was applied and the oxidative stress was assessed by measuring the extent of lipid peroxidation (LPO) and the changes in corticosterone levels. Upon exposure to the cold-stress, a significant (P<0.05) increase in immobilization with decrease in rearing, grooming, and ambulation behavior was seen in open field. Following cold-exposure, significant increase in the LPO and corticosterone levels was observed. Oral administration of Triphala (1 g/kg/animal body weight) for 48 days significantly prevented these cold stress-induced behavioral and biochemical abnormalities in albino rats. The results of this study suggest that Triphala supplementation can be regarded as a protective drug against stress.


Reduced vision-related quality of life in people living with dystonia.
Purpose: Dystonia is a neurological movement disorder with negative impact on function and quality of life. It is currently unclear whether vision-related quality of life is affected. The aim of this study was to determine whether vision-related quality of life is reduced by dystonia.Materials and methods: A vision-related quality of life questionnaire was delivered online to probe visual function in people living with dystonia. Scores for each of six domains were compared to normative data of 819 healthy participants using one sample t-tests. Respondents were divided into two groups based on whether they had botulinum toxin injections and compared using independent samples t-tests.Results: There were 42 completed responses. There was a difference from norm for two domains; ocular symptoms (t(41) = 2.31, p = 0.026) and role performance (t(41) = 2.85, p = 0.007). There was variation in responses for all six domains. No difference in scores for the botulinum toxin injection group was found for either domain (both p > 0.74).Conclusions: Some people with dystonia experience reduced vision-related quality of life, which has potential to contribute to their disability. Health professionals should be aware of vision-related issues when managing people with dystonia and consider appropriate rehabilitative interventions to reduce disability and enhance quality of life.Implications for rehabilitationDystonia is a neurological movement disorder resulting in abnormal postures and movements.Vision-related quality of life is reduced by dystonia which may contribute to disability and reduced function.Strategies to improve vision-related quality of life should be included in rehabilitation programmes for people living with dystonia.


Primary petrous bone Ewing's sarcoma.
A case of primary Ewing's sarcoma involving a large portion of the petrous temporal bone in an eighteen month old child is reported. The lesion was treated by radical surgery and adjuvant chemotherapy and radiotherapy. An extremely rare age of presentation, an unusual location and an excellent response to treatment are the highlights of this case.


Factors influencing calving difficulty in beef heifers.
Records of 547, 2-yr-old heifers of three breed groups were used to evaluate the relative influence of dam's body and pelvic measurements, calf birth weight, sire birth weight and some relative measures (ratios) of calf birth weight and dam weight at calving on calving difficulty. The data were analyzed by regression and least squares procedures. The full model explained 32.5% of the variation in calving difficulty score. The linear effect of calf birth weight was the most important variable, accounting for 17.8% reduction in the coefficient of determination, and together with dam weight at calving and the quadratic effect of calf birth weight it accounted for 92% for all the variation explained by the full model. Dam weight at calving was negatively related to calving difficulty. Breed, year and sex of calf did not influence calving difficulty score, except when the calf birth weight or dam weight or both were excluded from the model. When calf birth weight was expressed as a ratio of the dam's weight at calving, hip height and pelvic measurements, the total model explained 34.8% of the variation in calving difficulty score. The ratio of calf birth weight to dam weight was the most important variable (R2 = 26.8%). Ratios of calf to dam weight at calving and calf weight to the vertical pelvic diameter (R2 = 29.3%) were the only significant factors when the effects of calf birth weight and dam weight were removed from the model. Pelvic measurements, on their own, did not influence calving difficulty score in this study (P greater than .1), but small pelvic dimensions tended to be associated with higher calving difficulty scores.


