Body mass index as a predictor of colorectal neoplasia in ethnically diverse screening population.
Recent guidelines from the American College of Gastroenterology for screening for colorectal cancer have included obesity as an important risk factor. The recommendation for screening obese people at earlier age was tempered by the need for more data regarding obesity and colorectal neoplasia. We designed a cross-sectional study to further examine the predictive value of obesity for colorectal adenomas in asymptomatic patients. We prospectively collected demographic, medical, lifestyle, and dietary history from asymptomatic patients presenting for screening colonoscopy. Patients underwent complete colonoscopy using high-definition colonoscope to detect colorectal adenomas. We defined advanced neoplasia as large (≥ 1 cm) adenoma, villous adenoma, high-grade dysplasia or cancer. Six hundred patients with median age of 56 years completed the study. Over 40% of these patients did not consider themselves Caucasian, and less than 5% had a first-degree relative with colorectal cancer. Overall, 40 patients (6.7%) had advanced neoplasia and 216 (36.3%) had any adenoma. There were 185 obese patients (30.8%), who had a prevalence of 44.3% for any adenoma and 13.0% for advanced neoplasia. After multivariate analysis, obesity [body mass index (BMI) ≥ 30 kg/m(2)] was significantly associated with increased risk of advanced neoplasia [odds ratio (OR) = 3.83; 95% confidence interval (CI): 1.94-7.55]. Obesity was associated with advanced neoplasia in this screening population. Our data regarding the association of colorectal neoplasia with this modifiable risk factor has implications for screening and prevention of colorectal cancer.


Template-Directed Replication and Chiral Resolution during Wet-Dry Cycling in Hydrothermal Pools.
The commonly supposed template-based format for RNA self-replication requires both duplex assembly and disassembly. This requisite binary provision presents a challenge to the development of a serviceable self-replication model since chemical reactions are thermochemically unidirectional. We submit that a solution to this problem lies in volcanic landmasses that engage in continuous cycles of wetting and drying and thus uniquely provide the twofold state required for self-replication. Moreover, they offer conditions that initiate chain branching, and thus furnish a path to autocatalytic self-replication. The foundations of this dual thermochemical landscape arise from the broad differences in the properties of the bulk water phase on the one hand, and the air/water interfacial regions that emerge in the evaporative stages on the other. With this reaction system as a basis and employing recognized thermochemical and kinetic parameters, we present simulations displaying the spontaneous and autocatalyzed conversion of racemic and unactivated RNA monomers to necessarily homochiral duplex structures over characteristic periods of years.


Motor responses to experimental Achilles tendon pain.
Achilles tendinopathies are characterised by pain and reduced function, and heavy-load exercises have been shown to be effective in the treatment of painful chronic Achilles tendinopathies. However, basic information is needed on how the biomechanics and neuromuscular control of the exercise are affected by Achilles tendon pain. The authors aimed to determine the effects of experimental Achilles tendon pain on motor function during one-legged weight bearing ankle plantar and dorsal flexion exercises. In a crossover study, with 16 healthy subjects tested on two different days separated by 1 week, three-dimensional ground reaction forces, ankle joint kinematics and surface electromyography (EMG) of the lower leg muscles were recorded during one-legged full weight-bearing ankle plantar (concentric) and dorsal (eccentric) flexion exercises. Measurements were done before, during and after either experimental Achilles tendon pain or a non-painful control condition. Pain was induced by intratendinous injections of hypertonic saline with isotonic saline injections as control. Joint kinematics, ground reaction force frequency contents and average EMG amplitudes were calculated. Compared with the control condition experimental Achilles tendon pain reduced the EMG activity in agonistic, synergistic and antagonistic muscles, and increased the ground reaction force frequency content around 10 Hz, during both eccentric and concentric movement phases. These data show that experimental Achilles tendon pain causes widespread and reduced motor responses with functional effects on the ground reaction force.


Synthetic dimension band structures on a Si CMOS photonic platform.
Synthetic dimensions, which simulate spatial coordinates using nonspatial degrees of freedom, are drawing interest in topological science and other fields for modeling higher-dimensional phenomena on simple structures. We present the first realization of a synthetic frequency dimension on a silicon ring resonator integrated photonic device fabricated using a CMOS process. We confirm that its coupled modes correspond to a one-dimensional tight-binding model through acquisition of up to 280-GHz bandwidth optical frequency comb-like spectra and by measuring synthetic band structures. Furthermore, we realized two types of gauge potentials along the frequency dimension and probed their effects through the associated band structures. An electric field analog was produced via modulation detuning, whereas effective magnetic fields were induced using synchronized nearest- and second nearest-neighbor couplings. Creation of coupled mode lattices and two effective forces on a monolithic Si CMOS device represents a key step toward wider adoption of topological principles.


Herbal medicine: beneficial effects, side effects, and promising new research in the treatment of arrhythmias.
Herbal medications and dietary supplements are unregulated in the United States. The use of these medications has dramatically increased over the past decade. Many of these drugs are biologically active, yet physicians are often unaware their patients are using a traditional remedy. Physicians are frequently unfamiliar with the medications being used and the intended effect, as well as the side-effect profiles that accompany them. Recently, some of the herbal mediations that are commonly used in the general population have been shown to be beneficial for the treatment of arrhythmias. Unfortunately, many more have been shown to be detrimental. In this article, the background behind herbal medication and the degree to which herbal medications are being used is reviewed. Herbal medications known to have beneficial effects in the treatment of arrhythmias, as well as those that have known detrimental effects with regard to cardiac arrhythmias, are highlighted. Finally, research that has been done in this field, focusing on those compounds that have been shown to be biologically active in the treatment of cardiac arrhythmias, are reviewed.


KNOW-Ped CKD (KoreaN cohort study for outcomes in patients with pediatric CKD): Design and methods.
The global prevalence of chronic kidney disease (CKD) is increasing. In children, CKD exhibits unique etiologies and can have serious impacts on children's growth and development. Therefore, an aggressive approach to preventing the progression of CKD and its complications is imperative. To improve the understanding and management of Asian pediatric patients with CKD, we designed and launched KNOW-Ped CKD (KoreaN cohort study for Outcome in patients With Pediatric Chronic Kidney Disease), a nationwide, prospective, and observational cohort study of pediatric CKD with funding from the Korean government. From seven major centers, 450 patients <20 years of age with CKD stages I to V are recruited for the comprehensive assessment of clinical findings, structured follow-up, and bio-specimen collection. The primary endpoints include CKD progression, defined as a decline of estimated glomerular filtration rate by 50 %, and a requirement for renal replacement therapy or death. The secondary outcomes include the development of left ventricular hypertrophy or hypertension, impairment of growth, neuropsychological status, behavioral status, kidney growth, and quality of life. With this study, we expect to obtain more information on pediatric CKD, which can be translated to better management for the patients. NCT02165878 (ClinicalTrials.gov), submitted on June 11, 2014.


Lower urinary tract dysfunction in pediatrics progress to kidney disease in adolescents: Toward precision medicine in treatment.
Newborn infants who had neurogenic bladder dysfunction (NBD) have a normal upper urinary tract at birth. Most of them will develop deterioration of renal function and chronic kidney disease if they do not receive proper management. Children with NBD can develop renal damage at adolescence or earlier, which is due to high detrusor pressures resulted from poor compliance of the bladder, detrusor overactivity against a closed sphincter or detrusor sphincter dyssynergia. To preserve renal function and prevent deterioration of the kidneys, NBD must be treated immediately after being diagnosed. Over the last few years there was great progress in the treatment of children with the NBD. We searched PubMed and the Cochrane Library for peer-reviewed articles published in any language up to March 10, 2021, using the search term "neurogenic bladder children." Our search excluded diagnosis, pathophysiology, surgical treatment of spinal cord injury and spina bifida. The research identified the effectiveness of treatment regimens targeting prevention of chronic kidney disease and the indications of kidney transplantation. The results of the research showed that NBD in children should be diagnosed early in life, and the child should receive the proper management. The literature search concluded that the management of NBD in children would be personalized for every case and could be changed according to response to treatment, side effects, child compliance, availability of treatment modality and costs of treatment. The objectives of the study are to present the different options of management of NBD in children and the selection of the proper method in a personalized manner.


Kinetically Selective Inhibitors of Histone Deacetylase 2 (HDAC2) as Cognition Enhancers.
Aiming towards the development of novel nootropic therapeutics to address the cognitive impairment common to a range of brain disorders, we set out to develop highly selective small molecule inhibitors of HDAC2, a chromatin modifying histone deacetylase implicated in memory formation and synaptic plasticity. Novel ortho-aminoanilide inhibitors were designed and evaluated for their ability to selectively inhibit HDAC2 versus the other Class I HDACs. Kinetic and thermodynamic binding properties were essential elements of our design strategy and two novel classes of ortho-aminoanilides, that exhibit kinetic selectivity (biased residence time) for HDAC2 versus the highly homologous isoform HDAC1, were identified. These kinetically selective HDAC2 inhibitors (BRD6688 and BRD4884) increased H4K12 and H3K9 histone acetylation in primary mouse neuronal cell culture assays, in the hippocampus of CK-p25 mice, a model of neurodegenerative disease, and rescued the associated memory deficits of these mice in a cognition behavioural model. These studies demonstrate for the first time that selective pharmacological inhibition of HDAC2 is feasible and that inhibition of the catalytic activity of this enzyme may serve as a therapeutic approach towards enhancing the learning and memory processes that are affected in many neurological and psychiatric disorders.


Mycobacterium septicum sp. nov., a new rapidly growing species associated with catheter-related bacteraemia.
Rapidly growing mycobacteria are capable of causing several clinical diseases in both immunosuppressed and immunocompetent individuals. A previously unidentified, rapidly growing mycobacterium was determined to be the causative agent of central line sepsis in a child with underlying metastatic hepatoblastoma. Four isolates of this mycobacterium, three from blood and one from the central venous catheter tip, were studied. Phenotypic characterization, HPLC and genetic analysis revealed that while this organism most closely resembled members of the Mycobacterium fortuitum complex and Mycobacterium senegalense, it differed from all previously described species. Phenotypic tests useful in differentiating this species from similar rapidly growing mycobacteria included: growth at 42 degrees C, hydrolysis of acetamide, utilization of citrate, production of arylsulfatase (3-d), acidification of D-mannitol and i-myo-inositol, and susceptibility to erythromycin, vancomycin and tobramycin. The name Mycobacterium septicum is proposed for this new species. The type strain has been deposited in Deutsche Sammlung von Mikroorganismen und Zellkulturen as DSM 44393T and in the American Type Culture Collection as strain ATCC 700731T.


