Intermolecular (119)Sn,(31)P Through-Space Spin-Spin Coupling in a Solid Bivalent Tin Phosphido Complex.
A bivalent tin complex [Sn(NP)2] (NP = [(2-Me2NC6H4)P(C6H5)](-)) was prepared and characterized by X-ray diffraction and solution and solid-state nuclear magnetic resonance (NMR) spectroscopy. In agreement with the X-ray structures of two polymorphs of the molecule, (31)P and (119)Sn CP/MAS NMR spectra revealed one crystallographic phosphorus and tin site with through-bond (1)J((117/119)Sn,(31)P) and through-space (TS)J((117/119)Sn,(31)P) spin-spin couplings. Density functional theory (DFT) calculations of the NMR parameters confirm the experimental data. The observation of through-space (TS)J((117/119)Sn,(31)P) couplings was unexpected, as the distances of the phosphorus atoms of one molecule and the tin atom of the neighboring molecule (>4.6 Å) are outside the sum of the van der Waals radii of the atoms P and Sn (4.32 Å). The intermolecular Sn···P separations are clearly too large for bonding interactions, as supported by a natural bond orbital (NBO) analysis.


Repurposing of Plasmodium falciparum var genes beyond the blood stage.
A commonly observed survival strategy in protozoan parasites is the sequential expression of clonally variant-surface antigens to avoid elimination by the host's immune response. In malaria-causing P. falciparum, the immunovariant erythrocyte-membrane protein-1 (PfEMP1) adhesin family, encoded by var genes, is responsible for both antigenic variation and cytoadherence of infected erythrocytes to the microvasculature. Until recently, the biological function of these variant genes was believed to be restricted to intraerythrocytic developmental stages. With the advent of new technologies, var gene expression has been confirmed in transmission and pre-erythrocytic stages. Here, we discuss how repurposing of var gene expression beyond chronic blood-stage infection may be critical for successful transmission.


Assessing the efficacy of 2 screening measures for depression in people with epilepsy.
The aim of this study was to compare the efficacy of the Neurological Depressive Disorders Inventory for Epilepsy (NDDI-E) and the depression component of the Hospital Anxiety Depression Scale (HADS-D) for identifying depression and suicide risk in adults with epilepsy. A total of 147 (87 female [59% ]) outpatients attending a tertiary epilepsy center in Sydney Australia completed the NDDI-E and HADS-D. They then completed the depression and suicide sections of the Mini International Neuropsychiatric Inventory (MINI) with a clinician blind to symptom measure scores. Receiver operator characteristic analysis was performed for the clinical cutoff scores for depression on the NDDI-E ≥ 15 and HADS-D ≥ 8 to identify MINI-determined depression and suicidality. The NDDI-E indicated strong sensitivity (84%) and acceptable specificity (78%), whereas the HADS-D had poor sensitivity (42%) but good specificity (97%) for identifying depression. For identifying suicide risk, the NDDI-E indicated strong sensitivity (81%) and reasonable specificity (66%), whereas the HADS-D had poor sensitivity (43%) but acceptable specificity (90%). Area under the curve comparisons for these measures were not significant. In clinical practice, it is essential that screening measures have the highest possible sensitivity values to limit the chances of false-negative results. In accordance with these guidelines, the NDDI-E was a superior screening measure compared with the HADS-D. Our results demonstrate the efficacy of the NDDI-E for identifying both major and minor depression and serious suicide risk. The poor sensitivity of the HADS-D suggests that it should not be used as a screen for depression or suicidality in adults with epilepsy.


Nitric oxide-mediated intracellular growth restriction of pathogenic Rhodococcus equi can be prevented by iron.
Rhodococcus equi is an intracellular pathogen which causes pneumonia in young horses and in immunocompromised humans. R. equi arrests phagosome maturation in macrophages at a prephagolysosome stage and grows inside a privileged compartment. Here, we show that, in murine macrophages activated with gamma interferon and lipopolysaccharide, R. equi does not multiply but stays viable for at least 24 h. Whereas infection control of other intracellular pathogens by activated macrophages is executed by enhanced phagosome acidification or phagolysosome formation, by autophagy or by the interferon-inducible GTPase Irgm1, none of these mechanisms seems to control R. equi infection. Growth control by macrophage activation is fully mimicked by treatment of resting macrophages with nitric oxide donors, and inhibition of bacterial multiplication by either activation or nitric oxide donors is annihilated by cotreatment of infected macrophages with ferrous sulfate. Transcriptional analysis of the R. equi iron-regulated gene iupT demonstrates that intracellular R. equi encounters iron stress in activated, but not in resting, macrophages and that this stress is relieved by extracellular addition of ferrous sulfate. Our results suggest that nitric oxide is central to the restriction of bacterial access to iron in activated macrophages.


Blunt abdominal trauma due to handlebar injury.
Bicycle accidents are a frequent cause of blunt abdominal trauma in children. In Chile, there are no scientific articles about such accidents, their presentation and management. The aim of this study is to describe three cases of blunt abdominal trauma due to handlebar injury in children, in order to illustrate the different kinds of lesions, their presentation, and management. 1) 11-year-old boy presented to Emergency Department (ED) after falling on a bi cycle handlebar, hitting his epigastric region. A CT scan showed signs of duodenal perforation. A la parotomy was performed and the duodenal perforation repaired. 2) 14-year-old boy seen at ED after a bicycle accident in which the handlebar hit him in the abdomen area. A CT scan showed a splenic injury with multiple lacerations and active bleeding that was treated with angioembolization. After 6 weeks of follow-up, he presented resolution of the lesion and viability of the spleen. 3) 9-year-old boy admitted due to a hit with the bicycle handlebar on the abdomen area. A CT scan showed a he patic injury that was managed with non-surgical procedures, achieving resolution of the lesion after 8 weeks of follow-up. Blunt abdominal trauma caused by handlebar can be potentially serious in pediatric patients, since it may affect solid and hollow abdominal viscera. Non-surgical ma nagement is becoming more used for stable patients, achieving high success rates. Unstable patients or those with suspicion of hollow viscera perforation will require surgery as first approach.


Association of ARNT splice variants with estrogen receptor-negative breast cancer, poor induction of vascular endothelial growth factor under hypoxia, and poor prognosis.
The aryl hydrocarbon receptor nuclear translocator (ARNT) is a basic helix-loop-helix transcription factor that forms heterodimers with the aryl hydrocarbon receptor (AhR) or hypoxia inducible factor-1alpha to activate transcription via xenobiotic response element or hypoxia response element, respectively. Thus, it plays a major role in two key biochemical pathways involved in tumor growth. We previously showed that estrogen receptor (ER)-negative breast cancer cell lines expressed a splice variant of ARNT that was associated with Ah nonresponsiveness. We have now used a sensitive PCR method to analyze the expression of the variant in a series of 92 breast cancers to assess interactions with the ER and prognosis. The splice variant could be detected in all of the cases examined, with high ratios of variant:full-length ARNT (> or =10) characterized in 10 cases. When the patient group was split into quartiles by increasing splice variant ratios, there was an inverse relationship of ER status to ARNT splice-variant ratios (P = 0.01, chi(2)). Univariate analysis showed that cases with high ARNT splice-variant ratios > or =10 had a worse relapse-free and overall survival (P > or = 0.03; hazard ratio, 2.7; and P = 0.006; hazard ratio, 3.9, respectively). In multivariate analysis for relapse-free and overall survival, ARNT splice-variant ratio was the strongest independent factor and, although inversely related to ER, remained a separate risk factor. At least two potential mechanisms could explain this phenomenon: the loss of aryl hydrocarbon receptor-mediated antiestrogenic activity or the blockade of a proapoptotic pathway induced by hypoxia. Because several enzymes involved in drug resistance are induced through a xenobiotic response element, the tumors presenting high ARNT splice-variant ratios may be specifically targeted by drugs normally degraded or inactivated. This study shows the biological importance of ARNT splice variants in the behavior of human breast cancer and suggests that the breast cell lines in which the splice variant was discovered may be useful models for further investigation.


The Association Between the Metabolic Syndrome and Metabolic Syndrome Score and Urine Microalbumin/Urine Creatinine Ratio and Glomerular Filtration Rate in Korean Adults With Obesity.
This study assessed the association between metabolic syndrome (MetS) and metabolic syndrome score (MSS) and the levels of urine microalbumin-urine creatinine ratio (uACR) and glomerular filtration rate (GFR) in Korean adults with obesity. Analyses of data obtained during the 2012 Korean National Health and Nutrition Examination Survey were restricted to that obtained from 1,612 adults aged ≥20 years with obesity. After adjusting for relevant variables (excluding age), uACR levels were positively associated with MetS (P < .001) and MSS (P < .001), and GFR levels were inversely associated with MetS (P < .001) and MSS (P < .001). However, when further adjusting for age, uACR levels were positively associated with MetS (P < .001) and MSS (P < .001) levels, but GFR levels were not associated with MetS (P = .632) and MSS (P = .275) levels. MetS and MSS were positively associated with uACR levels in Korean adults with obesity, but were not associated with GFR levels.


Relationship of clinic medical home scores to health care costs.
Multilevel, multivariate models examined the relationship between Primary Care Medical Home (PCMH) practice systems as measured by the Physician Practice Connections®-Readiness Survey™ (PPC®-RS™) and costs (total, outpatient, and inpatient) using 2008 patient data from 21 primary care clinics. Overall, PPC-RS scores were associated with insignificant changes in total (-$75/person, 1.1%) outpatient (-$67/person, 1.2%), and inpatient ($68/person, 0.5%) costs. However, improved PPC-RS scores were associated with significant decreases in total ($2378, 4.4%) and outpatient ($1282/person, 3.5%) costs among patients with 11 or more prescriptions suggesting higher functioning PCMHs may lead to reduced costs among the most complex and costly patients.


