A Comprehensive Analysis and Anti-Cancer Activities of Quercetin in ROS-Mediated Cancer and Cancer Stem Cells.
Reactive oxygen species (ROS) induce carcinogenesis by causing genetic mutations, activating oncogenes, and increasing oxidative stress, all of which affect cell proliferation, survival, and apoptosis. When compared to normal cells, cancer cells have higher levels of ROS, and they are responsible for the maintenance of the cancer phenotype; this unique feature in cancer cells may, therefore, be exploited for targeted therapy. Quercetin (QC), a plant-derived bioflavonoid, is known for its ROS scavenging properties and was recently discovered to have various antitumor properties in a variety of solid tumors. Adaptive stress responses may be induced by persistent ROS stress, allowing cancer cells to survive with high levels of ROS while maintaining cellular viability. However, large amounts of ROS make cancer cells extremely susceptible to quercetin, one of the most available dietary flavonoids. Because of the molecular and metabolic distinctions between malignant and normal cells, targeting ROS metabolism might help overcome medication resistance and achieve therapeutic selectivity while having little or no effect on normal cells. The powerful bioactivity and modulatory role of quercetin has prompted extensive research into the chemical, which has identified a number of pathways that potentially work together to prevent cancer, alongside, QC has a great number of evidences to use as a therapeutic agent in cancer stem cells. This current study has broadly demonstrated the function-mechanistic relationship of quercetin and how it regulates ROS generation to kill cancer and cancer stem cells. Here, we have revealed the regulation and production of ROS in normal cells and cancer cells with a certain signaling mechanism. We demonstrated the specific molecular mechanisms of quercetin including MAPK/ERK1/2, p53, JAK/STAT and TRAIL, AMPKα1/ASK1/p38, RAGE/PI3K/AKT/mTOR axis, HMGB1 and NF-κB, Nrf2-induced signaling pathways and certain cell cycle arrest in cancer cell death, and how they regulate the specific cancer signaling pathways as long-searched cancer therapeutics.


A Review of the Clinical Evidence for Complementary and Alternative Medicine in Huntington's Disease.
There is a lack of published guidelines related to the use of complementary and alternative medicine (CAM) for Huntington's disease (HD). We conducted a review of the literature to summarize the available evidence for various mind-body practices and nutraceuticals. PubMed and Cochrane Library electronic databases were searched independently from inception to February 2019 by two independent raters. Studies were classified for the level of evidence (Class I, II, III, or IV) according to the American Academy of Neurology (AAN) classification scale. Randomized controlled trials in HD were reviewed for mind-body interventions (dance therapy, music therapy, and exercise), alternative systems (traditional Chinese medicine [TCM]), and nutraceuticals/diet (aminooxyacetic acid [AOAA], coenzyme q10, creatine, cannabinoids, alpha-tocopherol, eicosapentaenoic acid, idebenone, levocarnitine, and triheptanoin). Few studies met AAN Class I or II level of evidence for benefits, and these are highlighted. There is a relative paucity of clinical trials examining CAM modalities in HD when compared to other neurodegenerative disorders. Currently, there is no evidence supporting disease modification or symptom improvement with any specific dietary or nutraceutical supplement for HD. Supervised exercise and contemporary dance are safe for people with HD, but more robust studies are warranted to guide specific recommendations for these and other mind-body interventions.


Cloning of the laminin alpha 3 chain gene (LAMA3) and identification of a homozygous deletion in a patient with Herlitz junctional epidermolysis bullosa.
Laminin 5 and laminin 6 are basement membrane proteins synthesized by the basal cells of stratifying squamous epithelia. Altered expression of laminin 5 has been associated with Herlitz junctional epidermolysis bullosa (H-JEB), a severe epidermal blistering disorder inherited as an autosomal recessive disease. We have isolated cDNA clones encoding the alpha 3 chain of laminin 5 and searched for mutations in the LAMA3 gene in H-JEB patients. In one H-JEB family, an affected individual exhibited drastically reduced immunoreactivity to antibodies directed against the alpha 3 chain of laminin 5 and an impaired expression of the corresponding mRNA transcripts. RT-PCR analysis of mRNA extracted from the proband's keratinocytes identified a homozygous single basepair deletion in the transcripts encoding the laminin alpha 3A and alpha 3B isoforms. The mutation causes a frameshift and premature termination codon in both alleles of the LAMA3 gene. Inheritance of the clinical H-JEB phenotype was consistent with the segregation of the mutated allele in the family. We also report the identity of the alpha chains of laminin 5 and epiligrin and provide evidence that LAMA3 transcripts are distinct from the laminin 6 alpha chain mRNA.


Nowhere land: The evicted space of Black tenants' rights in Montreal.
Property relations in 1980s Montreal were a venue of struggle and change. In this period, a well-organized tenants' movement and the election of progressive governments spawned a series of legal and policy changes that strengthened tenants' rights in the city. During the same period, however, an emerging police, government and media discourse cast Black communities as criminal 'ghettos', and a variety of mechanisms, including new policies meant to protect tenants' rights, were used to evict criminalized Black tenants. Guided by recent work on property and Black geographies, respectively, this article examines how racial subjects are constituted in struggles over tenants' rights. The racial limits of tenants' rights in Montreal, it argues, are traceable to the socio-spatial relations of slavery and the intensifying criminalization of Black life in the 1980s, each of which nullified Black spatial belonging in the city. The tenant, the article concludes, is never just a tenant, but also a racial subject - a subject formed at the edges of blackness. In a terrain forged by slavery and its afterlives, the possibility of expansive tenants' rights presupposes a right systemically denied in advance for Black people in the Americas: the right to exist here in the first place.


Glucagon-like peptide 1 receptor agonists in type 1 diabetes mellitus.
The role of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in the treatment of type 1 diabetes mellitus (T1DM), including efficacy and safety evidence, is reviewed. Currently approved treatment options for glycemic control in T1DM include insulin, which combats insulin deficiency but does not effectively target disease progression or alpha cell dysfunction; and pramlintide, whose use requires multiple daily doses and involves a high likelihood of gastrointestinal side effects. GLP-1 RAs have a unique mechanism of action in T1DM, addressing alpha cell dysfunction and thereby suppressing inappropriate glucagon secretion. GLP-1 RA dosing varies from once weekly to twice daily, and the class is well tolerated in patients with type 2 diabetes. Among the GLP-1 RAs, exenatide and liraglutide have been studied in patients with T1DM, with published evidence consistently demonstrating weight loss, decreases in total daily insulin requirements, and modest improvements in glycemic control. GLP-1 RA therapy appears to be well tolerated in patients with T1DM and is associated with nonsignificant increases in hypoglycemia risk. GLP-1 RA therapy represents an important add-on therapy option for achieving decreased insulin doses, weight loss, and modest improvements in HbA1c levels without significantly increasing hypoglycemia risk in patients with T1DM. Patients who have detectable C-peptide and/or are overweight or cannot achieve glycemic goals without hypoglycemia have been found to benefit the most from GLP-1 RA therapy. Further studies are warranted to evaluate these agents' potential impact on clinical outcomes such as microvascular and macrovascular complications.


Molecular epidemiology and phylogeography of Schistosoma mansoni around Lake Victoria.
Intestinal schistosomiasis continues to be a major public health problem in sub-Saharan Africa, and is endemic in communities around Lake Victoria. Interest is growing in the molecular evolution and population genetic structure of Schistosoma mansoni and we describe a detailed analysis of the molecular epidemiology and phylogeography of S. mansoni from Lake Victoria. In total, 388 cytochrome oxidase 1 (COI) sequences were obtained from 25 sites along the Ugandan, Tanzanian and Kenyan shorelines of Lake Victoria, and 122 unique barcodes were identified; 9 corresponded to previously discovered barcodes from Lakes Victoria and Albert. A subset of the data, composed of COI sequences from miracidia from 10 individual children, was used for population genetics analyses; these results were corroborated by microsatellite analysis of 4 isolates of lab-passaged adult worms. Overall, 12 barcodes were found to be shared across all 3 countries, whereas the majority occurred singly and were locally restricted. The population genetics analyses were in agreement in revealing high diversity at the level of the human host and negligible population structuring by location. The lack of correlation between genetic distance and geographical distance in these data may be attributed to the confounding influence of high intra-individual diversity as well as human migration between communities.


Safety of clopidogrel being continued until the time of coronary artery bypass grafting in patients with acute coronary syndrome: a meta-analysis of 34 studies.
AIMS Guidelines suggest that patients should discontinue clopidogrel for 5 days prior to coronary artery bypass grafting (CABG) where possible. Those with acute coronary syndrome (ACS) are at elevated risk of further myocardial infarction (MI) and death without clopidogrel. This meta-analysis aims to determine the risk of CABG in ACS patients while continuing clopidogrel. METHOD AND RESULTS Thirty-four studies with 22 584 patients undergoing CABG were assessed. Patients with recent clopidogrel exposure (CL) were compared with those without recent clopidogrel (NC). Although mortality is increased in CL vs. NC [odds ratio (OR) 1.6, 95% CI 1.30-1.96, P < 0.00001], it is influenced by the ACS status and case urgency in these mainly non-randomized studies. In ACS patients, there is no significant difference in mortality (OR 1.44, 95% CI 0.97-2.1, P= 0.07) or in postoperative MI (OR 0.57, 95% CI 0.31-1.07, P = 0.08) and stroke rates (OR 1.23, 95% CI 0.66-2.29, P = 0.52). Combined major adverse cardiovascular event (stroke, MI, and death) was not different in the two groups (OR 1.10, 95% CI 0.87-1.41, P= 0.43). Reoperation rates are elevated on clopidogrel but have reduced over time, and were specifically not different in ACS patients (OR 1.5, 95% CI 0.88-2.54, P= 0.13). CONCLUSION Previous studies focused on surrogate endpoints and compared higher risk ACS patients with elective cases. However, many patients have safely undergone CABG on clopidogrel and surgical expertise is growing. Multinational trials are required to fully determine the balance of ischaemia and bleeding. While results are awaited we suggest ACS patients requiring urgent CABG proceed with surgery without delay for a clopidogrel-free period.