The Clinical Importance of Measurement of Hematological Indices in the Breast Cancer Survivals: A Comparison Between Premenopausal and Postmenopausal Women.
Determination of the hematological indices is a useful prognostic laboratory investigation in the cancer research. The neutrophil to lymphocyte ratio (LNR), red cell distribution width (RDW) and the platelet distribution width (PDW) are useful markers for the prediction and the prognosis of breast cancer. The aims of this study were to assess the hematological indices in breast cancer women survivals and to show if there were significant differences in these indices between pre- and postmenopausal women. This observational study was carried out in the Nanakali Hospital in Erbil, Kurdistan region, Iraq. A total number of 120 women with breast cancer under different modalities of management were enrolled in this study. The patients were grouped into premenopausal (group I, n = 30) and postmenopausal (group II, n = 90) women and the hematological indices of all patients were determined. Significant low hemoglobin levels and red cell counts were observed among group II compared with group I patients. Group II women had significant high values of RDW and mean platelet volume (MPV) (16.68 ± 2.51 and 9.980 ± 1.271) compared with group I (15.12 ± 2.27 and 9.535 ± 1.082). There were insignificant differences between group I and group II regarding the values of the PWD, plateletcrit (PCT), NLR and platelet to lymphocyte ratio (PLR). We conclude that the low hemoglobin levels, and the high RDW and PDW are significantly existing in postmenopausal compared with premenopausal survival women, indicating that there are specific hematological indices associated with the postmenopausal survival of the breast cancer.


Research on psychoimmunology.
Several lines of evidence suggest a role for the immune system in the multifactorial pathogenesis of schizophrenia and other psychiatric and neurodegenerative disease. Later, the role of immune mediators like cytokines became a source of main interest related to the process on inflammation in the CSM. In this article we report the results of our research on cytokines in a different groups of psychiatric patients following their clinical symptomatology and the course of diseases. In particular, we observed a prevalent type 1 cytokine profile in acute multiple sclerosis patients, while IL-10 production predominated in stable multiple sclerosis individuals. The modifications of cytokine profiles observed in schizophrenic patients suggests that clinical improvement is associated with a reduction in the inflammatory-like situation present in those not currently under treatment. Our data on Alzheimer's disease (AD) support the role of the inflammatory process in the pathogenesis of AD and reinforce the hypothesis that the neurodegenerative processes in the AD patients are associated with an abnormal antigen-specific immune response. The activation of immune system mechanisms observed in obsessive compulsive disorders could be due to the combination of endogenous (hormonal alterations associated to the modifications in the hypothalamic-pituitary-adrenal axis) and exogenous (viral or bacterial infections) factors.


Pregnancy and the risk of autoimmune disease.
Autoimmune diseases (AID) predominantly affect women of reproductive age. While basic molecular studies have implicated persisting fetal cells in the mother in some AID, supportive epidemiological evidence is limited. We investigated the effect of vaginal delivery, caesarean section (CS) and induced abortion on the risk of subsequent maternal AID. Using the Danish Civil Registration System (CRS) we identified women who were born between 1960 and 1992. We performed data linkage between the CRS other Danish national registers to identify women who had a pregnancy and those who developed AID. Women were categorised into 4 groups; nulligravida (control group), women who had 1st child by vaginal delivery, whose 1st delivery was by CS and who had abortions. Log-linear Poisson regression with person-years was used for data analysis adjusting for several potential confounders. There were 1,035,639 women aged >14 years and 25,570 developed AID: 43.4% nulligravida, 44.3% had their first pregnancy delivered vaginally, 7.6% CS and 4.1% abortions. The risk of AID was significantly higher in the 1st year after vaginal delivery (RR = 1.1[1.0, 1.2]) and CS (RR = 1.3[1.1, 1.5]) but significantly lower in the 1st year following abortion (RR = 0.7[0.6, 0.9]). These results suggest an association between pregnancy and the risk of subsequent maternal AID. Increased risks of AID after CS may be explained by amplified fetal cell traffic at delivery, while decreased risks after abortion may be due to the transfer of more primitive fetal stem cells. The increased risk of AID in the first year after delivery may also be related to greater testing during pregnancy.


Efficacy of scalp acupuncture for migraine: A protocol for systematic review and meta-analysis.
Migraine is a disorder that is prevalent worldwide. However, there is still no clear and effective treatment for migraine. Recently, acupuncture as a treatment has been attracting attention and studies have shown the value of scalp acupuncture. Therefore, this protocol for a systematic review and meta-analysis was created to assess the evidence of effectiveness and safety of scalp acupuncture in the treatment of migraine. All published randomized controlled trials (RCTs) in the following databases will be searched from their inception to September 2022: PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), OASIS, Korean Studies Information Service System (KISS), Korean Medical Database and NDSL, CiNii (Citation Information by NII), and the China National Knowledge Infrastructure (CNKI), without language restrictions. The data collection and analysis will be conducted independently by two reviewers. The Cochrane Collaboration tool will be used to evaluate the risk of bias by evaluating the available studies. A meta-analysis will be conducted using RevMan V.5.4 software. The purpose of the proposed systemic review is to systematically assess the effectiveness and safety of scalp acupuncture for the treatment of migraine. To sum up, this review will assess the effectiveness and safety of scalp acupuncture for the treatment of migraine. The results of this review are expected to provide new guidelines for the treatment of migraine. The review and meta-analysis will not require ethical approval because personal information from individuals will not be involved. The results will be published in a peer-reviewed journal.


Chromosome 5 imbalance mapping in breast tumors from BRCA1 and BRCA2 mutation carriers and sporadic breast tumors.
Comparative genomic hybridization (CGH) analysis has shown that chromosome 5q deletions are the most frequent aberration in breast tumors from BRCA1 mutation carriers. To map the location of putative 5q tumor suppressor gene(s), 26 microsatellite markers covering chromosome 5 were used in loss of heterozygosity (LOH) analysis of breast tumors from BRCA1 (n = 42) and BRCA2 mutation carriers (n = 67), as well as in sporadic cases (n = 65). High-density array CGH was also used to map chromosome 5 imbalance in 10 BRCA1 tumors. A high LOH frequency was found in BRCA1 tumors (range 19-82%), as compared to BRCA2 and sporadic tumors (ranges 11-44% and 7-43%, respectively). In all, 11 distinct chromosome 5 regions with LOH were observed, the most frequent being 5q35.3 (82%), 5q14.2 (71%) and 5q33.1 (69%) in BRCA1 tumors; 5q35.3 (44%), 5q31.3 (43%) and 5q13.3 (43%) in BRCA2 tumors and 5q31.3 (43%) in sporadic tumors. Array CGH analysis confirmed the very high frequency of 5q deletions, including candidate tumor suppressor genes such as XRCC4, RAD50, RASA1, APC and PPP2R2B. In addition, 2 distinct homozygous deletions were identified, spanning regions of 0.7-1.5 Mbp on 5q12.1 and 5q12.3-q13.1, respectively. These regions include only a few genes, most notably BRCC3/DEPDC1B (pleckstrin/G protein interacting and RhoGAP domains) and PIK3R1 (PI3 kinase P85 regulatory subunit). Significant association (p < or = 0.05) was found between LOH at certain 5q regions and factors of poor prognosis, including negative estrogen and progesterone receptor status, high grade, large tumor size and high portion of cells in S-phase. In conclusion, our results confirm a very high prevalence of chromosome 5q alterations in BRCA1 tumors, pinpointing new regions and genes that should be further investigated.


Popcorn calcification in osteogenesis imperfecta: incidence, progression, and molecular correlation.
Osteogenesis imperfecta (OI) is a heritable disorder characterized by osteoporosis and increased susceptibility to fracture. All children with severe OI have extreme short stature and some have "popcorn" calcifications, areas of disorganized hyperdense lines in the metaphysis and epiphysis around the growth plate on lower limb radiographs. Popcorn calcifications were noted on radiographs of two children with non-lethal type VIII OI, a recessive form caused by P3H1 deficiency. To determine the incidence, progression, and molecular correlations of popcorn calcifications, we retrospectively examined serial lower limb radiographs of 45 children with type III or IV OI and known dominant mutations in type I collagen. Popcorn calcifications were present in 13 of 25 type III (52%), but only 2 of 20 type IV (10%), OI children. The mean age of onset was 7.0 years, with a range of 4-14 years. All children with popcorn calcifications had this finding in their distal femora, and most also had calcifications in proximal tibiae. While unilateral popcorn calcification contributes to femoral growth deficiency and leg length discrepancy, severe linear growth deficiency, and metaphyseal flare do not differ significantly between type III OI patients with and without popcorn calcifications. The type I collagen mutations associated with popcorn calcifications occur equally in both COL1A1 and COL1A2, and have no preferential location along the chains. These data demonstrate that popcorn calcifications are a frequent feature of severe OI, but do not distinguish cases with defects in collagen structure (primarily dominant type III OI) or modification (recessive type VIII OI).