"We are our own community": Immigrant Latinx transgender people community experiences.
Little is known about how immigrant Latinx transgender people experience support from their communities in the U.S. and back in their country of origin. The present study aimed to understand how immigrant Latinx transgender people reported support within their communities. A community sample of 18 immigrant Latinx transgender people in a large metropolitan city in Florida participated in semi-structured interviews. Thematic analysis revealed four themes depicting the varying levels of support that participants received within their communities in the U.S., including: (a) neighborhood belonging, (b) organizations as a source of well-being, (c) friends as a source of protection and safety, and (d) supporting undocumented individuals. In addition, three themes emerged about participants' experiences of discrimination and oppression within their communities, including: (a) discrimination and violence, (b) police profiling and restriction of public space, and (c) lack of safety for undocumented individuals. Participants also shared narratives about the perceived level of community support they received in the U.S. versus in their countries of origin. Drawing on gender minority stress and intersectionality, the community experiences of immigrant Latinx transgender people are examined and interpreted to provide important research, advocacy, and practice implications. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


[Research progress in diagnosis and treatment of HPV-associated oropharyngeal squamous cell carcinoma].
Oropharyngeal carcinoma is one of the most common malignant tumors of head and neck. In recent years, the incidence of Human papilloma virus-associated oropharyngeal squamous cell carcinoma(HPV-OPSCC) has been increasing year by year. With the advancement of minimally invasive surgical techniques, the wide application of intensity modulated radiation therapy, and the demand of patients for organ function protection and higher quality of life, the unique biological behavior and better prognosis of HPV-OPSCC have led to the exploration of a series of attenuated treatment modes. This article reviews the diagnosis and treatment status of oropharyngeal cancer and related research progress based on relevant reports.


A comparison of large volume spacer, breath-activated and dry powder inhalers in older people.
To see if elderly people can use the breath-activated (Easi-breathe) and dry powder (Turbohaler) inhalers as effectively as the metered-dose inhaler and Volumatic system. 102 inhaler-naive patients (aged 75-101, mean 84 years), without cognitive impairment, were randomly allocated one of Easi-breathe, Turbohaler or metered-dose inhaler and Volumatic placebo inhalers. Standardized tuition was done on enrolment and at 6 h review. Inhaler technique was assessed immediately after enrolment tuition and at 6 and 24 h. Assessment was by scoring (0 = poor, 1 = moderate, 2 = perfect) five aspects of technique. Mean total scores were significantly (P < 0.005) higher for Turbohaler and Easi-breathe than metered-dose inhaler and Volumatic on enrolment and 6 h and at 24 h (P < 0.045). Fewer patients achieved excellent scores of 9 or 10 when using metered-dose inhaler and Volumatic. The main difficulties were in assembling the metered-dose inhaler and Volumatic and detecting when the metered-dose inhaler and Volumatic or Easi-breathe was empty. Breath-activated and dry powder inhalers were more likely to be used correctly than metered-dose inhalers with large volume spacers.


The combination of 64 multislice CT angiography and optical coherence tomography optimally characterizes coronary plaques.
The European Society of Cardiology designated 2008 as the year of imaging. However, despite the intense focus on the many types of imaging and the relative benefits of each one, the optimal modalityfor the diagnosis of coronary artery disease remains controversial. Among the currently available techniques, coronary angiography (CA) is the most widely used. In light of the many recent improvements in imaging, a comparison of the different modalities for CAD diagnosis and treatment evaluation is urgently needed. of the 1583 patients examined by computed tomography CA (CTCA) in the past 2 years, 28 with unstable angina also underwent CA and optical coherence tomography (OCT) evaluation. The coronary artery indices obtained with the three modalities were compared in this subset of patients. Minimal lumen diameter and reference lumen diameter were calculated independently based on the data obtained from each modality. The diameters measured by CTCA were significantly larger than those measured by CA or OCT (p < 0.05). Minimal cross-section area calculation was feasible only from the CTCA and OCT data, but not from the CA data. Again, the cross-sectional area measured by CTCA was significantly larger than that measured by OCT. Plaque diameter, remodelling index, plaque volume, and CT value could be measured only by CTCA. Disease extent was measured by CTCA using the method of J.K. Min and by CA using the Syntax Score. Intimal thickness and the thickness of the thrombus and fibrous cap could be evaluated only by OCT. A comparison of the three different imaging modalities (CA, CTCA, and OCT) in CAD pointed out the benefits as well as the limits. A combination of CA, CTCA, and OCT was found to provide the best approach to evaluating the coronary arteries. CTCA best revealed the vessel wall while OCT provided optimal visualization of the intima. The extent of coronary artery disease was best detered with CA and CTCA.


Obesity framing for health policy development in Australia, France and Switzerland.
The obesity epidemic is a consequence of the interaction of cultural, environmental, genetic and behavioural factors; framing the issue is central to determining appropriate solutions. This study used content and thematic framing analysis to explore portrayal of responsibility for obesity in policy documents in Australia, France and Switzerland. For Australia and France, obesity causality was a combination of individual and environmental factors, but for Switzerland, it was predominantly individual. The primary solutions for all countries were health promotion strategies and children's education. Industry groups proposed more school education while health advocates advised government intervention. Where France emphasized cultural attitudes towards taste, Australia focused on sport. The French were most keen on legislating against unhealthy foods compared with Switzerland where there was opposition towards regulation of individual's choices. To curb the increasing prevalence of obesity, allocation of responsibility needs to be considered and initiatives enacted accordingly.


Evidence for a Proapoptotic Role of Matrix Metalloproteinase-26 in Human Prostate Cancer Cells and Tissues.
Matrix metalloproteinases (MMPs) play intricate roles in cancer progression; some promote invasion and angiogenesis while others suppress tumor growth. For example, human MMP-26/endometase/matrilysin-2 was reported to be either protective or pro-tumorigenic. Our previous reports suggested pro-invasion and anti-inflammation properties in prostate cancer. Here, we provide evidence for a protective role of MMP-26 in the prostate. MMP-26 expression levels in androgen-repressed human prostate cancer (ARCaP) cells, transfected with sense or anti-sense MMP-26 cDNA, are directly correlated with those of the pro-apoptotic marker Bax. Immunohistochemical staining of prostate cancer tissue samples shows similar protein expression patterns, correlating the expression levels of MMP-26 and Bax in benign, neoplastic, and invasive prostate cancer tissues. The MMP-26 protein levels were upregulated in high grade prostate intraepithelial neoplasia (HGPIN) and decreased during the course of disease progression. Further analysis using an indirect terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay showed that many tumor cells expressing MMP-26 were undergoing apoptosis. This study showed that the high level of MMP-26 expression is positively correlated with the presence of apoptotic cells. This pro-apoptotic role of MMP-26 in human prostate cancer cells and tissues may enhance our understanding of the paradoxical roles of MMP-26 in tumor invasion and progression.


Curcumin abates hypoxia-induced oxidative stress based-ER stress-mediated cell death in mouse hippocampal cells (HT22) by controlling Prdx6 and NF-κB regulation.
Oxidative stress and endoplasmic reticulum (ER) stress are emerging as crucial events in the etiopathology of many neurodegenerative diseases. While the neuroprotective contributions of the dietary compound curcumin has been recognized, the molecular mechanisms underlying curcumin's neuroprotection under oxidative and ER stresses remains elusive. Herein, we show that curcumin protects HT22 from oxidative and ER stresses evoked by the hypoxia (1% O(2) or CoCl(2) treatment) by enhancing peroxiredoxin 6 (Prdx6) expression. Cells exposed to CoCl(2) displayed reduced expression of Prdx6 with higher reactive oxygen species (ROS) expression and activation of NF-κB with IκB phosphorylation. When NF-κB activity was blocked by using SN50, an inhibitor of NF-κB, or cells treated with curcumin, the repression of Prdx6 expression was restored, suggesting the involvement of NF-κB in modulating Prdx6 expression. These cells were enriched with an accumulation of ER stress proteins, C/EBP homologous protein (CHOP), GRP/78, and calreticulin, and had activated states of caspases 12, 9, and 3. Reinforced expression of Prdx6 in HT22 cells by curcumin reestablished survival signaling by reducing propagation of ROS and blunting ER stress signaling. Intriguingly, knockdown of Prdx6 by antisense revealed that loss of Prdx6 contributed to cell death by sustaining enhanced levels of ER stress-responsive proapoptotic proteins, which was due to elevated ROS production, suggesting that Prdx6 deficiency is a cause of initiation of ROS-mediated ER stress-induced apoptosis. We propose that using curcumin to reinforce the naturally occurring Prdx6 expression and attenuate ROS-based ER stress and NF-κB-mediated aberrant signaling improves cell survival and may provide an avenue to treat and/or postpone diseases associated with ROS or ER stress.


Comparison of MEMS switches and PIN diodes for switched dual tuned RF coils.
To evaluate the performance of micro-electromechanical systems (MEMS) switches against PIN diodes for switching a dual-tuned RF coil between 19 F and 1 H resonant frequencies for multi-nuclear lung imaging. A four-element fixed-phase and amplitude transmit-receive RF coil was constructed to provide homogeneous excitation across the lungs, and to serve as a test system for various switching methods. The MR imaging and RF performance of the coil when switched between the 19 F and 1 H frequencies using MEMS switches, PIN diodes and hardwired configurations were compared. The performance of the coil with MEMS or PIN diode switching was comparable in terms of RF measurements, transmit efficiency and image SNR on both 19 F and 1 H nuclei. When the coil was not switched to the resonance frequency of the respective nucleus being imaged, reductions in the transmit efficiency were observed of 32% at the 19 F frequency and 12% at the 1 H frequency. The coil provides transmit field homogeneity of ±12.9% at the 1 H frequency and ±14.4% at the 19 F frequency in phantoms representing the thorax with the air space of the lungs filled with perfluoropropane gas. MEMS and PIN diodes were found to provide comparable performance in on-state configuration, while MEMS were more robust in off-state high-powered operation (>1 kW), providing higher isolation and requiring a lower DC switching voltage than is needed for reverse biasing of PIN diodes. In addition, clear benefits of switching between the 19 F and 1 H resonances were demonstrated, despite the proximity of their Larmor frequencies.


Prevention of corneal opacification in open sky vitrectomy: Part I. An in vitro study.
We tested the effects of various physiologic solutions with known osmotic pressures on maintenance of corneal transparency in vitro and compared them with the effects of other solutions that exert both oncotic and osmotic pressures. Normal saline solution, 5% glucose and normal saline solution, tissue culture 199, and plasma were bathing solutions tested. Increases in hydration and endothelial cell damage for the various media were compared. We found that plasma preserved corneal dehydration and endothelial viability better than other physiologic solutions.


Physiology of muscarinic functions.
The general features and distributions of muscarinic and nicotinic receptors are compared. The unusual aspects of the transmission of cholinergic impulses to the muscarinic receptors of eccrine sweat glands are discussed, and evidence is presented for an intermediate adrenergic step. The modulating roles of muscarinic receptors in sympathetic ganglia are considered as well as possible sources of the catecholamine involved in producing the inhibitory potential. The responses to activation of muscarinic receptors in the central nervous system suggest that they may regulate the level of neuronal excitability. Recent directions of research on the function of muscarinic receptors is summarized.