A baseline of atmospheric greenhouse gases for prospective UK shale gas sites.
We report a 24-month statistical baseline climatology for continuously-measured atmospheric carbon dioxide (CO2) and methane (CH4) mixing ratios linked to surface meteorology as part of a wider environmental baselining project tasked with understanding pre-existing local environmental conditions prior to shale gas exploration in the United Kingdom. The baseline was designed to statistically characterise high-precision measurements of atmospheric composition gathered over two full years (between February 1st 2016 and January 31st 2018) at fixed ground-based measurement stations on, or near to, two UK sites being developed for shale gas exploration involving hydraulic fracturing. The sites, near Blackpool (Lancashire) and Kirby Misperton (North Yorkshire), were the first sites approved in the UK for shale gas exploration since a moratorium was lifted in England. The sites are operated by Cuadrilla Resources Ltd. and Third Energy Ltd., respectively. A statistical climatology of greenhouse gas mixing ratios linked to prevailing local surface meteorology is presented. This study diagnoses and interprets diurnal, day-of-week, and seasonal trends in measured mixing ratios and the contributory role of local, regional and long-range emission sources. The baseline provides a set of contextual statistical quantities against which the incremental impacts of new activities (in this case, future shale gas exploration) can be quantitatively assessed. The dataset may also serve to inform the design of future case studies, as well as direct baseline monitoring design at other potential shale gas and industrial sites. In addition, it provides a quantitative reference for future analyses of the impact, and efficacy, of specific policy interventions or mitigating practices. For example, statistically significant excursions in measured concentrations from this baseline (e.g. >99th percentile) observed during phases of operational extraction may be used to trigger further examination in order to diagnose the source(s) of emission and links to on-site activities at the time, which may be of importance to regulators, site operators and public health stakeholders. A guideline algorithm for identifying these statistically significant excursions, or "baseline deviation events", from the expected baseline conditions is presented and tested. Gaussian plume modelling is used to further these analyses, by simulating approximate upper-limits of CH4 fluxes which could be expected to give observable enhancements at the monitoring stations under defined meteorological conditions.


Heparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis in mice.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is closely associated with colon cancer. Expression of the enzyme heparanase is clearly linked to colon carcinoma progression, but its role in UC is unknown. Here we demonstrate for what we believe to be the first time the importance of heparanase in sustaining the immune-epithelial crosstalk underlying colitis-associated tumorigenesis. Using histological specimens from UC patients and a mouse model of dextran sodium sulfate-induced colitis, we found that heparanase was constantly overexpressed and activated throughout the disease. We demonstrate, using heparanase-overexpressing transgenic mice, that heparanase overexpression markedly increased the incidence and severity of colitis-associated colonic tumors. We found that highly coordinated interactions between the epithelial compartment (contributing heparanase) and mucosal macrophages preserved chronic inflammatory conditions and created a tumor-promoting microenvironment characterized by enhanced NF-κB signaling and induction of STAT3. Our results indicate that heparanase generates a vicious cycle that powers colitis and the associated tumorigenesis: heparanase, acting synergistically with the intestinal flora, stimulates macrophage activation, while macrophages induce production (via TNF-α-dependent mechanisms) and activation (via secretion of cathepsin L) of heparanase contributed by the colon epithelium. Thus, disruption of the heparanase-driven chronic inflammatory circuit is highly relevant to the design of therapeutic interventions in colitis and the associated cancer.


Prostate-derived ETS factor is a mediator of metastatic potential through the inhibition of migration and invasion in breast cancer.
Cell migration and invasion are critical events during the progression to metastasis. Without motile function, cancer cells are unable to leave the primary tumor site, invade through the basement membrane, and form secondary tumors. Expression of the epithelial-specific ETS factor prostate-derived ETS factor (PDEF) is reduced in human invasive breast tissue and lost in invasive breast cancer cell lines. Gain-of-function studies that examine different aspects of cell migration show that constitutive or inducible PDEF reexpression inhibits migration and invasion in multiple breast cancer cell lines, and loss-of-function studies show a stimulation of migration in noninvasive breast cancer cells. Furthermore, the introduction of PDEF into invasive breast cancer cells led to a remodeling of the actin cytoskeleton and altered focal adhesion localization and adherence levels. Cells expressing PDEF no longer form the defined morphologic polarity required for efficient, directional migration. Collectively, these data indicate that PDEF down-regulation in invasive breast cancer may promote actin-mediated cell migration through the extracellular matrix.


Ensemble analysis of angiogenic growth in three-dimensional microfluidic cell cultures.
We demonstrate ensemble three-dimensional cell cultures and quantitative analysis of angiogenic growth from uniform endothelial monolayers. Our approach combines two key elements: a micro-fluidic assay that enables parallelized angiogenic growth instances subject to common extracellular conditions, and an automated image acquisition and processing scheme enabling high-throughput, unbiased quantification of angiogenic growth. Because of the increased throughput of the assay in comparison to existing three-dimensional morphogenic assays, statistical properties of angiogenic growth can be reliably estimated. We used the assay to evaluate the combined effects of vascular endothelial growth factor (VEGF) and the signaling lipid sphingoshine-1-phosphate (S1P). Our results show the importance of S1P in amplifying the angiogenic response in the presence of VEGF gradients. Furthermore, the application of S1P with VEGF gradients resulted in angiogenic sprouts with higher aspect ratio than S1P with background levels of VEGF, despite reduced total migratory activity. This implies a synergistic effect between the growth factors in promoting angiogenic activity. Finally, the variance in the computed angiogenic metrics (as measured by ensemble standard deviation) was found to increase linearly with the ensemble mean. This finding is consistent with stochastic agent-based mathematical models of angiogenesis that represent angiogenic growth as a series of independent stochastic cell-level decisions.


The mTOR signalling pathway in cancer and the potential mTOR inhibitory activities of natural phytochemicals.
The mammalian target of rapamycin (mTOR) kinase plays an important role in regulating cell growth and cell cycle progression in response to cellular signals. It is a key regulator of cell proliferation and many upstream activators and downstream effectors of mTOR are known to be deregulated in various types of cancers. Since the mTOR signalling pathway is commonly activated in human cancers, many researchers are actively developing inhibitors that target key components in the pathway and some of these drugs are already on the market. Numerous preclinical investigations have also suggested that some herbs and natural phytochemicals, such as curcumin, resveratrol, timosaponin III, gallic acid, diosgenin, pomegranate, epigallocatechin gallate (EGCC), genistein and 3,3'-diindolylmethane inhibit the mTOR pathway either directly or indirectly. Some of these natural compounds are also in the clinical trial stage. In this review, the potential anti-cancer and chemopreventive activities and the current status of clinical trials of these phytochemicals are discussed.


[Cytomegalovirus infection as a possible factor in the progression of neuroblastoma].
There is evidence that the infection with human cytomegalovirus is clinically associated with enhanced metastasis and progression of neuroblastoma disease. An in vitro model with HCMV-infected neuroblastoma cells (NB) was used to investigate whether HCMV modulates the metastatic potential of NB. The neuroblastoma cell line UKF-NB-4 and its productively and persistently HCMV-infected variant UKF-NB-4AD169 were cocultured with human endothelial cells (EC). The rate of NB adherent to the endothelial monolayer and the rate of transmigrating NB was determined by means of combined reflexion interference contrast/phase contrast microscopy. UKF-NB-4AD169 adhered to and transmigrated through cocultured EC monolayer to a significantly higher extent compared with the non-infected cell line UKF-NB-4. At the cell-to-cell contact sites between UKF-NB-4AD169 and EC the intercellular endothelial contacts loosened resulting in the formation of reversible focal openings in the monolayer. This phenomenon was not observed with UKF-NB-4. The transendothelial migration rate of UKF-NB-4AD169 was therefore significantly higher than that of UKF-NB-4. The formation of focal openings in the endothelial monolayer and the enhanced transmigration rate of UKF-NB-4AD169 was suppressed in the presence of phenantroline, suggesting that HCMV-induced proteinases might be responsible for this phenomenon. The results confirm our assumption that HCMV has the ability to modulate functional properties of NB which are essential for the interactions with endothelial cells and thus for metastasation. The clinical relevance of these findings has to be further defined yet by means of prospective studies with HCMV-infected neuroblastoma patients. Proteinase inhibitors could be valuable in the therapeutic treatment of these patients.


Prevalence and risk factors of workplace violence against health care workers in emergency department in Ismailia, Egypt.
Emergency department is one of the high-risk areas, where violence against health care workers (HCWs) is a prevalent and serious problem. Violence has negative effects on HCWs, and therefore on the quality of care provided in emergency department. This study aimed to determine the prevalence, types, sources and risk factors of violence reported by HCWs in emergency department. A cross-sectional study was conducted using a standardized questionnaire developed by the WHO. One hundred thirty four questionnaires were included in this study (94.4% response rate). WPV was reported by 59.7% of HCWs. Verbal violence was the most reported (58.2%), compared to physical violence (15.7%). The most reported reasons for violence were waiting time and that patient and family expectations not being met. Only 29.5% of HCWs who experienced verbal violence and 23.8% of who experienced physical violence reported it to hospital authority. About 75% of HCW thought that work place violence could be prevented, and about 60% said that no action was taken against the attacker by hospital authority. Violence against HCWs in emergency department is a significant issue that cannot be ignored. There are multiple reasons. The key point in dealing with the problem is to treat its specific causes.


The extruding implant.
In both the treatment and prevention of implant extrusion, exacting surgical technique is necessary. The techniques involved are direct reimplantation of the implant, reinforcement of the tissue with patching and, for additional cosmetic revision, subperiosteal glass bead implantation or fornix reconstruction.


James Hillman: the unmaking of a psychologist. Part one: His legacy.
This two-part essay offers a critical assessment of Hillman's archetypal psychology and enquires into its viability as a psychological model. The first part explores his legacy and reviews the metapsychological frame in which his work operates. It considers the relation between his thought and Jung's, and argues that Hillman's work is not so much post-Jungian as pre-Jungian. The second part is primarily intrapsychic; it explores Hillman's character, as discerned through his writings and interviews, and considers his work as an expression of the puer aeternus. It is argued that the puer prefers to live in an eternal dream-state resistant to growing up: yet denial of the maturational impulse will only lead to it happening anyway but in a negative form. The paper considers how Hillman's model was 'unmade' by the missing developmental element of his thought. Development is an archetypal and bio-psychological necessity, and if rejected it can ruin any system that refuses to take it seriously. In Hillman's case this manifested in the form of a repressed masculine shadow, destroying the credibility of his earlier work. The two-part paper attempts to weave an objective appraisal with a running commentary based on the author's personal engagement with the man and his work.