Nitric oxide synthase expression and activity in the tight-skin mouse model of fibrosis.
Nitric oxide (*NO) is an important physiological signalling molecule and a potent vasodilator. We have previously demonstrated abnormal *NO metabolism in the plasma of patients with systemic sclerosis (SSc; scleroderma), a disease that features vascular dysfunction as well as collagen overproduction and fibrosis. The aim of the present study was to examine nitric oxide synthase (NOS) expression and activity and assess the potential role of antioxidants in the scleroderma-like syndrome of the tight-skin 1 (TSK-1/+) mouse, an experimental animal model for fibrosis. Skin, lung or plasma was taken from TSK-1/+ (n = 15) and wild-type (WT; n = 12) littermate mice. Type 1 collagen, endothelial NOS (eNOS), haemoxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) protein and gene expression were determined by western blot and reverse transcriptase-polymerase chain reaction. eNOS expression was further determined by immunohistochemistry. NOS activity was evaluated by conversion of [14C] L-arginine to [14C] L-citrulline. Levels of circulating plasma nitrite/nitrate (NO(x)) were also measured. Total antioxidant activity was evaluated by ABTS+ production (ABTS = 2,2'-azino-bis-[3-ethylbenz-thiazoline-6-sulphonic acid). In the skin, eNOS was present in the epidermal layer, hair follicles and also in the endothelial cells lining the blood vessels. Expression of both the eNOS protein and gene was significantly reduced in TSK-1/+ skin tissue, while type 1 collagen protein was elevated compared with WT. Furthermore, there was decreased NOS activity in TSK-1/+ skin tissue; however, there was no measurable difference in plasma NO(x). Correspondingly, the protective antioxidant enzyme HO-1 and the associated transcription factor Nrf2 showed reduced protein and gene expression levels in TSK-1/+ skin, while there was also less total antioxidant activity. In TSK-1/+ lung tissue, however, we observed no difference in collagen protein expression, *NO metabolism or HO-1 expression and total antioxidant activity compared with WT. The findings suggest that there is also abnormal *NO metabolism in the TSK-1/+ mouse model of fibrosis, particularly in the skin, while expression and activity of protective antioxidants are reduced. The TSK-1/+ mouse may also be useful for testing treatments that target vascular endothelial cell function in patients with SSc.


Feeding and healing the world: through regenerative agriculture and permaculture.
The study of soil is a mature science, whereas related practical methods of regenerative agriculture and permaculture are not. However, despite a paucity of detailed peer reviewed research published on these topics, there is overwhelming evidence both that the methods work and they may offer the means to address a number of prevailing environmental challenges, e.g. peak oil, climate change, carbon capture, unsustainable agriculture and food shortages, peak phosphorus (phosphate), water shortages, environmental pollution, desert reclamation, and soil degradation. What is lacking is a proper scientific study, made in hand with actual development projects. By elucidating the scientific basis of these remarkable phenomena, we may obtain the means for solving some of the otherwise insurmountable problems confronting humanity, simply by observing, and working with, the patterns and forces of nature. This article is intended as a call to arms to make serious investment in researching and actualising these methods on a global scale. Despite claims that peak oil is no longer a threat because vast resources of gas and shale oil (tight oil) can now be recovered by fracking (hydraulic fracturing) combined with horizontal drilling, the reality is that proven actual reserves are only adequate to delay the peak by a few years. Furthermore, because of the rapid depletion rates of flow from gas wells and oil wells that are accessed by fracking, it will be necessary to drill continuously and relentlessly to maintain output, and there are material limits of equipment, technology and trained personnel to do this. Moreover, to make any sensible difference to the liquid fuel crisis, which is the most immediate consequence of peak oil, it would be necessary to convert the worlds one billion vehicles to run on natural gas rather than liquid fuels refined from crude oil, and this would take some considerable time and effort. The loss of widespread personalised transportation is thus inevitable and imminent, meaning a loss of globalised civilisation and a mandatory return to living in smaller localised communities. Permaculture and regenerative agriculture offer potentially the means to provide food and materials on the small scale, and address the wider issues of carbon emissions, and resource shortages. Since over half the World's population lives in cities, it seems likely that strengthening the resilience of these environments, using urban permaculture, may be a crucial strategy in achieving a measured descent in our use of energy and other resources, rather than an abrupt collapse of civilization.


Behavior of dioxin during thermal remediation in the zone combustion process.
In the previous study, a new process concept for the thermal remediation of particulate/powder materials contaminated by polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) has been verified. It leads to removal efficiencies of more than 99.9% in the soil contaminated by PCDD/Fs in terms of toxicity equivalent quantity (TEQ). However, details of the reactions and phenomena during the process, i.e., decomposition, vaporization, reformation and trap of PCDD/Fs and their relating compounds, have not sufficiently been clarified yet. The present study aims to examine experimentally the transport and fate of PCDD/Fs in the process. In the experiment, a laboratory-scale process simulator and a soil sample preliminary mixed with octachlorinated dibenzo-p-dioxin spiked by carbon-13 isotope (13C-OCDD) were used. The distribution of 13C-OCDD in the soil bed during the process was measured by applying a quench technique that rapidly cools-down the bed. Further, the total amount of 13C-OCDD discharged with outlet gas was measured. Using the obtained data, mass balance of 13C-OCDD in the process was estimated. The results show that about 99% of 13C-OCDD preliminary admixed with the soil was decomposed rather than released to the outlet gas. Only a trace amount of 13C-OCDD remained in the treated soil. In addition, a very small amount of other congeners having the 13C-cycles was detected in the treated soil and outlet gas although its TEQ values are not significant. These were probably formed by dechlorination reactions occurring in the process.


Variation and adaptation: learning from success in patient safety-oriented simulation training.
Simulation is traditionally used to reduce errors and their negative consequences. But according to modern safety theories, this focus overlooks the learning potential of the positive performance, which is much more common than errors. Therefore, a supplementary approach to simulation is needed to unfold its full potential. In our commentary, we describe the learning from success (LFS) approach to simulation and debriefing. Drawing on several theoretical frameworks, we suggest supplementing the widespread deficit-oriented, corrective approach to simulation with an approach that focusses on systematically understanding how good performance is produced in frequent (mundane) simulation scenarios. We advocate to investigate and optimize human activity based on the connected layers of any setting: the embodied competences of the healthcare professionals, the social and organizational rules that guide their actions, and the material aspects of the setting. We discuss implications of these theoretical perspectives for the design and conduct of simulation scenarios, post-simulation debriefings, and faculty development programs.


Effect of the mechanical harvest of drupes on the quality characteristics of green fermented table olives.
Because of damage caused by mechanical harvesting, the drupes for table olive production are traditionally hand harvested. Until now, no data have been available on the microbiological and chemical features of mechanically harvested drupes during fermentation. Drupes mechanically harvested and inoculated with Lactobacillus pentosus OM13 were characterized by the lowest concentrations of potential spoilage microorganisms. On the other hand, drupes mechanically harvested and subjected to spontaneous fermentation showed the highest concentration of Enterobacteriaceae and pseudomonads during transformation. The lowest decrease of pH (4.20) was registered for the trials inoculated with the starter culture. Differences in terms of volatile organic compounds were estimated among trials. Multivariate analysis showed that the olives processed from the drupes mechanically harvested and inoculated with starter were closely related to control production (drupes manually harvested) in terms of microbiological and pH values. Sensory analysis evidenced negative evaluations only for the uninoculated trials. Drupes mechanically harvested and subjected to a driven fermentation with Lactobacillus pentosus OM13 determined the production of table olives with appreciable organoleptic features. Thus mechanical harvesting performed using a trunk shaker equipped with an inverse umbrella and the addition of starter lactic acid bacteria represents a valuable alternative to manual harvesting for table olive production at the industrial level.


Early consequences of 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on the activation and survival of antigen-specific T cells.
TCDD is a potent immunotoxicant that suppresses adaptive immunity by mechanisms that are not well defined. To gain insight at the level of the T cell, we used the DO11.10 transgenic T-cell receptor (TCR) mouse model in an adoptive transfer approach to characterize the influence of TCDD on the responsiveness of antigen-specific CD4+ T cells in vivo. Flow cytometry was used to track the response of the OVA-specific transgenic CD4+ T cells in syngeneic recipients using an antibody specific for the transgenic TCR (KJ1-26 [KJ]). Consistent with a previous report, exposure of the recipient mice to TCDD (15 microg/kg po) did not alter the initial expansion of the CD4+KJ+ T cells in the spleen following immunization with OVA but resulted in a significant decline in the number of cells present on and after day 4. The degree of decline was dependent on the dose of TCDD. On day 3 after OVA injection, a higher percentage of the CD4+KJ+ T cells in the spleens of TCDD-treated mice had down-regulated the expression of CD62L, a phenotype associated with T-cell activation. Also on day 3, an increased number of CD4+KJ+ T cells were found in the blood of TCDD-treated mice. However, as in the spleen, the number of CD4+KJ+ T cells in the blood rapidly declined on day 4. CD4+KJ+ T cells in both the spleen and blood of TCDD-treated mice failed to up-regulate CD11a, an adhesion molecule important for sustained interaction between T cells and DC whereas the up-regulation of the adhesion molecule CD49d was not altered. Based on analysis of cell division history, CD4+KJ+ T cells in vehicle-treated mice continued to divide through day 4 whereas CD4+KJ+ T cells in TCDD-treated mice showed no further division after day 3. Increased annexin V staining on CD4+KJ+ T cells in TCDD-treated mice was also observed but not until days 5 and 6. Fas-deficient CD4+KJ+ T cells were depleted from the spleen of TCDD-treated mice in a manner similar to wild-type CD4+KJ+ T cells, suggesting that Fas signaling does not play a critical role in this model. On the other hand, gene array analysis of purified CD4+KJ+ T cells on day 3 showed that the expression of several genes associated with cell survival/death were altered by TCDD. Taken together, the results are consistent with our hypothesis that TCDD provides an early but inappropriate activation signal to the antigen-specific T cells that allows, and possibly enhances, the initial activation and proliferation of the T cells, yet at the same time, interferes with the vital expression of certain adhesion/costimulatory molecules that serve to enhance the survival of the T cells. These changes result in truncated proliferation, increased T-cell death, and suppression of the adaptive immune response.


Behavioral deficits and cortical damage loci in cerebral achromatopsia.
Lesions to ventral occipital cortex can produce severe deficits in color vision, a syndrome known as cerebral achromatopsia. Because most studies examine relatively few cases, however, uncertainty remains about precisely which cortical loci, when damaged, produce the syndrome. In addition, the extents of the associated perceptual deficits remain unclear. To address these issues, we performed a meta-analysis of 92 case reports from the literature. The severity of color vision deficits of the cases varied greatly, although nearly all showed some deficit in color discrimination. Almost all cases tested also showed some loss of spatial vision. Lesion overlap analyses revealed a relatively small region of high overlap in ventral occipital cortex. The region of high overlap was located near areas identified by neuroimaging studies as important for color perception. For comparison, we performed a similar analysis of prosopagnosia, a disorder of face perception, and found several regions of high lesion overlap adjacent to the region associated with achromatopsia. Because the behavioral deficits in achromatopsia are often incomplete and never restricted to color vision, the region of high lesion overlap may be one critical stage within a stream of many visual areas that participate nonexclusively in color perception.


