cssi/SciSciGPT-SciSciNet huggingface dataset:
Research on Ginkgolide B increases Cisplatin sensitivity in ovarian cancer cell via down-regulation of excision repair cross-complementing 1(ERCC1) in vitro

Objective: To investigate the effects and mechanisms of ginkgolide B(GB),extract of Ginkgo biloba,on increasing the sensitivity of cisplatin-resistant ovarian cancer cell line(SKOV3/DDP-luc).Methods: SKOV3/DDP-luc cells were pretreated with 25μmol/L of GB for 3,7,and 14 days.Then,cells were exposed to different concentrations of CDDP and incubated for 72 hours.MTT assay was performed to determine the viability of the cells and the IC50 of CDDP was calculated according to the viability curve.Meanwhile,proteins were extracted from the cells treated by GB at different time point and the expression of ERCC1 was detected by Western Blot.Results: After cells were pretreated with GB for 3,7 and 14 days,IC50 of CDDP was significantly decreased to 24.2(P=0.07),18.2(P=0.001) and 11.6μmol/L(P=0.0004),respectively.The expression of ERCC1 protein in every group was decreased accordingly(P0.01).Conclusion: GB can increase the drug sensitivity of CDDP-resistant human ovarian cancer cells significantly,which was implemented through down regulation of the expression of ERCC1.Our results suggested that GB could be a potential supplementary drug in ovarian cancer therapy.
Nucleophilic Polymers and Gels in Hydrolytic Degradation of Chemical Warfare Agents

Water- and solvent-soluble polymeric materials based on polyalkylamines modified with nucleophilic groups are introduced as catalysts of chemical warfare agent (CWA) hydrolysis. A comparative study conducted at constant pH and based on the criteria of the synthetic route simplicity, aqueous solubility, and rate of hydrolysis of CWA mimic, diisopropylfluorophosphate (DFP), indicated that 4-aminopyridine-substituted polyallylamine (PAAm-APy) and polyvinylamine substituted with 4-aminopyridine (PVAm-APy) were advantageous over 4-pyridinealdoxime-modified PVAm and PAAm, poly(butadiene-co-pyrrolidinopyridine), and PAAm modified with bipyridine and its complex with Cu(II). The synthesis of PVAm-APy and PAAm-APy involved generation of a betaine derivative of acrylamide and its covalent attachment onto the polyalkylamine chain followed by basic hydrolysis. Hydrogel particles of PAAm-APy and PVAm-APy cross-linked by epichlorohydrin exhibited pH-dependent swelling and ionization patterns that affected the rate constants of DFP nucleophilic hydrolysis. Deprotonation of the aminopyridine and amine groups increased the rates of the nucleophilic hydrolysis. The second-order rate of nucleophilic hydrolysis was 5.5- to 10-fold higher with the nucleophile-modified gels compared to those obtained by cross-linking of unmodified PAAm, throughout the pH range. Testing of VX and soman (GD) was conducted in 2.5-3.7 wt % PVAm-APy suspensions or gels swollen in water or DMSO/water mixtures. The half-lives of GD in aqueous PVAm-APy were 12 and 770 min at pH 8.5 and 5, respectively. Addition of VX into 3.5-3.7 wt % suspensions of PVAm-APy in DMSO-d6 and D2O at initial VX concentration of 0.2 vol % resulted in 100% VX degradation in less than 20 min. The unmodified PVAm and PAAm were 2 orders of magnitude less active than PVAm-APy and PAAm-APy, with VX half-lives in the range of 24 h. Furthermore, the PVAm-APy and PAAm-APy gels facilitated the dehydrochlorination reaction of sulfur mustard (HD) and its analogue 2-chloroethyl ethylsulfide (CEES). The ability of the reported aminopyridine-modified polyalkylamine materials to degrade the most persistent of CWAs, coupled with aqueous solubility, and the presence of numerous amino groups that provide convenient "handles" for covalent attachment on polymeric and inorganic supports yields promise for applications such as protective fabric and textile treatment and components of decontaminating materials.
How much are built environments changing, and where?: Patterns of change by neighborhood sociodemographic characteristics across seven U.S. metropolitan areas

Investments in neighborhood built environments could increase physical activity and overall health. Disproportionate distribution of these changes in advantaged neighborhoods could inflate health disparities. Little information exists on where changes are occurring. This paper aims to 1) identify changes in the built environment in neighborhoods and 2) investigate associations between high levels of change and sociodemographic characteristics. Using Geographic Information Systems, neighborhood land-use, local destinations (for walking, social engagement, and physical activity), and sociodemographics were characterized in 2000 and 2010 for seven U.S. cities. Linear and change on change models estimated associations of built environment changes with baseline (2000) and change (2010-2000) in sociodemographics. Spatial patterns were assessed using Global Moran's I to measure overall clustering of change and Local Moran's I to identify statistically significant clusters of high increases surrounded by high increases (HH). Sociodemographic characteristics were compared between HH cluster and other tracts using Analysis of Variance (ANOVA). We observed small land-use changes but increases in the destination types. Greater increases in destinations were associated with higher percentage non-Hispanic whites, percentage households with no vehicle, and median household income. Associations were present for both baseline sociodemographics and changes over time. Greater increases in destinations were associated with lower baseline percentage over 65 but higher increases in percentage over 65 between 2000 and 2010. Global Moran's indicated changes were spatially clustered. HH cluster tracts started with a higher percentage non-Hispanic whites and higher percentage of households without vehicles. Between 2000 and 2010, HH cluster tracts experienced increases in percent non-Hispanic white, greater increases in median household income, and larger decreases in percent of households without a vehicle. Changes in the built environment are occurring in neighborhoods across a diverse set of U.S. metropolitan areas, but are patterned such that they may lead to increased health disparities over time.
Pediatric radiation protection.