Potential Therapeutic Effects of Short-chain Fatty Acids on Chronic Pain.
The intestinal homeostasis maintained by the gut microbiome and relevant metabolites is essential for health, and its disturbance leads to various intestinal or extraintestinal diseases. Recent studies suggest that gut microbiome-derived metabolites short-chain fatty acids (SCFAs) are involved in different neurological disorders (such as chronic pain). SCFAs are produced by bacterial fermentation of dietary fibers in the gut and contribute to multiple host processes, including gastrointestinal regulation, cardiovascular modulation, and neuroendocrine-immune homeostasis. Although SCFAs have been implicated in the modulation of chronic pain, the detailed mechanisms that underlie such roles of SCFAs remain to be further investigated. In this review, we summarize currently available research data regarding SCFAs as a potential therapeutic target for chronic pain treatment and discuss several possible mechanisms by which SCFAs modulate chronic pain.


The bad and the good of mesenchymal stem cells in cancer: Boosters of tumor growth and vehicles for targeted delivery of anticancer agents.
In cancer biology, mesenchymal stem cells (MSCs) display aspects that can appear contradictory. On one hand, these cells possess several features which give them the ability to specifically target and then sustain cancer cells in their ability to survive the multifaceted host response against cancer. On the other hand, due to this excellent aptitude to home-in on tumor tissues, regardless their location in the host's body, MSCs are considered to be extremely selective vehicles to reach cancer cells specifically. Recently, MSC sustainment of cancer cell growth is a hot research topic. Indeed, these cells are known to sustain tumor angiogenesis and metastasis formation, to create a microenvironment favorable for cancer cell growth and to down-modulate the immune system capabilities in the host organism. On the other hand, since scientists became able to take advantage of their extremely selective capability to target cancer cells, MSCs are now also thought of in a different light. Indeed, MSCs are now considered a promising vehicle for local expression or delivery of even particularly toxic anticancer agents, ranging from Herpes Simplex Virus to locally-acting antineoplastic drugs. On this basis, investigation is now focused on how to impair the pro-neoplastic features of MSCs on one hand whilst taking advantage of their specific tropism toward cancer cells, on the other. As with the two faces of Janus, this review will concisely explore the research activity in these two apparently conflicting fields.


Hospitalizations for injury: United States, 1996.
This report presents national estimates of the 1996 hospitalizations for injury in the United States. Numbers and rates of discharges are shown within sex, age, and racial groups by type of injury. Average lengths of stay and days of care data by injury type are also included. Estimates are based on medical abstract data collected in the National Hospital Discharge Survey. Diagnoses are coded according to the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). Injuries are defined as ICD-9-CM codes 800-999. External causes of injury are defined as codes E800-E999 (E-codes). In 1996, there were 2.6 million hospitalizations for injury. Fractures resulted in over a million hospitalizations; medical injuries, including adverse effects and complications, were responsible for 666,000 hospitalizations. The medical records for 64 percent of the patients hospitalized for injuries had an external cause-of-injury code (E-code). Elderly people had the largest number and rate of injuries. Data on injuries requiring hospitalization and characteristics of patients differentially affected can be used to design and target more effective injury prevention programs. Preventing injuries would decrease the considerable pain, disability, and economic impact associated with these conditions.


DNA typing for HLA-A and HLA-B identifies disparities between patients and unrelated donors matched by HLA-A and HLA-B serology and HLA-DRB1.
High incidences of graft failure and graft-versus-host disease in the recipients of bone marrow transplantations (BMT) from unrelated donors (URD) may reflect the existence of allelic disparities between the patient and the URD despite apparent HLA identity at HLA-A, HLA-B, and HLA-DRB1 loci. To identify the extent and pattern of allelic disparities at HLA-A and HLA-B loci, 128 patients and 484 potential URD were evaluated by DNA typing. DNA typing for HLA-A, HLA-B, and HLA-DRB1 was performed at Memorial Sloan Kettering Cancer Center. HLA-A and HLA-B serotyping on URD was provided by the registries. By original typing (serology for HLA-A and HLA-B; DNA typing for DRB1) 187, 164, and 133 URD were 6/6, 5/6, and 4/6 matches, respectively. Following DNA typing, however, only 52.9% of the originally 6/6 matched URD remained 6/6, while 38.5%, 7.5%, and 1.1% were found to be 5/6, 4/6, and 3/6 matches. The level of disparity was higher in the originally 5/6 (P <.01) and 4/6 (P <.01) matched URD. A higher level of disparity was seen for HLA-B as compared to HLA-A. In addition, a serotype related variation was also noticed. For example, 24.1% of HLA-A2 and 60.1% of HLA-B35 seromatched URD were genotypically disparate, but no disparities were seen for HLA-A1 and HLA-B8. A higher percentage of HLA-A (67. 4%) compared with HLA-B (35.4%) serologic homozygous URD remained genotypically homozygous (P =.01). The level of allelic disparity was lower (P <.01 for 6/6; P =.02 for 5/6) if the patient had one of the 15 most common haplotypes (A1B8DR3, A2B7DR15, A3B7DR15, etc) in comparison to the rest of the group. Outcome studies will answer the question whether these disparities are associated with a higher rate of immunological complications seen with URD-BMT.


Blood cis-eQTL analysis fails to identify novel association signals among sub-threshold candidates from genome-wide association studies in restless legs syndrome.
Restless legs syndrome (RLS) is a common neurologic disorder characterized by nightly dysesthesias affecting the legs primarily during periods of rest and relieved by movement. RLS is a complex genetic disease and susceptibility factors in six genomic regions have been identified by means of genome-wide association studies (GWAS). For some complex genetic traits, expression quantitative trait loci (eQTLs) are enriched among trait-associated single nucleotide polymorphisms (SNPs). With the aim of identifying new genetic susceptibility factors for RLS, we assessed the 332 best-associated SNPs from the genome-wide phase of the to date largest RLS GWAS for cis-eQTL effects in peripheral blood from individuals of European descent. In 740 individuals belonging to the KORA general population cohort, 52 cis-eQTLs with pnominal<10(-3) were identified, while in 976 individuals belonging to the SHIP-TREND general population study 53 cis-eQTLs with pnominal<10(-3) were present. 23 of these cis-eQTLs overlapped between the two cohorts. Subsequently, the twelve of the 23 cis-eQTL SNPs, which were not located at an already published RLS-associated locus, were tested for association in 2449 RLS cases and 1462 controls. The top SNP, located in the DET1 gene, was nominally significant (p<0.05) but did not withstand correction for multiple testing (p = 0.42). Although a similar approach has been used successfully with regard to other complex diseases, we were unable to identify new genetic susceptibility factor for RLS by adding this novel level of functional assessment to RLS GWAS data.


Glycogen storage disease type IV: a case report.
Glycogen storage disease type IV (GSD-IV) is a rare autosomal recessive disease caused by deficient glycogen branching enzyme (GBE). We report a 15-month-old female patient with GSD-IV who exhibited an abdominal distension and failure to thrive for 9 months. The patient showed hepatosplenomegaly with massive ascites. The laboratory findings showed abnormal liver functions including prolongation of prothrombin time and partial thromboplastin time. The light microscopic and electron microscopic findings of the liver biopsy specimen were consistent with GSD-IV. Measurement of glycogen quantity in the red blood cells showed increased storage of glycogen in the patient and interestingly, in her mother. The GBE activity of the patient's red blood cells was undetectable. The patient's ascites, general condition, and laboratory findings have been improved with supportive treatment with diuretics and a low dose of prednisolone.


Validity of Wrist-Wearable Activity Devices for Estimating Physical Activity in Adolescents: Comparative Study.
The rapid advancements in science and technology of wrist-wearable activity devices offer considerable potential for clinical applications. Self-monitoring of physical activity (PA) with activity devices is helpful to improve the PA levels of adolescents. However, knowing the accuracy of activity devices in adolescents is necessary to identify current levels of PA and assess the effectiveness of intervention programs designed to increase PA. The study aimed to determine the validity of the 11 commercially available wrist-wearable activity devices for monitoring total steps and total 24-hour total energy expenditure (TEE) in healthy adolescents under simulated free-living conditions. Nineteen (10 male and 9 female) participants aged 14 to 18 years performed a 24-hour activity cycle in a metabolic chamber. Each participant simultaneously wore 11 commercial wrist-wearable activity devices (Mi Band 2 [XiaoMi], B2 [Huawei], Bong 2s [Meizu], Amazfit [Huamei], Flex [Fitbit], UP3 [Jawbone], Shine 2 [Misfit], GOLiFE Care-X [GoYourLife], Pulse O2 [Withings], Vivofit [Garmin], and Loop [Polar Electro]) and one research-based triaxial accelerometer (GT3X+ [ActiGraph]). Criterion measures were total EE from the metabolic chamber (mcTEE) and total steps from the GT3X+ (AGsteps). Pearson correlation coefficients r for 24-hour TEE ranged from .78 (Shine 2, Amazfit) to .96 (Loop) and for steps ranged from 0.20 (GOLiFE) to 0.57 (Vivofit). Mean absolute percent error (MAPE) for TEE ranged from 5.7% (Mi Band 2) to 26.4% (Amazfit) and for steps ranged from 14.2% (Bong 2s) to 27.6% (Loop). TEE estimates from the Mi Band 2, UP3, Vivofit, and Bong 2s were equivalent to mcTEE. Total steps from the Bong 2s were equivalent to AGsteps. Overall, the Bong 2s had the best accuracy for estimating TEE and total steps under simulated free-living conditions. Further research is needed to examine the validity of these devices in different types of physical activities under real-world conditions.


Development of bone and cartilage in tissue-engineered human middle phalanx models.
Human middle phalanges were tissue-engineered with midshaft scaffolds of poly(L-lactide-epsilon-caprolactone) [P(LA-CL)], hydroxyapatite-P(LA-CL), or beta-tricalcium phosphate-P(LA-CL) and end plate scaffolds of bovine chondrocyte-seeded polyglycolic acid. Midshafts were either wrapped with bovine periosteum or left uncovered. Constructs implanted in nude mice for up to 20 weeks were examined for cartilage and bone development as well as gene expression and protein secretion, which are important in extracellular matrix (ECM) formation and mineralization. Harvested 10- and 20-week constructs without periosteum maintained end plate cartilage but no growth plate formation. They also consisted of chondrocytes secreting type II collagen and proteoglycan, and they were composed of midshaft regions devoid of bone. In all periosteum-wrapped constructs at like times, end plate scaffolds held chondrocytes elaborating type II collagen and proteoglycan and cartilage growth plates resembling normal tissue. Chondrocyte gene expression of type II collagen, aggrecan, and bone sialoprotein varied depending on midshaft composition, presence of periosteum, and length of implantation time. Periosteum produced additional cells, ECM, and mineral formation within the different midshaft scaffolds. Periosteum thus induces midshaft development and mediates chondrocyte gene expression and growth plate formation in cartilage regions of phalanges. This work is important for understanding developmental principles of tissue-engineered phalanges and by extension those of normal growth plate cartilage and bone.