Manipulating dietary PUFA in animal feed: implications for human health.
Milk, meat and eggs tend not to be regarded as an important source of PUFA. They are disproportionally high in SFA compared with their PUFA content, especially those from cattle and sheep, since their rumen microbes are responsible for the loss of over 90% of PUFA intake by livestock. This need not necessarily be the case since the relative proportion of PUFA in these foods is dictated by livestock management, especially feeding, and this can be manipulated to boost their content of crucial long-chain n-3 fatty acids and conjugated linoleic fatty acids. The present paper considers the fatty acid composition in animal-derived foods and how these can be manipulated to be more conducive for consumers' health. The importance of recognising the effect of livestock production systems on fat composition is also highlighted along with the fact that we may have to compromise between intensive, high levels of production and this particular aspect of food quality.


Lessons learned from the DIG trial.
The Digitalis Investigation Group (DIG) trial was the first large simple trial conducted by the National Heart, Lung, and Blood Institute in conjunction with the Department of Veterans Affairs. A large simple trial is a major undertaking. Simplification at the sites requires careful planning and discipline. Lessons learned from the DIG trial were: (1) keep a large simple trial very simple and keep all study procedures very simple; (2) ancillary studies are important and can complement a large simple trial but require careful advanced planning; (3) anticipate special needs when shipping study drugs internationally; (4) regional coordinating centers can be very useful; (5) recruit as many capable sites as possible; (6) provide research-inexperienced sites/investigators with extra help to obtain federalwide assurance statements from the Office for Human Research Protections and institutional review board approvals; (7) adequately reimburse sites for the work completed; (8) maintain investigator enthusiasm; (9) monitor the slow performers and sites with numerous personnel changes; (10) choose an endpoint that is easy to ascertain; (11) keep the trial simple for participants; and (12) plan early for closeout and for activities between the end of the trial and publication of results.


Treatment of recurrent genital herpes simplex infections with oral acyclovir. A controlled trial.
Two hundred fifty patients were entered into a multicenter trial to evaluate the efficacy and toxicity of orally administered acyclovir for treatment of recurrent genital herpes. The study consisted of part A, in which patients entered the study within 48 hours of the onset of lesions, and part B, in which patients self-initiated therapy as soon as possible after the onset of a recurrent episode. In both parts, patients received either acyclovir (200 mg) or placebo, five times daily for five days. In both parts, the duration of virus shedding and the time to crusting and healing of lesions were shorter among acyclovir recipients than among placebo recipients. In part B, fewer acyclovir recipients formed new lesions during the study medication period than did placebo recipients. When parts A and B were compared directly, the duration of virus shedding and the times required for crusting and healing of lesions were significantly shorter among acyclovir recipients in part B than among acyclovir recipients in part A. No significant differences in the duration of itching and pain or in the times of subsequent recurrence were noted between acyclovir and placebo groups in either part A or part B. No significant toxic or adverse reactions were seen in acyclovir recipients. Oral acyclovir shortens the duration of virus shedding and the duration of lesions in patients with recurrent genital herpes. These effects are more pronounced when therapy is self-initiated by patients early in the course of a recurrent episode.


Community perceptions of malaria and malaria treatment behaviour in a rural district of Ghana: implications for artemisinin combination therapy.
Artesunate-amodiaquine (AS-AQ) was introduced in Ghana as the first line drug for treatment of uncomplicated malaria in 2004. We report the perceptions of malaria and malaria treatment behaviour, the community awareness of and perceptions about AS-AQ two years after the introduction of this ACT treatment for malaria. Two surveys were conducted; a cross-sectional survey of 729 randomly selected household heads (urban-362, rural-367) and 282 women with children < 5 years (urban-121, rural-161) was conducted in 2006. A district wide survey was conducted in 2007 to assess awareness of AS-AQ. These were complemented with twenty-eight focus group discussions (FGDs) and 16 key informant interviews (KII) among community members and major stakeholders in the health care delivery services. All nine (9) health facilities and five (5) purposively selected drug stores were audited in order to identify commonly used anti-malarials in the study area at the time of the survey. Majority of respondents ( > 75%) in the sampled survey mentioned mosquito bites as the cause of malaria. Other causes mentioned include environmental factors (e.g. dirty surroundings) and standing in the sun. Close to 60% of the household heads and 40% of the care-givers interviewed did not know about AS-AQ. The community respondents who knew about and had ever taken AS-AQ perceived it to be a good drug; although they mentioned they had experienced some side effects including headaches and body weakness. Co-blistered AS-AQ was available in all the government health facilities in the study area. Different formulations of ACTs were however found in urban chemical shops but not in rural chemical stores where monotherapy antimalarials were predominant. The knowledge of fever as a symptom of malaria is high among the study population. The awareness of AS-AQ therapy and its side-effect was low in the study area. Community education and sensitization, targeting all categories of the population, has to be intensified to ensure an efficient implementation process.


Activity of mitomycin C for aerobic and hypoxic cells in vitro and in vivo.
We have observed the selective toxicity of mitomycin C toward hypoxic as compared to aerobic cells in vitro for three established cell lines (Chinese hamster ovary, Chinese hamster V-79, and human HeLa) and for cells from the transplantable KHT murine tumor. The magnitude of the selective toxicity was cell line dependent. We have studied the in vivo effects of mitomycin C against aerobic and hypoxic cells of two transplantable murine tumors: the KHT fibrosarcoma and the 16/C mammary carcinoma. Either mitomycin C was given with radiation to kill most of the aerobic cells, or it was given alone. Endpoints of response were cell survival assessed by lung colony assay for the KHT tumor, and growth delay for the 16/C tumor. In some experiments, mitomycin C appeared more effective when used with radiation than when used alone, but the results of combined treatment fell just within the range of additivity as defined by isobologram analysis. The effects of combined treatment were independent of the order in which drug and radiation were given. Mitomycin C was also used in combination with Adriamycin to treat the 16/C tumor, since we have found previously that Adriamycin spares hypoxic cells in this tumor. In three of four experiments, combined drug effects were slightly greater than predicted by an additive relationship. We conclude that mitomycin C is active against hypoxic cells in two murine tumors, but that it has at most minor specificity for hypoxic as compared to aerobic cells in vivo.


Oral contraceptive use may protect against low bone mass. Henry Ford Hospital Osteoporosis Cooperative Research Group.
This cross-sectional retrospective epidemiologic study investigated risk factors for low bone mineral density (BMD) in a group of 2297 women, 76% of whom were postmenopausal. Reproductive information, history of oral contraceptive use, BMD measurements, and other data were available from women presenting to 12 osteoporosis screening centers in 1986 and 1987. Each woman was classified into a BMD category based on the range of BMD measurements at her respective center. Menopause, increasing age and years since menopause, and decreasing body mass index were associated with low BMD. A history of oral contraceptive use was protective against low BMD (odds ratio = 0.35, 95% confidence interval = 0.23 to 0.53). Multivariate analyses confirmed this result and further demonstrated that increasing duration of use was protective. These data suggest that prior use of oral contraceptive agents is associated with higher levels of BMD and that the degree of protection from lower BMD is related to duration of exposure.


N-methylation of peptides on selected positions during the elongation of the peptide chain in solution phase.
[reactions: see text] An efficient and general solution-phase method for the site-specific N-methylation of peptides has been developed. This novel procedure involves synthesis of N-nosyl protected peptides and their subsequent N-methylation with diazomethane. Its efficiency was proved by the successful synthesis of various hindered oligopeptides containing N-methyl amino acid residues with excellent yield and purity. The method is particularly attractive in that the adopted conditions do not cause any detectable racemization of the peptide stereocenters and the process does not require chromatographic purification of the methylated products. A further advantage is the compatibility of this methodology with Fmoc solution-phase peptide synthesis.


Quantitative measurement of immunoglobulins and free light chains using mass spectrometry.
Serum free light chain (sFLC) assays are well established in the diagnosis and monitoring of plasma cell disorders. However, current FLC immunoassays are subject to several analytical issues, which results in a lack of harmonized results. To facilitate sFLC standardization, we investigated the strengths and limitations of mass spectrometry as a novel technological platform for sFLC quantification. Stable isotope labeled reference peptides are added to serum samples for quantitation by selected reaction monitoring (SRM). The use of redundant peptide sets allows for quality control measures during data analysis. Measurements on serum provide information on intact immunoglobulins, but depletion of these intact molecules from the sera during sample processing permits the quantitation of sFLC. sFLC concentrations measured with SRM were comparable to those obtained by nephelometry and showed excellent linearity (r(2) > 0.99). In samples with high levels of sFLC, SRM data was more consistent with serum protein electrophoresis than nephelometric data and SRM is unaffected by antigen excess. The lower limits of quantitation were 3.8 and 2.7 mg/L for κ and λ sFLC. Errors due to polymorphic sequences were prevented by comparison of redundant peptide pairs. The application of stable isotope labeling combined with SRM can overcome many of the current potential analytical issues of sFLC analysis. We describe which hurdles still need to be taken to make SRM a robust and more accurate method for sFLC measurements.


A Novel Classification of Intrahepatic Cholangiocarcinoma Phenotypes Using Machine Learning Techniques: An International Multi-Institutional Analysis.
Patients with intrahepatic cholangiocarcinoma (ICC) generally have a poor prognosis, yet there can be heterogeneity in the patterns of presentation and associated outcomes. We sought to identify clusters of ICC patients based on preoperative characteristics that may have distinct outcomes based on differing patterns of presentation. Patients undergoing curative-intent resection of ICC between 2000 and 2017 were identified using a multi-institutional database. A cluster analysis was performed based on preoperative variables to identify distinct patterns of presentation. A classification tree was built to prospectively assign patients into cluster assignments. Among 826 patients with ICC, three distinct presentation patterns were noted. Specifically, Cluster 1 (common ICC, 58.9%) consisted of individuals who had a small-size ICC (median 4.6 cm) and median carbohydrate antigen (CA) 19-9 and neutrophil-to-lymphocyte ratio (NLR) levels of 40.3 UI/mL and 2.6, respectively; Cluster 2 (proliferative ICC, 34.9%) consisted of patients who had larger-size tumors (median 9.0 cm), higher CA19-9 levels (median 72.0 UI/mL), and similar NLR (median 2.7); Cluster 3 (inflammatory ICC, 6.2%) comprised of patients with a medium-size ICC (median 6.2 cm), the lowest range of CA19-9 (median 26.2 UI/mL), yet the highest NLR (median 13.5) (all p < 0.05). Median OS worsened incrementally among the three different clusters {Cluster 1 vs. 2 vs. 3; 60.4 months (95% confidence interval [CI] 43.0-77.8) vs. 27.2 months (95% CI 19.9-34.4) vs. 13.3 months (95% CI 7.2-19.3); p < 0.001}. The classification tree used to assign patients into different clusters had an excellent agreement with actual cluster assignment (κ = 0.93, 95% CI 0.90-0.96). Machine learning analysis identified three distinct prognostic clusters based solely on preoperative characteristics among patients with ICC. Characterizing preoperative patient heterogeneity with machine learning tools can help physicians with preoperative selection and risk stratification of patients with ICC.