Primary low-grade extrauterine endometrial stromal sarcoma: analysis of 10 cases with a review of the literature.
This study aimed to analyze the clinical and pathological features of extrauterine endometrial stromal sarcoma (EESS) and explore an effective therapeutic regimen to reduce the recurrence rate in low-grade EESS patients. Ten LG-EESS patients who were treated at the Chinese Academy of Medical Sciences Cancer Institute and Hospital from June 1999 to June 2019 were collected and analyzed. (1) Patient demographics are summarized in manuscript. Preoperative CA125 examination showed that 8 patients had a median level of 49.5 U/L (15.4-168.0 U/L). (2) All ten patients underwent tumor cytoreductive surgery. Five patients underwent optimal tumor resection and achieved an R0 resection. After the initial surgery, 7 patients who had multiple metastasis were treated with adjuvant chemotherapy, 2 patients with vaginal ESS were treated with chemotherapy and radiation therapy, and 6 patients with ER/PR positive received hormone therapy with or without chemotherapy. (2) Most EESS patients had multiple tumors. The omentum was the most commonly affected site, followed by the ovaries. (3) The median follow-up was 94 (range: 27-228) months, and recurrence was observed in 3 patients (n = 10, 30%) who underwent non-optimal surgery and no hormone therapy. The 5-year and 10-year DFS rates were both 70%, as shown in Fig. 2. OS was both 100% at 5 and 10 years. As a conclusion, EESS is a rare disease and LG-EESS has a good prognosis. Surgery remains the available treatment for patients. LG-EESS has a risk of late recurrence which requires a long-term follow-up. With a limited sample size, our study shows optimal tumor reductive surgery and adjuvant hormone therapy may significantly reduce the risk of recurrence.


Defective female reproductive function in 1,25(OH)2D-deficient mice results from indirect effect mediated by extracellular calcium and/or phosphorus.
We used mice with targeted deletion of 25-hydroxyvitamin D 1α-hydroxylase [1α(OH)ase(-/-)] to investigate the effects of calcium and phosphorus on defects in the reproductive system of 1,25-dihydroxyvitamin D [1,25(OH)(2)D]-deficient female mice. The 1α(OH)ase(-/-) mice and their wild-type littermates were fed either a normal diet or a rescue diet (high calcium, phosphate, and lactose) starting from weaning until 3 mo of age. We then determined serum calcium and phosphorus levels, assessed gonadotropin and gonadal hormone production, and evaluated folliculogenesis, corpus luteum formation, ovarian angiogenesis, uterus development, and fertility. Results showed that hypocalcemic and hypophosphatemic female 1α(OH)ase(-/-) mice developed infertility accompanied by decreased estrogen and progestogen levels, elevated follicle-stimulating hormone and luteinizing hormone levels, defects in follicular development and corpus luteum formation, uterine hypoplasia, and decreased ovarian expression of angiogenic factors including vascular endothelial growth factor (VEGF), angiopoietin-1 and -2, and Tie-2. When serum calcium and phosphorus were normalized by the rescue diet, the defective reproductive phenotype in the female 1α(OH)ase(-/-) mice, including the dysfunction in the hypothalamic-pituitary-ovarian axis, and ovarian angiogenesis were reversed. These results indicate that the infertility seen in 1,25(OH)(2)D-deficient mice is not a direct effect of active vitamin D deficiency on the reproductive system but is an indirect effect mediated by extracellular calcium and phosphorus.


Cross-sectional imaging of metal-on-metal hip arthroplasties. Can we substitute MARS MRI with CT?
Metal artifact reduction sequence (MARS) MRI is widely advocated for surveillance of metal-on-metal hip arthroplasties (MOM-HAs). However, its use is limited by susceptibility artifact at the prosthesis-bone interface, local availability, patient compliance, and cost (Hayter et al. 2011a). We wanted to determine whether CT is a suitable substitute for MARS MRI in evaluation of the painful MOM-HA. 50 MOM-HA patients (30 female) with unexplained painful prostheses underwent MARS MRI and CT imaging. 2 observers who were blind regarding the clinical data objectively reported the following outcomes: soft tissue lesions (pseudotumors), muscle atrophy, and acetabular and femoral osteolysis. Diagnostic test characteristics were calculated. Pseudotumor was diagnosed in 25 of 50 hips by MARS MRI and in 11 of 50 by CT. Pseudotumors were classified as type 1 (n=2), type 2A (n=17), type 2B (n=4), and type 3 (n=2) by MARS MRI. CT did not permit pseudotumor classification. The sensitivity of CT for diagnosis of pseudotumor was 44% (95% CI: 25-65). CT had "slight" agreement with MARS MRI for quantification of muscle atrophy (κ=0.23, CI: 0.16-0.29; p<0.01). Osteolysis was identified in 15 of 50 patients by CT. 4 of these lesions were identified by MARS MRI. CT was found to be superior to MRI for detection of osteolysis adjacent to MOM-HA, and should be incorporated into diagnostic algorithms. CT was unable to classify and failed to detect many pseudotumors, and it was unreliable for assessment of muscle atrophy. Where MARS MRI is contraindicated or unavailable, CT would be an unsuitable substitute and other modalities such as ultrasound should be considered.