OBJECTIVES: After completing this article, readers should be able to: Discuss the importance of pediatric radiation protection. List several means for reducing pediatric radiation exposure. Discuss pediatric immobilization and sedation. List and describe equipment used in pediatric radiology. Enumerate several ways to balance quality control and dose reduction. Address the radiation protection of others during pediatric radiology.
Congenic rats with higher arylamine N-acetyltransferase 2 activity exhibit greater carcinogen-induced mammary tumor susceptibility independent of carcinogen metabolism.

Recent investigations suggest role(s) of human arylamine N-acetyltransferase 1 (NAT1) in breast cancer. Rat NAT2 is orthologous to human NAT1 and the gene products are functional homologs. We conducted in vivo studies using F344.WKY-Nat2 rapid/slow rats, congenic at rat Nat2 for high (rapid) and low (slow) arylamine N-acetyltransferase activity, to assess a possible role for rat NAT2 in mammary tumor susceptibility. Mammary carcinogens, methylnitrosourea (MNU) and 7,12-dimethylbenzanthracene (DMBA) neither of which is metabolized by N-acetyltransferase, were administered to assess mammary tumors. MNU was administered at 3 or 8 weeks of age. DMBA was administered at 8 weeks of age. NAT2 enzymatic activity and endogenous acetyl-coenzyme A (AcCoA) levels were measured in tissue samples and embryonic fibroblasts isolated from the congenic rats. Tumor latency was shorter in rapid NAT2 rats compared to slow NAT2 rats, with statistical significance for MNU administered at 3 and 8 weeks of age (p = 0.009 and 0.050, respectively). Tumor multiplicity and incidence were higher in rapid NAT2 rats compared to slow NAT2 rats administered MNU or DMBA at 8 weeks of age (MNU, p = 0.050 and 0.035; DMBA, p = 0.004 and 0.027, respectively). Recombinant rat rapid-NAT2, as well as tissue samples and embryonic fibroblasts derived from rapid NAT2 rats, catalyzed p-aminobenzoic acid N-acetyl transfer and folate-dependent acetyl-coenzyme A (AcCoA) hydrolysis at higher rates than those derived from rat slow-NAT2. Embryonic fibroblasts isolated from rapid NAT2 rats displayed lower levels of cellular AcCoA than slow NAT2 rats (p < 0.01). A novel role for rat NAT2 in mammary cancer was discovered unrelated to carcinogen metabolism, suggesting a role for human NAT1 in breast cancer.
Medicaid Expansion Increased Coverage, Improved Affordability, And Reduced Psychological Distress For Low-Income Parents

Despite receiving less attention than their childless counterparts, low-income parents also experienced significant expansions of Medicaid eligibility under the Affordable Care Act (ACA). We used d...
Acute and chronic in vivo effects of exposure to nicotine and propylene glycol from an E-cigarette on mucociliary clearance in a murine model.

Objective: To determine the effect of an acute (1 week) and chronic (3 weeks) exposure to E-cigarette (E-cig) emissions on mucociliary clearance (MCC) in murine lungs.Methods: C57BL/6 male mice (ag...
Effect of Amlodipine on the Survival of Patients With Severe Chronic Heart Failure Due to a Nonischemic Cardiomyopathy: Results of the PRAISE-2 Study (Prospective Randomized Amlodipine Survival Evaluation 2)

Objectives This study was designed to test the hypothesis of whether amlodipine reduces the risk for death in patients with heart failure due to a nonischemic cardiomyopathy. Background A pre-specified subgroup analysis in an earlier, large-scale, placebo-controlled study suggested that amlodipine might reduce the risk for death in patients with heart failure due to a nonischemic cardiomyopathy. Methods To evaluate this hypothesis, 1654 patients with severe heart failure due to a nonischemic cardiomyopathy (ejection fraction Results There were 278 deaths in the amlodipine group and 262 deaths in the placebo group (hazard ratio: 1.09; 95% confidence interval [CI]: 0.92 to 1.29; p = 0.33). The differences between the 2 groups in the risks for cardiovascular death and hospitalization were also not significant. When the results from patients with a nonischemic cardiomyopathy in both the earlier trial and in the current study were combined, there was no evidence of a favorable or unfavorable effect of amlodipine on mortality (hazard ratio: 0.97; 95% CI: 0.83 to 1.13; p = 0.66). Both trials, however, observed higher frequencies of peripheral edema and pulmonary edema and lower frequencies of uncontrolled hypertension and chest pain in patients treated with amlodipine. Conclusions These results of the current trial, viewed together with the results from the earlier study, indicate that amlodipine does not exert favorable effects on the clinical course of patients with heart failure, regardless of the presence or absence of underlying coronary artery disease. These findings indicate the need for great caution when striking benefits are observed in subgroups of patients or in trials not primarily designed to assess such effects.
Acquired methemoglobinemia after hydroxocobalamin administration in a patient with burns and inhalation injury.