[Proposing a data mining scaffolding for preventing harmful alcohol consumption in Chilean adolescents].
Adolescent alcohol and drug consumption are important public health problems in the Chilean young population. The purpose of this study was to examine the potential ofa data mining approach in scaffolding policy making, using the particular case of differential risks of harmful alcohol consumption in adolescent students. Index and control groups were composed by 7918 and 7138 participants respectively (drawn from a CONACE survey 2009), aged 16 ± 2 years, 52% mole. Heavy drinking at last month was the independent variable. As dependent variables parenting style, peer group influence, age and sex were used. For data analysis, a data mining approach was applied (CART, SPSS version 15). The peer group influence was the main discriminant variable in males and the total sample, proving to be the only relevant variable in the case of women. The results suggest how a data mining approach may be useful in order to develop a hard data scaffolding for making and implementing policies in general and policies addressing adolescent alcohol consumption in particular.


Progression of nodular poorly differentiated lymphocytic lymphoma to Burkitt's-like lymphoma.
Histologic conversion of nodular lymphomas to more aggressive patterns has been well described and occurs in 15% to 40% of cases. Most conversions have involved changes from nodular to diffuse patterns and often from small to larger cell types. Conversions to undifferentiated lymphomas, but not specifically to the Burkitt's type, have infrequently been described. This report describes three cases of nodular poorly differentiated lymphocytic lymphoma that converted to a Burkitt's-like lymphoma. Conversion was associated with short survivals, increasing lactate dehydrogenase (LDH) levels, and changes in DNA stemline, RNA content, and S-phase values, as determined by flow cytometry. Karyotypes in two cases revealed a t(14;18). Surface immunoglobulin could be demonstrated on transformed Burkitt's-like cells from lymph node in one case, but in none of the cases on cells from bone marrow.


EGF stimulates mesangial cell mitogenesis via PI3-kinase-mediated MAPK-dependent and AKT kinase-independent manner: involvement of c-fos and p27Kip1.
Epidermal growth factor (EGF) is a potent mitogen for mesangial cells. The mechanism by which EGF induces DNA synthesis is not precisely understood. We investigated the role of phosphatidylinositol (PI)3-kinase in regulating mitogenesis. EGF increased PI3-kinase activity resulting in stimulation of PDK-1 and Akt kinase activities. Blocking of PI3-kinase activity using LY-294002 or adenoviral expression of PTEN, which dephosphorylates PI3,4,5-tris-phosphate and thus inactivates PI3-kinase signaling, significantly inhibits EGF-induced DNA synthesis. Expression of dominant-negative Akt kinase, however, had no effect on DNA synthesis. But it inhibited EGF-induced phosphorylation of FoxO3a transcription factor, thus demonstrating its functional consequences. These data indicate that EGF increases the DNA synthesis in a PI3-kinase-dependent but Akt-independent manner. In addition to activating PI3-kinase signaling, EGF increased Erk1/2 MAPK activity, leading to transcriptional activation of its nuclear target Elk-1 and resulting in c-fos expression. Inhibition of MAPK activity by MEK inhibitor U-0126 abolished EGF-induced DNA synthesis. Because EGF activates PI3-kinase, which also regulates DNA synthesis, the effect of PI3-kinase on MAPK activity was also examined. Inhibition of PI3-kinase signaling blocked EGF-induced MAPK activity as well as Elk-1-dependent reporter transcription and c-fos gene transcription. To further determine the mechanism of EGF-induced DNA synthesis, we investigated the effect of EGF on the cyclin-dependent kinase inhibitor p27(Kip1). EGF reduced the expression of p27(Kip1). Inhibition of PI3-kinase action or MAPK activity abolished the reduction in p27(Kip1) expression induced by EGF. These data provide the evidence that a linear signal transduction pathway involving PI3-kinase-dependent MAPK regulates EGF-induced DNA synthesis in mesangial cells by regulating c-fos and p27(Kip1) expression.


Pervasive sharing of genetic effects in autoimmune disease.
Genome-wide association (GWA) studies have identified numerous, replicable, genetic associations between common single nucleotide polymorphisms (SNPs) and risk of common autoimmune and inflammatory (immune-mediated) diseases, some of which are shared between two diseases. Along with epidemiological and clinical evidence, this suggests that some genetic risk factors may be shared across diseases-as is the case with alleles in the Major Histocompatibility Locus. In this work we evaluate the extent of this sharing for 107 immune disease-risk SNPs in seven diseases: celiac disease, Crohn's disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. We have developed a novel statistic for Cross Phenotype Meta-Analysis (CPMA) which detects association of a SNP to multiple, but not necessarily all, phenotypes. With it, we find evidence that 47/107 (44%) immune-mediated disease risk SNPs are associated to multiple-but not all-immune-mediated diseases (SNP-wise P(CPMA)<0.01). We also show that distinct groups of interacting proteins are encoded near SNPs which predispose to the same subsets of diseases; we propose these as the mechanistic basis of shared disease risk. We are thus able to leverage genetic data across diseases to construct biological hypotheses about the underlying mechanism of pathogenesis.


Reduction in voltage-gated K+ channel activity in primary sensory neurons in painful diabetic neuropathy: role of brain-derived neurotrophic factor.
Abnormal hyperexcitability of primary sensory neurons plays an important role in neuropathic pain. Voltage-gated potassium (Kv) channels regulate neuronal excitability by affecting the resting membrane potential and influencing the repolarization and frequency of the action potential. In this study, we determined changes in Kv channels in dorsal root ganglion (DRG) neurons in a rat model of diabetic neuropathic pain. The densities of total Kv, A-type (IA) and sustained delayed (IK) currents were markedly reduced in medium- and large-, but not in small-, diameter DRG neurons in diabetic rats. Quantitative RT-PCR analysis revealed that the mRNA levels of IA subunits, including Kv1.4, Kv3.4, Kv4.2, and Kv4.3, in the DRG were reduced approximately 50% in diabetic rats compared with those in control rats. However, there were no significant differences in the mRNA levels of IK subunits (Kv1.1, Kv1.2, Kv2.1, and Kv2.2) in the DRG between the two groups. Incubation with brain-derived neurotrophic factor (BDNF) caused a large reduction in Kv currents, especially IA currents, in medium and large DRG neurons from control rats. Furthermore, the reductions in Kv currents and mRNA levels of IA subunits in diabetic rats were normalized by pre-treatment with anti-BDNF antibody or K252a, a TrkB tyrosine kinase inhibitor. In addition, the number of medium and large DRG neurons with BDNF immunoreactivity was greater in diabetic than control rats. Collectively, our findings suggest that diabetes primarily reduces Kv channel activity in medium and large DRG neurons. Increased BDNF activity in these neurons likely contributes to the reduction in Kv channel function through TrkB receptor stimulation in painful diabetic neuropathy.


Ordered hexagonal patterns via notch-delta signaling.
Many developmental processes in biology utilize notch-delta signaling to construct an ordered pattern of cellular differentiation. This signaling modality is based on nearest-neighbor contact, as opposed to the more familiar mechanism driven by the release of diffusible ligands. Here, exploiting this 'juxtacrine' property, we present an exact treatment of the pattern formation problem via a system of nine coupled ordinary differential equations. The possible patterns that are realized for realistic parameters can be analyzed by considering a co-dimension 2 pitchfork bifurcation of this system. This analysis explains the observed prevalence of hexagonal patterns with high delta at their center, as opposed to those with central high notch levels (referred to as anti-hexagons). We show that outside this range of parameters, in particular for lowcis-coupling, a novel kind of pattern is produced, where high delta cells have high notch as well. It also suggests that the biological system is only weakly first order, so that an additional mechanism is required to generate the observed defect-free patterns. We construct a simple strategy for producing such defect-free patterns.


Enhanced external counterpulsation reduces indices of central blood pressure and myocardial oxygen demand in patients with left ventricular dysfunction.
Enhanced external counterpulsation (EECP) therapy decreases angina episodes and improves quality of life in patients with left ventricular (LV) dysfunction. However, the underlying mechanisms relative to the benefits of EECP therapy in patients with LV dysfunction have not been fully elucidated. The purpose of this study was to investigate the effects of EECP on indices of central haemodynamics, aortic pressure wave reflection characteristics, and estimates of LV load and myocardial oxygen demand in patients with LV dysfunction. Patients with chronic stable angina and LV ejection fraction < 40% but > 30%, were randomized to either an EECP group (LV ejection fraction = 35.1 ± 4.6%; n = 10) or sham-EECP group (LV ejection fraction = 34.3 ± 4.2%; n = 7). Pulse wave analysis of the central aortic pressure waveform and LV function were evaluated by applanation tonometry before and after 35 1-h sessions of EECP or sham-EECP. Enhanced external counterpulsation therapy was effective in reducing indices of LV wasted energy and myocardial oxygen demand by 25% and 19%, respectively. In addition, indices of coronary perfusion pressure and subendocardial perfusion were increased by 9% and 30%, respectively, after EECP. Our data indicate that EECP may be useful as adjuvant therapy for improving functional classification in heart failure patients through reductions in central blood pressure, aortic pulse pressure, wasted LV energy, and myocardial oxygen demand, which also suggests improvements in ventricular-vascular interactions.