[Light-guide instruments for low-intensity laser therapy in ORL practice].
Manipulators with monofibre light-guides have been specially designed for otorhinolaryngologic instruments commonly used in routine drug therapy for intracavital treatments. Quartz enclosed in a protective polyethylene sheath is used as the monofibre light-guide with a light conductor 400 microns in diameter and 2 to 3 m in length. It can be built in the following instruments: an ear catheter, a maxillary sinus lavage cannula, a subclavian artery catheter, and a laryngeal bougie. The use of monofibres allows considerable widening the application field of the low power laser therapy in otorhinolaryngologic practice. Moreover, in compliance with human engineering requirements it managed to preserve most standard manipulations otolaryngologist makes use in the course of routine clinical practice with conventional instruments.


Novel association of HLA-haplotypes with primary sclerosing cholangitis (PSC) in a southern European population.
In patients with with primary sclerosing cholangitis we investigated the major histocompatibility complex (MHC) genes and mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In 64 PSC patients and 183 normal controls of the same population (Northern Italy), allelic polymorphisms at the DNA level were investigated in MHC region genes: HLA-DRB1, HLA-DQB1 and HLA-B, tumour necrosis factor A (TNFA), and in CFTR gene, with polymerase chain reaction-based methodologies. Frequencies of DRB1*01, DQA1*0101, DQB1*0102 (14 vs. 8%, p<0.05), DRB1*16, DQA1*0102, DQB1*0502 (8 vs. 3%, p<0.025) and DRB1*04, DQA1*03, DQB1*0301 (10 vs. 4%, p<0.005) haplotypes were more elevated in PSC patients. The frequency of patients positive for HLA DRB1*01, *1601 or *04 related haplotypes was significantly increased (32 vs. 14%, p<0.00025). DRB1*07, DQA1*0201, DQB1*02 haplotype frequency was significantly decreased (4 vs. 15%, p<0.001). After removing HLA-DRB1*01, *1601, *04 related haplotype sharing patients, HLA-DRB1*03, DQA1*0501, DQB1*02 haplotype frequency was significantly increased (32 vs. 14%, p<0.01). TNFA2 allele frequency was significantly increased in PSC patients (23 vs. 14%, p<0.025), as well as the TNFA2 homozygous genotype (9 vs. 0.5%, p=0.0013). No mutations were found on the CFTR gene and the allelic frequency of the 5T polymorphism in intron 8 was not increased. These data suggest that the role of genes in the HLA region is relevant, but not necessarily disease-specific and it might be different in populations with divergent ancestries.


Wnt transmembrane signaling and long-term spatial memory.
Transmembrane signaling mechanisms are critical for regulating the plasticity of neuronal connections underlying the establishment of long-lasting memory (e.g., Linden and Routtenberg (1989) Brain Res Rev 14:279-296; Sossin (1996) Trends Neurosci 19:215-218; Mayr and Montminy (2001) Nat Rev Mol Cell Biol 2:599-609; Chen et al. (2011) Nature 469:491-497). One signaling mechanism that has received surprisingly little attention in this regard is the well-known Wnt transmembrane signaling pathway even though this pathway in the adult plays a significant role, for example, in postsynaptic dendritic spine morphogenesis and presynaptic terminal neurotransmitter release (Inestrosa and Arenas (2010) Nat Rev Neurosci 11:77-86). The present report now provides the first evidence of Wnt signaling in spatial information storage processes. Importantly, this Wnt participation is specific and selective. Thus, spatial, but not cued, learning in a water maze selectively elevates the levels in hippocampus of Wnt 7 and Wnt 5a, but not the Wnt 3 isoform, indicating behavioral selectivity and isoform specificity. Wnt 7 elevation is subfield-specific: granule cells show an increase with no detectable change in CA3 neurons. Wnt 7 elevation is temporally specific: increased Wnt signaling is not observed during training, but is seen 7 days and, unexpectedly, 30 days later. If the Wnt elevation after learning is activity-dependent, then it may be possible to model this effect in primary hippocampal neurons in culture. Here, we evaluate the consequence of potassium or glutamate depolarization on Wnt signaling. This represents, to our knowledge, the first demonstration of an activation-dependent elevation of Wnt levels and surprisingly an increased number of Wnt-stained puncta in neurites suggestive of trafficking from the cell body to neuronal processes, probably dendrites. It is proposed that Wnt signaling pathways regulate long-term information storage in a behavioral-, cellular-, and isoform-specific manner.