AbstractContext: Hydroxocobalamin is an effective cyanide antidote. While erythema, hypertension, and chromaturia are recognized side effects, methemoglobinemia has not been reported. Methemoglobin levels are most accurately measured by co-oximetry. We describe an extensively burned patient who developed methemoglobinemia within an hour of hydroxocobalamin administration.Case details: A 47-year old man without genetic deficiencies or abnormal hemoglobin variants presented with 61% body surface area thermal burns and grade 1 inhalation injury sustained during a tugboat engine explosion. On admission, lactate was 9.24 mmol/L, methemoglobin 1%, and carboxyhemoglobin 0.2% by blood gas analysis with co-oximetry. Despite large-volume resuscitation, lactate remained elevated (7–8 mmol/L). Intravenous hydroxocobalamin (5 g) was administered at postburn hour 19 for possible cyanide toxicity. Immediately thereafter, he became hypertensive with reflex bradycardia. Lactate decreased to 5.51 mmol/L, methemoglobin rose...
Identification of potential antimicrobials against Salmonella typhimurium and Listeria monocytogenes using Quantitative Structure-Activity Relation modeling

The shelf-life of fresh carcasses and produce depends on the chemical and physical properties of antimicrobials currently used for treatment. For many years the gold standard of these antimicrobials has been Cetylpyridinium Chloride (CPC) a quaternary ammonium compound (QAC). CPC is very effective at removing bacterial pathogens from the surface of chicken but has not been approved for other products due to a toxic residue left behind after treatment. Currently there is also a rising trend in QAC resistant bacteria. In order to find new compounds that can combat both antimicrobial resistance and the toxic residue we have developed two Quantitative Structure-Activity Relationship (QSAR) models for Salmonella typhimurium and Listeria monocytogenes. These models have been shown to be accurate and reliable through multiple internal and external validation techniques. In processing these models we have also identified important descriptors and structures that may be key in producing a viable compound. With these models, development and testing of new compounds should be greatly simplified.
Toward a First-Principles Determination of Transport Coefficients

The efficiency of a thermoelectric device depends on its geometrical design and on the transport coefficients of the material that constitutes the active thermoelements. The figure of merit of the material $$ Z = \frac{{\sigma S^2 }} {\kappa } $$ (1) is an expression involving the electrical conductivity a, the thermopower or Seebeck coefficient Sand the thermal conductivity κ. This quantity that has units of inverse temperature is the key to determine if a particular material has potential for thermoelectric applications.
Capacity credit evaluation of grid-connected photovoltaic generation based on improved particle swarm optimization

In order to assess the contribution of photovoltaic generation (PV) to distribution network, this paper presents a capacity credit evaluation method in the power side and load side. Firstly, the sequential Monte Carlo method is used to calculate the loss of load expectation (LOLE), which keeps the sequential information of units output. On this basis, an improved particle swarm optimization (PSO) algorithm is used to solve the capacity confidence of grid-connected PV, with the target of unchanged system reliability before and after PV connects with the grid. Consequently, the effectiveness of proved evaluation method is verified through the simulation on IEEE-RTS79 system. And the simulation results show that the confidence level in the power side and load side have the same trend with the increase of PV permeability.
Teachers’ enactments of curriculum: Fidelity to Procedure versus Fidelity to Goal for scientific argumentation

Fidelity of implementation (FOI) has received attention in calls for funding and research; however, there are numerous ways of conceptualising and measuring this construct. We argue that this conce...
Treatment of Childhood Anxiety in the Context of Limited Cognitive Functioning

Children with intellectual disabilities (ID) may be more susceptible to developing anxiety disorders than those without ID; however, research on the phenomenology, diagnosis, and treatment of anxiety disorders in this population is scarce. This chapter reviews the available literature on this topic in children with mild to moderate ID. A case study showcases considerations needed when conceptualizing and treating anxiety disorders in children with ID.
Introduction to the Phenomena and Their Conceptualization

To study and to help schizophrenic persons is to explore the range and depth of the human condition. As a group of people, those persons called schizophrenic represent every nationality, religion, ethnic origin, socioeconomic status, variety of intellectual endowment, emotional experience, and value system that may be encountered. None of their mental or emotional experiences are truly outside the capacity of other human beings, though our fear of them is often so great that we would deny any similarity between ourselves and people labeled schizophrenic. Ironically, the fear that we have in common with schizophrenic persons leads us to deny our similarities with them and makes us unable, therefore, to ascertain the true variations in the human condition that can be meaningfully assessed and how we can be of genuine help.
Nobody’s home: the ecology of Terrence Malick

This article assesses Malick’s broadly ‘ecological’ claim against human intention and construction, including the auteur frame, which dictate narrative expectations and other aesthetics inc...
Radiosity view factor model for sources with general distribution