A prospective study of hormone therapy and depression in community-dwelling elderly women: the Three City Study.
The potential benefits of hormone therapy (HT) in treating depressed postmenopausal women are controversial, and data on depression (re)emergence in the context of HT discontinuation are lacking. To determine whether HT is associated with a modified risk of new-onset depressive symptoms in elderly women. Current depressive symptomatology was evaluated in 4,069 community-dwelling postmenopausal women aged 65 years and over who were randomly recruited from 3 French cities between 1999 and 2001. Depressive symptomatology was assessed using the Center for Epidemiologic Studies-Depression Scale at baseline and as part of the 2- and 4-year follow-up. Over the follow-up period, multivariate logistic regression analyses adjusted for sociodemographic variables, measures of physical health, and cognitive impairment failed to find a significant association between HT at baseline and the incidence of depressive symptoms. However further analysis indicated an increased risk of incident depressive symptoms for women using transdermal estradiol treatment combined with synthetic progestin specifically (odds ratio [OR] = 1.59; 95% CI, 1.01-2.50; P = .046). In addition, while women taking HT continuously over the 4-year follow-up did not show an increased risk of depressive symptoms, women who stopped their treatment early after study inclusion, had a significantly higher risk (OR = 2.63; 95% CI, 1.52-4.55; P = .0005). Hormone therapy was not associated with a protective effect against the emergence of depressive symptoms in elderly postmenopausal women. However, discontinuing treatment could increase the risk of depressive symptoms. Data on the appropriate management of depression in the context of HT discontinuation among postmenopausal women require further investigation.


Accumulation of rifampicin by Escherichia coli and Staphylococcus aureus.
A centrifugation method was used to investigate the accumulation of 14C-rifampicin by Staphylococcus aureus and Escherichia coli, and to characterize the mechanism of rifampicin transport into S. aureus. For both species, drug accumulation was rapid with the steady-state concentration (SSC) reached within 40 s of drug exposure. Rifampicin accumulation by S. aureus was temperature and pH dependent; the lower the experimental temperature and the lower the experimental pH, the lower was the concentration of rifampicin accumulated. Accumulation was unaffected by the presence of inhibitors of antibiotic efflux, carbonyl cyanide m-chlorophenylhydrazone (CCCP), dinitrophenol (DNP), or reserpine. Exposure to increasing concentrations of rifampicin suggested that the accumulation process was saturable above a rifampicin concentration of 0.2 mg/L. Michaelis-Menten kinetics gave an apparent Km and Vmax for rifampicin, calculated from a Lineweaver-Burk plot, of 0.05 mg/L (0.06 microM) and 3.8 ng rifampicin per second, respectively. However, calculations suggest that these values reflect those for binding of rifampicin to its target, RNA polymerase.


Multimodal management of arteriovenous malformations of the basal ganglia and thalamus: factors affecting obliteration and outcome.
Arteriovenous malformations (AVMs) of the basal ganglia and thalamus are particularly difficult lesions to treat, accounting for 3%-13% of all AVMs in surgical series and 23%-44% of malformations in radiosurgery series. The goal of this study was to report the results of multimodal management of basal ganglia and thalamic AVMs and investigate the factors that influence radiographic cure and good clinical outcomes. This study was a retrospective analysis of a prospectively maintained database of all patients treated at the authors' institution. Clinical, radiological, follow-up, and outcome data were analyzed. Univariate and multivariate analyses were conducted to explore the influence of various factors on outcome. The results and data analysis pertaining to 123 patients treated over 32 years are presented. In this cohort, radiographic cure was achieved in 50.9% of the patients. Seventy-five percent of patients had good clinical outcomes (stable or improved performance scores), whereas 25% worsened after treatment. Inclusion of surgery and radiosurgery independently predicted obliteration, whereas nidus diameter and volume predicted clinical outcomes. Nidus volume/diameter and inclusion of surgery predicted the optimal outcome, i.e., good clinical outcomes with lesion obliteration. Good outcomes are possible with multimodal treatment in these complex patients. Increasing size and, by extension, higher Spetzler-Martin grade are associated with worse outcomes. Inclusion of multiple modalities of treatment as indicated could improve the chances of radiographic cure and good outcomes.


Prognostic significance of natural killer cell activity in patients with gastric carcinoma: a multivariate analysis.
Natural cytotoxicity, mediated by natural killer (NK) cells, has been believed to play an important role in inhibiting experimental tumor metastasis, and diminished NK cell activities leads to a high incidence of tumor occurrence. Despite convincing evidence from experimental studies, the role of NK cells in the immunological surveillance against cancer in human is poorly defined. The present study was based on a retrospective analysis of data on 156 patients with gastric cancer, who were surgically treated in the Department of Surgery II, Kyushu University Hospital from 1993 to 1996. All patients were examined for NK cell activity based on a peripheral blood sampling done preoperatively. Significant association between NK cell activity and clinicopathological parameters including tumor size, lymphatic involvement, vascular involvement, and lymph node metastases was evident. When comparing the two groups according to NK cell activity, tumors with low NK cell activity tend to have lymphatic involvement. The 5-yr survival rates were 94.6% and 72.3% for those with NK cell activity > 25% lysis and < or = 25% lysis, respectively, the value being statistically significant (p < 0.05). The independent risk factors for prognosis examined by logistic regression analysis were lymphatic involvement. NK cell activity, depth of tumor invasion, and lymph node dissection. These current data showed that NK cell activity may be related to tumor volume and dissemination. Measurement of preoperative NK cell activity may be pertinent for the prognosis of patients with gastric cancer and for follow-up clinical management.


The role of voltage-dependent calcium channels in angiotensin-stimulated glomerulosa cells.
The concept that voltage-dependent Ca2+ influx is essential in the aldosterone stimulating action of angiotensin II (AII) has been recently challenged by the demonstration of the dihydropyridine (DHP) insensitive 'capacitative' Ca2+ uptake mechanism. The DHP-sensitivity of AII-induced aldosterone secretion is still to be explained. In rat glomerulosa cells the lag phase of AII-induced depolarization is more than 30 s, and there is no enhanced Ca2+ influx within the first min of stimulation. Yet we observed that DHPs as well as diltiazem influenced also the peak of cytoplasmic Ca2+ signal, although the peak (approximately 12 s) is attributed to Ca2+ release alone. Nifedipine reduced the Ca2+ transient induced by AII even after complete inhibition of Ca2+ channel activity. Recalling the loose attachment of InsP3 receptors (IP3R) to the plasma membrane, and the homology between the cytosolic domain of IP3R and the Ca2+ release channel (ryanodine receptor) of skeletal muscle, we proposed that DHP-sensitive L-type Ca2+ channels (DHP receptors) influence InsP3-induced Ca2+ release rather than Ca2+ influx in AII-stimulated cells. Although the dominant isoform is the neuroendocrine (D) one, the skeletal muscle isoform of L-type voltage-dependent Ca2+ channel is also expressed in rat glomerulosa cells. This isoform may be a candidate for protein-protein interaction between DHPR and subplasmalemmal IP3R, similarly to that occurring between DHP receptors and ryanodine receptors in skeletal muscle.


Lysophosphatidic acid (LPA) and its receptors: role in airway inflammation and remodeling.
Lysophosphatidic acid (LPA), a simple bioactive phospholipid, is present in biological fluids such as plasma and bronchoalveolar lavage (BAL). It appears to have both pro- and anti-inflammatory roles in inflammatory lung diseases. Exogenous LPA promotes inflammatory responses by regulating the expression of chemokines, cytokines, and cytokine receptors in lung epithelial cells. In addition to the modulation of inflammatory responses, LPA regulates cytoskeleton rearrangement and confers protection against lung injury by enhancing lung epithelial cell barrier integrity and remodeling. The biological effects of LPA are mediated through its cell surface G-protein coupled LPA(1-7) receptors. The roles of LPA receptors in lung fibrosis, asthma, and acute lung injury have been investigated using genetically engineered LPA receptor deficient mice and there appears to be a definitive role for endogenous LPA and its receptors in the pathogenesis of pulmonary inflammatory diseases. This review summarizes recent reports on the role of LPA and its receptors in the regulation of lung epithelial inflammatory responses and remodeling. This article is part of a Special Issue entitled: Advances in Lysophospholipid Research.


The nuclear receptor corepressor SMRT inhibits interstitial collagenase (MMP-1) transcription through an HRE-independent mechanism.
Nuclear receptors inhibit synthesis of collagenase-1 (matrix metalloproteinase-1; MMP-1), an enzyme that degrades interstitial collagens and contributes to joint pathology in rheumatoid arthritis. SMRT (Silencing Mediator for Retinoid and Thyroid hormone receptors) mediates the repressive effect of nuclear receptors at hormone responsive elements (HREs), prompting us to investigate whether this co-repressor could also regulate transcription of MMP-1, which lacks any known HREs. We find that primary synovial fibroblasts express SMRT. When over-expressed by transient transfection, SMRT inhibits MMP-1 promoter activity induced by interleukin-1 (IL-1), phorbol phorbol myristate acetate (PMA) or v-Src. SMRT apparently inhibits MMP-1 gene expression by interfering with one or more transcriptional elements clustered in a region between -321 and +63. We conclude that SMRT negatively regulates MMP-1 synthesis through a novel, HRE-independent mechanism that involves proximal regions of the MMP-1 promoter.


The autoradiolytic and the gamma-induced demethylation of solid thymine-(methyl-14C).
The autoradiolytic and the gamma-induced demethylation of solid thymine were measured qualitatively and quantitatively for the first time with specially purified thymine-(methyl-14C). Analogous experiments with thymine-(methyl-3H) and radio-gaschromatographic analysis provided proof for the formation of molecular hydrogen and methane. Ethane was not detected. The results are discussed in connection with e.s.r.-spectroscopic studies.