Rescue of a foreign gene by Sendai virus.
A simple protocol for the rescue of a synthetic genome into a paramyxovirus has been developed. First, a synthetic Sendai virus-like RNA, containing the antisense coding region of the chloramphenicol acetyltransferase gene replacing the coding region of the Sendai virus genome, was transcribed from a cDNA. When introduced into cells that are infected with Sendai virus, this RNA construct was transcribed, replicated, and packaged into infectious virions. The addition of infected cell extract to the RNA prior to transfection markedly enhanced levels of chloramphenicol acetyltransferase expression and rescue. However, this enhancement is not due to encapsidation of the RNA into nucleocapsids as the RNA remains nuclease-sensitive. Uninfected cell extract also enhances expression and rescue efficiency, implying involvement of a cellular factor(s) with the synthetic viral-like RNA construct that allows for enhanced polymerase recognition. This system should allow for the dissection of the various cis-acting RNA signals within the paramyxovirus genome.


Operational characteristics of a prototype x-ray needle device.
A prototype x-ray needle, which emits 62.5 kVp x-rays at the tip of a 20 cm long, 4 mm diameter steel needle, has been developed by Titan Pulse Sciences Incorporated (PSI) (Albuquerque, NM) and was tested for its suitability in brachytherapy applications in comparison with a similar device by the Photoelectron Corporation. The depth dose profiles were also compared with those of two common brachytherapy sources (125I and 192Ir). The depth dose characteristics of the radiation were comparable with the two brachytherapy sources with a slightly reduced attenuation gradient. The dose rate from the x-ray needle tip was relatively isotropic at the needle tip and was continuously adjustable over the range of 0 cGy min(-1) to upwards of 62 cGy min(-1) at a reference distance of 1 cm in air. We detected a significant proportion of x-rays generated along the needle shaft, and not at the needle tip, as intended. The energy spectrum emitted from this device had a peak intensity at 21 keV and an average energy of 28 keV. The beam was attenuated in both aluminium (the first half-value layer being less than 0.1 mm) and in water (50% dose at approximately 2 mm). These studies confirm that although there is potential for a system similar to this one for clinical applications, the simplistic electron guidance used in this particular prototype device limits it to research applications. Further optimization is required in focusing and steering the electron beam to the target, improving x-ray production efficiency and using x-ray target cooling to achieve higher dose rates.


Brain SIRT1: anatomical distribution and regulation by energy availability.
SIRT1 is a nicotinamide adenosine dinucleotide-dependent deacetylase that orchestrates key metabolic adaptations to nutrient deprivation in peripheral tissues. SIRT1 is induced also in the brain by reduced energy intake. However, very little is known about SIRT1 distribution and the biochemical phenotypes of SIRT1-expressing cells in the neuraxis. Unknown are also the brain sites in which SIRT1 is regulated by energy availability and whether these regulations are altered in a genetic model of obesity. To address these issues, we performed in situ hybridization histochemistry analyses and found that Sirt1 mRNA is highly expressed in metabolically relevant sites. These include, but are not limited to, the hypothalamic arcuate, ventromedial, dorsomedial, and paraventricular nuclei and the area postrema and the nucleus of the solitary tract in the hindbrain. Of note, our single-cell reverse transcription-PCR analyses revealed that Sirt1 mRNA is expressed in pro-opiomelanocortin neurons that are critical for normal body weight and glucose homeostasis. We also found that SIRT1 protein levels are restrictedly increased in the hypothalamus in the fasted brain. Of note, we found that this hypothalamic-specific, fasting-induced SIRT1 regulation is altered in leptin-deficient, obese mice. Collectively, our findings establish the distribution of Sirt1 mRNA throughout the neuraxis and suggest a previously unrecognized role of brain SIRT1 in regulating energy homeostasis.