New superfamily members identified for Schiff-base enzymes based on verification of catalytically essential residues.
Enzymes that utilize a Schiff-base intermediate formed with their substrates and that share the same alpha/beta barrel fold comprise a mechanistically diverse superfamily defined in the SCOPS database as the class I aldolase family. The family includes the "classical" aldolases fructose-1,6-(bis)phosphate (FBP) aldolase, transaldolase, and 2-keto-3-deoxy-6-phosphogluconate aldolase. Moreover, the N-acetylneuraminate lyase family has been included in the class I aldolase family on the basis of similar Schiff-base chemistry and fold. Herein, we generate primary sequence identities based on structural alignment that support the homology and reveal additional mechanistic similarities beyond the common use of a lysine for Schiff-base formation. The structural and mechanistic correspondence comprises the use of a catalytic dyad, wherein a general acid/base residue (Glu, Tyr, or His) involved in Schiff-base chemistry is stationed on beta-strand 5 of the alpha/beta barrel. The role of the acid/base residue was probed by site-directed mutagenesis and steady-state and pre-steady-state kinetics on a representative member of this family, FBP aldolase. The kinetic results are consistent with the participation of this conserved residue or position in the protonation of the carbinolamine intermediate and dehydration of the Schiff base in FBP aldolase and, by analogy, the class I aldolase family.


Healthy Lifestyle Behaviors: Nursing Considerations for Social Determinants of Health.
Nurses develop meaningful and deep connections with patients, making them particularly skilled to consider how social determinants of health (SDOH) affect patients. SDOH include one's neighborhood and built environment, health and health care, social and community context, education, and economic stability. Consideration of SDOH, in addition to individual factors, allows nurses to better support patient engagement in health behaviors. This article aims to explore how nurses consider SDOH when talking about health behaviors with patients and to provide case exemplars of how incorporation of the SDOH can be increased in holistic, patient-centered nursing care. A secondary data analysis was conducted to identify how practicing oncology nurses (N = 75) take SDOH into account when talking about physical activity with patients. Of the 124 considerations that nurses made when talking about physical activity with patients, most did not relate to SDOH.


Tuberculosis and COVID-19 in the elderly: factors driving a higher burden of disease.
Mycobacterium tuberculosis (M.tb) and SARS-CoV-2 are both infections that can lead to severe disease in the lower lung. However, these two infections are caused by very different pathogens (Mycobacterium vs. virus), they have different mechanisms of pathogenesis and immune response, and differ in how long the infection lasts. Despite the differences, SARS-CoV-2 and M.tb share a common feature, which is also frequently observed in other respiratory infections: the burden of disease in the elderly is greater. Here, we discuss possible reasons for the higher burden in older adults, including the effect of co-morbidities, deterioration of the lung environment, auto-immunity, and a reduced antibody response. While the answer is likely to be multifactorial, understanding the main drivers across different infections may allow us to design broader interventions that increase the health-span of older people.


Cardiovascular effects of adenosine A2 agonists in the conscious spontaneously hypertensive rat: a comparative study of three structurally distinct ligands.
The hemodynamic responses to 5'-N-ethylcarboxamide adenosine (NECA), a nonselective adenosine agonist, were compared to those elicited by the sodium salt of 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamido adenosine (CGS 21680C) and N6-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl adenosine (CGS 24012), two structurally dissimilar selective A2 agonists in conscious spontaneously hypertensive rats (SHR). Dose-related reductions in mean arterial pressure occurred after bolus administration of NECA, CGS 21680C and CGS 24012. Dose-dependent tachycardia was seen with both CGS 21680C and CGS 24012, whereas NECA produced a biphasic response on heart rate. At high doses (3 and 10 micrograms/kg), NECA evoked an immediate and dramatic fall in heart rate, followed by a more gradual and long-lasting tachycardia. At equihypotensive doses, both CGS 21680C and CGS 24012 produced significant increases in cardiac output, but NECA had no effect. Although each of the adenosine agonists reduced total peripheral resistance, the greatest change was produced by CGS 21680C. Hindquarter, renal and mesenteric vascular resistances were significantly reduced by both CGS 21680C and CGS 24012, whereas only mesenteric vascular resistance was reduced with NECA. CGS 24012 reduced renal vascular resistance to the greatest extent and produced a concomitant significant increase in renal blood flow. Marked elevation in plasma renin activity occurred with CGS 24012 and CGS 21680C, whereas no change was seen after NECA. The hemodynamic responses to NECA, CGS 21680C and CGS 24012 were significantly reduced by the adenosine antagonist, 8-(p-sulfophenyl) theophylline, suggesting that these agents act through stimulation of adenosine receptors in the conscious SHR. Furthermore, blockade of the beta adrenergic receptor with metoprolol (1 mg/kg, i.v.) significantly attenuated the increase in heart rate produced by NECA, CGS 21680C and CGS 24012. The cardiovascular pattern of responses to the two selective A2 agonists, CGS 21680C and CGS 24012, are distinct from those of NECA, the nonselective adenosine agonist. The responses to both CGS 21680C and CGS 24012 indicate that systemic vasodilation, with resultant cardioexcitation and stimulation of renin release, are the predominant hemodynamic effects of selective A2 agonists in the conscious SHR. In contrast, the cardiovascular effects produced by NECA are mediated by activation of both A1 and A2 receptors.


Liposomes in silicosis investigations.
The effects of quartz and sodium metasilicate on liposomes were studied in order to understand the mechanism of silicosis. 8-Hydroxyquinoline-5-sulfonic acid was tested for its in situ silicosis-prevention capacity. Two types of liposomes--(A) those incorporating cholesterol and (B) those without cholesterol--were used. The tests consisted of measuring permeability changes caused by the above-mentioned chemicals. Permeabilities were found to depend on membrane composition. Tests on quartz action led us to the conclusion that liposomes of this composition did not simulate the erythrocytes very well. It was also observed that absence or presence of cholesterol and the mode of contact altered the effect of quartz. Silicate destabilized type A liposomes, but this was less than that caused by quartz. This was explained by the concentration of monosilicic acid that dissolves out from quartz and silicate. When quartz was pretreated with the preventive, the type A liposomes were stabilized, but a slight destabilizing effect was observed on type B. 8-Hydroxyquinoline-5-sulfonic acid augmented the destabilizing effect of silicate, whereas it decreased the hemolytic activity of uncoated quartz, indicating a preventive potential in in vivo.


The Crd1 gene encodes a putative di-iron enzyme required for photosystem I accumulation in copper deficiency and hypoxia in Chlamydomonas reinhardtii.
Chlamydomonas reinhardtii adapts to copper deficiency by degrading apoplastocyanin and inducing Cyc6 and Cpx1 encoding cytochrome c(6) and coproporphyrinogen oxidase, respectively. To identify other components in this pathway, colonies resulting from insertional mutagenesis were screened for copper- conditional phenotypes. Twelve crd (copper response defect) strains were identified. In copper-deficient conditions, the crd strains fail to accumulate photosystem I and light-harvesting complex I, and they contain reduced amounts of light-harvesting complex II. Cyc6, Cpx1 expression and plastocyanin accumulation remain copper responsive. The crd phenotype is rescued by a similar amount of copper as is required for repression of Cyc6 and Cpx1 and for maintenance of plastocyanin at its usual stoichiometry, suggesting that the affected gene is a target of the same signal transduction pathway. The crd strains represent alleles at a single locus, CRD1, which encodes a 47 kDa, hydrophilic protein with a consensus carboxylate-bridged di-iron binding site. Crd1 homologs are present in the genomes of photosynthetic organisms. In Chlamydomonas, Crd1 expression is activated in copper- or oxygen-deficient cells, and Crd1 function is required for adaptation to these conditions.


Area-Specific Mapping of Binocular Disparity across Mouse Visual Cortex.
Depth perception is a fundamental feature of many visual systems across species. It is relevant for crucial behaviors, like spatial orientation, prey capture, and predator detection. Binocular disparity, the difference between left and right eye images, is a powerful cue for depth perception, as it depends on an object's distance from the observer [1,2]. In primates, neurons sensitive to binocular disparity are found throughout most of the visual cortex, with distinct disparity tuning properties across primary and higher visual areas, suggesting specific roles of different higher areas for depth perception [1-3]. Mouse primary visual cortex (V1) has been shown to contain disparity-tuned neurons, similar to those found in other mammals [4,5], but it is unknown how binocular disparity is processed beyond V1 and whether it is differentially represented in higher areas. Beyond V1, higher-order, lateromedial (LM) and rostrolateral (RL) areas contain the largest representation of the binocular visual field [6,7], making them candidate areas for investigating downstream processing of binocular disparity in mouse visual cortex. In turn, comparison of disparity tuning across different mouse visual areas might help delineating their functional specializations, which are not well understood. We find clear differences in neurons' preferred disparities across areas, suggesting that higher visual area RL is specialized for encoding visual stimuli very close to the mouse. Moreover, disparity preference is related to visual field elevation, likely reflecting an adaptation to natural image statistics. Our results reveal ethologically relevant areal specializations for binocular disparity processing across mouse visual cortex.


Executive functioning trajectories and their prospective association with inflammatory biomarkers in schizophrenia and non-psychiatric comparison participants.
Cognitive change in people with schizophrenia (PwS) is challenging to assess, but important to understand. Previous studies with limited age ranges and follow-up were subject to practice effects. Controlling for practice effects in a well-established cohort, we examined executive functioning trajectories and their association with inflammatory biomarkers, hypothesizing that PwS will have worsening executive functioning over time compared to non-psychiatric comparison participants (NCs), predicted by higher baseline inflammation with a stronger relationship in PwS than NCs. Executive functioning was assessed in 350 participants (n = 186 PwS, 164 NCs) at 12-16-month intervals (0 to 7 follow-up visits). Inflammatory biomarkers at baseline included high sensitivity C-Reactive Protein (hs-CRP), Interferon-gamma, Tumor Necrosis Factor (TNF)-alpha, and Interleukin(IL)-6, -8, and - 10. Executive functioning trajectories across diagnostic groups were estimated using a linear mixed-effects model controlling for age, sex, race/ethnicity, and education level, with additional models to assess prediction by baseline inflammation. Over 4.4 years average follow-up, improvements in executive functioning were attenuated in PwS and older participants. Controlling for practice effects negated improvements, revealing declines among highly educated participants regardless of diagnosis. Higher baseline hs-CRP predicted worse executive functioning only among NCs, while TNF-alpha was predictive of change in all participants only after controlling for practice effects. Only the main effect of hs-CRP on executive function was significant after adjusting for multiple comparisons. None of the other inflammatory biomarkers predicted executive functioning or trajectories of performance among study participants. Systemic inflammation as reflected by baseline inflammatory biomarker levels did not predict longitudinal declines in executive functioning. Additional studies examining the temporal dynamics of inflammation and cognition in PwS will help further clarify their relationship and associated mechanisms.