Abstract The radiosity view factor model commonly used in radiation heat transfer and computer graphics is applied to a free-molecular flow problem. This paper extends the model to sources with general distribution and includes the diffuse reflections from surfaces, while the previous model is only compatible with an isotropic source distribution. The derivations of the particle flow rate and density are presented, and the numerical implementation is described. The view factor model is compared to the Monte Carlo particle model for density distributions obtained using two different velocity distribution functions for two sources: (1) a Maxwellian distribution with streaming components in both axial and tangential directions and (2) an arbitrary distribution with a discontinuous feature. In these validation studies, it is shown that the radiosity view factor model predicts the correct density distribution that is much smoother and with less simulation run-time compared to the Monte Carlo particle model. While the model herein is applied to a free-molecular flow problem, it can easily be applied to the other problems with a complex source distribution where intensity as a function of wavelength cannot be integrated analytically.
Comprehensive assessment of the associations between maternal diabetes and structural birth defects in offspring: a phenome-wide association study.

Abstract Purpose Our objective was to comprehensively evaluate the risk of a broad range of birth defects among offspring of women with diabetes, overall and stratified by pregestational versus gestational diagnosis, using the phenome-wide association (PheWAS) methodology. Methods We performed a registry linkage study of all live births (>6,500,000) and birth defects cases (>290,000) in Texas, 1999–2015. We ascertained diabetes from birth and fetal death certificates. We calculated prevalence rate ratios (PRR) for phenotypes with ≥10 cases among exposed offspring (n = 130). Results Diabetes was associated with the prevalence of any defect (PRR 1.40, 95% confidence interval [CI] 1.38–1.42), multiple defects (PRR 1.86, 95% CI 1.81–1.91), and 60 specific phenotypes, including novel (hypospadias, mitral stenosis) and previously reported phenotypes (renal a-/dysgenesis, spinal anomalies). Pregestational diabetes was a stronger risk factor for any defect (PRR 2.00, 95% CI 1.93–2.07), multiple defects (PRR 3.27, 95% CI 3.11–3.44), and the 60 specific phenotypes evaluated. Gestational diabetes was associated with any defect (PRR 1.21, 95% CI 1.19–1.23) and 47 specific birth defects phenotypes, although associations were weaker than for pregestational diabetes. Conclusions The PheWAS is an efficient way to identify risk factors for disease using population-based registry data. Pregestational diabetes is associated with a broader range of phenotypes than previously reported. Because diabetes is diagnosed in 1% of women prior to pregnancy and 6%–9% during pregnancy, our results highlight a significant public health concern.
1D Discontinuous Galerkin Methods for Hyperbolic Equations

In Chs. 6 and 9 we discussed the implementation of discontinuous Galerkin methods in one dimension for hyperbolic and elliptic equations, respectively. In Ch. 15 we described the CG discretization for hyperbolic equations in two-dimensions and discussed the addition of second order operators to these equations. This chapter focuses on the DG method for hyperbolic equations in two-dimensions although we also discuss the addition of elliptic operators. In order to construct a DG discretization of these equations, we make extensive use of the results presented in Ch. 6 for the DG discretization of one-dimensional hyperbolic systems and the results from Ch. 13 for the DG discretization of two-dimensional elliptic systems.
Fuzzy logic and Lyapunov-based non-linear controllers for HCV infection.

Hepatitis C is the liver disease caused by the Hepatitis C virus (HCV) which can lead to serious health problems such as liver cancer. In this research work, the non-linear model of HCV having three state variables (uninfected hepatocytes, infected hepatocytes and virions) and two control inputs has been taken into account, and four non-linear controllers namely non-linear PID controller, Lyapunov Redesign controller, Synergetic controller and Fuzzy Logic-Based controller have been proposed to control HCV infection inside the human body. The controllers have been designed for the anti-viral therapy in order to control the amount of uninfected hepatocytes to the desired safe limit and to track the amount of infected hepatocytes and virions to their reference value which is zero. One control input is the Pegylated interferon (peg-IFN-α) which acts in reducing the infected hepatocytes and the other input is ribavirin which blocks the production of virions. By doing so, the uninfected hepatocytes increase and achieve the required safe limit. Lyapunov stability analysis has been used to prove the stability of the whole system. The comparative analysis of the proposed nonlinear controllers using MATLAB/Simulink have been done with each other and with linear PID. These results depict that the infected hepatocytes and virions are reduced to the desired level, enhancing the rate of sustained virologic response (SVR) and reducing the treatment period as compared with previous strategies introduced in the literature.
Correspondence on SARS-CoV-2 vaccination in rituximab-treated patients: evidence for impaired humoral but inducible cellular immune response" by Bonelli et al ."