STED nanoscopy reveals the ubiquity of subcortical cytoskeleton periodicity in living neurons.
In the axons of cultured hippocampal neurons, actin forms various structures, including bundles, patches (involved in the preservation of neuronal polarity), and a recently reported periodic ring-like structure. Nevertheless, the overlaying organization of actin in neurons and in the axon initial segment (AIS) is still unclear, due mainly to a lack of adequate imaging methods. By harnessing live-cell stimulated emission depletion (STED) nanoscopy and the fluorescent probe SiR-Actin, we show that the periodic subcortical actin structure is in fact present in both axons and dendrites. The periodic cytoskeleton organization is also found in the peripheral nervous system, specifically at the nodes of Ranvier. The actin patches in the AIS co-localize with pre-synaptic markers. Cytosolic actin organization strongly depends on the developmental stage and subcellular localization. Altogether, the results of this study reveal unique neuronal cytoskeletal features.


Treatment of cardiac arrhythmias with phenytoin.
Phenytoin was given intravenously in 37 patients with cardiac arrhythmias-21 had acute myocardial infarction and 16 had other conditions. There was a favourable response in 18 of the 21 cases with acute myocardial infarction, with a return to sinus rhythm in six of the nine cases with supraventricular arrhythmias, and a return to sinus rhythm in 10 of the 12 cases of ventricular arrhythmias, the remaining two showing a significant reduction in the number of ventricular extra-systoles.In the second group of 16 cases which had various causes there was a satisfactory response in only six. Digitalis played no part in producing any of the arrhythmias. Phenytoin was used orally for suppressing and preventing abnormal rhythm in five patients, and three of these responded favourably. The number of patients treated orally is too small to draw any definite conclusion.


Universal Lesion Detection Utilising Cascading R-CNNs and a Novel Video Pretraining Method.
According to the WHO, approximately one in six individuals worldwide will develop some form of cancer in their lifetime. Therefore, accurate and early detection of lesions is crucial for improving the probability of successful treatment, reducing the need for more invasive treatments, and leading to higher rates of survival. In this work, we propose a novel R-CNN approach with pretraining and data augmentation for universal lesion detection. In particular, we incorporate an asymmetric 3D context fusion (A3D) for feature extraction from 2D CT images with Hybrid Task Cascade. By doing so, we supply the network with further spatial context, refining the mask prediction over several stages and making it easier to distinguish hard foregrounds from cluttered backgrounds. Moreover, we introduce a new video pretraining method for medical imaging by using consecutive frames from the YouTube VOS video segmentation dataset which improves our model's sensitivity by 0.8 percentage points at a false positive rate of one false positive per image. Finally, we apply data augmentation techniques and analyse their impact on the overall performance of our models at various false positive rates. Using our introduced approach, it is possible to increase the A3D baseline's sensitivity by 1.04 percentage points in mFROC.


On the origin and specificity of antibodies to neuromuscular blocking (muscle relaxant) drugs: an immunochemical perspective.
Following the demonstration 25 years ago that substituted ammonium groups on neuromuscular blocking drugs (NMBDs) are the main allergenic structures recognized by IgE antibodies in the sera of some patients who experience anaphylaxis during anaesthesia, immunoassays for these drugs were quickly applied to supplement skin tests in the diagnostic assessment of suspected adverse reactions to anaesthetic agents. Many subjects who react to an NMBD do so on first exposure and this led to the speculation that the origin of allergic sensitization is an environmental agent(s) or another drug containing an ammonium ion. Direct antibody binding and hapten inhibition studies revealed that morphine, which contains a tertiary amino group, was strongly recognized by IgE in sera from anaphylactic patients and a morphine-solid phase immunoassay was found to be superior to NMBD-based assays for the detection of NMBD-reactive IgE antibodies. Extensive inhibition experiments indicate the likelihood of antibody combining site heterogeneity with recognition at the fine structural level of features additional, and adjacent to, ammonium ions. Further quantitative investigations are needed to identify these neighbouring groups on different NMBDs. Recent work has implicated the morphine analogue pholcodine as the sensitizing agent in Norway where, unlike Sweden, anaphylactic reactions to NMBDs are not uncommon and the medicament is available over-the-counter. This has led to the suggestion that allergenic sensitization to the ammonium group of pholcodine may account for the different incidences of anaphylaxis during anaesthesia in the two countries. This work is subjected to critical review and some alternative speculations on the nature and origin of the sensitizing agent(s) are presented.