Sertoli Cell-Specific Activation of Transforming Growth Factor Beta Receptor 1 Leads to Testicular Granulosa Cell Tumor Formation.
The transforming growth factor β (TGFβ) superfamily, consisting of protein ligands, receptors, and intracellular SMAD transducers, regulates fundamental biological processes and cancer development. Our previous study has shown that sustained activation of TGFβ receptor 1 (TGFBR1) driven by anti-Mullerian hormone receptor type 2 (Amhr2)-Cre in the mouse testis induces the formation of testicular granulosa cell tumors (TGCTs). As Amhr2-Cre is expressed in both Sertoli cells and Leydig cells, it remains unclear whether the activation of TGFBR1 in Sertoli cells alone is sufficient to induce TGCT formation. Therefore, the objective of this study was to determine whether Sertoli cell-activation of TGFBR1 drives oncogenesis in the testis. Our hypothesis was that overactivation of TGFBR1 in Sertoli cells would promote their transdifferentiation into granulosa-like cells and the formation of TGCTs. To test this hypothesis, we generated mice harboring constitutive activation of TGFBR1 in Sertoli cells using anti-Mullerian hormone (Amh)-Cre. Disorganized seminiferous tubules and tumor nodules were found in TGFBR1CA; Amh-Cre mice. A histological analysis showed that Sertoli cell-specific activation of TGFBR1 led to the development of neoplasms resembling granulosa cell tumors, which derailed spermatogenesis. Moreover, TGCTs expressed granulosa cell markers including FOXL2, FOXO1, and INHA. Using a dual fluorescence reporter line, the membrane-targeted tdTomato (mT)/membrane-targeted EGFP (mG) mouse, we provided evidence that Sertoli cells transdifferentiated toward a granulosa cell fate during tumorigenesis. Thus, our findings indicate that Sertoli cell-specific activation of TGFBR1 leads to the formation of TGCTs, supporting a key contribution of Sertoli cell reprogramming to the development of this testicular malignancy in our model.


[Effectiveness of combined use of monoamine oxidase inhibitors and psychotherapy in the treatment of chronic alcoholism].
The purpose of the study was to examine the efficacy of nuredal to correct cognitive disorders in patients with alcoholism. The drug treatment was combined with psychotherapy. The study was carried out in the main and control groups by the double blind method. The patients' status was assessed by means of the clinical observation as well as with the aid of a number of psychodiagnostic methods. The data obtained point to positive shifts in the mental status of patients treated with nuredal combined with psychotherapy.


Ex Vivo Method for Assessing the Mouse Reproductive Tract Spontaneous Motility and a MATLAB-based Uterus Motion Tracking Algorithm for Data Analysis.
Dysmenorrhea, or painful cramping, is the most common symptom associated with menses in females and its severity can hinder women's everyday lives. Here, we present an easy and inexpensive method that would be instrumental for testing new drugs decreasing uterine contractility. This method utilizes the unique ability of the entire mouse reproductive tract to exhibit spontaneous motility when maintained ex vivo in a Petri dish containing oxygenated Krebs buffer. This spontaneous motility resembles the wave-like myometrial activity of the human uterus, referred to as endometrial waves. To demonstrate the effectiveness of the method, we employed a well-known uterine relaxant drug, epinephrine. We demonstrate that the spontaneous motility of the entire mouse reproductive tract can be quickly and reversibly inhibited by 1 µM epinephrine in this Petri dish model. Documenting the changes of uterine motility can be easily done using an ordinary smart phone or a sophisticated digital camera. We developed a MATLAB-based algorithm allowing motion tracking to quantify spontaneous uterine motility changes by measuring the rate of uterine horn movements. A major advantage of this ex vivo approach is that the reproductive tract remains intact throughout the entire experiment, preserving all intrinsic intrauterine cellular interactions. The major limitation of this approach is that up to 10-20% of uteri may exhibit no spontaneous motility. Thus far, this is the first quantitative ex vivo method for assessing spontaneous uterine motility in a Petri dish model.


A simple assessment of haemothoraces thickness predicts abundant transfusion: a series of 525 blunt trauma patients.
The goal of this study was to evaluate the performance of haemothorax quantification to predict an abundant transfusion in blunt thoracic trauma patients. This study included all severe trauma patients admitted into our trauma centre from January 2005 to January 2010, who presented a blunt thoracic trauma (thoracic AIS ≥1) and had a CT scan within the first hour following admission. For each haemothorax, thickness of dominant side and the cumulated thicknesses of both sides (Dominant-t, Cumulated-t), as well as lengths (Dominant-l, Cumulated-l) and the calculated volumes (Dominant-v, Cumulated-v provided by a previously validated formula) were retrospectively measured by CT scan. A multiple logistic regression was performed to define the independent risk factors for an abundant transfusion (≥5 packed red blood cells in the first 24h). Finally, ROC curves have been drawn on an isolated thoracic trauma subgroup to predict abundant transfusion. The more specific cut-offs were extracted from this analysis. From the 525 blunt thoracic trauma patients (75% males, mean age 38.2 (SD18.7) years, mean ISS 22.5 (SD16.4)), 31% received an abundant transfusion. In multivariable analysis, Cumulated-t was significantly associated with an abundant transfusion (OR 1.3 [95% CI 1.1-1.4], P=0.002). In isolated thoracic trauma subgroup (n=251), the global abilities of different CT measurements to predict abundant transfusion were significantly comparable (AUCs 0.69-0.70). The more specific cut-offs were established at 28mm for Cumulated-t (specificity 92%, positive predictive value 47%) and at 24mm for Dominant-t (specificity 92%; positive predictive value 43%). The haemothorax quantification upon admission may help to predict transfusion needs. Cumulated-t was found independent risk factor for abundant transfusion in a large population of severe trauma patients. Beyond a Cumulated-t of 28mm or a Dominant-t of 24mm, abundant transfusion will be very frequently necessary. Retrospective review, level III.


[Mechanism of inhibition of fibrin polymerization by fibrinogen and its active fragments].
The specific inhibition of fibrin monomer polymerization by fibrinogen and some of its degradation products shows an unusual concentration dependence. Namely, in a certain region of the inhibitor concentration scale the slope of the activity curve increases considerably with an increase in concentration to reach a high constant steepness. This peculiar relationship indicates that the mechanism of inhibition is rather complicated. It has been assumed that this mechanism includes two steps: the first, preliminary step can presumably consist in an inhibitor induced transformation of fibrin (monomer or rather intermediate polymers), while the second one--a competitively inhibiting complex formation. At low inhibitor concentrations the rate of fibrin transformation is slow and limits the delay in clotting. At higher concentrations the modification is progressively accelerated and its rate gradually ceases, influencing the extent of the inhibition. The second stage, with its linear concentration dependence, becomes therefore exclusively rate-limiting. A kinetic analysis revealed that three molecules of the inhibitor are involved in the fibrin modification act. The theoretical curve obtained on the basis of the two-step model was found to be in good agreement with the experimental data.


Pattern of glomerular diseases among adults in Rajshahi, the Northern Region of Bangladesh.
To obtain a recent and comprehensive insight into the pattern of glomerular diseases in the Bangladeshi population, we studied 95 adequate renal biopsies done during July 2008 to June 2009, by light and direct immunofluorescence microscopy in the Department of Pathology, Rajshahi Medical College, Northern Region of Bangladesh. Of these, 38 (40%) were males and 57 (60%) were females, with a male to female ratio of 1:1.5. The most frequent clinical presentation was nephrotic syndrome (67.37%). Primary glomerular disease accounted for 91.25% of all glomerular disease and, of them, focal and segmental mesangial proliferative glomerulonephritis was the most common histological lesion in 29.47%. Diffuse mesangial proliferative glomerulonephritis (GN) was the second most common lesion (15.79%), followed by focal segmental GN (11.58%), minimal change disease (10.53%), membranous GN (7.37%), IgA nephropathy (6.85%), chronic sclerosing GN (2.11%) and crescentic GN (2.11%). Lupus nephritis was the most prevalent among secondary GN.


Activating Autophagy Enhanced the Antitumor Effect of Antibody Drug Conjugates Rituximab-Monomethyl Auristatin E.
Antibody drug conjugate (ADC) showed potent therapeutic efficacy in several types of cancers. The role of autophagy in antitumor effects of ADC remains unclear. In this study, the ADC, Rituximab-monomethyl auristatin E (MMAE) with a Valine-Citrulline cleavable linker, was designed to investigate its therapeutic efficacy against non-Hodgkin lymphoma (NHL) as well as the underlying mechanisms. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) was used to detect growth inhibition in B-cell lymphoma cell lines, Ramos and Daudi cells, which were treated by Rituximab-MMAE alone or combined with autophagy conditioner. Apoptosis was detected by flow cytometry and immunohistochemistry, and apoptosis inhibitor was employed to discover the relationship between autophagy and apoptosis during the Rituximab-MMAE treatment. Autophagy was determined by three standard techniques which included confocal microscope, transmission electron microscope, and western blots. Ramos xenograft tumors in BALB/c nude mice were established to investigate the antitumor effect of combination use of Rituximab-MMAE and autophagy conditioner in B-NHL therapy. Our results showed that Rituximab-MMAE elicited caspase-3-dependent apoptosis in NHL cells and exhibited potent therapeutic efficacy in vivo. Autophagy, which was characterized by upregulated light chain 3-II expression, and accumulation of autophagosomes, was triggered during the Rituximab-MMAE treatment. Meanwhile, inactivation of Akt/mTOR pathway was shown to be involved in the autophagy triggered by Rituximab-MMAE, indicating a probable mechanism of the ADC-initiated autophagy. Importantly, inhibition of autophagy by chloroquine suppressed the Rituximab-MMAE-induced apoptosis, while activating autophagy by rapamycin significantly enhanced the therapeutic effect of Rituximab-MMAE both in vitro and in vivo. Our data elucidated the critical relationship between autophagy and apoptosis in Rituximab-MMAE-based therapy and highlighted the potential approach for NHL therapy by combined administration of the ADC and autophagy activator.