Reproductive justice in the time of COVID-19: a systematic review of the indirect impacts of COVID-19 on sexual and reproductive health.
Despite gendered dimensions of COVID-19 becoming increasingly apparent, the impact of COVID-19 and other respiratory epidemics on women and girls' sexual and reproductive health (SRH) have yet to be synthesized. This review uses a reproductive justice framework to systematically review empirical evidence of the indirect impacts of respiratory epidemics on SRH. We searched MEDLINE and CINAHL for original, peer-reviewed articles related to respiratory epidemics and women and girls' SRH through May 31, 2021. Studies focusing on various SRH outcomes were included, however those exclusively examining pregnancy, perinatal-related outcomes, and gender-based violence were excluded due to previously published systematic reviews on these topics. The review consisted of title and abstract screening, full-text screening, and data abstraction. Twenty-four studies met all eligibility criteria. These studies emphasized that COVID-19 resulted in service disruptions that effected access to abortion, contraceptives, HIV/STI testing, and changes in sexual behaviors, menstruation, and pregnancy intentions. These findings highlight the need to enact policies that ensure equitable, timely access to quality SRH services for women and girls, despite quarantine and distancing policies. Research gaps include understanding how COVID-19 disruptions in SRH service provision, access and/or utilization have impacted underserved populations and those with intersectional identities, who faced SRH inequities notwithstanding an epidemic. More robust research is also needed to understand the indirect impact of COVID-19 and epidemic control measures on a wider range of SRH outcomes (e.g., menstrual disorders, fertility services, gynecologic oncology) in the long-term.


Loud calls, startle behaviour, social organisation and predator avoidance in arboreal langurs (Cercopithecidae: Presbytis).
Linking predator avoidance and social organisation predicts that large groups are favoured under heavy predation pressure but that small, inconspicuous groups may do equally well by avoiding detection altogether. We explored the relationships between antipredator behaviour (vocalisation, concealment, fleeing), detectability (colouration, group size) and social organisation in arboreal langurs. Three clear antipredation conditions emerged: (1) exemplified by Presbytis melalophos--brightly-coloured species (red, yellow) with contrasting colours, living in large unimale-multifemale groups (>10 individuals), that vocalised frequently and that flee loudly through the canopy; (2) exemplified by P. comata--greyish species (some contrasting colours), living in intermediate, unimale-multifemale or 1-male-1-female groups (approx. 7 individuals), that vocalise infrequently and that flee through the middle forest layers; (3) exemplified by P. frontata--dull-coloured species without contrast, living in small unimale-multifemale or 1-male-1-female groups (<5 individuals), that may freeze upon detection, and that may vocalise mainly during the night. Crypsis as an antipredator strategy is restricted to taxa that occur in 1-male-1-female groups. This wide range of antipredator strategies within a monophyletic taxon living in the same general area with a similar suite of predators facing similar predator pressures appears to be unique among the order Primates.


The association between BCG treatment in patients with bladder cancer and subsequent risk of developing Alzheimer and other dementia.-A Swedish nationwide cohort study from 1997 to 2019.
Alzheimer's disease (AD) affects 50 million people worldwide. The immune system plays a major role in the pathogenesis of AD. Several retrospective analyses have reported a decreased risk of AD and other dementias in bladder cancer patients treated with immunotherapy in the form of Bacillus Calmette-Guerin (BCG) bladder instillations. We tested this hypothesis in a Swedish population-based prospective cohort of patients with non-muscle invasive bladder cancer (NMIBC). We utilized the BladderBaSe 2.0 database, which contains tumor-specific, health-related, and socio-demographic information for patients diagnosed with NMIBC between 1997 and 2019. The database also includes a matched comparison cohort sampled from the general population, consisting of individuals free from urinary tract cancer at the time of the index case's diagnosis. Five controls were randomly selected for each index case without replacement on the date of the index case's diagnosis. Our inclusion criteria identified participants diagnosed with NMIBC who had received BCG as primary treatment, along with their corresponding comparison cohort. We excluded those diagnosed with dementia before or within 6 months of NMIBC diagnosis. To compare the NMIBC cohort with their matched comparison cohort, we used a stratified Cox model, treating each case with its controls as a stratum. We identified 38,934 patients in the NMIBC cohort, with 6,496 receiving BCG after primary diagnosis (cases). AD/dementia was diagnosed during follow-up in 6.1% of cases and 7.4% of controls. Cases had a slightly lower risk of dementia than controls, with a hazard ratio (HR) of 0.88 (95% confidence interval [CI] 0.780-0.991), and a HR of 0.89 (CI 0.703-1.119) for AD. Subgroup analysis for dementia showed that age over 75 years had an HR of 0.73 (CI 0.616-0.863), and female gender had an HR of 0.73 (CI 0.552-0.971). The associations were similar for AD specifically, but not statistically significant. Similar to previous studies, we analyzed bladder cancer patients treated with and without BCG therapy. Multivariate Cox analysis indicated that those treated with BCG had a lower risk of dementia (HR 0.81, 95% CI 0.71-0.92), and an HR of 0.98 (95% CI 0.75-1.27) for AD specifically. High age was a significant risk modifier; the HR was 3.8 (CI 3.44-4.11) for dementia and 3.1 (CI 2.59-3.73) for AD. Even patients not receiving BCG had a significantly lower risk for AD than controls (HR 0.86, CI 0.77-0.96). This study observed a marginally decreased risk of developing AD/dementia associated with earlier intravesical BCG treatment in NMIBC patients. This small benefit was most pronounced in those with high age and female gender. The disparity from previous highly positive studies underscores the importance of using an appropriate control cohort.


[Pathologic anatomy of childhood diseases today].
The main problems developed by M. A. Skvortsov, the founder of pathology of childhood diseases in the USSR, are dealt with. M. A. Skvortsov worked on pathology mainly of infectious diseases analysing them from the point of view of the patterns of responsiveness of the child. New information which has at present enriched the theory of child's responsiveness is given: enzymatic systems and their defects, endocrine regulation and the importance of the enterine system, immune responsiveness and the importance of its defects. The current status of pathology of modern infectious diseases of childhood, in particular, umbilical sepsis, oncological diseases, etc. are dealt with. The role of organization of the childhood pathological service for further development of the M. A. Skvortsov's theory concerning pathology of childhood diseases is indicated.


HIV risk behaviours among male-to-female transgenders in comparison with homosexual or bisexual males and heterosexual females.
Issues and concerns among six directors, one counsellor and one consultant for transgender programmes in San Francisco are described. Additionally, 173 clients who were enrolled in programmes in eight AIDS service organizations were interviewed using a structured survey questionnaire. This study examined the relationships between HIV risk behaviours and social and cognitive factors among transgendered females (male-to-female transgenders) (n = 25) in comparison with homosexual or bisexual males (n = 122) and heterosexual females (n = 26). Transgendered females engaged in riskier behaviours than the other groups in terms of the number of sex partners in the past 30 days and the past six months, commercial sex activities, and having a steady sex partner who injected drugs. Adverse socioeconomic conditions and transgender-specific risk behaviours such as injecting hormones in relation to HIV risk behaviours must be targeted by future intervention studies.


EVOKED POTENTIALS AND CORRELATED JUDGEMENTS OF BRIGHTNESS AS FUNCTIONS OF INTERFLASH INTERVALS.
Computer-averaged evoked potentials were recorded from subjects presented with pairs of flashes having equal light energy but differing in duration of the brief interval separating the flashes. For the experimental conditions studied, the pair was always subjectively fused. Although the brightness did not change noticeably as the interval was varied, the use of the forced-choice psychophysical technique showed that apparent brightness declined with increase in the interval. Analysis of the evoked potentials revealed a correlated change in amplitude and wave form previously demonstrated for changes in flash flux alone.


Why are there hotspot mutations in the TP53 gene in human cancers?
The p53 gene contains homozygous mutations in ~50-60% of human cancers. About 90% of these mutations encode missense mutant proteins that span ~190 different codons localized in the DNA-binding domain of the gene and protein. These mutations produce a protein with a reduced capacity to bind to a specific DNA sequence that regulates the p53 transcriptional pathway. Eight of these mutations are localized in codons that account for ~28% of the total p53 mutations and these alleles appear to be selected for preferentially in human cancers of many tissue types. This article explores the question 'Why are there hotspot mutations in the p53 gene in human cancers?' Four possible reasons for this are considered; (1) the hotspot mutant alleles produce a protein that has a highly altered structure, (2) environmental mutagens produce allele-specific changes in the p53 gene, (3) these mutations arise at selected sites in the gene due to a specific DNA sequence, such as a methylated cytosine residue in a CpG dinucleotide, which has a higher mutation rate changing C to T nucleotides, (4) along with the observed change in mutant p53 proteins, which produce a loss of function (DNA binding and transcription), some mutant proteins have an allele-specific gain of function that promotes cancer. Evidence is presented that demonstrates the first three possibilities all contribute some property to this list of hotspot mutations. The fourth possibility remains to be tested.


The effect of lifelong exercise dose on cardiovascular function during exercise.
An increased "dose" of endurance exercise training is associated with a greater maximal oxygen uptake (Vo2max), a larger left ventricular (LV) mass, and improved heart rate and blood pressure control. However, the effect of lifelong exercise dose on metabolic and hemodynamic response during exercise has not been previously examined. We performed a cross-sectional study on 101 (69 men) seniors (60 yr and older) focusing on lifelong exercise frequency as an index of exercise dose. These included 27 who had performed ≤ 2 exercise sessions/wk (sedentary), 25 who performed 2-3 sessions/wk (casual), 24 who performed 4-5 sessions/wk (committed) and 25 who performed ≥ 6 sessions/wk plus regular competitions (Masters athletes) over at least the last 25 yr. Oxygen uptake and hemodynamics [cardiac output, stroke volume (SV)] were collected at rest, two levels of steady-state submaximal exercise, and maximal exercise. Doppler ultrasound measures of LV diastolic filling were assessed at rest and during LV loading (saline infusion) to simulate increased LV filling. Body composition, total blood volume, and heart rate recovery after maximal exercise were also examined. Vo2max increased in a dose-dependent manner (P < 0.05). At maximal exercise, cardiac output and SV were largest in committed exercisers and Masters athletes (P < 0.05), while arteriovenous oxygen difference was greater in all trained groups (P < 0.05). At maximal exercise, effective arterial elastance, an index of ventricular-arterial coupling, was lower in committed exercisers and Masters athletes (P < 0.05). Doppler measures of LV filling were not enhanced at any condition, irrespective of lifelong exercise frequency. These data suggest that performing four or more weekly endurance exercise sessions over a lifetime results in significant gains in Vo2max, SV, and heart rate regulation during exercise; however, improved SV regulation during exercise is not coupled with favorable effects on LV filling, even when the heart is fully loaded.