Comparison of benefits provided by different hearing aid technologies.
The performance of 40 hearing-impaired adults with the GN ReSound digital BZ5 hearing instrument was compared with performance with linear hearing aids with input compression limiting (AGC-I) or two-channel analog wide dynamic range compression (WDRC) instruments. The BZ5 was evaluated with an omnidirectional microphone, dual-microphone directionality, and a noise reduction circuit in combination with dual-microphone directionality. Participants were experienced hearing aid users who were wearing linear AGC-I or analog WDRC instruments at the time of enrolment. Performance was assessed using the Connected Speech Test (CST) presented at several presentation levels and under various conditions of signal degradation and by the Profile of Hearing Aid Benefit (PHAB). Subjective ratings of speech understanding, listening comfort, and sound quality/naturalness were also obtained using 11-point interval scales. Small performance advantages were observed for WDRC over linear AGC-I, although WDRC did not have to be implemented digitally for these performance advantages to be realized. Substantial performance advantages for the dual microphones over the omnidirectional microphone were observed in the CST results in noise, but participants generally did not perceive these large advantages in everyday listening. The noise reduction circuit provided improved listening comfort but little change in speech understanding.


Ureteral fibropapilloma in a dog.
A fibropapilloma was found to involve the left ureter in a 7-year-old castrated male Doberman Pinscher dog. Severe unilateral hydronephrosis and hydroureter were associated with the ureteral mass. Treatment consisted of unilateral nephrectomy and ureterectomy. This case represents an additional type of primary ureteral neoplasm found in the dog.


Anomalous molecular form of acetylcholinesterase in cerebrospinal fluid in histologically diagnosed Alzheimer's disease.
The possibility that the different molecular forms of acetylcholinesterase (AChE) in cerebrospinal fluid (CSF) which can be revealed by isoelectric focusing may reflect changes in AChE in pathologically affected neurons in Alzheimer's disease was tested in a retrospective study. CSF samples obtained at necropsy from 33 patients with clinically diagnosed dementia, 9 with possible dementia, and 19 without a diagnosis of dementia were examined by isoelectric focusing. An additional band indicating an anomalous molecular form of AChE was present in CSF from 19 of 23 patients with a histological diagnosis of Alzheimer's disease and no other central nervous system disorder but in none of the 19 non-demented patients (without a histological diagnosis of Alzheimer's disease). The band was also present in 2 of 8 patients with histologically defined Alzheimer's disease plus other neurological disorders and in 4 of 8 patients with possible dementia who did not meet histopathological criteria for Alzheimer's disease. The absence of the anomalous form of AChE from the CSF of non-demented patients and its presence in the CSF of the majority of patients with Alzheimer's disease has implications for our understanding of the biological basis of the disease and might form the basis of an antemortem diagnostic test.


Intake of Wild Blueberry Powder Improves Episodic-Like and Working Memory during Normal Aging in Mice.
The number of Americans older than 65 years old is projected to more than double in the next 40 years. Cognitive changes associated to aging can affect an adult's day-to-day functioning. Among these cognitive changes, reasoning, episodic memory, working memory, and processing speed decline gradually over time. Early memory changes include a decline in both working and episodic memory. The aim of the present study was to determine whether chronic (up to 75 days) daily administration of wild blueberry extract or a wild blueberry full spectrum powder would help prevent memory failure associated with aging in tasks involving various forms of memory. Both blueberry ingredients were used in a study comparing young mice (6 months old) to aged mice (18 months old). At this age, mice exhibit memory decline due to aging, which is exacerbated first by a loss in working and contextual (episodic-like) memory. Contextual memory (episodic-like memory) was evaluated using the contextual serial discrimination test. Working and spatial memory were evaluated using the Morris-Water maze test and the sequential alternation test. Statistical analysis was performed using an ANOVA with the Bonferroni post-hoc test. Supplementation with wild blueberry full spectrum powder and wild blueberry extract resulted in significant improvement of contextual memory, while untreated aged mice experienced a decline in such memory. Only the wild blueberry full spectrum powder significantly contributed to an improvement of spatial and working memory versus untreated aged mice. These improvements of cognitive performance may be related to brain oxidative status, acetylcholinesterase activity, neuroprotection, or attenuation of immunoreactivity.