Simulating carbon capture by enhanced weathering with croplands: an overview of key processes highlighting areas of future model development.
Enhanced weathering (EW) aims to amplify a natural sink for CO2 by incorporating powdered silicate rock with high reactive surface area into agricultural soils. The goal is to achieve rapid dissolution of minerals and release of alkalinity with accompanying dissolution of CO2 into soils and drainage waters. EW could counteract phosphorus limitation and greenhouse gas (GHG) emissions in tropical soils, and soil acidification, a common agricultural problem studied with numerical process models over several decades. Here, we review the processes leading to soil acidification in croplands and how the soil weathering CO2 sink is represented in models. Mathematical models capturing the dominant processes and human interventions governing cropland soil chemistry and GHG emissions neglect weathering, while most weathering models neglect agricultural processes. We discuss current approaches to modelling EW and highlight several classes of model having the potential to simulate EW in croplands. Finally, we argue for further integration of process knowledge in mathematical models to capture feedbacks affecting both longer-term CO2 consumption and crop growth and yields.


[Eosinophilic oesophagitis and eosinophilic gastrointestinal diseases].
Eosinophilic oesophagitis (EoE) was first described as an orphan disease in the 1990s, but its incidence and prevalence has increased dramatically in the last 20 years. EoE is now the most common cause of dysphagia in young adulthood. EoE is diagnosed endoscopically (with biopsies taken from the oesophagus). Treatment options consist of dietary measures and medications. The latter include PPI (as an off-label medication) and the approved drugs Jorveza (budesonide, topical cortisone preparation) and the monoclonal antibody Dupixent (dupilumab, subcutaneous). The response to therapy is high and the long-term outcome, if treated early, is excellent. However, the disease often remains undetected, mostly due to compensation mechanisms on the part of the patients. Much rarer than EoE are the non-EoE eosinophilic gastrointestinal diseases (EGIDs), in which the eosinophilic tissue infiltration is found in gastrointestinal segments distal to the oesophagus. Their clinical presentation is often non-specific. Pathophysiologically, overlaps with EoE are present. Therapies are also analogous to EoE. An increasing prevalence and incidence is to be expected.


Testosterone receptor blockade after hemorrhage in males. Restoration of the depressed immune functions and improved survival following subsequent sepsis.
Recent studies suggest that androgen depletion by castration before hemorrhage has protective effects on cell-mediated immunity in male mice after soft tissue trauma and hemorrhagic shock. To determine whether treatment with an androgen receptor blocker (eg, flutamide) after trauma-hemorrhage and sepsis has any salutary effects on cell-mediated immunity and on the survival of male animals under those conditions. Male C3H/HeN mice were either sham operated or subjected to hemorrhagic shock (mean [+/- SEM] blood pressure, 35 +/- 5 mm Hg for 90 minutes) followed by adequate fluid resuscitation (with shed blood and lactated Ringer solution). The animals then received either vehicle or 25-mg/kg body weight flutamide subcutaneously immediately after the resuscitation as well as 24 and 48 hours thereafter. At 48 hours after shock, sepsis was induced by cecal ligation and puncture. Sham-operated animals underwent laparotomy only. At 24 hours after cecal ligation and puncture, the animals were killed, blood was collected, and splenocytes and splenic macrophages were harvested to produce nonadherent and adherent cultures. Splenocytes were evaluated for splenocyte proliferation and interleukin 2 release, while interleukin 1 and interleukin 6 release were assayed in splenic macrophages. Plasma testosterone and corticosterone levels were also measured by radioimmunoassay. In a separate set of experiments, survival was measured over a period of 9 days after the induction of sepsis. Hemorrhage followed by sepsis produced a significant (P < .05) depression of splenocyte and macrophage functions in vehicle-treated animals. In contrast, animals treated with flutamide showed markedly improved immune functions, as evidenced by restoration of splenocyte proliferation, interleukin 2 release, splenic macrophage interleukin 1 release, and improvement of splenic macrophage interleukin 6 release. Plasma corticosterone levels were notably elevated while testosterone levels were depressed after hemorrhage and the induction of sepsis. The survival rate of the animals in the flutamide-treated group was also notably higher than the survival rate of animals in the vehicle-treated group subjected to hemorrhage and sepsis. The findings that flutamide not only markedly improves the depressed immune functions but also the survival of animals after hemorrhage and the induction of sepsis suggest that the short-term administration of androgen receptor blocker in males after trauma represents a safe and novel approach for preventing immune deficiency and decreasing the mortality rate from subsequent sepsis.


Dynamics of supercoiled DNA with complex knots: large-scale rearrangements and persistent multi-strand interlocking.
Knots and supercoiling are both introduced in bacterial plasmids by catalytic processes involving DNA strand passages. While the effects on plasmid organization has been extensively studied for knotting and supercoiling taken separately, much less is known about their concurrent action. Here, we use molecular dynamics simulations and oxDNA, an accurate mesoscopic DNA model, to study the kinetic and metric changes introduced by complex (five-crossing) knots and supercoiling in 2 kbp-long DNA rings. We find several unexpected results. First, the conformational ensemble is dominated by two distinct states, differing in branchedness and knot size. Secondly, fluctuations between these states are as fast as the metric relaxation of unknotted rings. In spite of this, certain boundaries of knotted and plectonemically-wound regions can persist over much longer timescales. These pinned regions involve multiple strands that are interlocked by the cooperative action of topological and supercoiling constraints. Their long-lived character may be relevant for the simplifying action of topoisomerases.


Rituximab in AChR subtype of myasthenia gravis: systematic review.
Myasthenia gravis (MG) is a chronic autoimmune disorder of the neuromuscular junction characterised by an autoantibody against acetylcholine receptor (AChR-Ab), autoantibody against muscle-specific kinase (MuSK-Ab), lipoprotein-related protein 4 or agrin in the postsynaptic membrane at the neuromuscular junction. Many patients are resistant to conventional treatment and effective therapies are needed. Rituximab (RTX) is a monoclonal antibody directed against CD20 antigen on B cells which has been successfully employed in anti-MuSK-Ab+MG, but the efficacy in anti-AChR-Ab+MG is still debated. The purpose of this systematic review was to describe the best evidence for RTX in the acetylcholine receptor subtype. The authors undertook a literature search during the period of 1999-2019 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analys methodology, employing (myasthenia)+(gravis)+(RTX) as search terms. The analysis was confined to studies that include at least five patients with confirmed anti-AChR-Ab+MG. Thirteen studies have been selected, showing a good safety. The data obtained were heterogeneous in terms of posology, administration scheme and patients' evaluation, ranging from a minimum of two to a maximum of three cycles. RTX led to a sustained clinical improvement with prolonged time to relapse, in parallel to a reduction or discontinuation of other immunosuppressive therapies. Treatment with RTX appears to work in some but not all patients with anti-AChR-Ab+MG, but randomised controlled trials are needed. Future studies should take into account the subtype of MG and employ reliable measures of outcome and severity focusing on how to identify patients who may benefit from the treatment. Trial registration number: NCT02110706.


The proximal femoral growth plate in Perthes disease.
We hypothesized the extent of involvement of the proximal femoral growth plate in Perthes disease determined the final radiographic outcome after containment by shelf acetabuloplasty. We retrospectively evaluated the extent of growth plate involvement using a modified version of the method described by Yasuda and Tamura. In our modification, we used only the epiphyseal border for measurements, which was clearly visible as a thin white line, unlike Yasuda and Tamura who used the metaphyseal and epiphyseal borders. We could not clearly demarcate the metaphyseal border in the radiographs of our patient population between 1944 and 1998, which consisted of 69 patients who had surgery at a mean age of 9 years (range, 6.0-14.1 years). From these measurements, we formulated an index termed "growth plate involvement." Radiographic results were classified as described by Stulberg et al A growth plate involvement index less than 0.25 resulted in a good radiographic outcome. We found 93.2% sensitivity and 100% specificity in predicting Stulberg's outcomes. The growth plate involvement index is a reliable and reproducible measurement method and may be used prospectively as a useful prognostic factor to predict radiographic outcomes after containment acetabuloplasty.


Impact of family planning programs in reducing high-risk births due to younger and older maternal age, short birth intervals, and high parity.
Several studies show that maternal and neonatal/infant mortality risks increase with younger and older maternal age (<18 and >34 years), high parity (birth order >3), and short birth intervals (<24 months). Family planning programs are widely viewed as having contributed to substantial maternal and neonatal mortality decline through contraceptive use--both by reducing unwanted births and by reducing the burden of these high-risk births. However, beyond averting births, the empirical evidence for the role of family planning in reducing high-risk births at population level is limited. We examined data from 205 Demographic and Health Surveys (DHS), conducted between 1985 and 2013, to describe the trends in high-risk births and their association with the pace of progress in modern contraceptive prevalence rate (yearly increase in rate of MCPR) in 57 developing countries. Using Blinder-Oaxaca decomposition technique, we then examine the contributions of family planning program, economic development (GDP per capita), and educational improvement (secondary school completion rate) on the progress of MCPR in order to link the net contribution of family planning program to the reduction of high-risk births mediated through contraceptive use. Countries that had the fastest progress in improving MCPR experienced the greatest declines in high-risk births due to short birth intervals (<24 months), high parity births (birth order >3), and older maternal age (>35 years). Births among younger women <18 years, however, did not decline significantly during this period. The decomposition analysis suggests that 63% of the increase in MCPR was due to family planning program efforts, 21% due to economic development, and 17% due to social advancement through women's education. Improvement in MCPR, predominately due to family planning programs, is a major driver of the decline in the burden of high-risk births due to high parity, shorter birth intervals, and older maternal age in developing countries. The lack of progress in the decline of births in younger women <18 years of age underscores the need for more attention to ensure that quality contraceptive methods are available to adolescent women in order to delay first births. This study substantiates the significance of family planning programming as a major health intervention for preventing high-risk births and associated maternal and child mortality, but it highlights the need for concerted efforts to strengthen service provision for adolescents.