SARS-CoV-2 vaccination elicited high levels of immunogenicity in immunocompetent people in the original vaccine trials1 2 though recent studies have shown blunted immunogenicity in patients with rheumatic diseases treated with lymphocyte depleting agents.3 4 B-lymphocytes have been implicated in the pathogenesis of anti-neutrophil cytoplasmic antibidy (ANCA)-associated vasculitis (AAV) and B-cell-targeted therapy with rituximab is recognised as an established induction and maintenance strategy in management.5 6 SARS-CoV-2 infection in patients with AAV has been associated with severe outcomes,7 while rituximab has been associated with worse outcomes among patients infected with SARS-CoV-2.8 9 A recent study by Bonelli et al found evidence of an ameliorated humoral response but possible inducible cellular response in five patients treated with rituximab.10 We studied the tolerability and humoral response to the SARS-CoV-2 vaccine series in 48 patients with a diagnosis of AAV. Patients underwent SARS-CoV-2 antispike antibody testing to assess humoral response. Antibody testing was performed using antispike IgG enzyme immunoassay (Roche Elecsys via Quest, DiaSorin Liaison assay via LabCorp or Euroimmun via Hopkins lab). Demographics, clinical information including immunosuppressive therapy were extracted from medical records. Time from last rituximab administration to receipt of the first dose of the vaccine was recorded. We recorded serum creatinine, white blood cell count, serum immunoglobulins, Cluster of CD19 and …
Incidence, Predictors and Outcomes of Delirium in Critically Ill Patients With COVID-19

Background and Purpose:A variety of neurological manifestations have been attributed to COVID-19, but there is currently limited evidence regarding risk factors and outcomes for delirium in critica...
Microsurgical Management of a Marginal Sinus Dural Arteriovenous Fistula: 2-Dimensional Operative Video.

Dural arteriovenous fistulas (DAVFs) are benign but may present with life-threatening hemorrhage or symptoms of venous hypertension (eg, progressive myelopathy).1-3 DAVFs follow well-described anatomic patterns.4 The marginal sinus is located between the layers of the dura, circumferentially around the foramen magnum. It communicates with the basal venous plexus of the clivus anteriorly and the occipital sinus posteriorly.5,6 Arterial supply to the dura in this region that fistulizes into the sinus arises from meningeal branches from the V3 or V4 segments. A man in his early 70s presented with chronic neck pain and new onset of left arm and face paresthesias. He had brisk patellar reflexes bilaterally and a marginal sinus DAVF, with numerous dilated veins around the cisterna magna, causing dorsal cervicomedullary compression. Angiography confirmed the diagnosis of DAVF rather than arteriovenous malformation. Endovascular embolization was considered, but surgery was preferable because of poor transarterial access. The patient underwent left far lateral craniotomy and C1 laminectomy with exposure of the condylar fossa. The dura was carefully elevated laterally, revealing a network of dilated tortuous veins, with multiple points of fistulous connection within the dura emanating in a large venous varix. Indocyanine green videoangiography showed the aberrant flow dynamics. The fistulous point was occluded with aneurysm clips on the venous side, then cauterized and interrupted. The patient was discharged within 3 d of surgery and had full resolution of symptoms at 6 wk. Angiography confirmed complete obliteration of the DAVF. The patient provided written informed consent for treatment. Used with permission from Barrow Neurological Institute, Phoenix, Arizona.
Mitochondrial enzyme GPT2 regulates metabolic mechanisms required for neuron growth and motor function in vivo.

The metabolic needs for postnatal growth of the human nervous system are vast. Recessive loss-of-function mutations in the mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2) in humans cause postnatal undergrowth of brain, and cognitive and motor disability. We demonstrate that GPT2 governs critical metabolic mechanisms in neurons required for neuronal growth and survival. These metabolic processes include neuronal alanine synthesis and anaplerosis, the replenishment of tricarboxylic acid (TCA) cycle intermediates. We performed metabolomics across postnatal development in Gpt2-null mouse brain to identify the trajectory of dysregulated metabolic pathways: alterations in alanine occur earliest; followed by reduced TCA cycle intermediates and reduced pyruvate; followed by elevations in glycolytic intermediates and amino acids. Neuron-specific deletion of GPT2 in mice is sufficient to cause motor abnormalities and death pre-weaning, a phenotype identical to the germline Gpt2-null mouse. Alanine biosynthesis is profoundly impeded in Gpt2-null neurons. Exogenous alanine is necessary for Gpt2-null neuronal survival in vitro, but is not needed for Gpt2-null astrocytes. Dietary alanine supplementation in Gpt2-null mice enhances animal survival, and improves the metabolic profile of Gpt2-null brain, but does not alone appear to correct motor function. In surviving Gpt2-null animals, we observe smaller upper and lower motor neurons in vivo. We also observe selective death of lower motor neurons in vivo with worsening motor behavior with age. In conclusion, these studies of the pathophysiology of GPT2 Deficiency have identified metabolic mechanisms required for neuronal growth and that potentially underlie selective neuronal vulnerabilities in motor neurons.
The Defense Economics and the Military Reform in Russia

In 2018, the total strength of the Armed Forces (AF) of the Russian Federation did not change. Early in February 2018, the President of the Russian Federation increased by 200 persons to 10,740 persons the ultimate staff number of the Central Office of the Ministry of Defense (without the guarding and building maintenance personnel taken into account), which is not included in the strength of the Armed Forces.
Reemergence of Tuberculosis in Animals in the United States