Effects of water, sanitation, handwashing and nutritional interventions on soil-transmitted helminth infections in young children: A cluster-randomized controlled trial in rural Bangladesh.
Soil transmitted helminths (STH) infect >1.5 billion people. Mass drug administration (MDA) effectively reduces infection; however, there is evidence for rapid reinfection and risk of potential drug resistance. We conducted a randomized controlled trial in Bangladesh (WASH Benefits, NCT01590095) to assess whether water, sanitation, hygiene and nutrition interventions, alone and combined, reduce STH in a setting with ongoing MDA. In 2012-2013, we randomized 720 clusters of 5551 pregnant women into water treatment, sanitation, handwashing, combined water+sanitation+handwashing (WSH), nutrition, nutrition+WSH (N+WSH) or control arms. In 2015-2016, we enrolled 7795 children, aged 2-12 years, of 4102 available women for STH follow-up and collected stool from 7187. We enumerated STH infections with Kato-Katz. We estimated intention-to-treat intervention effects on infection prevalence and intensity. Participants and field staff were not blinded; laboratory technicians and data analysts were blinded. Prevalence among controls was 36.8% for A. lumbricoides, 9.2% for hookworm and 7.5% for T. trichiura. Most infections were low-intensity. Compared to controls, the water intervention reduced hookworm by 31% (prevalence ratio [PR] = 0.69 (0.50,0.95), prevalence difference [PD] = -2.83 (-5.16,-0.50)) but did not affect other STH. Sanitation improvements reduced T. trichiura by 29% (PR = 0.71 (0.52,0.98), PD = -2.17 (-4.03,-0.38)), had a similar borderline effect on hookworm and no effect on A. lumbricoides. Handwashing and nutrition interventions did not reduce any STH. WSH and N+WSH reduced hookworm prevalence by 29-33% (WSH: PR = 0.71 (0.52,0.99), PD = -2.63 (-4.95,-0.31); N+WSH: PR = 0.67 (0.50,0.91), PD = -3.00 (-5.14,-0.85)) and marginally reduced A. lumbricoides. Effects on infection intensity were similar. In a low-intensity infection setting with MDA, we found modest but sustained hookworm reduction from water treatment and combined WSH interventions. Impacts were more pronounced on STH species with short vs. long-term environmental survival. Our findings suggest possible waterborne transmission for hookworm. Water treatment and sanitation improvements can augment MDA to interrupt STH transmission. NCT01590095.


1/(2+Rc): A simple predictive formula for laboratory shrinkage-stress measurement.
This paper presents and verifies a simple predictive formula for laboratory shrinkage-stress measurement in dental composites that can account for the combined effect of material properties, sample geometry and instrument compliance. A mathematical model for laboratory shrinkage-stress measurement that includes the composite's elastic modulus, shrinkage strain, and their interaction with the sample's dimensions and the instrument's compliance has previously been developed. The model contains a dimensionless parameter, Rc, which represents the compliance of the instrument relative to that of the cured composite sample. A simplified formula, 1/(2+Rc), is proposed here for the normalized shrinkage stress to approximate the original model. The accuracy of the simplified formula is examined by comparing its shrinkage-stress predictions with those given by the exact formula for different cases. These include shrinkage stress measured using instruments with different compliances, samples with different thicknesses and composites with different filler fractions. The simplified formula produces shrinkage-stress predictions that are very similar to those given by the full formula. In addition, it correctly predicts the decrease in shrinkage stress with an increasing configuration factor for compliant instruments. It also correctly predicts the value of the so-called flow factor of composites despite the fact that creep is not considered in the model. The new simple formula significantly simplifies the prediction of shrinkage stress for disc specimens used in laboratory experiments without much loss in precision. Its explicit analytical form shows clearly all the important parameters that control the level of shrinkage stress in such measurements. It also helps to resolve much of the confusion caused by the seemingly contradictory results reported in the literature. Further, the formula can be used as a guide for the design of dental composite materials or restorations to minimize their shrinkage stress.


Refractive index maps and membrane dynamics of human red blood cells parasitized by Plasmodium falciparum.
Parasitization by malaria-inducing Plasmodium falciparum leads to structural, biochemical, and mechanical modifications to the host red blood cells (RBCs). To study these modifications, we investigate two intrinsic indicators: the refractive index and membrane fluctuations in P. falciparum-invaded human RBCs (Pf-RBCs). We report experimental connections between these intrinsic indicators and pathological states. By employing two noninvasive optical techniques, tomographic phase microscopy and diffraction phase microscopy, we extract three-dimensional maps of refractive index and nanoscale cell membrane fluctuations in isolated RBCs. Our systematic experiments cover all intraerythrocytic stages of parasite development under physiological and febrile temperatures. These findings offer potential, and sufficiently general, avenues for identifying, through cell membrane dynamics, pathological states that cause or accompany human diseases.


Cervical screening during the COVID-19 pandemic: optimising recovery strategies.
Disruptions to cancer screening services have been experienced in most settings as a consequence of the COVID-19 pandemic. Ideally, programmes would resolve backlogs by temporarily expanding capacity; however, in practice, this is often not possible. We aim to inform the deliberations of decision makers in high-income settings regarding their cervical cancer screening policy response. We caution against performance measures that rely solely on restoring testing volumes to pre-pandemic levels because they will be less effective at mitigating excess cancer diagnoses than will targeted measures. These measures might exacerbate pre-existing inequalities in accessing cervical screening by disregarding the risk profile of the individuals attending. Modelling of cervical screening outcomes before and during the pandemic supports risk-based strategies as the most effective way for screening services to recover. The degree to which screening is organised will determine the feasibility of deploying some risk-based strategies, but implementation of age-based risk stratification should be universally feasible.


Low responders to endurance training exhibit impaired hypertrophy and divergent biological process responses in rat skeletal muscle.
What is the central question of this study? The extent to which genetics determines adaptation to endurance versus resistance exercise is unclear. Previously, a divergent selective breeding rat model showed that genetic factors play a major role in the response to aerobic training. Here, we asked: do genetic factors that underpin poor adaptation to endurance training affect adaptation to functional overload? What is the main finding and its importance? Our data show that heritable factors in low responders to endurance training generated differential gene expression that was associated with impaired skeletal muscle hypertrophy. A maladaptive genotype to endurance exercise appears to dysregulate biological processes responsible for mediating exercise adaptation, irrespective of the mode of contraction stimulus. Divergent skeletal muscle phenotypes result from chronic resistance-type versus endurance-type contraction, reflecting the principle of training specificity. Our aim was to determine whether there is a common set of genetic factors that influence skeletal muscle adaptation to divergent contractile stimuli. Female rats were obtained from a genetically heterogeneous rat population and were selectively bred from high responders to endurance training (HRT) or low responders to endurance training (LRT; n = 6/group; generation 19). Both groups underwent 14 days of synergist ablation to induce functional overload of the plantaris muscle before comparison to non-overloaded controls of the same phenotype. RNA sequencing was performed to identify Gene Ontology biological processes with differential (LRT vs. HRT) gene set enrichment. We found that running distance, determined in advance of synergist ablation, increased in response to aerobic training in HRT but not LRT (65 ± 26 vs. -6 ± 18%, mean ± SD, P < 0.0001). The hypertrophy response to functional overload was attenuated in LRT versus HRT (20.1 ± 5.6 vs. 41.6 ± 16.1%, P = 0.015). Between-group differences were observed in the magnitude of response of 96 upregulated and 101 downregulated pathways. A further 27 pathways showed contrasting upregulation or downregulation in LRT versus HRT in response to functional overload. In conclusion, low responders to aerobic endurance training were also low responders for compensatory hypertrophy, and attenuated hypertrophy was associated with differential gene set regulation. Our findings suggest that genetic factors that underpin aerobic training maladaptation might also dysregulate the transcriptional regulation of biological processes that contribute to adaptation to mechanical overload.


Results of transcervical thymectomy for myasthenia gravis in 100 consecutive patients.
To review the results of the authors' most recent 100 consecutive cases of transcervical thymectomy for myasthenia gravis (MG) in terms of complications and outcome in comparison with other reported techniques. Myasthenia gravis is believed to be an autoimmune disorder characterized by increasing fatigue with exertion. The role of thymectomy in the management of the disease remains unproven, but there is widespread acceptance of the notion that complete thymectomy improves the course of the disease. Complete excision of the thymus is the goal in all cases; however, the best technique to achieve complete thymectomy remains controversial. The authors favor a transcervical approach through a small collar incision aided by a specially designed sternal retractor. Others prefer a transsternal, a combined transcervical and transsternal ("maximal"), or a video-assisted thoracoscopic surgical approach. A retrospective review of the authors' most recent 100 consecutive transcervical thymectomies for nonthymoma-associated MG was performed using medical records and telephone interviews. Patients' symptoms were graded before surgery and at the most recent (within the last 6 months) postoperative time point, using the modified Osserman classification: 0 = asymptomatic, 1 = ocular signs and symptoms, 2 = mild generalized weakness, 3 = moderate generalized weakness, bulbar dysfunction, or both, and 4 = severe generalized weakness, respiratory dysfunction, or both. There were 61 female patients and 39 male patients with a mean age of 38 years (range, 14 to 84). The median hospital stay was 1 day. There were no deaths and no significant complications. Seventy-eight patients who had undergone surgery >12 months ago were available for analysis. In these patients, with a mean follow-up time of 5 years (median 5.3; range, 12 months to 10 years), the median preoperative Osserman grade improved from 3.0 (mean 2.73) before surgery to 1.0 after surgery (mean 0.94). The transcervical approach for thymectomy for the treatment of MG produces results similar to those of other surgical approaches, with the added benefits of shortened hospital stay, decreased complications, reduced cost, and broader physician and patient acceptance of surgical treatment.


Predicting implicit attitudes with natural language data.
Large-scale language datasets and advances in natural language processing offer opportunities for studying people's cognitions and behaviors. We show how representations derived from language can be combined with laboratory-based word norms to predict implicit attitudes for diverse concepts. Our approach achieves substantially higher correlations than existing methods. We also show that our approach is more predictive of implicit attitudes than are explicit attitudes, and that it captures variance in implicit attitudes that is largely unexplained by explicit attitudes. Overall, our results shed light on how implicit attitudes can be measured by combining standard psychological data with large-scale language data. In doing so, we pave the way for highly accurate computational modeling of what people think and feel about the world around them.