DWI in the Assessment of Breast Lesions.
Diffusion-weighted imaging (DWI) holds promise to address some of the shortcomings of routine clinical breast magnetic resonance imaging (MRI) and to expand the capabilities of imaging in breast cancer management. DWI reflects tissue microstructure, and provides unique information to aid in characterization of breast lesions. Potential benefits under investigation include improving diagnostic accuracy and guiding treatment decisions. As a result, DWI is increasingly being incorporated into breast MRI protocols and multicenter trials are underway to validate single-institution findings and to establish clinical guidelines. Advancements in DWI acquisition and modeling approaches are helping to improve image quality and extract additional biologic information from breast DWI scans, which may extend diagnostic and prognostic value.


The 4051-Angstroms band of C3 (A 1Piu-X 1Sigmag +, 000-000): perturbed low-J lines and lifetime measurements.
Rotational analyses have been carried out at high resolution for the 000-000 and 000-100 bands of the A (1)Pi(u)-X (1)Sigma(g) (+) transition of supersonic jet-cooled C(3). Two different spectra have been recorded for each band, using time gatings of 20-150 and 800-2300 ns. At the shorter time delay the spectra show only the lines observed by many previous workers. At the longer time delay many extra lines appear, some of which have been observed previously by [McCall et al.Chem. Phys. Lett. 374, 583 (2003)] in cavity ring-down spectra of jet-cooled C(3). Detailed analysis of these extra lines shows that at least two long-lived states perturb the A (1)Pi(u), 000 state. One of these appears to be a (3)Sigma(u) (-) vibronic state, which may possibly be a high vibrational level of the b (3)Pi(g) state, and the other appears to be a P = 1 state with a low rotational constant B. Our spectra also confirm the reassignment by McCall et al. of the R(0) line of the 000-000 band, which is consistent with the spectra recorded towards a number of stars that indicate the presence of C(3) in the interstellar medium. Fluorescence lifetimes have been measured for a number of upper-state rotational levels. The rotational levels of the A (1)Pi(u) state have lifetimes in the range of 230-190 ns, decreasing slightly with J; the levels of the perturbing states have much longer lifetimes, with some of them showing biexponential decays. An improved value has been obtained for the nu(1) vibrational frequency of the ground state, nu(1) = 1224.4933 +/- 0.0029 cm(-1).


Estimated carotid-femoral pulse wave velocity has similar predictive value as measured carotid-femoral pulse wave velocity.
Carotid-femoral pulse wave velocity (cfPWV) adds significantly to traditional cardiovascular risk prediction, but is not widely available. Therefore, it would be helpful if cfPWV could be replaced by an estimated carotid-femoral pulse wave velocity (ePWV) using age and mean blood pressure, and previously published equations. The aim of this study was to investigate whether ePWV could predict cardiovascular events independently of traditional cardiovascular risk factors and/or cfPWV. cfPWV was measured and ePWV was calculated in 2366 patients from four age groups of the Danish MONICA10 cohort. Additionally, the patients were divided into four cardiovascular risk groups based on Systematic COronary Risk Evaluation (SCORE) or Framingham risk score (FRS). In 2006, the combined cardiovascular endpoint of cardiovascular death, nonfatal myocardial infarction, stroke and hospitalization for ischemic heart disease was registered. Most results were retested in 1045 hypertensive patients from a Paris cohort. Bland-Altman plot demonstrated a relative difference of -0.3% [95% confidence interval (CI) -15 to 17%] between ePWV and cfPWV. In Cox regression models in apparently healthy patients, ePWV and cfPWV (per SD) added independently to SCORE in prediction of combined endpoint [hazard ratio (95%CI) = 1.38(1.09-1.76) and hazard ratio (95%CI) = 1.18(1.01-1.38)] and to FRS [hazard ratio (95%CI) = 1.33(1.06-1.66) and hazard ratio (95%CI) = 1.16(0.99-1.37)]. If healthy patients with ePWV and/or cfPWV at least 10 m/s were reclassified to a higher SCORE risk category, net reclassification index was 10.8%, P less than 0.01. These results were reproduced in the Paris cohort. ePWV predicted major cardiovascular events independently of SCORE, FRS and cfPWV indicating that these traditional risk scores have underestimated the complicated impact of age and blood pressure on arterial stiffness and cardiovascular risk.


Platelet derived growth factor and fibroblast growth factor basic levels in the vitreous of patients with vitreoretinal disorders.
To determine the potential role of basic fibroblast growth factor (bFGF) and platelet derived growth factor (PDGF) in the pathogenesis of proliferative vitreoretinopathy (PVR). An enzyme linked immunosorbent assay technique was used to determine the quantities of bFGF and PDGF in 38 vitreous samples taken from patients undergoing trans pars plana vitrectomy (PPV) for a variety of vitreoretinal disorders. bFGF levels ranged from undetectable to 318.7 pg/ml. The mean concentration was 27.57 pg/ml. PDGF levels ranged from undetectable to 160 pg/ml, the mean concentration being 40.06 pg/ml. Eight of 13 patients with clinical evidence of retinal detachment (RD) and PVR had significantly elevated bFGF concentrations, whereas only one of 11 patients with RD and no PVR had detectable bFGF; seven of eight patients with RD and PVR had elevated PDGF concentrations in the vitreous, whereas all 10 patients with RD and no PVR had no detectable vitreous PDGF. Eight patients with vitreous haemorrhage had raised PDGF concentrations, and the levels were particularly high (> 120 pg/ml) in those two patients with active neovascularisation. Two out of nine patients with vitreous haemorrhage had raised bFGF levels. bFGF and PDGF concentrations are elevated in PVR even in the absence of vitreous haemorrhage, and not in patients with RD uncomplicated by PVR. This observation suggests that both cytokines may be involved in the pathogenesis of PVR.


Risk Ranking of Antimicrobial-Resistant Hazards Found in Meat in Switzerland.
Human exposure to bacteria resistant to antimicrobials and transfer of related genes is a complex issue and occurs, among other pathways, via meat consumption. In a context of limited resources, the prioritization of risk management activities is essential. Since the antimicrobial resistance (AMR) situation differs substantially between countries, prioritization should be country specific. The objective of this study was to develop a systematic and transparent framework to rank combinations of bacteria species resistant to selected antimicrobial classes found in meat, based on the risk they represent for public health in Switzerland. A risk assessment model from slaughter to consumption was developed following the Codex Alimentarius guidelines for risk analysis of foodborne AMR. Using data from the Swiss AMR monitoring program, 208 combinations of animal species/bacteria/antimicrobial classes were identified as relevant hazards. Exposure assessment and hazard characterization scores were developed and combined using multicriteria decision analysis. The effect of changing weights of scores was explored with sensitivity analysis. Attributing equal weights to each score, poultry-associated combinations represented the highest risk. In particular, contamination with extended-spectrum β-lactamase/plasmidic AmpC-producing Escherichia coli in poultry meat ranked high for both exposure and hazard characterization. Tetracycline- or macrolide-resistant Enterococcus spp., as well as fluoroquinolone- or macrolide-resistant Campylobacter jejuni, ranked among combinations with the highest risk. This study provides a basis for prioritizing future activities to mitigate the risk associated with foodborne AMR in Switzerland. A user-friendly version of the model was provided to risk managers; it can easily be adjusted to the constantly evolving knowledge on AMR.


Short-term effects of ambient gaseous pollutants and particulate matter on daily mortality in Shanghai, China.
Identification of the specific pollutants contributing most to the health hazard of the air pollution mixture may have important implications for environmental and social policies. In the current study, we conducted a time-series analysis to examine the specific effects of major air pollutants [particulate matter less than 10 microns in diameter (PM(10)), sulfur dioxide (SO(2)), and nitrogen dioxides (NO(2))] on daily mortality in Shanghai, China, using both single-pollutant and multiple-pollutant models. In the single-pollutant models, PM(10), SO(2), and NO(2) were found to be associated with mortality from both all non-accidental causes and from cardiopulmonary diseases. Unlike some prior studies in North America, we found a significant effect of gaseous pollutants (SO(2) and NO(2)) on daily mortality even after adjustment for PM(10) in the multiple-pollutant models. Our findings, combined with previous Chinese studies showing a consistent, significant effect of gaseous pollutants on mortality, suggest that the role of outdoor exposure to SO(2) and NO(2) should be investigated further in China.


Lubrication properties of protein aggregate dispersions in a soft contact.
The lubrication, rheological, and molecular properties of two different protein aggregate dispersions were compared: globular aggregates of whey protein isolate (WPI) and fibrillar aggregates of ovalbumin from egg white. These dispersions are models for the lubricating fluid that is present between the tongue and the palate when consuming liquid or gelled products. To simulate oral conditions, a commercial tribometer was modified so that soft rubber surfaces could be used. This allowed us to measure friction at low contact pressures similar to those present between the tongue and palate. Clear correlations were observed between the measured friction coefficients and specific properties of the lubricating fluid such as protein concentration and aggregate size and shape. Furthermore, surface properties like elasticity, surface-surface interactions, and surface roughness had a significant effect on the friction under conditions that are relevant for texture perception. We conclude that in vitro measurements at low contact pressure provide valuable information for understanding and controlling food properties that modulate oral friction.


Loss of heterozygosity of multiple tumor suppressor genes in human gastric cancers by polymerase chain reaction.
Loss of heterozygosity (LOH) occurring on various chromosomes has been described in the majority of human tumors and its targets are believed to be tumor suppressor genes. Although allelic deletion of the p53 gene (over 60%) has been frequently observed in gastric cancer, as well as in other human malignancies, LOH of other tumor suppressor genes is still discrepant in gastric cancer. To our knowledge, simultaneous analysis of LOH using PCR in adenomatous polyposis coli (APC), deleted in colon cancer (DCC), and retinoblastoma susceptibility (Rb) genes has not yet been reported in sporadic gastric cancer. We examined 21 advanced gastric cancers (12 intestinal type and 9 diffuse type) for LOH at the APC, DCC, and Rb loci using PCR. Inclusion of these tumor suppressor genes in the allelic deletions was directly ascertained by performing PCR at polymorphic sites within the genes. LOH occurred in 30% of informative cases at APC, in 27% of informative cases at DCC, and in 30% of informative cases at Rb. Thirty-three percent of tumors informative at all loci (fully informative) lost heterozygosity at all three loci. There were no significant differences among histologic types in the prevalence of LOH at any locus and no correlations between losses involving APC, DCC, and Rb genes. These data suggest that inactivation of APC, DCC, and Rb is involved in the development and progression of some human gastric cancers regardless of histologic type.