Intracytoplasmic oxidative stress reverses epigenetic modifications in polycystic ovary syndrome.
In polycystic ovary syndrome (PCOS), substantial genetic and environmental alterations, along with hyperandrogenism, affect the quality of oocytes and decrease ovulation rates. To determine the mechanisms underlying these alterations caused specifically by an increase in plasma androgens, the present study was performed in experimentally-induced PCOS mice. As the study model, female B6D2F1 mice were treated with dehydroepiandrosterone (DHEA, 6mg per 100g bodyweight). After 20 days, oocytes at the germinal vesicle and metaphase II stages were retrieved from isolated ovaries and subsequent analyses of oocyte quality were performed for each mouse. DHEA treatment resulted in excessive abnormal morphology and decreased polar body extrusion rates in oocytes, and was associated with an increase in oxidative stress. Analysis of fluorescence intensity revealed a significant reduction of DNA methylation and dimethylation of histone H3 at lysine 9 (H3K9) in DHEA-treated oocytes, which was associated with increased acetylation of H4K12. Similarly, mRNA expression of DNA methyltransferase-1 and histone deacetylase-1 was significantly decreased in DHEA-treated mice. There was a significant correlation between excessive reactive oxygen species (ROS) production and increased histone acetylation, which is a novel finding and may provide new insights into the mechanism causing PCOS. The results of the present study indicate that epigenetic modifications of oocytes possibly affect the quality of maturation and ovulation rates in PCOS, and that the likely mechanism may be augmentation of intracytoplasmic ROS.


Long-term efficacy and safety of drug-eluting stent implantation for patients with multiple coronary chronic total occlusions.
Data on the efficacy and safety of drug-eluting stent (DES) for treatment of multiple coronary chronic total occlusion (CTO) lesions are scanty. The aim of the present study was to compare the long-term outcomes of DES versus bare metal stent (BMS) implantation for multiple coronary CTO lesions. We analyzed 188 patients who underwent coronary stenting for at least two de novo CTO lesions in our center from November 2000 to November 2006. Among them, 118 patients (62.8%) received DES and 70 patients (37.2%) received BMS implantation after the recanalization for CTO lesions. All patients were followed up for up to 5 years for the occurrence of major adverse cardiac events (MACE). Long-term survival rates were estimated with the Kaplan-Meier method. There were no significant differences in baseline clinical characteristics and procedural success rate between DES group and BMS group. Compared with the BMS group, the DES group showed a significantly higher rate of long CTO (> or = 15 mm) (62.0% vs. 50.6%, P = 0.023). The number of stents per lesion (1.39 +/- 0.71 vs. 1.17 +/- 0.66, P = 0.007) and the mean length of stents in the DES group were also higher than those in the BMS group ((40.8 +/- 11.4) mm vs. (23.4 +/- 8.7) mm, P < 0.001). But the mean diameter of stents in the DES group was smaller than that in the BMS group ((3.1 +/- 0.2) mm vs. (3.3 +/- 0.5) mm, P < 0.001). Average follow-up time was 4.8 +/- 0.7 (1.5 - 5.0) years in the BMS group and 4.3 +/- 0.5 (1.3 - 5.0) years in the DES group. Both the 5-year cumulative survival rates and the target vessel revascularization (TVR)-free survival rates of the DES group were significantly higher than those in the BMS group (83.1% vs. 72.9%, Log-rank P = 0.044; 77.1% vs. 62.9%, Log-rank P = 0.009). The cumulative MACE-free survival rates in the DES group were significantly higher than those in the BMS group (71.2% vs. 51.4%, Log-rank P = 0.001). Multivariable Cox regression analysis demonstrated that DES implantation for multiple CTO lesions could significantly reduce the long-term MACE risk after percutaneous coronary intervention (PCI) (HR: 0.436; 95%CI 0.327 - 0.665, P < 0.001). Age over 65 years (HR: 2.018; 95%CI 1.491 - 3.127, P < 0.001) and left ventricular ejection fraction < 50% (HR: 1.494; 95%CI 1.125 - 2.376, P < 0.001) were identified as the independent predictors of long-term MACE. This study demonstrates the long-term (up to 5 years) efficacy and safety of DES for treatment of multiple coronary CTO lesions, and its superiority compared to BMS in reducing the rates of TVR and MACE.


The effects of peritoneal dialysis on the physiological disposition of oxacillin, ampicillin and tetracycline in patients with renal disease.
Seven patients with acute or chronic renal failure who were receiving intermittent peritoneal dialysis and who required parenteral oxacillin, ampicillin or tetracycline were studied to determine the disposition of these antibiotics in severe renal disease and the effects of peritoneal dialysis. While severe renal impairment markedly prolongs persistence in the serum of ampicillin and tetracycline, there is little effect on oxacillin. Whereas required doses of ampicillin and tetracycline are lower in the presence of severe renal disease, oxacillin should be given in doses equivalent to those used for patients with normal renal function. Peritoneal dialysis does not alter these dosage requirements.Four patients receiving ampicillin or tetracycline in the infusing solution during peritoneal dialysis were studied to determine the amount of systemic absorption. Local prophylaxis alone is not achieved with this method of administration, since small amounts of both antibiotics are absorbed systemically from the infusing solution. The serum concentration of tetracycline attained is inadequate for treatment of systemic infections but is probably significant, with repeated use in intermittent dialysis, in causing adverse effects. Tetracycline should be abandoned in the local prophylaxis of peritonitis during peritoneal dialysis.


Quantifying Glioblastoma Drug Response Dynamics Incorporating Treatment Sensitivity and Blood Brain Barrier Penetrance From Experimental Data.
Many drugs investigated for the treatment of glioblastoma (GBM) have had disappointing clinical trial results. Efficacy of these agents is dependent on adequate delivery to sensitive tumor cell populations, which is limited by the blood-brain barrier (BBB). Additionally, tumor heterogeneity can lead to subpopulations of cells with different sensitivities to anti-cancer drugs, further impacting therapeutic efficacy. Thus, it may be important to evaluate the extent to which BBB limitations and heterogeneous sensitivity each contribute to a drug's failure. To address this challenge, we developed a minimal mathematical model to characterize these elements of overall drug response, informed by time-series bioluminescence imaging data from a treated patient-derived xenograft (PDX) experimental model. By fitting this mathematical model to a preliminary dataset in a series of nonlinear regression steps, we estimated parameter values for individual PDX subjects that correspond to the dynamics seen in experimental data. Using these estimates as a guide for parameter ranges, we ran model simulations and performed a parameter sensitivity analysis using Latin hypercube sampling and partial rank correlation coefficients. Results from this analysis combined with simulations suggest that BBB permeability may play a slightly greater role in therapeutic efficacy than relative drug sensitivity. Additionally, we discuss recommendations for future experiments based on insights gained from this model. Further research in this area will be vital for improving the development of effective new therapies for glioblastoma patients.


Prevalence and gender distribution of malocclusion among 13-15-year-old adolescents of Kerala, South India.
To determine the prevalence and gender distribution of malocclusion in 13-15-year-old adolescents of Dravidian ethnicity, residing in urban and rural areas of Kerala, South India. A total of 1554 children (779 males, 775 females), from both urban and rural areas were examined in school settings. Survey proforma for personal details and occlusal registration according to Bjork et al. (1964) were used. Chi-square test was used for analysis. Overall prevalence of malocclusion was 89.9% which included Angle's Class I, Class II (17.6%) and Class III (8%) malocclusions. Other anomalies detected were increased overjet (11.8%), anterior crossbite (27.5%), anterior open bite (1.6%), posterior crossbite (5.1%), scissor bite (4.4%), midline deviation (6.8%), bimaxillary protrusion (BMP-21.3%), crowding (66.6%), spacing (15.3%), rotations (45.4%), ectopic eruptions (11.1%), peg laterals (2.4%) and missing teeth (6.6%). Males showed a higher predilection for increased overjet, deep bite, spacing and missing teeth. Class III, BMP, midline deviations and rotations were found to be more prevalent among the rural group, whereas Class II, increased overjet, deep bite and ectopic eruptions were more prevalent among the urban. Information regarding the detailed pattern of malocclusion prevalence and the high prevalence of BMP among South Indian population of Kerala may provide a baseline data for planning orthodontic services.


Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition.
Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown. We conducted a phase II study of nilotinib 400 mg twice a day in two cohorts of patients with melanomas harboring KIT mutations or amplification: (A) those refractory or intolerant to a prior KIT inhibitor; and (B) those with brain metastases. The primary endpoint was 4-month disease control rate. Secondary endpoints included response rate, time-to-progression (TTP), and overall survival (OS). A Simon two-stage and a single-stage design was planned to assess for the primary endpoint in cohorts A and B, respectively. Twenty patients were enrolled and 19 treated (11 in cohort A; 8 in cohort B). Three patients on cohort A [27%; 95% confidence interval (CI), 8%-56%] and 1 on cohort B (12.5%; 90% CI, 0.6%-47%) achieved the primary endpoint. Two partial responses were observed in cohort A (18.2%; 90% CI, 3%-47%); none were observed in cohort B. The median TTP and OS was 3.3 (90% CI, 2.1-3.9 months) and 9.1 months (90% CI, 4.3-14.2 months), respectively, in all treated patients. Nilotinib may achieve disease control in patients with melanoma harboring KIT alterations and whose disease progressed after imatinib therapy. The efficacy of this agent in KIT-altered melanoma with brain metastasis is limited.


From Urges to Action: Negative Urgency and Nonsuicidal Self-Injury in an Acute Transdiagnostic Sample.
Urgency-rash action during strong emotion-is a robust correlate of nonsuicidal self-injury (NSSI). This study tested whether urgency is associated with time between NSSI urges and NSSI, and sought to replicate the finding that urgency is associated with NSSI history. Participants attending a partial hospitalization program (N = 669) completed self-report measures of urgency, NSSI history and latency, and psychiatric symptoms. Consistent with previous research in clinical samples, rates of lifetime engagement in NSSI were high. Using logistic regression to predict short vs. long latency between urges and NSSI, no significant relationship emerged between negative urgency and latency to self-injure. Negative urgency more than doubled the likelihood of NSSI history (p < .001, OR = 2.39). In addition, exploratory analyses revealed several links between NSSI latency and negative urgency. Results confirm that urgency is robustly related to NSSI, yet also suggest that more research is needed to understand how urgency relates to the parameters of NSSI within those who self-injure. Use of retrospective self-report measures may limit the ability to test links between urgency and latency of NSSI.