Mycobacterium tuberculosis and Mycobacterium bovis are members of a closely related group of organisms referred to as the M. tuberculosis complex, which also includes Mycobacterium africanum and Mycobacterium microti. M. tuberculosis is the primary cause of tuberculosis in humans and, world wide, is the leading cause of death from a single infectious agent. Animals with potential exposure to M. bovis through contact with infected cattle are skin tested and, in some cases, slaughtered to prevent the spread of tuberculosis to new herds. Tuberculosis caused by M. bovis and M. tuberculosis has been reported in zoos, game parks, and other exotic animal collections in the United States and throughout the world. The presence of a wildlife reservoir of tuberculosis in Michigan may prevent the United States from achieving the goal of eradication of tuberculosis in animals. To comprehend the pathogenesis of a disease, it is important to understand the routes of infection and mode of transmission between hosts as well as the host response and characteristics intrinsic to the pathogen. Tuberculosis in animals is chiefly acquired by inhalation or ingestion. Follow-up surveys of the wildlife in the area revealed no further evidence of tuberculosis in any of the wild animals that were examined. The best long-term approach to control of tuberculosis in the United Kingdom appears to be the development of a vaccine for cattle and improved diagnostic tests to discriminate infected from vaccinated cattle.
Seasonal timing and population divergence: when to breed, when to migrate

Understanding how populations adapt to constantly changing environments requires approaches drawn from integrative and evolutionary biology as well as population ecology. Timing of reproduction and migration reflect seasonal pulses in resources, are driven by day length, and are also responsive to environmental cues that change with climate. Researchers focusing on birds have discovered accelerated breeding, reductions in migration, and extensive variation in perception, transduction, and response to the environment. We consider situations in which individuals experience the same environment but differ in the timing of the annual cycle. Such scenarios provide exceptional opportunities to study mechanisms related to among-population differences in timing (allochrony) and distribution (sympatry–allopatry–heteropatry), which have the potential either to enhance or reduce population divergence and biodiversity.
Tissue harmonic imaging in echocardiography: better valve imaging, but at what cost?

BACKGROUND Tissue harmonic imaging (THI) improves echocardiographic image quality and is widely utilized. Unfortunately it also makes structures appear artificially thickened. We sought to examine its impact on the imaging of left-sided heart valves. METHODS A large echocardiographic database was searched for full, standard transthoracic echocardiographic exams performed 12-month periods before (n = 3,786) and after (n = 3,914) transition to THI at a single institution. Patients with prosthetic valves were excluded. RESULTS The mean age of patients was 63 +/- 17 years and 65% were men. No appreciable difference in demographics was observed between time periods. While inadequate visualization of the mitral valve was reduced by 30% using THI (P = 0.014), reports of leaflet thickening increased by 28% (P = 0.005). Similarly, inadequate aortic valve visualization was reduced by 53% with THI (P < 0.001), at the expense of more aortic sclerosis (+6%, P = 0.034). Among the 480 patients with echocardiograms using each modality (time interval between studies: 370 +/- 143 days), THI did not appreciably improve visualization of the either valve. Although no significant increase in mitral thickness was seen with THI, aortic sclerosis was increased by at least one grade in 24.5% (P < 0.006). CONCLUSION This study suggests that while THI enhances imaging of difficult to visualize valves, it may overestimate mitral and aortic valve thickness. This could lead to overdiagnosis and unnecessary follow-up studies. Cardiologists interpreting THI echocardiograms should become familiar with the modality's shortcomings.
Chapter 6 The adipocyte and adipose tissue as endocrine organs: Impact on the insulin resistance phenotype

Summary Adipose tissue (AT) is an essential metabolic tissue, important for both its role in lipid storage and mobilization. While long considered an inert tissue providing a site for passive fat accumulation, insulation against heat loss and mechanical and/or structural support, newly recognized endocrine, paracrine and autocrine activities of AT have forced a re-evaluation of this static view of AT biology. The effects of factors secreted from AT, termed adipokines, increase the impact of AT on multiple processes in other tissues. Importantly, the role of excess adiposity and alterations in adipokine production and secretion in the development of diabetes, cardiovascular and liver disease necessitates a better understanding of AT biology in general and factors influencing its expansion specifically. The formation and metabolism of AT, as well as the production of adipokines are under multiple forms of regulation. At the transcriptional level peroxisome proliferator-activated receptor peroxisome gamma (PPAR γ ) plays a key role. These factors will be discussed with particular emphasis on human data and the mechanisms for insulin resistance and the metabolic syndrome.
Volleyball scoring systems