Limited gene dispersal and spatial genetic structure as stabilizing factors in an ant-plant mutualism.
Comparative studies of the population genetics of closely associated species are necessary to properly understand the evolution of these relationships because gene flow between populations affects the partners' evolutionary potential at the local scale. As a consequence (at least for antagonistic interactions), asymmetries in the strength of the genetic structures of the partner populations can result in one partner having a co-evolutionary advantage. Here, we assess the population genetic structure of partners engaged in a species-specific and obligatory mutualism: the Neotropical ant-plant, Hirtella physophora, and its ant associate, Allomerus decemarticulatus. Although the ant cannot complete its life cycle elsewhere than on H. physophora and the plant cannot live for long without the protection provided by A. decemarticulatus, these species also have antagonistic interactions: the ants have been shown to benefit from castrating their host plant and the plant is able to retaliate against too virulent ant colonies. We found similar short dispersal distances for both partners, resulting in the local transmission of the association and, thus, inbred populations in which too virulent castrating ants face the risk of local extinction due to the absence of H. physophora offspring. On the other hand, we show that the plant populations probably experienced greater gene flow than did the ant populations, thus enhancing the evolutionary potential of the plants. We conclude that such levels of spatial structure in the partners' populations can increase the stability of the mutualistic relationship. Indeed, the local transmission of the association enables partial alignments of the partners' interests, and population connectivity allows the plant retaliation mechanisms to be locally adapted to the castration behaviour of their symbionts.


Radioembolization With Chemotherapy for Colorectal Liver Metastases: A Randomized, Open-Label, International, Multicenter, Phase III Trial.
To study the impact of transarterial Yttrium-90 radioembolization (TARE) in combination with second-line systemic chemotherapy for colorectal liver metastases (CLM). In this international, multicenter, open-label phase III trial, patients with CLM who progressed on oxaliplatin- or irinotecan-based first-line therapy were randomly assigned 1:1 to receive second-line chemotherapy with or without TARE. The two primary end points were progression-free survival (PFS) and hepatic PFS (hPFS), assessed by blinded independent central review. Random assignment was performed using a web- or voice-based system stratified by unilobar or bilobar disease, oxaliplatin- or irinotecan-based first-line chemotherapy, and KRAS mutation status. Four hundred twenty-eight patients from 95 centers in North America, Europe, and Asia were randomly assigned to chemotherapy with or without TARE; this represents the intention-to-treat population and included 215 patients in the TARE plus chemotherapy group and 213 patients in the chemotherapy alone group. The hazard ratio (HR) for PFS was 0.69 (95% CI, 0.54 to 0.88; 1-sided P = .0013), with a median PFS of 8.0 (95% CI, 7.2 to 9.2) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. The HR for hPFS was 0.59 (95% CI, 0.46 to 0.77; 1-sided P < .0001), with a median hPFS of 9.1 (95% CI, 7.8 to 9.7) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. Objective response rates were 34.0% (95% CI, 28.0 to 40.5) and 21.1% (95% CI, 16.2 to 27.1; 1-sided P = .0019) for the TARE and chemotherapy groups, respectively. Median overall survival was 14.0 (95% CI, 11.8 to 15.5) and 14.4 months (95% CI, 12.8 to 16.4; 1-sided P = .7229) with a HR of 1.07 (95% CI, 0.86 to 1.32) for TARE and chemotherapy groups, respectively. Grade 3 adverse events were reported more frequently with TARE (68.4% v 49.3%). Both groups received full chemotherapy dose intensity. The addition of TARE to systemic therapy for second-line CLM led to longer PFS and hPFS. Further subset analyses are needed to better define the ideal patient population that would benefit from TARE.


Verticalization Therapy for Acute Respiratory Distress Syndrome Patients Receiving Veno-Venous Extracorporeal Membrane Oxygenation.
Persistent hypoxemia during veno-venous extracorporeal membrane oxygenation (VV-ECMO) for supporting acute respiratory distress syndrome (ARDS) patients is a clinical challenge for intensive care medical providers. Prone positioning is an effective strategy to treat persistent hypoxemia; however, placing a patient in a prone position is resource intensive with significant risks to the patient. We present a patient with severe ARDS receiving VV-ECMO who underwent verticalization therapy and subsequently recovered pulmonary function.


ModL: exploring and restoring regularity when testing for positive selection.
Likelihood ratio tests are commonly used to test for positive selection acting on proteins. They are usually applied with thresholds for declaring a protein under positive selection determined from a chi-square or mixture of chi-square distributions. Although it is known that such distributions are not strictly justified due to the statistical irregularity of the problem, the hope has been that the resulting tests are conservative and do not lose much power in comparison with the same test using the unknown, correct threshold. We show that commonly used thresholds need not yield conservative tests, but instead give larger than expected Type I error rates. Statistical regularity can be restored by using a modified likelihood ratio test. We give theoretical results to prove that, if the number of sites is not too small, the modified likelihood ratio test gives approximately correct Type I error probabilities regardless of the parameter settings of the underlying null hypothesis. Simulations show that modification gives Type I error rates closer to those stated without a loss of power. The simulations also show that parameter estimation for mixture models of codon evolution can be challenging in certain data-generation settings with very different mixing distributions giving nearly identical site pattern distributions unless the number of taxa and tree length are large. Because mixture models are widely used for a variety of problems in molecular evolution, the challenges and general approaches to solving them presented here are applicable in a broader context. https://github.com/jehops/codeml_modl. Supplementary data are available at Bioinformatics online.


Long-term results of the AIEOP MH'96 childhood Hodgkin's lymphoma trial and focus on significance of response to chemotherapy and its implication in low risk patients to avoid radiotherapy.
Identify a subset of early-stage HL children (GR1) curable with limited chemotherapy+/-radiotherapy; improve outcome of intermediate (GR2) and high-risk (GR3) patients; establish impact of response to chemotherapy evaluated with conventional imaging (CI). One hundred and sixty GR1-patients received 3ABVD + involved-field (IF) low-dose (LD) (20 Gy) irradiation if mediastinal mass or partial response (PR) after chemotherapy. Eighty-five GR2- and 315 GR3-patients received 4 and 6 COPP/ABV + IFRT, respectively. The 63 GR1 patients spared from radiotherapy had 15-year survival and EFS of 100 and 84.5%, respectively. The GR2 and GR3 15-year FFP were 84.7 and 78.6%, respectively. No different prognosis for patients in CR or PR evaluated during and after chemotherapy was observed. In conclusion, low-risk patients in CR may be successfully treated with radiation-free, low-intensity chemotherapy. Good, but less satisfactory, results were registered in GR2 and GR3. Response evaluated with CI is not a prognostic factor, but permits identification of low-risk patients who can avoid radiotherapy.


Dissecting, Fixing, and Visualizing the Drosophila Pupal Notum.
The pupae of Drosophila melanogaster are immobile for several days during metamorphosis, during which they develop a new body with a thin transparent adult integument. Their immobility and transparency make them ideal for in vivo live imaging experiments. Many studies have focused on the dorsal epithelial monolayer of the pupal notum because of its accessibility and relatively large size. In addition to the studies of epithelial mechanics and development, the notum has been an ideal tissue to study wound healing. After an injury, the entire epithelial repair process can be captured by live imaging over 6-12 h. Despite the popularity of the notum for live imaging, very few published studies have utilized fixed notum samples. Fixation and staining are common approaches for nearly all other Drosophila tissues, taking advantage of the large repertoire of simple cellular stains and antibodies. However, the pupal notum is fragile and prone to curling and distortion after removal from the body, making it challenging to complement live imaging. This protocol offers a straightforward method for fixing and staining the pupal notum, both intact and after laser-wounding. With this technique, the ventral side of the pupa is glued down to a coverslip to immobilize the pupa, and the notum is carefully removed, fixed, and stained. The notum epithelium is mounted on a slide or between two coverslips to facilitate imaging from the tissue's dorsal or ventral side.


Clinical Practice Recommendations on Genetic Testing of CYP2C9 and VKORC1 Variants in Warfarin Therapy.
To systematically review evidence on genetic variants influencing outcomes during warfarin therapy and provide practice recommendations addressing the key questions: (1) Should genetic testing be performed in patients with an indication for warfarin therapy to improve achievement of stable anticoagulation and reduce adverse effects? (2) Are there subgroups of patients who may benefit more from genetic testing compared with others? (3) How should patients with an indication for warfarin therapy be managed based on their genetic test results? A systematic literature search was performed for VKORC1 and CYP2C9 and their association with warfarin therapy. Evidence was critically appraised, and clinical practice recommendations were developed based on expert group consensus. Testing of VKORC1 (-1639G>A), CYP2C9*2, and CYP2C9*3 should be considered for all patients, including pediatric patients, within the first 2 weeks of therapy or after a bleeding event. Testing for CYP2C9*5, *6, *8, or *11 and CYP4F2 (V433M) is currently not recommended. Testing should also be considered for all patients who are at increased risk of bleeding complications, who consistently show out-of-range international normalized ratios, or suffer adverse events while receiving warfarin. Genotyping results should be interpreted using a pharmacogenetic dosing algorithm to estimate the required dose. This review provides the latest update on genetic markers for warfarin therapy, clinical practice recommendations as a basis for informed decision making regarding the use of genotype-guided dosing in patients with an indication for warfarin therapy, and identifies knowledge gaps to guide future research.


Optical coherence tomography angiography in miliary tuberculosis.
A 14-year-old female was admitted with a history of high-grade fever. On admission, she underwent a comprehensive clinical, laboratory, and radiological evaluation. A contrast-enhanced computed tomography (CT) scan of the chest revealed multiple, tiny, nodular opacities in a ground-glass pattern bilaterally. Sputum studies were positive for Mycobacterium tuberculosis. Dilated fundus examination revealed multiple, yellow-white, deep choroidal lesions consistent with choroidal tubercles. She underwent optical coherence tomography angiography (OCTA) in both eyes, which revealed normal superficial and deep retinal plexuses but multiple areas of flow void in the choriocapillaris. The optical coherence tomography (OCT) sections showed hyperreflective areas in the choriocapillaris/superficial choroid with absence of choriocapillaris circulation.


Nucleotide sequences of five IncF plasmid finP alleles.
The nucleotide sequences of five finP alleles from various IncF plasmids (finP types I to V) as well as of three finP mutations were determined and compared. The finP gene specificity could be attributed to a variable, six-to-seven-nucleotide loop located between inverted repeats, and the sequence data were consistent with the product of finP being an RNA molecule rather than a protein. The finP mutations interrupted a proposed finP promoter or destabilized a predicted stem-and-loop structure in the finP RNA molecule.