[Comparison of various PCR methods for the detection of Chlamydia trachomatis, Ureaplasma urealyticum, and Mycoplasma hominis in women with impaired reproductive function].
The comparative evaluation of the PCR test "Polimik" (Research and Production Firm "Litekh", Moscow) and the PCR test of the Novosibirsk Institute of Bioorganic Chemistry (NIBC) was carried out. The results obtained with the use of the PCR test "Polimik" and the PCR test of the NIBC of the detection of C. trachomatis and M. hominis coincided in 97.8% and 97.4% of cases. For U. urealyticum, the coincidence of the results of both PCR tests was 81.2%. Among women who visited gynecologists for reproductive function disturbances, the use of the PCR tests made it possible to detect C. trachomatis in 19 (5.5%) out of 343 cases, U. urealyticum in 96 (39.0%) out of 246 cases and M. hominis in 25 (16.9%) out of 148 cases. The results of the investigation revealed that the occurrence of C. trachomatis infection in Novosibirsk was comparable with that in other regions of the world among the low-risk groups of the population. The detection frequency of M. hominis and U. urealyticum with the use of the PCR tests showed that the occurrence of infections caused by these causative agents coincided with the data obtained in other countries.


Psychosocial determinants of pertussis and influenza vaccine uptake in pregnant women: A prospective study.
To identify the psychosocial factors influencing women's uptake and willingness to receive pertussis and influenza vaccine during pregnancy. The study population comprised 1364 healthy nulliparous pregnant women who participated in a prospective cohort study at two obstetric hospitals in South Australia between 2015 and 2017. Information on women's vaccination status, sociodemographic, lifestyle and psychological state were collected at 9-16 weeks' gestation and medical case notes were checked post-delivery to verify the reported vaccination status. Poisson regression models were used to estimate the crude and adjusted prevalence ratios (aPRs) to identify psychosocial factors influencing uptake of vaccination during pregnancy. Willingness to receive the recommended maternal vaccines was high (90%). Overall, 79% and 48% received maternal pertussis and influenza vaccines respectively. There was no evidence to support the influence of psychosocial factors on women's willingness to receive immunization during pregnancy. High levels of anxiety (aPR 0.98, 95% CI: 0.87-1.09) was not associated with uptake of maternal pertussis vaccine. However, elevated depressive symptoms (aPR 1.14, 95% CI: 1.00-1.30) and very high-perceived stress during pregnancy were significantly associated with receipt of pertussis vaccination (aPR 0.87; 95% CI 0.76-0.99). Women with mild depressive symptoms (aPR 1.21, 95% CI 1.00-1.44) and mild anxiety symptoms (aPR 1.21, 95% CI: 0.99-1.48) were more likely to receive influenza vaccine during pregnancy (aPR 1.27, 95% CI: 1.08-1.49). A history of major depressive disorder was independently associated with receipt of pertussis (aPR 1.16, 95% CI 1.06-1.26) and influenza vaccination during pregnancy (aPR 1.32; 95% CI 1.14-1.58). Regardless of psychosocial factors, most women reported a positive willingness to receive the recommended vaccinations during pregnancy. However, psychosocial factors influenced the uptake of pertussis and influenza vaccines during pregnancy. Psychosocial factors should be taken into consideration in designing interventions and implementation of maternal pertussis and influenza immunization programs.


Audio-Recorded Discharge Instructions for Limited English Proficient Parents: A Pilot Study.
Parents with limited English proficiency (LEP) demonstrate lower comprehension of discharge instructions. A study was conducted to (1) determine the feasibility of providing a greeting card with language-specific, audio-recorded discharge instructions to LEP parents; (2) describe use of and satisfaction with the cards; and (3) evaluate card effect on instruction comfort with home care and comprehension. LEP parents of children undergoing day surgery from April to September 2016 were eligible. Participants were randomized to usual discharge instructions, or usual instructions plus a three-minute card with language-specific audio instructions that could be replayed repeatedly. Parents were surveyed by telephone two to seven days postdischarge to assess card use and satisfaction, comfort with home care, and discharge instruction recall (medications, home care, follow-up, and return precautions). Parent-reported instructions were compared to instructions in the medical record; concordance was determined by two blinded reviewers. Due to difficulty achieving recruitment goals, analysis focused on feasibility and acceptability. Of 83 parents enrolled, 66 (79.5%) completed the follow-up survey. Most had not completed high school (61.0%) and spoke Spanish (89.2%). Parents reported high satisfaction with the card (4.5/5 for ease of use, helpfulness, and understandability). Ninety-four percent shared the card with others, and 45.2% reported listening > 5 times. Besides reviewing the care instructions generally, parents reported using the card to review medications and engage others in the child's care. Providing language-concordant, audio-recorded discharge instructions was feasible, and parents reported high satisfaction with and frequent use of the cards with multiple caregivers.


5-Hydroxy-tryptamine modulates pheromone-evoked local field potentials in the macroglomerular complex of the sphinx moth Manduca sexta.
Extra- and intracellular recordings from an intact brain preparation were used to study the effects of 5-hydroxytryptamine (5-HT or serotonin) on projection neurons in the sexually dimorphic macroglomerular complex (MGC) in the antennal lobe of the male moth Manduca sexta. The MGC is a group of three identified glomeruli specialized for synaptic processing of primary afferent information about the multi-component sex pheromone of the female. We investigated the modulatory effects of 5-HT on pheromone-evoked local field potentials in the MGC. The magnitude and duration of these potentials, which are thought to be generated by a population of pheromone-sensitive projection neurons of the MGC, were increased by 5-HT. Using intracellular recordings from the neurites of individual MGC projection neurons, we found that 5-HT increased the number of action potentials in response to pheromonal stimulation. These findings correlate well with earlier experiments that used other recording techniques. Our results are further evidence that 5-HT modulates a population of pheromone-sensitive MGC projection neurons that relay information about the pheromonal stimulus from the MGC to higher-order centers in the protocerebrum and are therefore pivotal for mate-finding and odor-guided behavior.


Spontaneous regression of sarcoma.
Three pathologic processes generally regarded as nonneoplastic conditions are presented and discussed as examples of poorly controlled proliferations of lymphoid tissue. A study of these three disorders (infectious mononucleosis, hyperthyroidism, and Dilantin-induced lymphadenopathy) provides clues to an understanding of the pathogenesis and occasional spontaneous regression of the malignant lymphomas.


Under the influence with a child in the car: implications for child safety and caregiver intervention.
Injury is the leading cause of death for those aged 1 year to 44 years in the United States, with motor vehicle collisions (MVCs) the leading cause of injury-related deaths. Little data exist on the relationship between caregiver alcohol and drug use at the time of MVC and child passenger outcomes. We examined the relationship between caregiver substance use in MVCs and a number of demographic, crash severity, and medical outcomes for caregivers and children. We identified family groups treated in the emergency department of a regional Level II trauma center after an MVC in a 1-year period from July 1, 2005, to June 30, 2006. The distribution and means of characteristics for substance and nonsubstance users were compared using χ analysis and Student's t tests, respectively. One in 10 vehicles contained an intoxicated caregiver at the time of MVC. In 363 identified caregivers, intoxication was associated with being male (p < 0.001), lack of safety device use (p = 0.003), rollover (p = 0.008), and ejection (p = 0.016). In the 278 family groups, intoxicated caregivers were related to child ejection (p = 0.009), the need for child hospital admission (p < 0.001), and driver intoxication was related to child lack of restraint (p = 0.045). These findings suggest a substantial number of child MVC victims arrive at the emergency room after riding with an intoxicated caregiver. Findings support the need for prevention programs focusing on substance use and driving for male caregivers, and further investigation on the need for screening and intervention for caregivers' risky alcohol and drug use after a child's MVC.


The burden of smoking-related ill health in the UK.
Smoking is one of the biggest avoidable causes of morbidity and mortality in the United Kingdom. This paper quantifies the current health and economic burden of smoking in the UK. It provides comparisons with previous studies of the burden of smoking in the UK and with the costs for other chronic disease risk factors. A systematic literature review to identify previous estimates of National Health Service costs attributable to smoking was undertaken. Information from the World Health Organization's Global Burden of Disease Project and routinely collected mortality data were used to calculate mortality due to smoking in the UK. Population-attributable fractions for smoking-related diseases from the Global Burden of Disease Project were applied to NHS cost data to estimate direct financial costs. Previous studies estimated that smoking costs the NHS about 1.4 billion to 1.7 billion pound in 1991 and has been responsible for about 100,000 deaths per annum over the past 10 years. This paper estimates that the number of deaths attributable to smoking in 2005 was 109,164 (19% of all deaths, 27% deaths in men and 11% of deaths in women). Smoking was directly responsible for 12% of disability adjusted life years lost in 2002 (15.4% in men; 8.5% in women) and the direct cost to the NHS was 5.2 billion pound in 2005-6. Smoking is still a considerable public health burden in the UK. Accurately establishing the burden in terms of death, disability and financial costs is important for informing national public health policy.


Patient Perspective in Obesity Surgery: Goals for Weight Loss and Improvement of Body Shape in a Prospective Cohort Study.
Obesity surgery provides sustainable weight loss, improvement of comorbidities, and improved quality of life (QOL). There is few evidence on the patient perspective and goals. This study compared expected and achieved weight loss, body shape, and QOL. Patients completed the Moorehead-Ardelt QOL questionnaire (MAQOL) and questionnaires on actual and expected weight loss and body shape, comorbidities, and goals of obesity surgery preoperatively and within 24 months postoperatively. 44 patients completed questionnaires pre- and postoperatively. BMI, MAQOL and comorbidities significantly improved postoperatively. Patients' expected weight loss goal corresponded to a postoperative BMI of 32.6 ± 5.6 kg/m2 and was not different from their achieved BMI within 24 months after surgery (33.9 ± 6.3 kg/m2, p = 0.276). Self-reported body shape improved but did not reach preoperatively expected goals. During the weight loss period, patients adapted their weight loss and body shape goals to higher levels. Patients attributed a higher part of their success in weight loss to surgery postoperatively (79.5 ± 22.0 vs. 89.1 ± 18.4%, p = 0.028). Patients lost as much weight as they had expected and later modified the goals to even greater weight loss. Body shape improved but did not reach expected levels. QOL improved independently from weight loss and body shape. Patients attributed successful weight loss predominantly to surgery.


Oxazines: A New Class of Second-Order Nonlinear Optical Switches.
A combined experimental-theoretical investigation has revealed that oxazine-based compounds are multiaddressable, multistate, and multifunctional molecular switches exhibiting contrasts of both linear and second-order nonlinear optical properties. The switching properties are particularly large when the substituent is a donor group. In this study, the cleavage of the C-O bond at the junction of the indole and oxazine cycles (of the closed a forms) is acido-triggered, leading to an open form (b(+)) characterized by larger first hyperpolarizabilities (βHRS) and smaller excitation energies than in the closed form. These results are confirmed and interpreted utilizing ab initio calculations that have been carried out on a broad set of compounds to unravel the role of the substituent. With respect to acceptor groups, oxazines bearing donor groups are characterized not only by larger βHRS and βHRS contrast ratios but also by smaller excitation energies, larger opening-induced charge transfer, and reduction of the bond length alternation, as well as smaller Gibbs energies of the opening reaction. Compared to protonated open forms (b(+)), calculations on the zwitterionic open forms (b) have pointed out similarities in the long-wavelength UV/vis absorption spectra, whereas their βHRS values might differ strongly as a function of the substituent. Indeed, the open forms present two NLOphores, the indoleninium-substituent entity and the nitrophenol (present in the protonated open form, b(+)) or nitrophenolate (present in the zwitterionic open form, b) moiety. Then, nitrophenolate displays a larger first hyperpolarizability than nitrophenol and the β tensor of the two entities might reinforce or cancel each other.