Radiation dose to the fetus for pregnant patients undergoing multidetector CT imaging: Monte Carlo simulations estimating fetal dose for a range of gestational age and patient size.
To use Monte Carlo simulations of a current-technology multidetector computed tomographic (CT) scanner to investigate fetal radiation dose resulting from an abdominal and pelvic examination for a range of actual patient anatomies that include variation in gestational age and maternal size. Institutional review board approval was obtained for this HIPAA-compliant retrospective study. Twenty-four models of maternal and fetal anatomy were created from image data from pregnant patients who had previously undergone clinically indicated CT examination. Gestational age ranged from less than 5 weeks to 36 weeks. Simulated helical scans of the abdominal and pelvic region were performed, and a normalized dose (in milligrays per 100 mAs) was calculated for each fetus. Stepwise multiple linear regression was performed to analyze the correlation of dose with gestational age and anatomic measurements of maternal size and fetal location. Results were compared with several existing fetal dose estimation methods. Normalized fetal dose estimates from the Monte Carlo simulations ranged from 7.3 to 14.3 mGy/100 mAs, with an average of 10.8 mGy/100 mAs. Previous methods yielded values of 10-14 mGy/100 mAs. The correlation between gestational age and fetal dose was not significant (P = .543). Normalized fetal dose decreased linearly with increasing patient perimeter (R(2) = 0.681, P < .001), and a two-factor model with patient perimeter and fetal depth demonstrated a strong correlation with fetal dose (R(2) = 0.799, P < .002). A method for the estimation of fetal dose from models of actual patient anatomy that represented a range of gestational age and patient size was developed. Fetal dose correlated with maternal perimeter and varied more than previously recognized. This correlation improves when maternal size and fetal depth are combined.


Detection of Shiga toxin-producing Escherichia coli O26, O45, O103, O111, O113, O121, O145, and O157 serogroups by multiplex polymerase chain reaction of the wzx gene of the O-antigen gene cluster.
O-antigens on the surface of Escherichia coli are important virulence factors that are targets of both the innate and adaptive immune system and play a major role in pathogenicity. O-antigens that are responsible for antigenic specificity of the strain determine the O-serogroup. E. coli O26, O45, O103, O111, O113, O121, O145, and O157 have been the most commonly identified O-serogroups associated with Shiga toxin-producing E. coli (STEC) implicated in outbreaks of human illness all over the world. A multiplex polymerase chain reaction assay was developed to simultaneously detect the eight STEC O-serogroups targeting the wzx (O-antigen-flippase) genes of all O-antigen gene clusters. The sensitivity of the multiplex polymerase chain reaction was found to be 10 colony forming units for each O-group when enriched in broth and 100 colony forming units when enriched in artificially inoculated apple juice diluted with tryptic soy broth for 16 h at 37°C. The method can be used for detecting STEC O-groups simultaneously and may be exploited for improving the safety of food products.


Silver-coated zero-valent iron nanoparticles enhance cancer therapy in mice through lysosome-dependent dual programed cell death pathways: triggering simultaneous apoptosis and autophagy only in cancerous cells.
In this study, we demonstrated that zero-valent iron (ZVI), which is widely used to remediate environmental contamination through the production of high-energy reactive oxygen species (ROS), exhibited differential cytotoxicity in cancerous cells and nonmalignant cells. Nanoparticles (NPs) with different shells exhibited distinct potencies against cancerous cells, which depended on their iron-to-oxygen ratios. Silver-coated ZVI NPs (ZVI@Ag) had the highest potency among synthesized ZVI NPs, and they simultaneously exhibited adequate biocompatibility with nonmalignant keratinocytes. The assessment of the intracellular dynamics of iron species revealed that the uptake of ZVI@Ag was similar between cancerous cells and nonmalignant cells during the first 2 h; however, only cancerous cells rapidly converted NPs into iron ions and generated large amounts of intracellular ROS, which was followed by apoptosis and autophagy induction. The aforementioned processes were prevented in the presence of iron ion chelators or by preoxidizing NPs before administration. Neutralization of lysosomal pH effectively reduced ZVI@Ag NP-induced programmed cell death. In the xenograft mouse model, cancer growth was significantly inhibited by a single dose of systematically administered NPs without significant weight loss in animals.


Wave Phenomena and Beam-Plasma Interactions at the Magnetopause Reconnection Region.
This paper reports on Magnetospheric Multiscale observations of whistler mode chorus and higher-frequency electrostatic waves near and within a reconnection diffusion region on 23 November 2016. The diffusion region is bounded by crescent-shaped electron distributions and associated dissipation just upstream of the X-line and by magnetic field-aligned currents and electric fields leading to dissipation near the electron stagnation point. Measurements were made southward of the X-line as determined by southward directed ion and electron jets. We show that electrostatic wave generation is due to magnetosheath electron beams formed by the electron jets as they interact with a cold background plasma and more energetic population of magnetospheric electrons. On the magnetosphere side of the X-line the electron beams are accompanied by a strong perpendicular electron temperature anisotropy, which is shown to be the source of an observed rising-tone whistler mode chorus event. We show that the apex of the chorus event and the onset of electrostatic waves coincide with the opening of magnetic field lines at the electron stagnation point.


Autonomic reactivity to social rejection, peer difficulties, and the buffering effects of adolescent friendships following early psychosocial deprivation.
Autonomic nervous system reactivity has been posited to be a mechanism contributing to social and emotional problems among children exposed to early adversity. Leveraging data from the Bucharest Early Intervention Project, a longitudinal randomized controlled trial of foster care versus institutional care of abandoned children in Romania, we assessed whether altered sympathetic reactivity to peer rejection feedback in early adolescence mediated the relation between early institutional rearing and peer problems in later adolescence. We also assessed whether adolescent friendship quality or randomized placement in foster care early in life moderated these associations. Participants include 68 institutionalized children randomized to care as usual, 68 institutionalized children randomized to foster care, and 135 never-institutionalized children. At age 12, participants reported friendship quality with respect to a best friend and completed a social rejection task while electrocardiogram and impedance cardiography were recorded. Sympathetic nervous system reactivity to rejection feedback was assessed using preejection period (PEP). At ages 12 and 16, peer problems were reported by parents. Mediation analysis revealed that less PEP reactivity to social rejection at age 12 partially mediated the association between early institutionalization and greater peer problems at age 16. Further moderated mediation analysis revealed that this indirect effect was evidenced among previously institutionalized youths with low, but not high, quality friendships. We did not observe foster care intervention effects. These findings suggest that altered sympathetic reactivity to social rejection might be a mechanism linking early institutionalization to social difficulties into adolescence, however, positive adolescent friendships may buffer these effects. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Thymic stromal lymphopoietin overproduced by keratinocytes in mouse skin aggravates experimental asthma.
Atopic dermatitis (AD) is often the initial step in the "atopic march," given that more than half of AD patients with moderate to severe AD develop asthma later in life. Both AD and asthma share a similar "atopy" phenotype that includes T helper type 2 inflammation with eosinophilia and hyper-IgE immunoglobulinemia, but the molecular mechanisms underlying the "atopic march" remain elusive. In the present study, we show that induced expression of thymic stromal lymphopoietin (TSLP) in mouse epidermal keratinocytes upon topical application of MC903 (a low calcemic analogue of vitamin D3) not only triggers AD as we previously reported but also aggravates experimental allergic asthma induced by ovalbumin sensitization and challenge. Our study, which provides a mouse model to study human "atopic march," indicates that keratinocyte-produced TSLP may represent an important factor in the link of atopic dermatitis to asthma.


Factors impacting bladder underactivity and clinical implications.
Lower urinary tract symptoms in the voiding phase can be due to an underactive bladder, but are usually similar to symptoms of infravesical obstruction or dysfunctional voiding. The underactive bladder can be caused by an impaired detrusor contraction but also by a derangement of local and central neuro-cognitive regulatory systems or an impairment of bladder sensation. Potential risk factors of bladder underactivity include: ageing, diabetes, neurogenic disease, cardiovascular disease, obstruction and psychological causes. Comprehensive diagnostic and detection techniques for an underactive detrusor are necessary. To establish the diagnosis and follow up new treatments, useful urodynamic parameters and threshold values have to be determined. As neuro-cognitive regulation plays an important role in the control of voiding, psychological factors have to be taken into account during the assessment in these patients. Ambulatory urodynamic techniques therefore have to be considered. Voiding is determined by the balance of both the detrusor contraction and the resistance of the bladder outlet, a dysfunction in one factor can be compensated by a counter-acting function of the other factor. Therefore, to predict voiding problems in the future, it will be indicated to assess the compensatory capacity of the detrusor contractility, contractile reserve, and the outlet relaxation capacity. If novel treatments and evaluation techniques have become available, it is likely that in the future, many patients that get a TURP now, can be treated by pharmacological agents directed towards increasing the bladder contractility in a balanced combination with medication directed towards lowering the bladder outlet resistance.


Electrochemical hematocrit determination in a direct current microfluidic device.
Hematocrit (HCT) tests are widely performed to screen blood donors and to diagnose medical conditions. Current HCT test methods include conventional microhematocrit, Coulter counter, CuSO4 specific gravity, and conductivity-based point-of-care (POC) HCT devices, which can be either expensive, environmentally inadvisable, or complicated. In the present work, we introduce a new and simple microfluidic system for a POC HCT determination. HCT was determined by measuring current responses of blood under 100 V DC for 1 min in a microfluidic device containing a single microchannel with dimensions of 180 μm by 70 μm and 10 mm long. Current responses of red blood cell (RBC) suspensions in PBS or separately plasma at HCT concentrations of 10, 20, 25, 30, 35, 40, 45, 50, 55, 60, and 70 vol% were measured to show feasibility of the microfluidic system for HCT determination. Key parameters affecting current responses included electrolysis bubbles and irreversible RBC adsorption; parameters were optimized via addition of nonionic surfactant Triton X-100 into sample solution and carbonizing electrode surfaces. The linear trend line of current responses over a range of RBC concentrations were obtained in both PBS and plasma. This work suggested that a simple microfluidic device could be a promising platform for a new POC HCT device.