Lateral ankle injury. Literature review and report of two cases.
Injury to the ankle joint is the most common peripheral joint injury. The sports that most commonly produce high ankle injury rates in their participating athletes include: basketball, netball, and the various codes of football. To provide an up to date understanding of manual therapy relevant to lateral ligament injury of the ankle. A discussion of the types of ligament injury and common complicating factors that present with lateral ankle pain is presented along with a review of relevant anatomy, assessment and treatment. Also included is a discussion of the efficacy of manual therapy in the treatment of ankle sprain. A detailed knowledge of the anatomy of the ankle as well as the early recognition of factors that may delay the rate of healing are important considerations when developing a management plan for inversion sprains of the ankle. This area appears to be under-researched however it was found that movement therapy and its various forms appear to be the most efficient and most effective method of treating uncomplicated ankle injury. Future investigations should involve a study to determine the effect chiropractic treatment (manipulation) may have on the injured ankle.


Report of the health care delivery work group: behavioral research related to the establishment of a chronic disease model for diabetes care.
As one of four work groups for the November 1999 conference on Behavioral Science Research in Diabetes, sponsored by the National Institute on Diabetes and Digestive and Kidney Diseases, the health care delivery work group evaluated the status of research on quality of care, patient-provider interactions, and health care systems' innovations related to improved diabetes outcomes. In addition, we made recommendations for future research. In this article, which was developed and modified at the November conference by experts in health care delivery, diabetes and behavioral science, we summarize the literature on patient-provider interactions, diabetes care and self-management support among underserved and minority populations, and implementation of chronic care management systems for diabetes. We conclude that, although the quality of care provided to the vast majority of diabetic patients is problematic, this is principally not the fault of either individual patients or health care professionals. Rather, it is a systems issue emanating from the acute illness model of care, which still predominates. Examples of proactive population-based chronic care management programs incorporating behavioral principles are discussed. The article concludes by identifying barriers to the establishment of a chronic care model (e.g., lack of supportive policies, understanding of population-based management, and information systems) and priorities for future research in this area needed to overcome these barriers.


Combination therapy in cholesterol reduction: focus on ezetimibe and statins.
Although widely used in lipid lowering therapy, HMG CoA reductase inhibitors (even when administered at high doses) are frequently insufficient to achieve guideline-recommended LDL-C goals for many patients with hypercholesterolemia in everyday clinical practice. Many patients do not achieve LDL-C goal on the initial dose of statin and the majority of these patients does not reach their goal after 6 months. As a consequence, a wide therapeutic gap exists between target LDL-C levels and those typically achieved in clinical practice. A recent and more effective therapeutic hypocholesterolemic strategy is to treat the two main sources of cholesterol simultaneously (production of cholesterol, mainly in the liver, and absorption of cholesterol in the intestine) with a complementary mechanism of action, by co-administering ezetimibe, a novel agent inhibiting cholesterol absorption, with a statin, which inhibits cholesterol production in the liver. Ezetimibe can be effectively and safely co-administered with any dose of any statin and, compared with the single inhibition of cholesterol production, afforded by statins alone, provides consistently greater reductions in LDL-C through dual inhibition of both cholesterol production and absorption. We summarize the pivotal role of both the liver and intestine in the overall balance of cholesterol in the body and describe the clinical impact and relevance of using ezetimibe either alone or co-administered with statins in controlling elevated levels of plasma LDL cholesterol.


Contribution of dexamethasone to control of chemotherapy-induced nausea and vomiting: a meta-analysis of randomized evidence.
To synthesize the available randomized evidence on the efficacy of dexamethasone when used for protection against acute and delayed nausea and vomiting in patients receiving highly or moderately emetogenic cancer chemotherapy. A meta-analysis was performed using trials identified through MEDLINE (1966 to April 1999), Embase, Derwent Drug File, and the Cochrane Library's Database of Controlled Trials. Data on acute and delayed emesis and nausea were collected. All randomized studies comparing dexamethasone to placebo, no treatment, or other antiemetics qualified, including cross-over trials providing first-cycle data. Of 1,200 citations screened, 32 studies with 42 pertinent comparisons and 5,613 patients were included in the meta-analysis. Dexamethasone was superior to placebo or no treatment for complete protection from acute emesis (odds ratio, 2.22; 95% confidence interval [CI], 1.89 to 2.60) and for complete protection from delayed emesis (odds ratio, 2.04; 95% CI, 1.63 to 2.56). The results were similar for complete protection from nausea. The pooled risk difference for complete protection from emesis was 16% for both the acute and delayed phases (95% CI, 13% to 19% and 11% to 20%, respectively). The beneficial effect was similar in subgroups defined by various study design parameters. No trial addressed the efficacy of dexamethasone in the delayed phase without having administered dexamethasone for acute-phase protection as well. Dexamethasone is clearly effective in protecting from emesis both in the acute and delayed phases, with emesis avoided in one patient out of six treated. Future trials should determine whether the delayed-phase effect is independent of the acute-phase benefit.


[SWI], the prion formed by the chromatin remodeling factor Swi1, is highly sensitive to alterations in Hsp70 chaperone system activity.
The yeast prion [SWI+], formed of heritable amyloid aggregates of the Swi1 protein, results in a partial loss of function of the SWI/SNF chromatin-remodeling complex, required for the regulation of a diverse set of genes. Our genetic analysis revealed that [SWI+] propagation is highly dependent upon the action of members of the Hsp70 molecular chaperone system, specifically the Hsp70 Ssa, two of its J-protein co-chaperones, Sis1 and Ydj1, and the nucleotide exchange factors of the Hsp110 family (Sse1/2). Notably, while all yeast prions tested thus far require Sis1, [SWI+] is the only one known to require the activity of Ydj1, the most abundant J-protein in yeast. The C-terminal region of Ydj1, which contains the client protein interaction domain, is required for [SWI+] propagation. However, Ydj1 is not unique in this regard, as another, closely related J-protein, Apj1, can substitute for it when expressed at a level approaching that of Ydj1. While dependent upon Ydj1 and Sis1 for propagation, [SWI+] is also highly sensitive to overexpression of both J-proteins. However, this increased prion-loss requires only the highly conserved 70 amino acid J-domain, which serves to stimulate the ATPase activity of Hsp70 and thus to stabilize its interaction with client protein. Overexpression of the J-domain from Sis1, Ydj1, or Apj1 is sufficient to destabilize [SWI+]. In addition, [SWI+] is lost upon overexpression of Sse nucleotide exchange factors, which act to destabilize Hsp70's interaction with client proteins. Given the plethora of genes affected by the activity of the SWI/SNF chromatin-remodeling complex, it is possible that this sensitivity of [SWI+] to the activity of Hsp70 chaperone machinery may serve a regulatory role, keeping this prion in an easily-lost, meta-stable state. Such sensitivity may provide a means to reach an optimal balance of phenotypic diversity within a cell population to better adapt to stressful environments.


The involvement of methysergide-sensitive receptors and prostaglandins in the hyperthermia evoked by 5-HT in the cat.
In the unanesthetized cat, an injection of 0.01 or 0.03 M 5-hydroxytryptamine into the rostral hypothalamus produced an immediate, short-lasting increase or decrease in body temperature. A delayed and long-lasting hyperthermia often followed the initial response. When indomethacin, 10 mg/kg, was administered intraperitoneally 3 hours prior to an injection of 5-hydroxytryptamine at sites which produced an initial increase in body temperature, the secondary hyperthermia was reduced or abolished but the immediate response remained undiminished. Pretreatment with methysergide, 2 mg/kg i.p., attenuated or abolished the initial temperature increase but did not reduce the delayed hyperthermia. The results suggest that the initial rise in body temperature produced by 5-hydroxytryptamine is mediated by activation of methysergide-sensitive 5-HT receptors and that the response is independent of prostaglandin release. The secondary hyperthermia, on the other hand, is apparently mediated by a sustained release of prostaglandins.


Meiotic recombination and DNA synthesis in a new cell cycle mutant of Saccharomyces cerevisiae.
Vegetative cells carrying the new temperature-sensitive mutation cdc40 arrest at the restrictive temperature with a medial nuclear division phenotype. DNA replication is observed under these conditions, but most cells remain sensitive to hydroxyurea and do not complete the ongoing cell cycle if the drug is present during release from the temperature block. It is suggested that the cdc40 lesion affects an essential function in DNA synthesis. Normal meiosis is observed at the permissive temperature in cdc40 homozygotes. At the restrictive temperature, a full round of premeiotic DNA replication is observed, but neither commitment to recombination nor later meiotic events occur. Meiotic cells that are already committed to the recombination process at the permissive temperature do not complete it if transferred to the restrictive temperature before recombination is realized. These temperature shift-up experiments demonstrate that the CDC40 function is required for the completion of recombination events, as well as for the earlier stage of recombination commitment. Temperature shift-down experiments with cdc40 homozygotes suggest that meiotic segregation depends on the final events of recombination rather than on commitment to recombination.


Dynamic coupling of a small rigid probe to viscous ortho-terphenyl.
We have measured the dielectric relaxation of 2,2,6,6-tetramethyl-piperidine-1-oxyl (TEMPO) as a rotational probe in supercooled ortho-terphenyl (OTP). Due to the significant dipole moment of TEMPO compared with OTP, its contribution to the loss spectra can be identified already at moderate concentrations. For time scales ranging from 10 μs to 1 s, it is found that the tumbling mode of TEMPO is a true replica of the structural relaxation of OTP regarding average time constant, relaxation time dispersion, and the temperature dependence. While the present dielectric results are consistent with a decoupling of a spinning mode (about the nitroxyl dipole axis) of TEMPO from viscosity, they do not agree with the strong decoupling of the tumbling mode derived from electron spin resonance experiments.


Model-based parameter estimation using cardiovascular response to orthostatic stress.
This paper presents a cardiovascular model that is capable of simulating the short-term (< or approximately equal to 3 min) transient hemodynamic response to gravitational stress and a gradient-based optimization method that allows for the automated estimation of model parameters from simulated or experimental data. We perform a sensitivity analysis of the transient heart rate response to determine which parameters of the model impact the heart rate dynamics significantly. We subsequently include only those parameters in the estimation routine that impact the transient heart rate dynamics substantially. We apply the estimation algorithm to both simulated and real data and showed that restriction to the 20 most important parameters does not impair our ability to match the data.