Role of terminal warm blood cardioplegia in complex congenital heart surgery.
Introduction Myocardial protection is vital to ensure successful open heart surgery. Cardioplegic solution is one method to achieve good myocardial protection. Inevitably, ischemia-reperfusion injury occurs with aortic crossclamping. Histidine-tryptophan-ketoglutarate solution is a frequently used cardioplegia for complex congenital heart surgery. We postulated that addition of terminal warm blood cardioplegia before removal of the aortic crossclamp might improve myocardial protection. Method A randomized controlled trial was conducted on 109 cyanotic patients aged, 1 to 5 years who underwent complex biventricular repair. They were divided into a control group of 55 patients who had histidine-tryptophan-ketoglutarate only and a treatment group of 54 who had histidine-tryptophan-ketoglutarate with terminal warm blood cardioplegia. Endpoints were clinical parameters, troponin I levels, and caspase-3 as an apoptosis marker. Results The incidence of low cardiac output syndrome was 34%, with no significant difference between groups (35.2% vs. 33.3%, p = 0.84). The incidence of arrhythmias in our treatment group was lower compared to the control group (36% vs. 12%, p = 0.005). Troponin I and caspase-3 results did not show any significant differences between groups. For cases with Aristotle score ≥ 10, weak expression of caspase-3 in the treatment group post-cardiopulmonary bypass was lower compared to the control group. Conclusion For complex congenital cardiac surgery, the addition of terminal warm blood cardioplegia does not significantly improve postoperative clinical or metabolic markers.


Quantitative chemical analysis of single cells.
A fundamental perspective can be achieved by targeting single cells for analysis with the goal of deconvoluting complex biological functions. However, single-cell studies have their own difficulties, such as minute volumes and sample amounts. Quantitative chemical analysis of single cells has emerged as a powerful new area in recent years due to several technological advancements. The development of microelectrodes has allowed the measurement of redox-active species as a function of cellular dynamics. This miniaturization trend is also evident in the separation sciences with the application of small column separations to single cells. Desorption ionization methods with mass spectrometric detection have shown single-cell capability owing to numerous technological developments. Finally, fluorescence imaging has also progressed to the point where single-cell dynamics can be probed by native fluorescence utilizing either single or multiple photon excitation. The results of these studies are reviewed with an emphasis on the quantitation of single-cell dynamics.


[Anesthesia awareness].
Anesthesia awareness, or "unintended intra-operative awareness" occurs during general anesthesia, on the operating table, when a patient has not had enough general anesthetic or analgesic to prevent consciousness or waking up during surgery. According to international studies its global incidence ranges from 0.1 to 0.2%. Its impact on people can be as severe as other traumatic experiences such as natural disasters, violent fights or sexual abuse. The prevalence of symptoms compatible with post traumatic stress disorder can be as high as 50%, after experiencing the awareness phenomenon. This paper reviews the main issues of the awareness phenomenon.


Adjustments and coordination of hydraulic, leaf and stem traits along a water availability gradient.
Trait variability in space and time allows plants to adjust to changing environmental conditions. However, we know little about how this variability is distributed and coordinated at different organizational levels. For six dominant tree species in northeastern Spain (three Fagaceae and three Pinaceae) we quantified the inter- and intraspecific variability of a set of traits along a water availability gradient. We measured leaf mass per area (LMA), leaf nitrogen (N) concentration, carbon isotope composition in leaves (δ13 C), stem wood density, the Huber value (Hv, the ratio of cross-sectional sapwood area to leaf area), sapwood-specific and leaf-specific stem hydraulic conductivity, vulnerability to xylem embolism (P50 ) and the turgor loss point (Ptlp ). Differences between families explained the largest amount of variability for most traits, although intraspecific variability was also relevant. Species occupying wetter sites showed higher N, P50 and Ptlp , and lower LMA, δ13 C and Hv. However, when trait relationships with water availability were assessed within species they held only for Hv and Ptlp . Overall, our results indicate that intraspecific adjustments along the water availability gradient relied primarily on changes in resource allocation between sapwood and leaf area and in leaf water relations.


Terrestrial gross carbon dioxide uptake: global distribution and covariation with climate.
Terrestrial gross primary production (GPP) is the largest global CO(2) flux driving several ecosystem functions. We provide an observation-based estimate of this flux at 123 +/- 8 petagrams of carbon per year (Pg C year(-1)) using eddy covariance flux data and various diagnostic models. Tropical forests and savannahs account for 60%. GPP over 40% of the vegetated land is associated with precipitation. State-of-the-art process-oriented biosphere models used for climate predictions exhibit a large between-model variation of GPP's latitudinal patterns and show higher spatial correlations between GPP and precipitation, suggesting the existence of missing processes or feedback mechanisms which attenuate the vegetation response to climate. Our estimates of spatially distributed GPP and its covariation with climate can help improve coupled climate-carbon cycle process models.


[Transport of the fatty acids composing the phosphatidylcholines and sphingomyelins of the low- and very high-density lipoproteins in the blood plasma in myocardial hypertrophy].
A comparative analysis of the fatty acid composition of phosphatidylcholines (PC) and sphingomyelins (SP) of lipoproteins (LP) of low and very low density was performed in the blood plasma of Eskimos (indigenous population of the Chukot Peninsula) in myocardial hypertrophy and in the control group as well as in the control group of Muscovites. Some characteristic features of the fatty acid composition of low density LP PC and SP were revealed in Eskimos in myocardial hypertrophy. The role of changes in the transport of fatty acids of low density LP PC and SP of the blood plasma in the myocyte membrane liquidity as well as in the synthesis of biologically active prostacyclin revealed in myocardial hypertrophy was discussed.


Kenya and distance education: a model to advance graduate nursing.
Africa is faced with a myriad of challenges, such as HIV/AIDS, malaria, tuberculosis, and a variety of political and historical complications that have affected the educational system for advanced nursing practice. In Kenya, the current situation in the higher education sector does not give nurses an opportunity to pursue graduate education after they have acquired the basic diploma in nursing due to limited government support and the type of education system existing in the country today. Although distance education has been available in Kenya for professionals such as teachers, in public universities, this kind of opportunity is unreachable for nurses who are working and need to further their education. Nurses desire to have access to advanced practice education to equip them with the relevant knowledge to cope and address the complex health issues arising in the management and care of patients. A collaborative model is presented as a potential solution for this need. Four major constituents are identified including hospitals and agencies, communities of interest, Kenyan universities and international education partners. Each has a part to play including contributions to information, communication of opinion and expertise, money and support, infrastructure and in-kind resources. Distance education is cost-effective and will help in building capacity at various levels of nursing including leadership in clinical practice, teaching, administration and research.


Validation of Mayo Clinic risk adjustment model for in-hospital complications after percutaneous coronary interventions, using the National Heart, Lung, and Blood Institute dynamic registry.
We sought to validate the recently proposed Mayo Clinic risk score model for complications after percutaneous coronary interventions (PCI), using an independent data set. The Mayo Clinic risk score has eight simple clinical and angiographic variables for the prediction of complications defined as either death, Q-wave myocardial infarction, emergent or urgent coronary artery bypass graft surgery, or cerebrovascular accident after PCI. External validation using an independent data set is lacking. A total of 3,264 patients undergoing PCI at each of the 17 sites in the National Heart, Lung, and Blood Institute's Dynamic Registry during two enrollment periods (July 1997 to February 1998 and February to June 1999) were studied. Logistic regression was used to model the calculated risk score and major procedural complications. The expected number of complications, with 95% confidence bounds (CBs), was also calculated. There were 96 (2.94%) observed procedural complications, and the Mayo Clinic risk score predicted 93.5 events (2.86%; 95% CB 2.32% to 3.41%; p = NS). The Hosmer-Lemeshow goodness-of-fit p value was 0.28, and the area under the receiver operating curve was 0.76, indicating excellent overall discrimination. There were no statistical differences between observed and predicted procedural complications using the Mayo Clinic risk score among the most selected high- and low-risk subgroups. Eight variables were combined into a convenient risk scoring system that accurately predicts cardiovascular complications after PCI. The Mayo clinic predictive model for procedural complications yielded excellent results when applied to a multi-center external data set.


Risk factors for left atrial thrombus from transesophageal echocardiography findings in ischemic stroke patients.
To identify the cause of cerebral embolism, we performed transesophageal echocardiography (TEE) in patients suspected of embolic brain infarction including transient ischemic attack (TIA). We analyzed TEE findings and investigated factors associated with left atrial thrombus (LAT) detected by TEE. We enrolled 98 consecutive patients who underwent TEE and had acute brain infarction or TIA that was possibly due to embolism. We assessed age, sex, presence of atrial fibrillation (AF), days from admission to TEE and TEE findings, including the prevalence of LAT, spontaneous echo contrast (SEC), left atrial appendage (LAA) slow flow velocity, patent foramen ovale (PFO), atrial septal aneurysm and aortic plaque (ASA). LAT was detected with TEE in 20 patients (20%). The factors that were significantly associated with the presence of LAT were male sex (unadjusted odds ratio (OR), 3.94; 95% confidence interval (CI), 1.07-14.58; p=0.037), presence of AF (unadjusted OR, 9.58; 95% CI, 2.58-35.50; p< 0.001), SEC (unadjusted OR, 8.48; 95% CI, 2.57-28.00; p< 0.001) and LAA slow flow velocity (unadjusted OR, 5.18; 95% CI, 1.59-16.91; p=0.005). Multivariate logistic regression analysis revealed that male sex (adjusted OR, 5.30; 95% CI, 1.09-25.71; p=0.039), presence of AF (adjusted OR, 8.97; 95% CI, 1.10-73.20; p=0.041) and SEC (adjusted OR, 10.87; 95% CI, 1.001-118.0; p=0.049) were independently associated with LAT, but LAA slow flow velocity was not. SEC is an important risk factor associated with LAT in patients suspected of embolic brain infarction that is independent of AF.