Echocardiographically documented mitral-valve prolapse. Long-term follow-up of 237 patients.
We determined the long-term prognosis for patients with mitral-valve prolapse documented by echocardiography by following 237 minimally symptomatic or asymptomatic patients for a mean of 6.2 years (range, 1 to 10.4). The actuarial eight-year probability of survival was 88 per cent, which is not significantly different from that for a matched control population. An initial left ventricular diastolic dimension exceeding 60 mm was the best echocardiographic predictor of the subsequent need for mitral-valve replacement (17 patients). Of the 97 patients with redundant mitral-valve leaflets identified echocardiographically, 10 (10.3 per cent) had sudden death, infective endocarditis, or a cerebral embolic event; in contrast, of the 140 patients with nonredundant valves, only 1 (0.7 per cent) had such complications (P less than 0.001). Most patients with echocardiographic evidence of mitral-valve prolapse have a benign course, but subsets at high risk for the development of progressive mitral regurgitation, sudden death, cerebral embolic events, or infective endocarditis can be identified by echocardiography.


The dual nature of biomimetic melanin.
Melanin-inspired nanomaterials offer unique photophysical, electronic and radical scavenging properties that are widely explored for health and environmental preservation, or energy conversion and storage. The incorporation of functional melanin building blocks in more complex nanostructures or surfaces is typically achieved via a bottom-up approach starting from a molecular precursor, in most cases dopamine. Here we demonstrate that indeed, the oxidative polymerization of dopamine, for the synthesis of melanin-like polydopamine (PDA), leads to the simultaneous formation of more than one nanosized species with different compositions, morphologies and properties. In particular, a low-density polymeric structure and dense nanoparticles (NP) are simultaneously formed. The two populations could be separated and analyzed in real time using a chromatographic technique free of any stationary phase (flow field fractionation, FFF). The results following the synthesis of melanin-like PDA showed that the NP are formed only during the first 6 hours as a result of a supramolecular self-assembly-driven polymerization, while the formation of the polymer continues for about 36 hours. The two populations were also separated and characterized using TEM, UV-vis absorption spectroscopy, fluorescence and light scattering spectroscopy, DLS, FTIR, ζ-potential measurements, gel electrophoresis and pH titrations. Interestingly, very different properties between the two populations were observed: in particular the polymer contains a higher number of catechol units (8 mmol g-1 -OH) with respect to the NP (1 mmol g-1 -OH) and presents a much higher antioxidant activity. The attenuation of light by NP is more efficient than that by the polymer especially in the Vis-NIR region. Moreover, while the NP scatter light with an efficiency up to 27% they are not fluorescent, and the polymer does not scatter light but shows an excitation wavelength-dependent fluorescence typical of multi-fluorophoric uncoupled systems.


Effects of long term treatment with an alpha 1 adrenoceptor blocker on cardiac hypertrophy, contractility, and myosin isoenzymes in spontaneously hypertensive rats.
The aim was to investigate the effects of long-term treatment with an alpha 1 blocker, bunazosin hydrochloride, on blood pressure, heart weight, myocardial contractility, and ventricular myosin isoenzyme pattern in spontaneously hypertensive rats (SHR). Bunazosin hydrochloride was given orally in a dose of 10 mg.kg-1.d-1 for 8-9 weeks. Isometric tension development was measured in isolated left ventricular papillary muscles. The left ventricular myosin isoenzyme pattern was determined by pyrophosphate gel electrophoresis. 14 male SHR (seven treated and seven untreated rats) aged 23 to 24 weeks were studied. The blood pressure of the bunazosin treated rats was approximately 14% lower than that of the untreated rats at the end of the treatment period. The ventricular weight of treated SHR was significantly lower (around 8%) than that of untreated rats, but there were no significant differences between the two groups in the mechanical data obtained from isolated left ventricular papillary muscles. The myosin isoenzyme pattern of the left ventricle was significantly shifted toward VM-1 in the bunazosin treated SHR, the VM-1 concentration in the treated group being 38% greater than in the untreated group. These results indicate that long term treatment with bunazosin hydrochloride reduces blood pressure and leads to the regression of cardiac hypertrophy in SHR. Myocardial energetics (as represented by the myosin isoenzyme pattern) were affected, but there was no influence on myocardial tension development.


Meso-diaminopimelic acid and meso-lanthionine, amino acids specific to bacterial peptidoglycans, activate human epithelial cells through NOD1.
Peptidoglycans (PGNs) are ubiquitous constituents of bacterial cell walls and exhibit various immunobiological activities. Two types of minimum essential PGN structures for immunobiological activities were chemically synthesized and designated as muramyldipeptide; N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) and gamma-D-glutamyl-meso-diaminopimelic acid (iE-DAP), which are common constituents of both Gram-positive and Gram-negative bacteria, as well as most Gram-negative and some Gram-positive bacteria, respectively. Recently, intracellular receptors for MDP and iE-DAP have been demonstrated to be nucleotide-binding oligomerization domain (NOD)1 and NOD2, respectively. In this study, we demonstrated that chemically synthesized meso-DAP itself activated human epithelial cells from various tissues, through NOD1 to generate antibacterial factors, PGN recognition proteins and beta-defensin 2, and cytokines in specified cases, although the activities of meso-DAP were generally weaker than those of known NOD agonists. However, stereoisomers of meso-DAP, LL-DAP, and DD-DAP were only slightly activated or remained inactive, respectively. Synthetic meso-lanthionine, which is another diamino-type amino acid specific to PGN of the specified Gram-negative bacteria, was also recognized by NOD1. In human monocytic cells, in the presence of cytochalasin D meso-DAP induced slightly but significantly increased production of cytokines, although the cells did not respond to meso-DAP in the absent of cytochalasin D. Our findings suggest that NOD1 is a special sentinel molecule, especially in the epithelial barrier, allowing the intracellular detection of bacteria through recognizing meso-DAP or comparable moiety of PGN from specified bacteria in cooperation with NOD2, thereby playing a key role in innate immunity.


Effect of oral papaverine on cerebral blood flow in normals: evaluation by the xenon-133 inhalation method.
Several issues related to the use of vasoactive drugs in the treatment of neuropsychiatric disorders secondary to cerebrovascular insufficiency remain unresolved due to lack of a practical method for the quantitative measurement of cerebral blood flow (CBF). The present report concerns the use of a noninvasive CBF method in the evaluation of a commonly used vasoactive drug (oral papaverine). Series CBF measurements were made by the Xe133 inhalation method in 21 healthy young adults, using a double-blind crossover experimental design. The findings show that oral papaverine (300 mg b.i.d.) significantly increases blood flow under conditions of both normal breathing and hyperventilation, the latter being used to induce cerebral vasoconstriction. There were large variations in individual response to the drug, and the average increase in CBF (6 to 9%) was smaller than that observed by other investigators using intravenous papaverine. No adverse reactions or alterations in blood pressure were encountered.


Comprehensive gynecologic endoscopic hospital privileging program. Implementation and assessment.
To describe a comprehensive gynecologic endoscopic privileging program at an urban teaching hospital and evaluate its effect on complication rates. In 1996, a gynecologic endoscopy privileging program was instituted. Initially, experienced surgeons were invited to apply for advanced privileges based on submission of a case list. Afterwards, new applications were approved by proctorship. Since 1995, charts have been reviewed using the following indicators; operating time, estimated blood loss, length of stay, readmission, diagnosis of cancer, reexploration and admission for hysteroscopic fluid overload. Cases were also independently identified when a major vascular or visceral injury occurred. Among the 3,880 gynecologic endoscopic procedures performed during the review period, 2,702 medical records were randomly screened. Following institution of the program, there was no change noted in rates of hysteroscopic fluid overload, readmission, reexploration or unrecognized diagnosis of cancer. However, a decrease was noted in excess blood loss (odds ratio [OR] 0.6, 90% confidence interval [CI] 0.4, 0.9) and operating time greater than four hours (OR 0.6, CI 0.4, 0.9). Length of hospital stay was also reduced in the year following implementation of the privileging process (OR 0.2, CI 0.1, 0.3). Fifty-four cases of visceral or major vascular injury occurred during the three-year period. The risk of visceral injury revealed a trend from 1.9% to 1.0% after institution of the privileging process (OR 0.5, CI 0.3, 1.0). Establishment of a comprehensive gynecologic endoscopic hospital privileging program was associated with a reduction in rates of excess blood loss and operating times and a decreasing trend in visceral injuries.


Uncovering the septal Q wave and other electrocardiographic changes in pediatric patients with pre-excitation before and after ablation.
In patients with pre-excitation, a short PR interval and a delta wave are not always clearly seen, particularly if the pre-excitation is mild. Absent septal Q waves have been used as additional evidence suggestive of pre-excitation. The purpose of the present study was to determine the incidence of normalization of septal Q waves after successful ablation of a manifest accessory pathway in pediatric patients with normal hearts. We performed a retrospective review of electrocardiograms (ECGs) obtained before and after successful catheter ablation of a single manifest accessory pathway in patients <21 years old (84 pairs of ECGs). The ECGs obtained in patients before ablation for atrioventricular nodal re-entry tachycardia were used as controls (n = 62). The absence of Q waves in the lateral leads (V(5) to V(7)) and inferior leads (II, III, aVF) were determined. p Values <0.05 were considered significant. Before the ablation, 72 ECGs (85%) demonstrated absent Q waves in the lateral leads, and only 17 (20%) did not show evidence of Q waves after successful ablation of the accessory pathway (p <0.001). On the inferior leads, 37 ECGs (44%) showed no evidence of Q waves before ablation compared to 24 (29%) after ablation (p <0.05). The findings on the postablation ECG were not statistically different from the findings on the ECGs of the control patients. In conclusion, Q waves in the lateral and inferior leads are often absent in patients with manifest pre-excitation. Absent septal Q waves in the lateral and inferior leads frequently normalize after successful ablation of an accessory pathway.


Single-photon-level quantum memory at room temperature.
Room-temperature, easy-to-operate quantum memories are essential building blocks for future long distance quantum information networks operating on an intercontinental scale, because devices like quantum repeaters, based on quantum memories, will have to be deployed in potentially remote, inaccessible locations. Here we demonstrate controllable, broadband and efficient storage and retrieval of weak coherent light pulses at the single-photon level in warm atomic cesium vapor using the robust far off-resonant Raman memory scheme. We show that the unconditional noise floor of this technically simple quantum memory is low enough to operate in the quantum regime, even in a room-temperature environment.