Alternative methods for the assessment of mechanical dyssynchrony using phase analysis of gated single photon emission computed tomography myocardial perfusion imaging.
Measurement of left ventricular (LV) mechanical dyssynchrony from single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) allows optimization of cardiac resynchronization therapy in heart failure patients. We compared the discriminatory ability and reproducibility of a new software method, Corridor 4DM (4DM) to the established method, Emory Cardiac Toolbox (ECTb) in normals and heart failure patients. LV dyssynchrony was measured in 100 control (Group 1) and 100 patients with LVEF <35% (Group 2) using time to peak thickening with first harmonic, fourth harmonic, and volume curve methods with the 4DM software, and compared to ECTb. Of the 3 4DM methods, first harmonic had the best correlation with the ECTb (R = 0.88, slope = 1.00, P < 0.0001, bias = -0.18° [95% CI: -20°; 16°] for phase standard deviation; and similarly for histogram bandwidth, while volume curve analysis had the greatest variation. The intra and inter-observer reproducibility for 4DM time to peak thickening with first harmonic was very good (R = 0.99, P < 0.0001 and coefficient of variability 10% [95% CI 9.2-12%] for intra-observer, and R = 0.97, P < 0.0001, coefficient of variability 16% [15-17%] for inter-observer, respectively). Finally, in patients with LVEF <35%, the area under the curve on receiver operator characteristic analysis was 0.93 [95% CI: 0.89-0.97] to detect significant mechanical dyssynchrony (i.e. standard deviation ≥43°) using 4DM versus ECTb. The 4DM-software provides an accurate and reproducible alternative method of dyssynchrony analysis of SPECT MPI for evaluation and management of heart failure.


How to get top management support for MRP (materiel requirements planning) II.
Getting top management support for materiel requirements planning (MRP) is not impossible. When senior management supports the effort, the success rate skyrockets and companies experience results that improve their bottom-line performance. This article describes a step-by-step process for gaining top management's commitment to the effort.


Internal mammary lymph node recurrence: rare but characteristic metastasis site in breast cancer.
To assess the frequency of IMLN recurrence, its associated risk factors with disease-free interval (DFI) and its predicting factors on overall survival time. 133 cases of breast cancer IMLN recurrence were identified via the computerized CT reporting system between February 2003 and June 2008, during which chest CT for patients with breast cancer (n = 8867) were performed consecutively at Cancer Hospital, Fudan University, Shanghai, China. Patients' charts were retrieved and patients' characteristics, disease characteristics, and treatments after recurrence were collected for analysis. The frequency was 1.5% (133/8867). IMLN recurrence was presented as the first metastatic site in 121 (91%) patients while 88 (66.2%) had other concurrent metastases. Typical chest CT images included swelling of the IMLN at the ipsilateral side with local lump and sternal erosion located mostly between the second and third intercostal space. The median disease-free interval (DFI) of IMLN recurrence was 38 months. The independent factors that could delay the IMLN recurrence were small tumor size (HR 0.5 95%CI: 0.4 - 0.8; p = 0.002), and positive ER/PR disease (HR 0.6, 95% CI: 0.4 - 0.9; p = 0.006). The median survival time after IMLN recurrence was 42 months, with a 5-year survival rate of 30%. Univariate analysis showed four variables significantly influenced the survival time: DFI of IMLN recurrence (p = 0.001), no concurrent distant metastasis (p = 0.024), endocrine therapy for patients with positive ER/PR (p = 0.000), radiotherapy (p = 0.040). The independent factors that reduced the death risk were no concurrent distant metastases (HR: 0.7, 95% CI: 0.4 - 0.9; p = 0.031), endocrine therapy for patients with positive ER/PR status (HR: 0.2, 95% CI: 0.1 - 0.5; p = 0.001) and palliative radiotherapy (HR: 0.3, 95% CI: 0.1- 0.9; p = 0.026). The risk of IMLN recurrence is low and there are certain characteristics features on CT images. ER/PR status is both a risk factor for DFI of IMLN recurrence and a prognostic factor for overall survival after IMLN recurrence. Patients with only IMLN recurrence and/or local lesion have a good prognosis.