1. INTRODUCTION The widespread interest in sports in our culture provides a great opportunity to catch students' attention in mathematics and statistics classes. Many students, whose eyes would normally glaze over after ten minutes of algebra, will happily spend hours analyzing their favorite sport. In recent years the mathematical literature on sports (e.g. [1] and [2]) has expanded greatly and covers a broad spectrum of sports, including baseball, football, soccer, tennis, and track and field. Volleyball, an increasingly popular sport, has a mathematically interesting scoring system. The purpose of this paper is to show students, through an analysis of volleyball scoring systems, how we can model volleyball games as Markov chains, obtaining formulas for the proportion of points won by each team in the long run. We can also calculate the exact probabilities of winning a point, a game and a match for each scoring system. Under careful guidance of a faculty instructor, this paper can be well appreciated by college or high school students who have finished a first probability and statistics course. This study may also be of interest to volleyball players, coaches and fans, since the USA Volleyball official rules for scoring were changed in 1999. Our model predicts that the outcome of volleyball matches will rarely be affected by the change in scoring systems. 2. VOLLEYBALL SCORING There are two different scoring systems commonly used in volleyball: side-out scoring and rally point scoring. In both systems, a rally begins with a serve by one of the two teams and ends when the ball touches the floor or goes out, or a team commits a fault or fails to return the ball to the opponent's court. The team that wins the rally gains the right to serve in the next rally. Traditionally, side-out scoring has been used. This means that a point is awarded only when the serving team wins the rally. When the receiving team wins the rally it gains the right to serve next, but is not awarded a point. Recently, USA Volleyball (USAV) has followed the International Volleyball Federation (FIVB) in moving to rally point scoring. In rally point scoring a point is awarded after each rally to the team that won the rally. Games are played either to 15 or 25 points. If there is no scoring cap, then the winning team must be ahead by at least two points. For example, in a 15 point game, if the score reaches 15-14 or 14-15, the game goes on indefinitely until one of the two teams is two points ahead. If there is a scoring cap, a team's score cannot exceed 17. …
Prevention of Infection in Xenotransplantation

The central hypothesis for this chapter is that some of the infectious risks associated with xenotransplantation can be assessed before the broad application of this emerging technology. Epidemiologic exposures in the transplant recipient take two forms: those occurring within the hospital or the community, and those exposures carried with the transplanted organ. On the basis of experience with human allograft recipients and with immunosuppressed miniature swine, common infections in the first month after xenotransplantation are likely to be due to bacteria and fungi common to swine and to primates: staphylococci, streptococci, Candida spp., Aspergillus spp., Salmonella spp., and Actinomyces spp., which are routinely isolated from swine and from non-human primates. With prolonged xenograft survival, the susceptibility of the xenograft recipient to infection reflects the individual's epidemiologic exposures and the immune suppression and manipulations of donor and host needed to prevent graft rejection. While breeding strategies may enhance the safety of xenotransplantation, the greatest potential risk to the recipient and to the general community by xenograft-derived organisms may be due to infection by unknown pathogens that cause minimal or novel clinical syndromes and for which clinical laboratory testing is not available. Chimerism and False Positive Assays for Infection of the Host and Routine Monitoring for Xenogeneic Infection are among the issues discussed for maintaining safety in clinical trials of xenotransplantation. Further research is essential regarding the behavior of organisms known to be present in prospective donor species in xenograft recipients and on the detection of novel potential pathogens.
Preface to the special issue to honor Gerhard Levy and 50 years of PK/PD.

In a reflection published in The Annals of Pharmacotherapy in 2006 [1] Gerhard Levy (known to his friends as Gary) defined pharmacodynamics (PD) as being concerned ‘‘with the quantitative, temporal aspects of drug action, and particularly with the relationship between the concentration of drugs (and their active metabolites) in plasma or other biologic fluids and the intensity and time course of their pharmacological effects’’. When one types in the search word ‘‘pharmacodynamics’’ in the PubMed database, over 5.5 million citations dating back to 1873 were found [2]. Obviously, many of the older citations did not report studies that would fit into the definition of PD given above, because the quantitative aspects of the field did not begin until the 1960s when Gary and his students published their seminal articles that described the mathematical relationships between drug concentrations and pharmacological effects [3–5]. With this caveat in mind, in the decade between 2005 and 2014, an average of about 186 thousand records that included the pharmacodynamics term were indexed in PubMed per year. Gary’s key publication on the ‘‘Kinetics of pharmacological effects’’ was first presented at the IVth International Congress of Chemotherapy in October 1965 in Washington DC [4]. This and his many subsequent publications provided key insights into the connections between pharmacokinetics, pharmacology, and physiology that evolved into the breadth of pharmacodynamic theory, models, methods, and diverse applications that exist today and utilized in academia, the pharmaceutical industry, and regulatory agencies. With this issue of the Journal of Pharmacokinetics and Pharmacodynamics, we mark the 50th anniversary of Gary’s seminal paper and honor his numerous contributions to pharmaceutical sciences and the PK/PD field. We have invited a number of Gary’s former students and postdoctoral fellows, plus his faculty colleagues at the University at Buffalo, to provide research or review articles in this theme issue. Additionally, we have asked other former students and colleagues of Gary to provide short commentaries on how his work has influenced their own careers and the PK/PD field in general. Our overview of the history and contributions of Gary Levy and these brief commentaries form the first article in this special issue [6].
EXPRESSION OF NEURON-SPECIFIC TUBULIN DEFINES A NOVEL POPULATION IN THE PROLIFERATIVE LAYERS OF THE DEVELOPING TELENCEPHALON

We have used a monoclonal antibody against the neuron-specific class III beta-tubulin (TuJ1; Lee et al., 1990b) to study the distribution and morphology of immature neurons in the proliferative ventricular and subventricular zones of the developing telencephalon. Mouse brains from embryonic day 12 (E12) to postnatal day 5 (P5) were fixed either with a non-cross-linking agent, HistoChoice, or with 4% paraformaldehyde, and processed for TuJ1 immunohistochemistry. TuJ1 immunoreactivity first appeared in the proliferative zones of the developing cerebral cortex at E13-E14 as the cortical plate was emerging. After E14, tangentially oriented TuJ1-positive cells were abundant at the interface between the ventricular and subventricular zones. This tangential pattern was less conspicuous in the developing striatum. Within the cortical and striatal ventricular zone TuJ1-positive cells were less numerous and displayed a variety of orientations and morphologies. Postnatally, after the period of neurogenesis has ended, TuJ1 immunoreactivity continued to increase in the subventricular zone and remained high until the last developmental stage examined (P5). Anti-MAP2, another neuron-specific marker, never labeled the cells of the ventricular and subventricular zones, pre- or postnatally. To determine the birthdates of TuJ1-positive cells in the cortical-ventricular and subventricular zones, brains were double labeled with TuJ1 and bromodeoxyuridine according to different pulse-chase schedules. TuJ1-positive cells were postmitotic and generated throughout the period of cortical neurogenesis. Collectively, the results suggest that TuJ1 immunoreactivity distinguishes two neuronal populations: those that remain for an indefinite period of time in the proliferative zones, and those that leave the proliferative zones soon after being generated. Although the fate of the TuJ1-positive cells that reside in the proliferative zones remains unclear, their tangentially aligned orientation and their distribution suggest that they migrate independent of radial glial fibers.
Medication adherence decision-making among adolescents and young adults with cancer.

Abstract Purpose Nearly half of all adolescents and young adults (AYAs) with cancer struggle to adhere to oral chemotherapy or antibiotic prophylactic medication included in treatment protocols. The mechanisms that drive non-adherence remain unknown, leaving health care providers with few strategies to improve adherence among their patients. The purpose of this study was to use qualitative methods to investigate the mechanisms that drive the daily adherence decision-making process among AYAs with cancer. Methods Twelve AYAs (ages 15–31) with cancer who had a current medication regimen that included oral chemotherapy or antibiotic prophylactic medication participated in this study. Adolescents and young adults completed a semi-structured interview and a card sorting task to elucidate the themes that impact adherence decision-making. Interviews were transcribed verbatim and coded twice by two independent raters to identify key themes and develop an overarching theoretical framework. Results Adolescents and young adults with cancer described adherence decision-making as a complex, multi-dimensional process influenced by personal goals and values, knowledge, skills, and environmental and social factors. Themes were generally consistent across medication regimens but differed with age, with older AYAs discussing long-term impacts and receiving physical support from their caregivers more than younger AYAs. Conclusions The mechanisms that drive daily adherence decision-making among AYAs with cancer are consistent with those described in empirically-supported models of adherence among adults with other chronic medical conditions. These mechanisms offer several modifiable targets for health care providers striving to improve adherence among this vulnerable population.
A Conserved Gammaherpesvirus Cyclin Specifically Bypasses Host p18INK4c To Promote Reactivation From Latency

ABSTRACT Gammaherpesviruses (GHVs) carry homologs of cellular genes, including those encoding a viral cyclin that promotes reactivation from latent infection. The viral cyclin has reduced sensitivity to host cyclin-dependent kinase inhibitors in vitro ; however, the in vivo significance of this is unclear. Here, we tested the genetic requirement for the viral cyclin in mice that lack the host inhibitors p27 Kip1 and p18 INK4c , two cyclin-dependent kinase inhibitors known to be important in regulating B cell proliferation and differentiation. While the viral cyclin was essential for reactivation in wild-type mice, strikingly, it was dispensable for reactivation in mice lacking p27 Kip1 and p18 INK4c . Further analysis revealed that genetic ablation of only p18 INK4c alleviated the requirement for the viral cyclin for reactivation from latency. p18 INK4c regulated reactivation in a dose-dependent manner so that the viral cyclin was dispensable in p18 INK4c heterozygous mice. Finally, treatment of wild-type cells with the cytokine BAFF, a known attenuator of p18 INK4c function in B lymphocytes, was also able to bypass the requirement for the viral cyclin in reactivation. These data show that the gammaherpesvirus viral cyclin functions specifically to bypass the cyclin-dependent kinase inhibitor p18 INK4c , revealing an unanticipated specificity between a GHV cyclin and a single cyclin-dependent kinase inhibitor. IMPORTANCE The gammaherpesviruses (GHVs) cause lifelong infection and can cause chronic inflammatory diseases and cancer, especially in immunosuppressed individuals. Many GHVs encode a conserved viral cyclin that is required for infection and disease. While a common property of the viral cyclins is that they resist inhibition by normal cellular mechanisms, it remains unclear how important it is that the GHVs resist this inhibition. We used a mouse GHV that either contained or lacked a viral cyclin to test whether the viral cyclin lost importance when these inhibitory pathways were removed. These studies revealed that the viral cyclin was required for optimal function in normal mice but that it was no longer required following removal or reduced function of a single cellular inhibitor. These data define a very specific role for the viral cyclin in bypassing one cellular inhibitor and point to new methods to intervene with viral cyclins.