Impact of unemployment variations on suicide mortality in Western European countries (2000-2010).
A scientific debate is currently taking place on whether the 2008 economic crisis caused an increase in suicide rates. Our main objective was to assess the impact of unemployment rate on suicide rate in Western European countries between 2000 and 2010. We then tried to estimate the excess number of suicides attributable to the increase of unemployment during the 2008-2010 economic crisis. The yearly suicide rates were modelled using a quasi-Poisson model, controlling for sex, age, country and a linear time trend. For each country, the unemployment-suicide association was assessed, and the excess number of suicides attributable to the increase of unemployment was estimated. Sensitivity analyses were performed, notably in order to evaluate whether the unemployment-suicide association found was biased by a confounding context effect ('crisis effect'). A significant 0.3% overall increase in suicide rate for a 10% increase in unemployment rate (95% CI 0.1% to 0.5%) was highlighted. This association was significant in three countries: 0.7% (95% CI 0.0% to 1.4%) in the Netherlands, 1.0% (95% CI 0.2% to 1.8%) in the UK and 1.9% (95% CI 0.8% to 2.9%) in France, with a significant excess number of suicides attributable to unemployment variations between 2008 and 2010 (respectively 57, 456 and 564). The association was modified inconsistently when adding a 'crisis effect' into the model. Unemployment and suicide rates are globally statistically associated in the investigated countries. However, this association is weak, and its amplitude and sensitivity to the 'crisis effect' vary across countries. This inconsistency provides arguments against its causal interpretation.


Antibody targeting tumor-derived soluble NKG2D ligand sMIC provides dual co-stimulation of CD8 T cells and enables sMIC+ tumors respond to PD1/PD-L1 blockade therapy.
Insufficient co-stimulation accounts for a great deal of the suboptimal activation of cytotoxic CD8 T cells (CTLs) and presumably unsatisfactory clinical expectation of PD1/PD-L1 therapy. Tumor-derived soluble NKG2D ligands are associated with poor clinical response to PD1/PD-L1 blockade therapy in cancer patients. One of the mostly occurring tumor-derived soluble NKG2D ligands, the soluble MHC I chain related molecule (sMIC) can impair co-stimulation to CD8 T cells. We investigated whether co-targeting sMIC can provide optimal co-stimulation to CTLs and enhance the therapeutic effect of PD1/PD-L1 blockades. Single agent therapy of a PD1/PD-L1 blockade antibody or a sMIC-targeting non-blocking antibody or a combination therapy of the two antibodies were implied to well-characterized pre-clinical MIC/sMIC+ tumor models that closely resemble the NKG2D-mediated oncoimmune dynamics of MIC+ cancer patients. Therapeutic efficacy and associated effector mechanisms were evaluated. We show that antibody co-targeting sMIC enables or enhances the response of sMIC+ tumors to PD1/PD-L1 blockade therapy. The therapy response of the combination therapy was associated with enhanced antigen-specific CD8 T cell enrichment and function in tumors. We show that co-targeting sMIC with a nonblocking antibody provides antigen-specific CD8 T cells with NKG2D and CD28 dual co-stimulation, in addition to elimination of inhibitory signals, and thus amplifies antigen-specific CD8 T cell anti-tumor responses. Our findings provide the proof-of-concept rationale and previously undiscovered mechanisms for co-targeting sMIC to enable and enhance the response to PD1/PD-L1 blockade therapy in sMIC+ cancer patients.


Neonatal sepsis and meningitis due to alpha-hemolytic Streptococcus.
We have reported a case of septicemia and meningitis due to alpha-hemolytic Streptococcus in a 5-day-old infant. The microbiologic and clinical characteristics of neonatal infection with this organism lead us to conclude that this bacterium can be pathogenic in the newborn and should not be dismissed as a contaminant.